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Following drug groups are considered

Antidepressant Antipsychotics (neuroleptics) Mood stabilizers.

Drugs for anxiety and sleep disorders.

ANTIDEPRESSANT AGENTS

BASIC PHARMACOLOGY OF ANTIDEPRESSANTS CHEMISTRY A variety of different chemical structures have been found to have antidepressant activity.

A. Tricyclics
Imipromine and amitriptyline are prototypical drugs of the class.

B. Heterocyclics, second generation drugs


Amoxapine and maprotiline resemble the structure of the tricyclic agents, while trazodone and bupropion are distinctive. Venlafaxine is a newe.

C. Selective serotonin reuptake inhibitors (SSRI)


The antimuscarinic, antihistaminic, and alpha adreneaceptor-blocking actions of tricyclic antidepressant contribute only to the toxicity of these agents.

Fluoxetine, antidepressant with minimal autonomic toxicity, a highly selective serotonin reuptake inhibitor.

Three selective serotonin reuptake inhibitor : (1) paroxetine (2) sertraline (3) fluvaxamine.

D. Monoamine oxidase (MAO) inhibitors MAO inhibitors may be classified as hydrazides, exemplified by the C-N-N moiety, as in the case of phenelzine and isocarboxazid; or nonhydrozides. Tranycypromine a weak inhibitor of MAO.

Tranycypromine retains some of the sympthomimetic characteristic of the amphetamines. Older MAO inhibitors nonselective inhibitors of both MAO-A and MAO-B.

Moclobemide is a new, shortacting, selective MAO-A inhibitor.

E. Sympthomimetic stimulants Dextroamphetamine, other amphetamines, and amphetamine surrogates such as methylphenidate occasionally used ad antidepressants.

PHARMACOKINETICS A. Tricyclics

Most tricylics incompletely absorbed and undergo signigicant first-pass metabolism.

High protein binding and relatively high lipid solubility volumes of distribution very large.

Tricylics metabolized by two major routes : transformation of the tricylics nucleus and alteration of the aliphatic side chain.

B. Heterocyclics
The pharmacokinetics of these drugs and of the tricyclics similar variable bioavailability, high protein binding, variable and large volumes of distribution, active metabolites. Trazodone and venlafaxine shortest plasma half-lives.

C. Selective serotonin reuptake inhibitors (SSRIs) Fluoxetine well absorbed, and peak plasma concentrations within 4-8 hours.
Its demethylated active metabolite, norfluoxetine halflife of 7-9 days at steady state; a slightly shorter half-life.

Fluoxetine inhibits various drug-metabolizing enzymes a number of significant drug-drug interactions with other antidepressants and with other drugs as well. Sertraline and paroxetine pharmacokinetic parameters similar to those of tricyclics.

D. MAO inhibitors

MAO inhibitors readily absorbed from the gastrointestinal tract. Hydrazide inhibitors (phenelzine and isocarboxazid) are acetylated in the liver and manifest differences in elimination depending on the acetylation phenotype of the individual.

The effect persist for from 7 days (tranycypromine) to 2 or 3 weeks (phenelzine, isocarbonazid) after discontinuance of the drug. Moclobemide is rapidly absorbed and excreted, with over 90% of the drug appearing a metabolites in the urine within 12 hours.

MECHANISM OF ACTION

The monoamine hypothesis propopse in depression deficiency of the neurotransmitters nonadrenaline and serotonin in the brain can be altered by antidepressants.

Drugs affects depression modify amine storage, release, or uptake concentration of amines in nerve endings and/or at postsynaptic receptors is enhanced. Specific serotonin reuptake inhibitors preventing serotonin reuptake and have more limited effects on nonadrenaline reuptake.

Tricylclic antidepressants inhibit noradrenaline reuptake, but effects on serotonin reuptake vary widely; desipramine and protriptyline minimal potential for raising, serotonin concentration.

MAO inhibitors block a major degradative pathway for the amine neurotransmitters permits more amines to accumulate in presynaptic and more to be released.

