Tubocurarine chloride - wikipedia Tubocurarine chloride Tubocurarine chloride Clinical data AHFS / Drugs.com International Drug Names MedlinePlus a682860 Pregnancy category AU : C Routes of administration IV ATC code M03AA02 ( WHO ) Legal status Legal status In general : ℞ ( Prescription only ) Pharmacokinetic data Bioavailability 100 % ( IV ) Protein binding 50 % Biological half - life 1 -- 2 hours Identifiers IUPAC name 6, 6 ′ - dimethoxy - 2, 2 ′, 2 ′ - trimethyltubocuraran - 2, 2 ′ - diium - 7 ′, 12 ′ - diol CAS Number 57 - 95 - 4 ( chloride hydrochloride ) 6989 - 98 - 6 ( chloride hydrochloride pentahydrate ) PubChem CID 6000 IUPHAR / BPS 2294 DrugBank DB01199 ChemSpider 5778 UNII 900961Z8VR ChEBI CHEBI : 9774 ChEMBL CHEMBL1687 ECHA InfoCard 100.108. 489 Chemical and physical data Formula C H Cl N O Molar mass 681.65 g / mol 3D model ( JSmol ) Interactive image SMILES Oc7ccc1cc7Oc5cc6 ( C@H ) ( Cc4ccc ( Oc2c3 ( C @ @ H ) ( C1 ) ( N+ ) ( C ) ( C ) CCc3cc ( OC ) c2O ) cc4 ) ( N+ ) ( C ) ( C ) CCc6cc5OC InChI InChI = 1S / C37H40N2O6 / c1 - 38 - 14 - 12 - 24 - 19 - 32 ( 42 - 4 ) 33 - 21 - 27 ( 24 ) 28 ( 38 ) 16 - 22 - 6 - 9 - 26 ( 10 - 7 - 22 ) 44 - 37 - 35 - 25 ( 20 - 34 ( 43 - 5 ) 36 ( 37 ) 41 ) 13 - 15 - 39 ( 2, 3 ) 29 ( 35 ) 17 - 23 - 8 - 11 - 30 ( 40 ) 31 ( 18 - 23 ) 45 - 33 / h6 - 11, 18 - 21, 28 - 29H, 12 - 17H2, 1 - 5H3, ( H -, 40, 41 ) / p + 1 / t28 -, 29 + / m0 / s1 Key : JFJZZMVDLULRGK - URLMMPGGSA - O ( what is this ? ) ( verify ) Tubocurarine ( also known as d - tubocurarine or DTC ) is a toxic alkaloid historically known for its use as an arrow poison. In the mid-1900s, it was used in conjunction with an anesthetic to provide skeletal muscle relaxation during surgery or mechanical ventilation. It is now rarely used as an adjunct for clinical anesthesia because safer alternatives, such as cisatracurium and rocuronium, are available. Contents 1 History 1.1 Etymology 1.2 Use as an anesthetic 2 Chemical properties 2.1 Biosynthesis 3 Biological effects 3.1 Clinical pharmacology 3.2 Use as spider bite treatment 4 Toxicology 5 References 6 External links History Tubocurarine is a naturally occurring mono - quaternary alkaloid obtained from the bark of the South American plant Chondrodendron tomentosum, a climbing vine known to the European world since the Spanish conquest of South America. Curare had been used as a source of arrow poison by South American natives to hunt animals, and they were able to eat the animals ' contaminated flesh subsequently without any adverse effects because tubocurarine can not easily cross mucous membranes. Thus, tubocurarine is effective only if given parenterally, as demonstrated by Bernard, who also showed that the site of its action was at the neuromuscular junction. Virchow and Munter confirmed the paralyzing action was limited to voluntary muscles. Etymology The word `` curare '' comes from the South American Indian name for the arrow poison, ourare. Presumably, the initial syllable was pronounced with a heavy glottal stop. Tubocurarine is so - called because the plant samples containing the curare were stored and shipped to Europe in tubes. Likewise, curare stored in calabash containers was called calabash curare. Use as an anesthetic Griffith and Johnson are credited with pioneering the formal clinical introduction of tubocurarine as an adjunct to anesthetic practice on 23 January 1942, at the Montreal Homeopathic