# Introduction to Pharmacology
## Pharmacology

Introduction to Pharmacology
Drugs—chemical substances used or intended to be used to modify or explore the physiological condition or pathological state for the benefit of the recipient. Drugs may be used for prevention, diagnosis and treatment.
Major divisions of pharmacology—
1. Pharmacokinetics.
2. Pharmacodynamics.
Other divisions—
1. Pharmacotherapeutics.
2. Clinical pharmacology.
3. Pharmacogenetics
4. Immunopharmacology
5. Pharmacognosy
6. Toxicology
7. Pharmacopoeia
Pharmacokinetics—(what the body does to the drug)—it is the branch of pharmacology that deals with drug dose, routes of administration and absorption, distribution, metabolism and excretion.
Pharmacodynamics—(what the drug does to the body)—it is a branch of pharmacology that deals with the mechanism of action, pharmacological effects, indication and contraindication of use and adverse effects of drugs.
Toxicology—it is the branch of pharmacology which deals with poisonous drugs, their source, properties, sign-symptoms they produce and management of poisoning.
Pharmacopoeia—it is a book published by authority of recognized body which contains the list of drug, their properties, description, preparation and method of prescribing.
Pharmacogenetics—it is that branch of pharmacology which deals with genetic variations in the drug response.
Ex—
§ Isoniazid is an anti-tubercular drug which is metabolized by acetylation. If acetylation process is increased by that person for the genetic factor then more drug is needed.
§ Patients with glucose-6-phosphate dehydrogenase deficiency may produce haemolytic anaemia if anti-malarial drug is given

## Learning Module Summary

To learn the overview of psychopharmacology in accordance with current observations with the underlying premise of the patients basic Bill of "Rights". That is for the practitioner to get the right drug to the right patient at the right time for the right condition with a a minimum of adverse effects.
Joel Lamoure 14:53, 24 December 2006 (UTC)
With the "Bill of Rights" comes patient safety, discontinuation syndrome, compliance, stigma. We will address DS to start and ultimately all 3 of these topics as they apply to psychopharmacology, under the umbrella and auspices of Patient Safety.Joel Lamoure 21:53, 17 March 2007 (UTC)

## Types of Reactions

The vast majority of adverse psychiatric drug reactions are of Type A in that they are dose-dependent or recognizably related to the known pharmacological properties of the drug. These could tritely be labelled as "Anticipated" reactions. the Type B reactions are those that encompass immunological like reactions, such as anaphylaxis demonstrated from penicllin class agents.