Table. Pharmacokinetic parameters of various antidepressants


Drug Bioavailability (%) 31-61 No data 60-80 No data 60-70 13-45 70 29-77 66-75 32-79 Protein binding (%) 82-96 No data 85 No data 73-90 No data 94 76-95 88 93-95 Plasma t1/2 (hours) 31-46 8 11-14 22-84 14-62 8-24 24-96 9-24 21-52 18-93 Active metabolites Volume of distribution (1/kg) 5-10 No data 20-30 7-20 22-59 9-33 12-97 15-30 15-28 21-57 Therapeutic plasma concentrations (ng/mL) 80-200 total No data 25-100 240-700 1452 30-150 No data > 180 total 200-300 50-150

Amitriptyline Amoxapine Bupropion


Clomipramine

Nortriptyline 7-8-Hydroxy ? Desmethyl No data Desmethyl Norfluoxetine Desipramine Desmethyl 10-Hydroxy

Desipramine Doxepin Flouxetine Imipramine Maprotiline Nortriptyline

Paroxeline
Protriptyline Sertraline Trazodone

50
77-93 No data No data

95
90-95 98 No data

24
54-198 22-35 4-9

None
No data Desmethyl m-Chlorophenylpiperazine

28-31
19-57 20 No data

No data
70-170 No data No data

CLINICAL INDICATIONS

A.Depression.
B.Panic disorder. C.Obsessive-compulsive disorders. D.Enuresis. E.Chronic pain.

DRUGS CHOICE
Antidepressant drugs are apt most successful in patients withvegetative characteristics, including psychomotor retardation, sleep disturbance, poor appetite and weight loss, and loss of libido.

DOSAGE
Table. Usual daily doses of antidepressant drugs __________________________________________ Drug Dose (mg) __________________________________________ Tricylics Amitriptyline 75-200 Clomipramine 75-300 Desipramine 75-200 Doxepin 75-300 Imipramine 75-200 Nortriptyline 75-150 Protriptyline 20-40 Trimipramine 75-200 __________________________________________

DOSAGE

__________________________________________

Drug
Second generation drugs

Dose (mg)

__________________________________________

Amoxapine
Bupropion Maprotiline Trazodone Venlafaxine

150-300
200-400 75-300 50-600 75-225

__________________________________________

DOSAGE

__________________________________________ Drug Dose (mg) __________________________________________ Monoamine oxidase inhibitors Isocarboxazid 20-50 Phenelzine 45-75 Tranylcypromine 10-30 Selective serotonin reuptake inhibitors Fluoxetine 10-60 Paroxetine 20-50 Sertraline 50-200 __________________________________________

ADVERSE EFFECTS

A. Tricyclic antidepressant
Unwanted effect antimuscarinic action, i.e. dry mouth (predisposing to tooth decay), blurred vision and difficulty with accommodation, raised intraocular pressure (glaucoma may be precipitated), bladder neck obstruction (may lead yo urinary retention in older males).

Postural hypotension, interference with sexual function, weight gain, prolongation of the QT interval of the ECG. Some TCAs (especially trimipramine and amitriptyline) heavily sedating through combination of antihistaminergic and -adrenergic blocking actions.

Clinical features of overdose (1) antimuscarinic effect (2) consciousness (3) respiration depression (4) hypothermia (5) neurological signs include hyperreflexia, myoclonus and divergent strabismues. Extensor plantar responses (6) sinus tachycardia.

B. Selective serotonin reuptake inhibitors Unwanted effects nausea, anorexia, dizziness, gastrointestinal disturbance, agitation, akathisia, (motor restlessness) and anorgasmia (failure to experience an orgasm).

Disrupt the pattern of sleep with increased awakenings, transient reduction in the amount of REM and increased REM latency but eventually sleep improves due to elevation of mood. The serotonin syndrome restlessness, tremor, shivering and myoclonus possibly on to convulsions, coma and death.

C. Monoamine oxide inhibitors

Adverse effect postural hypotension (especially in elderly) and dizziness.

Less common headache, irritability, apathy, insomnia, fatigue, ataxia, gastrointestinal disturbances including dry mouth and constipation, sexual dysfunction (especially anorgasmis), blurred vision, difficult micturition, sweating, peripheral, oedema, tremulousness, restlessness, and hyperthermia. Appetite may increase inappropriately, causing weight gain.

INTERACTIONS
A. TCAs and SSRIs

Pharmacodynamic interaction : TCAs cause sedation and coprescription with other sedative agents such as opioid analgesics, antihistamines, anxiolytics, hypnotics and alcohol excessive drowsiness and daytime somnolence.

Risk of QT prolongation with many other cardiovascular drugs. TCAs and SSRIs central nervous system toxicity of coprescribed with the dopaminergic drugs entacapone and selegiline (for Parkinsons disease).

SSRIs increase the risk of toxicity when combined with other drugs which upregulate serotonin transmission.