Hospital. In this sense, tubocurarine is the prototypical adjunctive neuromuscular non-depolarizing agent. However, others before Griffith and Johnson had attempted use of tubocurarine in several situations : some under controlled study conditions while others not quite controlled and remained unpublished. Regardless, all in all some 30,000 patients had been given tubocurarine by 1941, although it was Griffith and Johnson 's 1942 publication that provided the impetus to the standard use of neuromuscular blocking agents in clinical anesthestic practice -- a revolution that rapidly metamorphosized into the standard practice of `` balanced '' anesthesia : the triad of barbiturate hypnosis, light inhalational anesthesia and muscle relaxation. The technique as described by Gray and Halton was widely known as the `` Liverpool technique '', and became the standard anesthetic technique in England in the 1950s and 1960s for patients of all ages and physical status. Present clinical anesthetic practice still employs the central principle of balanced anesthesia though with some differences to accommodate subsequent technological advances and introductions of new and better gaseous anesthetic, hypnotic and neuromuscular blocking agents, and tracheal intubation, as well as monitoring techniques that were nonexistent in the day of Gray and Halton : pulse oximetry, capnography, peripheral nerve stimulation, noninvasive blood pressure monitoring, etc. Chemical properties Structurally, tubocurarine is a benzylisoquinoline derivative. For many years, its structure, when first elucidated in 1948, was wrongly thought to be bis - quaternary : in other words, it was thought to be an N, N - dimethylated alkaloid. In 1970, the correct structure was finally established, showing one of the two nitrogens to be tertiary, actually a mono - N - methylated alkaloid. Biosynthesis Tubocurarine biosynthesis involves a radical coupling of the two enantiomers of N - methylcoclaurine. ( R ) and ( S ) - N - methylcoclaurine come from a Mannich - like reaction between dopamine and 4 - hydroxyphenylacetaldehyde, facilitated by norcoclaurine synthase ( NCS ). Both dopamine and 4 - hydroxyphenylacetaldehyde originate from L - tyrosine. Methylation of the amine and hydroxyl substituents are facilitated by S - adenosyl methionine ( SAM ). One methyl group is present on each nitrogen atom prior to the radical coupling. The additional methyl group is transferred to form tubocurarine, with its single quaternary N, N - dimethylamino group. Biological effects Acetylcholine in the synaptic gap Without intervention, acetylcholine ( ACh ) in the peripheral nervous system activates skeletal muscles. Acetylcholine is produced in the body of the neuron by choline acetyltransferase and transported down the axon to the synaptic gap. Tubocurarine chloride acts as an antagonist for the nicotinic acetylcholine receptor ( nAChr ), meaning it blocks the receptor site from ACh. This may be due to the quaternary amino structural motif found on both molecules. Clinical pharmacology Unna et al. reported the effects of tubocurarine on humans : `` Forty - five seconds after the beginning of the injection, heaviness of the eyelids and transitory diplopia were perceived. At the completion of the injection, diplopia became fixed, but could be noticed only when the subject 's eyelids were raised by the operator. As curarization proceeded, it