## Psychiatric Disorders - Iatrogenic (Doctor Induced) Disease

| Drug | Psychiatric Effects |
| Antihypertensive Drugs ||
| Clonidine | Depression, mania, agitation |
| Propanolol | Depression, mania, delirium, psychosis |
| Nifedipine | Depression |
| Captopril | Mania, agitation |
| Antiarrhythmics Procaninamide | Depression, mania, delirium, psychosis |
| Lignocaine | Depression, delirium, psychosis |
| Disopyramide | Delirium, psychosis |
| Antimicrobial Agents ||
| Incomplete | Chart |
Drug Psychiatric Effects Antihypertensive drugs
-Clonidine: Depression, mania, agitation
-Propanolol: Depression, mania, delirium, psychosis
-Nifedipine: Depression
-Captopril: Mania, agitation
-Antiarrhythmics (Procaninamide): Depression, mania, delirium, psychosis
-Lignocaine: Depression, delirium, psychosis
-Disopyramide: Delirium, psychosis
Antimicrobial Agents
-Penicillins: Depression, agitation, visual hallucinations
-Tetracycline: Depression, hallucinations
-Cephalosporins: Delirium, psychosis
-Antimalarials: Psychosis, visual hallucinations
Antiparkinson drugs
-Anticholinergics: Delirium, psychosis, visual hallucinations, dementia
-Amantadine: Depression, agitation, delirium, psychosis visual hallucinations
-Levodopa: Depression, mania, anxiety, agitation, psychosis visual hallucinations, delirium, cognitive impairment
Antihistamines
-H1 Blockers (diphenhydramine/dimenhydrinate): Delirium
-H2 Blockers (cimetidine): Depression, mania, delirium, psychosis, visual hallucinations
Antineoplastic drugs
-Interferon: Depression, agitation, delirium
-Vincristine: Depression
-C-asparaginase: Depression, delirium, psychosis
Endocrine Agents
-Corticosteroids: Depression, mania, psychosis, delirium
-Oral contraceptives: Depression
-Thyroxine: Anxiety, agitation, mania, psychosis, visual hallucinations
Antiepileptic drugs
-Barbiturates (phenobarbitone, primidone): Hyperactivity (especially in children), sedation, sexual dysfunction, aggression, learning deficits, cognitive impairmant, depression, personality change
Positive effects: anxiolytic/hypnotic (hypnotic, or soporific drugs produce sleep by depressing brain function and often cause hangover effects in the morning)
-Benzodiazepines (clonazepam, diazepam): Aggression, confusion, depression, disinhibition, irritability, cognitive impairment
Positive effects: anxiolytic/hypnotic; antimanic (clonazepam)
-Carbamazepine: Depression, irritability, sexual dysfunction, mania
Positive effects: antidepressant, antimanic, treatment of aggression and bipolar disorder
-Clobazam: Similar side effect profile to other benzodiazepines but may have lower overall incidence of cognitive and behavioral side effects anxiolytic/positive psychotropic effects
-Gabapentin: Sedation, ataxia, (shaky movements) aggression and hyperactivity (children); Few drug interactions, positive psychotropic effects,
-Hydantoins (phenytoin): Sedation, ataxia, dementia, affective disorder, confusion, cognitive impairment, progressive encephalopathy (disease that affects functioning of the brain)
Positive effects: Antiaggressive, anxiolytic effects
-Lamotrigine: May have added toxicity when used with carbamazepine: ataxia, dizziness; positive psychotropic effects
-Succinimides (ethosuximide, methsuximide): Psychosis ("alternating psychosis"- adolescents, young adults) Drowsiness, insomnia, irritability, cognitive effects, personality change,
Positive effects: improvement in attention/concentration (likely related to seizure improvement)
-Topirimate: Sedation, confusion, cognitive dysfunction, asthenia (weakness loss of strength)
-Valproate: Progressive encephalopathy, dementia, depression, extra pyramidal effects (muscle spasms etc)
Positive effects: antimanic, treatment of aggression and bipolar disorder
-Vigabatrin: Depression and psychosis
Section Reference: Nursing Diagnosis in Psychiatric Nursing-Pocket Guide for Care Plan Construction