Tricyclics and SSRIs lower the convulsion threshold epilepsy more difficult to control by anti-epilepsy drugs and lengthening seizure time in electroconvulsive therapy.

Pharmacokinetic interactions : TCAs and SSRIs metabolised extensively by cytochrome P450 enzymes.

Table. Psychotropic (and selected other) drugs known to be CYP 2D6 substrates and inhibitors CYP 2D6 inhibitors Antidepressants. Paroxetine Fluoxetine

CYP 2D6 substrates Antidepressants Paroxetine Fluoxetine Citalopram Sertraline venlafaxine Amitriptyline Clomipramine Desipramine Imipramine Nortriptyline

Antipsychotics Chlorpromazine Haloperidol Thioridazine Zuclapenthixol Perphenazine Risperidone

Miscellaneous Dexfenfluramine Opioids Codeine Hydrocodeine Dihydrocodeine Tramadolol Ethyl morphine Tenamfetamine (ecstasy) Bupropion -blockers Propanolol Metoprolol Timolol Bufaralol

Table. Psychotropic (and selected other) drugs known to be CYP 3A4 substrates, inhibitors and inducers
CYP 3A4 inhibitors Antidepressants Nefazodone Fluoxetine CYP 3A4 substrates Antidepressants
Fluoxetine Sertraline Amitriptyline Imipramine Nortriptyline Trazodone Other drugs Cimetidine Erythromycin Ketoconazole (and grapefruit juice) Anxiolytics, hypnotics and antipsychotics Alprazolam Buspirone Diazepam Midazolam Triazolam Zopiclone Haloperidol Miscellaneous Buprenorphine Carbamazepine Cortisol Dexamethasone Testosterone Calcium chanel blockers Diltiazem Nifedipine Amlodipine Other drugs Amiodarone Omeprazole Oral contraceptives Simvastatin Miscellaneous Carbamazepine Phenobarbital Phenytoin

CYP 3A4 inducers Antidepressants St. Johns Wort

B. Monoamine oxidase inhibitors


Sympathomimetic substances highly dangerous hypertensive reactions if taken by patient using MAC inhibitors.

ANTIPSYCHOTIC AGENTS

The terms antipsychotic a group of drugs that have been used mainly for treating schizophrenia.

BASIC PHARMACOLOGY OF ANTIPSYCHOTIC AGENTS

CHEMICAL TYPES
The drugs can be classified into several groups.

A. Phenothiazine Derivatives

Three subfamilies of phenothiazines (1) Aliphatic derivatives [eg.chlorpromazine] (2) Piperidine derivatives [eg.thiodazine] (3) Piperazine derivatives.

B. Thioxanthene Derivatives C. Butyrophenone Derivatives. D. Miscellaneous Structures :


Diphenylbutylpiperidines (pimozide). Dihyroindolones (molindone). Dibenzoxazepines (loxapine). Dibenzodiasepines (clozapine). Benzamides (remoxipride).

PHARMACOKINETICS
A. Absorption & Distribution Most antipsychotic drugs are readily but incompletely absorbed. Many of these drugs undego significany first-pass metabolism.

Oral doses of chlorpromazine and thioridazine, haloperidol, which is less likely to be metabolized, has an average systemic availability of about 65%.

Highly lipid-soluble, proteinbound (93-99%). Metabolites of chlorpromizine may be excreted in the urine weeks after the last dose.

B. Metabolism.

Almost completely metabolized by a variety of processes.


C. Excretion.

Elimination half-lives vary from 10-24 hours.

PHARMACOLOGIC EFFECTS
The first phenothiazine antipsychotic drugs, with chlorpromazine as the prototype, proved to have a wide variety of CNS, autonomic, and endocrine effects.

These actions were traced to blocking effects at a remarkable number of receptors.

These include dopamine and alpha-adrenoceptor, muscarinie, H1 histaminic and serotonin (5HT2) receptors.

A. Dopaminergic systemic.
After dopamine was recognized as a neurotransmitter, various experiments showed that its effects on production of cAMP by adenylyl cyclase could be blocked by most antipsychotic drugs.

Antipsychotic action is now though to be produced by their ability to block dopamine in the mesolimbic and mesofrontal systems.

B. Dopamine Receptors and Their Effects. At present, five different dopamine receptors have been described, consisting of two separate families, the D1-like and D2-like receptor groups.

The D1 receptor is coded by a gene on chromosome 5, increases cAMP by activation of adelylyl cyclase, and is located mainly in the putamen, nucleus accumbens, and olfactory tubercle.