seemed to the subject as if the facial muscles, those of the tongue, pharynx, and lower jaw, the muscles of the neck and back, and the muscles of the extremities became relaxed in about that order. Accompanying the paralysis of the pharynx and the jaw muscles, inability of the subject to swallow was noted... Shortly after the injection was completed the subjects experienced a sensation of increased difficulty in breathing, as if an extra effort was necessary to maintain an adequate respiratory exchange. This sensation was present even though there was no objective evidence of impaired oxygenation or of carbon dioxide retention. It reached its maximum about five minutes after the injection, coinciding with the maximum depression of the vital capacity. In the majority of the experiments the respiratory rate was increased by about 50 -- 100 per cent the first minutes after the injection of any one of the drugs while the tidal volume decreased. '' Tubocurarine has a time of onset of around 5 minutes which is relatively slow among neuromuscular - blocking drugs, and has a duration of action of 60 to 120 minutes. It also causes histamine release, now a recognized hallmark of the tetrahydroisioquinolinium class of neuromuscular blocking agents. Histamine release is associated with bronchospasms, hypotension, salivary secretions, making it dangerous for asthmatics, children, and those who are pregnant or lactating. However, the main disadvantage in the use of tubocurarine is its significant ganglion - blocking effect, that manifests as hypotension, in many patients ; this constitutes a relative contraindication to its use in patients with myocardial ischaemia. Because of the shortcomings of tubocurare, much research effort was undertaken soon after its clinical introduction to find a suitable replacement. The efforts unleashed a multitude of compounds borne from structure - activity relations developed from the tubocurare molecule. Some key compounds that have seen clinical use are identified in the muscle relaxants template box below. Of the many tried as replacements, only a few enjoyed as much popularity as tubocurarine : pancuronium, vecuronium, rocuronium, atracurium, and cisatracurium. Succinylcholine is a widely used muscle relaxant drug which acts by activating, instead of blocking, the ACh receptor. The potassium channel blocker tetraethylammonium ( TEA ) has been shown to reverse the effects of tubocurarine. It is thought to do so by increasing ACh release, which counteracts the antagonistic effects of tubocurarine on the ACh receptor. Use as spider bite treatment Spiders of the genus Latrodectus have α - latrotoxin in their venom. The most well known spider in this genus is the black widow spider. α - latrotoxin causes the release of neurotransmitters into the synaptic gap, including acetylcholine. Bites are usually not fatal, but do cause a significant amount of pain in addition to muscle spasms. The venom is the most damaging to nerve endings, but the introduction of d - tubocurarine chloride blocks the nAChr, alleviating pain and muscle spasms while an antivenom can be administered. Toxicology An individual administered tubocurarine chloride will be unable to move any voluntary muscles, including the diaphragm. A large enough dose will therefore result in death from respiratory failure unless artificial ventilation is initiated. The LD for mice and rabbits are 0.13 mg / kg and 0.146 mg / kg intravenously, respectively.It releases histamine and cause hypotension. References Jump up ^ Bernard C ( 1856 ). `` Analyse physiologie des propriétés des actions de curare et de la nicotine sure systèmes musculaire et nerveux au moyen du curare ''. Compt. Rend. 43 : 305 -- 319. Jump up ^ Bechter AM ( 1977 ). `` The civilizing of curare : a history of its development and introduction into anesthesiology ''. Anesth Analg. 