## What are the most commonly used drugs in the Mental Health Setting? (Generic Names)

Section Reference: Nursing Diagnosis in Psychiatric Nursing - Pocket Guide for Care Plan Construction. 3rd Ed.
ANTIMANICS Lithium Carbonate – Carbamazapine Lamotrigine Olanzapine Valproic Acid
Lithium facts: • It works by enhancing reuptake of amines in the brain, thus lowering levels in the body & alters Na+ within nerve & muscle cells. • Drug of choice to tx/prevent bipolar mania. • Most common side effects - drowsiness, dizziness, headache, dry mouth, thirst, GI upset, nausea/vomiting, fine hand tremors, hypotension, irregular pulse, arrhythmias, polyuria, dehydration & weight gain. • Give with food or milk to  GI irritation. • Low Na+ levels may predispose to toxicity, teach pt to drink 2000-3000mL fluids & eat a diet moderate in salt. Also avoid excess coffee, tea or cola (has a diuretic effect). Avoid excess Na+ loss i.e. heavy exertion & exercise in hot weather & saunas (causes excess sweating). Other losses may be due to fever, vomiting & diarrhea. • The therapeutic range according to this reference is: • 0.7-1.0 mEq/L For acute mania • 0.6 –0.8 mEq/L For maintenance (prevention) • Anything above the range is toxic because there is an extremely narrow margin between the therapeutic & toxic levels. • Contraindicated in the first three months of pregnancy & in the elderly.
ANTIANXIETY Alprazolam Diazepam Lorazepam Chlordiazepoxide
Buspirone - interacts with neurotransmitters a.k.a anxiolytics, minor tranquilizers and sedatives. • Work by depressing the CNS EXCEPT for BuSpar that instead interacts with serotonin, dopamine & other neurotransmitters. • Side effects include the following: • Drowsiness, confusion & lethargy • Tolerance: physical & psychological dependence (shouldn't stop abruptly). • Potentates the effects of other CNS depressants i.e. alcohol & other meds. • Orthostatic hypotensions, paradoxical excitement, dry mouth, nausea, vomiting, blood dyscrasias & delayed onset with BuSpar (7-10 days - thus this is not an effective prn medication).
ANTIPSYCHOTICS
Newer Atypicals: Risperidone Olanzapine Quetiapine Clozapine Reference: Lamoure J, Bush H. Atypical Antipsychotics as Poison in Overdose. Cdn. J of CME 2005; 17(5):71-73)
Older Antipsychotics: Haloperidol Chlopromazine Trifluoperazine Zuclopenthioxol Methotrimeprazine + more
Antipsychotics - a.k.a. major tranquilizers, neuroleptics & antiemetics. • Are thought to act by blocking dopamine receptors throughout the brain.
* Are used to treat psychotic disorders, severe behavior problems in children & severe nausea, vomiting & intractable hiccups.
Noted side effects include: • Anticholingeric effects (dry mouth, blurred vision, constipation & urinary retention). • Nausea; GI upset (give with food). • Skin rash, orthostatic hypotension, photosensitivity & sedation (give at bedtime), weight gain, difficulty maintaining body temperature, urine may turn pink to reddish-brown, reduction in seizure threshold. • Hormonal effects - decreased Libido, retrograde ejaculation, gynecomastia (males), amenorrhea (females) • Agranulocytosis - a rare but serious side effect where WBC count drops extremely low HOWEVER 1%-2% of pts taking Clozaril (clozapine) develop it - so must have blood levels drawn weekly. If WBC count falls  3000mm3 or granulocyte count falls  1500mm3 the drug is discontinued. • Extra pyramidal Symptoms (EPS) (side effects) include: • Pseudoparkinsonism - tremor, shuffling gait, drooling & rigidity (can appear 1-5 days after starting the medication). • Akinesia - muscular weakness. • Akathisia - continuous restlessness & fidgeting (can occur 50-60 days after starting the med). • Dystonia - involuntary muscular movements (spasms) of the face, arms, legs & neck. • Oculogyric Crisis - uncontrolled rolling back of the eyes Tardive Dyskinesia - bizarre facial & tongue movements; stiff neck & difficulty swallowing. Neuroleptic Malignant Syndrome - rare but potentially fatal. S/S includes - hyperpyrexia ( to 107°F), tachycardia, tachypnea, and fluctuations in BP, diaphoresis, decreased in mental status. If Neuroleptic Malignant Syndrome occurs - the drug must be stopped immediately.
**Please note that the newer atypical agents have a far lower propensity to cause movement disorders. Risperidone over 6mg/day is linked with increased EPS however. Atypical Antipsychotics have their own unique side effect profiles that include metabolic changes, prolactin alterations and fluctuations in the patients sugars and cholesterol values.
ANTIDEPRESSANTS Fluoxetine (SSRI) - weight loss noted with drug. Sertraline (SSRI) Paroxetine (SSRI) Buproprion (SNRI) Amitriptylline (TCA) Trazodone (TCA) - priapism is a possible side effect. Phenylzine (MAOI) - hypertensive crisis possible Moclobemide (MAOI-B) Clomipramine (TCA) Nortriptylline (TCA) Imipramine (TCA) Mirtazapine (NASSA) Venlafaxine (SNRI) + more Work to increase the concentration of norepinephrine & serotonin in the body by blocking: • The reuptake of these chemicals by the neurons (such as with tricyclics & others). • Or inhibiting an enzyme (such as with MAO inhibitors). Work to elevate mood & alleviate other symptoms (use with psychotherapy). • Symptomatic relief is usually achieved in 1 to 4 weeks. • As mood lifts remember to assess for suicide, as potential often increases as depression lifts. Side effects include: • Anticholinergic effects (dry mouth, blurred vision, constipation & urinary retention). • Sedation, orthostatic hypotension, reduction of seizure threshold, tachycardia and arrhythmias and photosensitivity. • Hypertensive Crisis (with MAO inhibitors) to avoid such crisis teach the patients not to consume tyramine containing foods as follows: aged cheese, or other aged or fermented foods, pickled herring, beef & chicken livers, preserved sausages, beer, wine (esp. chianti), chocolate, caffeine, canned figs, sour cream, yogurt, soy
HYPNOTICS Temazapam Oxazepam Chloral Hydrate Hydroxyzine Flurazepam + more See same side effects as for antianxiety drugs. Addiction potential
STIMULANTS Methylphenidate Dexamphetamine +moreAddiction potential
ANTICONVULSANTS Valproic Acid Carbamazepine Primidone Lamotrigine
Phenytoin Topiramate With VPA - Monitor CBC & serum levels of valproic acid .A side effect to monitor with Depakote is prolonged bleeding time - noting any bruising or spontaneous bleeding. Monitor Dilantin levels - Therapeutic blood levels are between Topiramate- Weight Negative
ANTIPARKINSONISM Benztropine Procyclidine Diphenhydramine Antiparkinsonism drugs: • Work to restore the balance of neurotransmitters acetylcholine & dopamine  this imbalance results in excessive cholinergic activity. • Are used to TX all forms Parkinsonism & drug-induced extrapyramidal reactions. • Side effects: exacerbation of psychosis. • Anticholinergic effects - dry mouth, blurred vision, constipation, Paralytic Ileus, urinary retention, tachycardia, decreased sweating (body may not be able to cool self), elevated temperatures & orthostatic hypotension. • Nausea & GI upset. • Sedation: Given at bedtime if possible