The second member of this family, D5, is coded a gene on chromosome 4, also increases cAMP, and is found in the hypocampus and hypothalamus.

C. Differences Among
Antipsychotic Drugs. Although all effective antipsychotic drugs block D2 receptors, the degree of this blockade in relation to other actions on receptors varies considerably between drugs.

D. Neurophysiologic Effects.
Antipsychotic drugs produce shifts in the patient of electroencephalographic, frequencies. The slowing (hypersynchrony) is sometimes focal or unilateral, which.

E. Endocrine Effects.

Amenorrhea-galactorrhea, falsepositive pregnancy tests, and increased libido have been reported in women, whereas men have experienced decreased libido & gynecomastia.

F. Cardiovascular Effects.
Orthostatic hypotension and high resting pulse rates frequently result from use of the high dose (low potency) phenothiazines. Mean arterial pressur, peripheral resistance, and stroke volume are decreased.

CLINICAL PHARMACOLOGY OF ANTIPSYCHOTIC AGENTS

INDICATION
A. Psychiatric Indications. Schizophrenia is the primary indication for these drugs.

Other psychiatric indications for the use of antipsychotics include Tourettes syndrome and the need to control disturbed behavior in patients with senile dementia of the Alzheimer type.

Antipsychotics in small doses have been promoted for the relief of anxiety associated with minor emotional disorders.

B. Nonpsychiatric Indications Most antipsychotic drugs, a strong antiemetic effect.

DOSAGE

The range of effective dosage among various antipsychotics is quite broad.


Patients who fail to respond to one drug may respond to another.

ADVERSE REACTIONS
A. Behavioral Effects.

A pseudodepression that may be due to drug-induced akinesia usually responds to treatment with antiparkinsonism. Toxic-confusional states may occur.

B. Neurologic Effects.
Extrapyramidal reactions occuring early during treatment include typical Parkinsons syndrome, akathisia (uncontrollable restlessness), and acute dystonic reactions (spastic retrocollis or torticollis), tardive dyskinesia, seizures.

C. Autonomic Nervous System Effects. Most patients become tolerant to antimuscarinic adverse effects of antipsychotic drugs. Orthostatic hypotension or impaired ejaculation common complications of therapy with chlorpromazine or mesoridazine-should.

D. Metabolic and Endocrine Effects. Hyperprolactinemia in women results in the amenorrheagalactorrhea syndrome and infertility; in men, loss of libido, importance, and infertility may results.

E. Toxic or Allergic Reactions. Agranulocytosis, cholestatic jaundice, and skin eruptions occur rarely with the highpotency antipsychotic drugs currently used.

F. Ocular Complications.

Deposits in the anterior portion of the eye (cornea and lens) are a common complication of chlorpromazine therapy.

G. Cardiac Toxicity. Thioridazine in dose exceeding 300 mg daily is almost always associated with minor abnormalities of T waves.

H. Use in Pregnancy; Dysmorphogenesis.


I. Neuroleptic Malignant Syndrome.

MOOD STABILISERS

LITHIUM Mode of action not fully understood. Main effect inhibit hydrolysis of inositol phosphate reducing the recycling free inositol for synthesis of phosphatidylinositides.

Pharmacokinetics
Therapeutic plasma concentration close to the toxic concentration (low therapeutic index).

Orally rapidly absorbed.


Peak plasma lithium concentration 5 h.

Distributed throughout the total body water higher concentration in brain, bones and thyroid gland. Filtered by the glomerulus, 80% is reabsorbed by the proximal tubule.

Chronic use the plasma t1/2 of lithium 15-30 h. Lithium given 12 hourly to avoid unnecessary fluctuation, maintain a plasma concentration just below the toxic level.

A steady-state plasma concentration 5-6 days (i.e. 5 x t1/2) in patients with normal renal function. Old people and patients with impaired renal function a longer t1/2.

Indications and Use Lithium carbonate effective treatment in > 75% of episodes of acute mania of hypomania. Lithium used in combinations with benzodiazepine. For prophylaxis, lithium is indicated two episodes of mood disturbance in two years.

Adverse Effects Fine tremor (especially involving the fingers), constipation, polyuria and polydipsia, metallic taste in the mouth, weight gain, oedema, goitre, hypothyroidism, acne, rash, diabetes insipidus and cardiac arrhytmias. Mild cognitive and memory impairment.

Signs of infoxication (plasma concentration greater than 1.5 mmol/1) gastrointestinal (diarrhoea, anorexia, vomiting), neurological, (blurred vision, miscle weakness, drowsiness, sluggishness, coarse tremor, leading on to giddiness, ataxia, dysarhria).