56 ( 2 ) : 305 -- 319. doi : 10.1213 / 00000539 - 197703000 - 00032. PMID 322548. ^ Jump up to : Griffith HR, Johnson GE ( 1942 ). `` The use of curare in general anesthesia ''. Anesthesiology. 3 ( 4 ) : 418 -- 420. doi : 10.1097 / 00000542 - 194207000 - 00006. Jump up ^ Läwen A ( 1912 ). `` Ueber die verbindung der lokakanaesthesie und epidurale injektion anesthesiernder losungen bei tabischen magenkrisen ''. Beitr Klin Chir. 80 : 168 -- 189. Jump up ^ Wilkinson DJ ( 1991 ). `` Dr. F.P. de Caux - the first user of curare for anaesthesia in England ''. Anaesthesia. 46 ( 1 ) : 49 -- 51. doi : 10.1111 / j. 1365 - 2044.1991. tb09317. x. PMID 1996757. Jump up ^ Bennett AE ( 1941 ). `` Curare : a preventive of traumatic complications in electroconvulsive shock therapy ''. Am J Psychiatry. 97 : 1040 -- 1060. Jump up ^ West R ( 1984 ). `` An excursion into pharmacology : curare in medicine ''. Medical History. 28 ( 4 ) : 391 -- 405. doi : 10.1017 / s0025727300036279. PMC 1140012. PMID 6390032. Jump up ^ Burman MS ( 1939 ). `` Therapeutic use of curare and erythroidine hydrochloride for spastic and dystonic states ''. Arch Neurol Psychiatry. 41 : 307 -- 327. doi : 10.1001 / archneurpsyc. 1939.02270140093008. Jump up ^ Bevan DR. ( 1992 ) `` Curare ''. In : Maltby JR, Shephard DAE ( Eds. ), Harold Griffith -- His Life and Legacy Can J Anaesth 39 ( 1 ) : 49 - 55. ^ Jump up to : Gray TC, Halton J ( 1946 ). `` Technique for the use of d - tubocurarine chloride with balanced anaesthesia ''. Br Med J. 2 : 293 -- 295. doi : 10.1136 / bmj. 2.4469. 293. PMID 20996123. Jump up ^ King H ( 1948 ). `` 64. Curare alkaloids. Part VII. Constitution of dextrotubocurarine chloride ''. J Chem Soc : 265. doi : 10.1039 / jr9480000265. Jump up ^ Everett AJ, Lowe LA, Wilkinson S ( 1970 ). J. Chem. Soc. Chem. Commun. : 1020. Missing or empty title = ( help ) Jump up ^ Dewick, P.M. Medicinal Natural Products ; a Biosynthetic Approach. 3rd ed. ; John Wiley and Sons Ltd. : 2009. Jump up ^ Katzung BG ( 2001 ). Basic and clinical pharmacology : Introduction to autonomic pharmacology ( 8 ed. ). The McGraw Hill Companies. pp. 75 -- 91. ISBN 978 - 0 - 07 - 160405 - 5. Jump up ^ Wenningmann I, Dilger JP ( October 2001 ). `` The kinetics of inhibition of nicotinic acetylcholine receptors by ( + ) - tubocurarine and pancuronium ''. Molecular Pharmacology. 60 ( 4 ) : 790 -- 6. PMID 11562442. Jump up ^ Unna, K.R. ( March 1950 ). `` EVALUATION OF CURARIZING DRUGS IN MAN ''. The Journal of Pharmacology and Experimental Therapeutics. 98. Jump up ^ Thompson MA ( 1980 ). `` Muscle relaxant drugs ''. Br J Hosp Med. 23 ( 2 ) : 153 -- 4, 163 -- 4, 167 -- 8 passim. PMID 6102875. Jump up ^ Page 151 in : Rang, H.P. ( 2003 ). Pharmacology. Edinburgh : Churchill Livingstone. ISBN 0 - 443 - 07145 - 4. OCLC 51622037. Jump up ^ Maclagen J. ( 1976 ) In : Zaimis E. ( Ed. ), `` Neuromuscular Junction ''. Hand. Exp. Pharm. ; Vol. 42 ; Springer - Verlag, Berlin : 421 -- 486. Jump up ^ `` d - Tubocurarine ( Prototype Nondepolarizing Neuromuscular Blocker ) ''. Tulane University. Retrieved 4 May 2015. Jump up ^ Bowman WC, Webb SN ( 1972 ). `` Neuromuscular blocking and ganglion blocking activities of some acetylcholine antagonists in the cat ''. J Pharm Pharmacol. 