## Discontinuation Syndrome in Patients

Joel Lamoure 21:43, 17 March 2007 (UTC)

## The Principles of Discontinuation Syndrome

Joel Lamoure 21:43, 17 March 2007 (UTC)
(Adopted and modified from "Lamoure J. Discontinuation Syndrome: Relapse vs. Withdrawal. Cdn. J of Diagnosis 2006; 23(9):95-98")
Understanding discontinuation syndrome (DS) and becoming familiar with the medications that cause it are important issues in the treatment of patients with mental health conditions. The purpose of this article is to enhance the awareness of the potential that your patients may be experiencing DS. There is a challenge in this field, in that the symptoms of DS in the medications that will be explored in this article often mimics the initial condition for which they were employed. Even with antidepressants, only 72% of psychiatrists and 30% of GPs were aware that patients might experience DS. (1)
What is DS?
Discontinuation Syndrome (DS) is a condition where the patient experiences adverse effects that result from an abrupt discontinuation of the medication. Symptoms of DS begin to appear generally within the first 24-48 hours after drug discontinuation or dose reduction and last for up to 7-14 days depending on the medication. (2) Also, some adverse effects from discontinuation may persist from months after, as seen with paroxetine. Symptoms of DS are distinct from relapse of underlying disease and will resolve after drug reinstitution, but as alluded to, often mimic or appear to be a relapse of the initial mental health condition (2,3). In this article, we will address tricyclic antidepressants, atypical antipsychotics and benzodiazepines. There are discontinuation syndromes seen also with a myriad of agents including beta blockers (eg propranolol) and narcotics/ opiates, which will not be addressed herein. It becomes an issue for practitioners as inherently patients in mental health are not compliant, due to cost, adverse effects or stigma and also in medical situations where there is a decision to hold medications (e.g. pre and post-operatively). (4)

