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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.
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.
E. Sympthomimetic stimulants Dextroamphetamine, other amphetamines, and amphetamine surrogates such as methylphenidate occasionally used ad antidepressants.
PHARMACOKINETICS A. Tricyclics
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.
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.
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
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
ANTIPSYCHOTIC AGENTS
The terms antipsychotic a group of drugs that have been used mainly for treating schizophrenia.
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.
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.
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 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.
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.
DOSAGE
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.
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).
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.
Mode of action involve anonism in inhibitory GABA transmission at the GABA-benzodiazepine receptor complex.
Valproic Acid
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).
Treatment
The drugs SSRI, paroxetine,
POST-TRAUMATIC STRESS DISORDES (PTSD) Treatment is poorly researched. Benzodiazepines, TCAs and MAOIs; paroxetine (SSRI) (2050 mg/day p.o) licenced for this indications.
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.
TCAs benefit.
The Duration of Therapy
INSOMNIA
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.
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.
Overdose. Benzodiazepines are remarkably, safe in acute overdose and the therapeutic dose x 10. Deaths have occurred combination with alcohol.
Intermittent medication, taken only nights that symptoms occur, modern, short-acting, compound. Discontinuing hypotic drugs not a problem.