24 ( 10 ) : 762 -- 72. doi : 10.1111 / j. 2042 - 7158.1972. tb08880. x. PMID 4403972. Jump up ^ Coleman AJ, Downing JW, Leary WP, Moyes DG ( 1972 ). `` The immediate cardiovascular effects of pancuronium, alcuronium and tubocurarine in man ''. Anaesthesia. 27 ( 4 ) : 415 -- 22. doi : 10.1111 / j. 1365 - 2044.1972. tb08247. x. PMID 4264060. Jump up ^ Südhof, Thomas C ( March 2001 ). `` α - Latrotoxin and its receptors : Neurexins and CIRL / Latrophilins ''. Annual Review of Neuroscience. 24 : 933 -- 962. doi : 10.1146 / annurev. neuro. 24.1. 933. PMID 11520923. Jump up ^ Allen, George W. ( 1953 ). `` Black widow spider ( Latrodectus mactans ) poisoning treated with d - tubocurarine chloride ''. Annals of Internal Medicine. 3 : 624 -- 625. doi : 10.7326 / 0003 - 4819 - 39 - 3 - 624. Jump up ^ Gesler, H.M. ; Hoppe, James O. ( 1956 ). `` 3, 6 - bis ( 3 - diethylaminopropoxy ) pyridazine bismethiodide, a long - acting neuromuscular blocking agent ''. The Journal of Pharmacology and Experimental Therapeutics. 118. External links Curare -- History, Tubocurarine, a more detailed historical account of tubocurare Skeletal muscle relaxants ( M03 ) Peripherally acting ( primarily antinicotinic, NMJ block ) Non-depolarizing Curare alkaloids Alcuronium Dimethyltubocurarine Tubocurarine 4 ° ammonium agents ultra-short duration : Gantacurium short duration : Mivacurium Chandonium intermediate duration : Atracurium Cisatracurium Fazadinium Rocuronium Vecuronium long duration : Doxacurium Dimethyltubocurarine Pancuronium Pipecuronium Laudexium Gallamine unsorted : Hexafluronium ( Hexafluorenium ) Depolarizing Choline derivatives : Suxamethonium ( Succinylcholine ) Polyalkylene derivatives : Hexamethonium ACh release inhibitors Botulinum toxin Centrally acting Carbamic acid esters Carisoprodol Cyclarbamate Difebarbamate Febarbamate Meprobamate Phenprobamate Styramate Tybamate Benzodiazepines Bromazepam Diazepam Clonazepam Flunitrazepam Lorazepam Nitrazepam Temazepam Tetrazepam Nonbenzodiazepines Eszopiclone Thienodiazepines Etizolam Quinazolines Methaqualone Anticholinergics ( Antimuscarinics ) Cyclobenzaprine Orphenadrine Other Arbaclofen placarbil Baclofen Chlormezanone Chlorphenesin Chlorzoxazone Donepezil Eperisone Fenyramidol Flopropione Gabapentin GHB Inaperisone Lanperisone Mephenesin Mephenoxalone Metaxalone Methocarbamol Phenibut Pregabalin Pridinol Promoxolane Quinine Silperisone Thiocolchicoside Tizanidine Tolperisone Zoxazolamine Directly acting Dantrolene Nicotinic acetylcholine receptor modulators nAChRs Agonists 5 - HIAA A-84,543 A-366,833 A-582,941 A-867,744 ABT - 202 ABT - 418 ABT - 560 ABT - 894 Acetylcholine Altinicline Anabasine Anatoxin - a AR - R17779 Bephenium hydroxynaphthoate Butinoline Butyrylcholine Carbachol Choline Cotinine Cytisine Decamethonium Desformylflustrabromine Dianicline Dimethylphenylpiperazinium Epibatidine Epiboxidine Ethanol ( alcohol ) Ethoxysebacylcholine EVP - 4473 EVP - 6124 Galantamine GTS - 21 Ispronicline Ivermectin Levamisole Lobeline MEM - 63,908 ( RG - 3487 ) Morantel Nicotine ( tobacco ) NS - 1738 PHA - 543,613 PHA - 709,829 PNU - 120,596 PNU - 