## Medications causing DS

There are three classes of drugs implicated in DS we will cover in this subsection:
Selective serotonin reuptake inhibitors (SSRI)/ Serotonin-nor epinephrine reuptake inhibitor •(SNRI) agents. Although these agents are the cornerstones of therapy for depression, abrupt discontinuation may lead to major adverse reactions, as we shall visit.
•Antipsychotics (E.g.: Olanzapine, Quetiapine, Risperidone and Clozapine) used in psychosis, agitation, anxiety and as mood stabilizers
* Benzodiazepines for sleep disturbances, anxiety and agitation in psychiatry.
Discontinuation syndrome can occur with different agents, including opiates, beta- blockers and more for the purpose of this article, we will focus on the first three items. If we look at the numbers, up to 30% of the population may need one of these 3 classes for depression, schizophrenia or bipolar in their lifetime. For all intents and purposes, an agent that has physiological or psychological effects may result in patients experiencing discontinuation syndrome. however, certain agents are more susceptible to producing discontinuation syndrome. These are agents with very short half-lives, no active metabolites, dosed at high levels or agents that are used for a protracted period.

## Etiology (2,5,6,7)

Physiological dependence on these medications is a normal consequence of pharmacological receptor site activity. Receptors that may be involved with the TCA agents (e.g. imipramine) can be explained by adrenergic overdrive or cholinergic overdrive. In adrenergic overdrive, TCA’s inhibit NE uptake, increasing synaptic NE concentrations. Alpha2 receptor stimulation occurs via negative feedback resulting in decreased adrenergic firing. So prolonged TCA use causes blunting of this loop and thus when TCA’s are discontinued, the negative feedback loop inhibits adrenergic firing. In cholinergic overdrive, TCA bind to muscarinic receptors cebtrally and peripherally, leading to muscarinic up regulation. When the TCA is abruptly stopped, there are cholinergic symptoms from cholinergic hyperactivity.
Antidepressant DS may occur with tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and SSRIs. Symptoms usually start within a few days at most of treatment cessation, or rarely, when tapering down a dosage. Distinguishing antidepressant DS from the underlying depression is important. DS symptoms usually present within one day to three days, whereas depressive symptoms usually only present two weeks to three weeks after antidepressant medication is stopped. DS usually subsides in a few days, especially if antidepressant treatment is re-started. Up to 30% of patients who stop SSRI treatment will experience DS.
Proposed mechanisms with the SSRI agents include that there is an increased concentration of serotonin in the synapse. This then results in a desensitization of the postsynaptic serotonin receptor by down regulation. When the agents are discontinued, there is a temporary deficiency of serotonin in the synapse, which leads to the physical symptoms.
With the antipsychotics, DS was first identified in the late 1950’s with chlorpromazine when it was being trailed as an anti-TB agent. The DS occurred in 5/17 subjects. Most atypical agents have some serotonin-dopamergic antagonism and there are now case reports for all of the atypical agents. The proposed mechanism of action is that there is weak dopamine D2 antagonism and potent serotoninergic (5HT2) antagonism. Also they inherently have effects (antagonism) at the alpha-adrenergic, histaminergic and cholinergic receptors, the ratio depending on the individual agent. Thus, we see a rebound from these receptors when the agent is stopped. This also explains why the atypicals have a very specific DS for each different agent.
In benzodiazepines, they modulate the neurotransmitter activity of GABA and interact with binding sites on the GABA receptor complex. This results in an increased receptor affinity for GABA. When the benzodiazepine is stopped, there are decreased GABA binding sites/ inhibitory effects and the increased glutamate, which yield the excitatory effects. Chronic use of benzodiazepines leads to adaptive changes, including GABA receptor down regulation and increased glutamate. This contributes in part to the DS seen with benzodiazepines.