Severe overdosage or rapid reduction in renal clearance hyperreflexia, hyperextension of limbs, convulsions, toxic psychoses, syncope, oliguria, coma, death.

Interactions Drug interfere with lithium excretion by the renal tubules diuretics, ACE inhibitors and angiotensin-11 antagonis, non steroidal antiinflammatory analgesics.

Theophylline and sodiumcontaining antacids plasma lithium concentration.


Diltiazem, verapamil, carbamazepine and phenytoin neurotoxicity.

Concomitant use of thioridazine ventricular arrhythmias.

Carbamazepine Carbamazepine as an alternative of lithium for prophylaxis of bipolar affective disorder.

Mode of action involve anonism in inhibitory GABA transmission at the GABA-benzodiazepine receptor complex.

Valproic Acid

Valproic acid licenced for

use in the treatment of acute


mania unresponsive to lithium.

DRUGS USED IN ANXIETY AND SLEEP DISORDERS

PANIC DISORDER Treatment

Fast-acting benzodiazepine such as alprazolam (1-3 mg/day p.o.), drug with delayed efficacy but fewer problems of withdrawal such as a TCA, e.g. clomipramine (100-250 mg/day p.o) or an SSRI, e.g. paroxetine (20-50 mg/day p.o).

SOCIAL ANXIETY DISORDES

Treatment
The drugs SSRI, paroxetine,

the MAOI, phenelzine and the


RIMA, moclobemide in the

same doses as for depression.

Table. Relative effectiveness of pharmacological treatments for anxiety disordes

Table. Properties of anti-anxiety drugs

POST-TRAUMATIC STRESS DISORDES (PTSD) Treatment is poorly researched. Benzodiazepines, TCAs and MAOIs; paroxetine (SSRI) (2050 mg/day p.o) licenced for this indications.

GENERALISED ANXIETY DISORDER Buspirone

Structurally unrelated to other anxiolytics efficacy in GAD. Mode of action suppresses 5HT neurotransmission through a selective activation of the inhibitory presynaptic 5HT1A-receptor.

Buspirone a t1/2 of 7 h, metabolised in the liver, an active metabolite that, may accumulate over weeks. Twice daily dosing range being 15-30 mg/d p.o., max. 45 mg/d. Adverse effect can dizziness, headache, nervousness, excitement, nausea, tachycardia and drowsiness.

Paroxetine (SSRI) & Venlafaxine (SNRI) Effective.

TCAs benefit.
The Duration of Therapy

Depends on the nature of the underlying illness.

INSOMNIA

DRUGS FOR INSOMNIA


Benzodiazepines

All benzodiazepines and newer benzodiazepine safe and effective for insomnia.

Pharmacokinetics. Benzodiazepines effective after administration by mouth but enter the circulation at very different rates that are reflected in the speed of onset of action.

Liver metabolises usually to inactive metabolites, some compounds produce active metabolites, some with long t1/2 which greatly extends drug action.

Uses.
Benzodiazepine used for : insomnia, anxiety, alcohol withdrawal states, muscle spasm due to a variety of causes, including tetanus and cerebral spasticity, epilepsy (clonazepam), anaesthesia and sedation for endoscopies and cardioversion.

Doses.

Oral doses as anxiolytics given with their indications :


Intravenous formulations, e.g. diazepam 10-20 mg, given at 5 mg/min into a large vein (antecubital fossa) to minimise thrombosis: the dose may be repeated once in 10 min for status epilepticus or in 4 h for severe acute anxiety or agitation.

Intramuscular injection of diazepam is absorbed, slower in acting than an oral dose.

Table. Properties of drugs used cfor insomnia

Adverse Effects.
Benzodiazepines affect memory and balance. Paradoxical behaviour effect, perceptual disorders. Headache, giddiness, alimentary tract upset, skin rashes and reduced libido can occur. Extrapyramidal reaction.

Interactions. All potentiate the effects of

alcohol, other central


depressants.

Overdose. Benzodiazepines are remarkably, safe in acute overdose and the therapeutic dose x 10. Deaths have occurred combination with alcohol.

SUMMARY OF PHARMACOTHERAPY FOR INSOMNIA


Drug treatment : effective for a short period (2-4 weeks). Some patients need longterm medication.

Intermittent medication, taken only nights that symptoms occur, modern, short-acting, compound. Discontinuing hypotic drugs not a problem.