282,987 Pozanicline Pyrantel Rivanicline RJR - 2429 Sazetidine A SB - 206553 Sebacylcholine SIB - 1508Y SIB - 1553A SSR - 180,711 Suberyldicholine Suxamethonium ( succinylcholine ) Suxethonium ( succinyldicholine ) TC - 1698 TC - 1734 TC - 1827 TC - 2216 TC - 5214 TC - 5619 TC - 6683 Tebanicline Tribendimidine Tropisetron UB - 165 Varenicline WAY - 317,538 XY - 4083 Antagonists 18 - MAC 18 - MC α - Neurotoxins ( e.g., α - bungarotoxin, α - cobratoxin, α - conotoxin, many others ) ABT - 126 Alcuronium Allopregnanolone Amantadine Anatruxonium AQW051 Atracurium Barbiturates ( e.g., pentobarbital, sodium thiopental ) BNC - 210 Bungarotoxins ( e.g., α - bungarotoxin, κ - bungarotoxin ) Bupropion BW - A444 Candocuronium iodide ( chandonium iodide ) Chlorisondamine Cisatracurium Coclaurine Coronaridine Curare Cyclopropane Dacuronium bromide Decamethonium Dehydronorketamine Desflurane Dextromethorphan Dextropropoxyphene Dextrorphan Diadonium DHβE Dihydrochandonium Dimethyltubocurarine ( metocurine ) Dioscorine Dipyrandium Dizocilpine ( MK - 801 ) Doxacurium Encenicline Enflurane Erythravine Esketamine Fazadinium Gallamine Gantacurium chloride Halothane Hexafluronium Hexamethonium ( benzohexonium ) Hydroxybupropion Hydroxynorketamine Ibogaine Isoflurane Ketamine Kynurenic acid Laudanosine Laudexium ( laudolissin ) Levacetylmethadol Levomethadone Malouetine ME - 18 - MC Mecamylamine Memantine Methadone Methorphan ( racemethorphan ) Methyllycaconitine Metocurine Mivacurium Morphanol ( racemorphan ) Neramexane Nitrous oxide Norketamine Pancuronium bromide Pempidine Pentamine Pentolinium Phencyclidine Pipecuronium bromide Progesterone Promegestone Radafaxine Rapacuronium bromide Reboxetine Rocuronium bromide Sevoflurane Stercuronium iodide Surugatoxin Thiocolchicoside Toxiferine Tramadol Trimetaphan camsilate ( trimethaphan camsylate ) Tropeinium Tubocurarine Vanoxerine Vecuronium bromide Xenon Precursors ( and prodrugs ) Acetyl - coA Adafenoxate Choline ( lecithin ) Citicoline Cyprodenate Dimethylethanolamine Glycerophosphocholine Meclofenoxate ( centrophenoxine ) Phosphatidylcholine Phosphatidylethanolamine Phosphorylcholine Pirisudanol See also : Receptor / signaling modulators Muscarinic acetylcholine receptor modulators Acetylcholine metabolism / transport modulators Retrieved from `` https://en.wikipedia.org/w/index.php?title=Tubocurarine_chloride&oldid=812628724 '' Categories : Muscle relaxants Nicotinic antagonists Alkaloids Quaternary ammonium compounds Tetrahydroisoquinolines Phenol ethers Phenols Macrocycles Neuromuscular blockers Neurotoxins Hidden categories : Pages with citations lacking titles Template : drugs.com link with non-standard subpage Drugs with non-standard legal status Articles with changed CASNo identifier Articles with changed EBI identifier ECHA InfoCard ID from Wikidata Articles without KEGG source Drugboxes which contain changes to verified fields Drugboxes which contain changes to watched fields All articles with unsourced statements Articles with unsourced statements from August 2015 Talk Contents About Wikipedia Čeština Deutsch Ελληνικά Español Français Italiano 日本 語 Polski Português Română Русский Српски / srpski Srpskohrvatski / српскохрватски 中文 Edit links This page was last edited on 28 November 2017, at 23 : 21. 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Question: how does d-tubocurarine act as a muscle relaxant
Answer: activating