## Conclusions and impact to practice

Given the fact that up to 25% of the population may have depression in their lifetime, 1-2% schizophrenia and 5-7% bipolar disorder, physicians involved in mental health care need to be aware of the main factors precipitating DS. These include risk factors may be directly related to higher doses, or usage for prolonged duration of time As well as possibly a past history of substance abuse (8) considering the psychological “need” to continue with a medication. Additionally, by recognizing characteristic symptoms, avoiding abrupt discontinuation and providing adequate patient counseling and follow-up, physicians can play an active role in diminishing the occurrence of DS. A helpful tool for practitioners to identify DS in patients is the acronym FINISH:
•F Fever
•I Insomnia
•N Nausea
•I Irritability
•S Sensory Changes
•H Headache
We must be aware that if a patient presents with signs and symptoms listed above, it is may be as a result of medication discontinuation. In general, the discontinuation syndrome signs and symptoms occur before the relapse of the Axis I disorder as the DS occurs within hours of drug discontinuation. Considering all of the factors such as patient diet, hydration and compliance are generally patient specific factors. Also, there are medication specific variables. These include concurrent medications that may affect metabolism, half-life of the medication and active metabolites. Other factors may be the patient’s dependence lability (psychological vs. physical withdrawal syndromes) and duration of therapy with the agent. One can determine if the symptoms that present are as a result of DS by simply introducing a low dose of the agent suspected. Signs and symptoms are ameliorated within a very short time period depending on the dose, concentration, Cmax and Tmax plus half-life of the agent.

## Discontinuation Syndrome Section References:

1) Young A and Currie, A. Physician Knowledge of Antidepressant Withdrawal effects: A Survey. J Clin Psychiatry 1997:58 (suppl 7) pp 28-30
2) Cheng, L. What Pharmacists should know about medications Associated with Discontinuation Syndrome. CSHP Clinical Symposium September 18,2004
3) Lejoyeux M and Ades, J. Antidepressant Discontinuation: A review of the Literature. . J Clin Psychiatry 1997:58 (suppl 7) pp 11-16
4) Kaplan E. Antidepressant Noncompliance as a factor in the Discontinuation Syndrome. . J Clin Psychiatry 1997:58 (suppl 7) pp 31-36
5) Schatzberg, A, Haddad P, Kaplan E, Lejoyeux M, Rosenblum J et al. Possible Biological Mechanisms of the Serotonin Reuptake Inhibitor Discontinuation Syndrome. J Clin Psychiatry 1997:58 (suppl 7) pp 23-27
6) Healy D SSRI and Withdrawal/Dependence Briefing Paper http://www.socialaudit.org.uk/58092-DH.htm
7) Raffel S, Kochan I, Poland N, Hollister LE. The action of chlorpromazine upon Mycobacterium tuberculosis Am Rev Respir Dis. 1960 Apr;81: 555-61.
8) Psychiatric Quarterly 1998; 50 (4) 251-261
9) Haddad P. Newer Antidepressants and the Discontinuation Syndrome. . J Clin Psychiatry 1997:58 (suppl 7) pp 17- 22
10) Bhanji, N et al. Persistant Tarditive Rebound Panic Disorder, rebound Anxiety and Insomnia following paroxetine withdrawal: A Review of Rebound-Withdrawal Phenomena. Can J. Pharmacol. Jan 23 2006; 1: e69-e74
11) Haddad P et al., Depression, Stroke Diagnosis and SSRI Discontinuation Syndrome. Can J Psychiatry 2004; 49:344-345