TYPICAL ANTIPSYCHOTICSBy : Dr. Gajanand Verma

Dr. Anant kr. Rathi

Dr. khushboo Bairwa

HISTORY:- Phenothiazines were first effective antipsychotics. Were originally used as antihelminth in veternary

medicine and as urinary antiseptics in human. Paul Charpenteir at Rhone Poulenc Lab Paris

synthesised Chlorpromazine. In 1952 Jean Delay and Pierre Deniker administered

chlorpromazine in patients with mania and schizophrenia marking the beginning of modern psychopharmacology.

In 1958 first effective Butyrophenone, Haloperidol was introduced by Paul Janssen.

In the same year first Thioxanthene antipsychotics were introduced by P.V.Peterson.

In 1960s first long acting antipsychotic Fluphenazine enenthate was introduced.

CLASSIFICATION:-

A) PHENOTHIAZINES:- 1) ALIPHATICS: CHLORPROMAZINE, TRIFLUPROMAZINE 2) PIPERIDINES: THIORIDAZINE, MESORIDAZINE 3) PIPERAZINES: TRIFLUPERAZINE, FLUPHENAZINE

B) BUTYROPHENONES:- HALOPERIDOL, TRIFLUPERIDOL, DROPERIDOL

C) THIOXANTHINES:- 1) ALIPHATICS: CHLORPROTHEXINE 2) PIPERAZINES: THIOTHEXINE, CLOPENTHIXOL

FLUPENTHIXOL, ZUCLOPENTHIXOL

CONTINUED:-

D) DIPHENYLBUTYLPIPERIDINES:- PIMOZIDE

E) INDOLE DERIVATIVES:- MOLINDONE

F) DIBENZOXAZEPINES:- LOXAPINE

PHARMACOKINETICS:-

ABSORPTION:- In general well absorbed orally or parentrally, however oral absorption is less predictable then parenteral.

Peak plasma concentration usually achieved in 1 to 4 hrs after oral intake and 30 to 60 minutes after I.M. injection.

Steady state concentration achieved in 3 to 5 days. Bioavailability of I.M. injection is about 10 folds higher then

oral.

Distribution:- Initial decline in the plasma concentration after absorption is due to redistribution of the drug as they are lipophilics.

Most of the drugs are highly protein bound.

Metabolism:- Largely hepatic through conjugation. Metabolized by CYT P450 2D6 and P450 3A subfamily. Negligible amount of the unchanged drug excreted by

kidneys.

MECHANISM OF ACTION

Dopamine hypothesis:- Arvid Carlsson observed that haloperidol and chlorpromazine

raised the levels of dopamine metabolites in dopamine rich areas of mouse brain and interpreted them as dopamine receptor antagonists.

Antipsychotic potency has shown good correlation with their capacity to bind to D 2 receptor.

Low potency drugs are thioridazine, chlorpromazine, mesoridazine. While high potency drugs are pimozide, fluphenazine, haloperidol etc.

Blockade of dopaminergic projections to the mesolimbic system is responsible for the reduction of positive symptoms(hallucinations and delusions) of schizophrenia.

Blockade of dopaminergic projections to the mesocortical system is responsible for emotional blunting and cognitive side effects that mimics the negative symptoms of schizophrenia(Neuroleptic induced deficit syndrome.)

Blockade in the nigrostriatal pathway is responsible for movement disorders like Parkinson's disease, EPS.

Blockade in the tuberoinfundibular pathway is responsible for hyperprolactinemia causing galactorrhea, gynaecomastia, and amenorrhea.

INDICATIONS FOR DOPAMINE RECEPTOR ANTAGONISTS:-

Acute psychotic episode in schizophrenia and schizoaffective disorder.

Maintenance t/t in schizophrenia and schizoaffective disorder.

Mania. Depression with psychotic symptoms. Delusional disorders. Borderline personality disorder. Substance induced psychotic disorder. Delirium and dementia. Tourette’s syndrome and Huntington’s

disease.

PRECAUTIONS AND ADVERSE REACTIONS

1)NEUROLOGICAL SIDE EFFECTS:- These are the most serious side effects and largely confined to extra pyramidal motor system.

A)ACUTE EXTRAPYRAMIDAL SYNDROMES:-Appear within days to weeks of treatment.

a) Acute dystonia:-Mostly appear within first 3 days of starting the t/t and sometimes within hour. Intermittent and sustained spasms of head and neck muscles leading to involuntary movements, opisthotonus, retrocollis, torticollis of the neck, oculogyric crisis and rarely laryngeal dystonia leading to sudden death.

Can be managed by i.m. or i.v benzatropine(1-2 mg) or diphenhydramine(25-50mg).

b) Akathisia:- Most common side effect that appear after about 5 days but may appear within 2 days. There is inability to stand still and feeling of inner restlessness.

Can be managed by propranolol 10-80 mg/day.

c) Drug induced parkinsonism:-Motor symptoms of the disease including rigidity, bradykinesia, tremors, shuffling gait appearing within 5 to 30 days of t/t and may persist until the doses are lowered or discontinued.

First evidence of it may be diminished arm swing or decreased facial expressiveness.

Can be managed by centrally acting anticholinergics. B)Neuroleptic malignant syndrome:- It is uncommon but fatal complication characterized by

hyperthermia, severe muscular rigidity, autonomic instability including tachycardia, hypertension, tachypnea and diaphoresis with changing level of consciousness.

Early diagnosis and t/t is lifesaving. Neuroleptics should be discontinued and supportive and

symptomatic t/t should be started. Dantrolene 0.8-2.5 mg/kg i.v. 6 hrly may be effective for t/t.

C) CHRONIC EXTRAPYRAMIDAL SYNDROMES:-Appear after treatment for months or years.

a)Tardive dyskinesia:-Consist of mouth and tongue movements as lip smacking, sucking, puckering, facial grimacing and sometimes choreoathetoid like movements of fingers and toes with writhing movements of trunk.

Management:- severe and incapacitating movements should be managed by increasing the dose of antipsychotic. Rather decreasing the dose may worsen temporarily.

b) Perioral tremors or rabbit syndrome. 2)CARDIOVASCULAR SIDE EFFECTS. Low potency agents can induce ECG abnormalities as prolongation

of QT and PR intervals, blunting of T wave, ST depression and ventricular arrhythmias including torsades de pointes and sudden death.

Orthostatic postural hypotension due to alpha1 receptor blockade, should be managed by fluids and nor epinephrine.

GASTROINTESTINAL SIDE EFFECTS:- Peripheral anticholinergic effects as dry mouth, constipation,

urinary retention mostly seen with low potency antipsychotics.

ENDOCRINAL SIDE EFFECTS:-Hyperprolactinemia causing galactorrhea, menstrual irregularities in females while gynaecomastia in males.

SEXUAL DYSFUNCTIONS:-Decreased libido, erectile and ejaculatory dysfunctions.

SEIZURE THRESHOLD:-Tends to be lowered specially by low potency antipsychotics.

SUDDEN DEATH:-By cardiac arrhythmias, seizures, asphyxiation, heat stroke, malignant hyperthermia and NMS.

CHLORPROMAZINE, A REVIEW:- Aliphatic phenothiazine group of antipsychotic. Prescribed for :- Schizophrenia, mania, bipolar illness, hyperactive

children, intractable hiccoughs, tetanus etc. Combination of D2, Alpha1, H1 and M1 blockade responsible for multiple

actions . Reduces positive symptoms of schiz but does not eliminate them. After reaching satisfactory plateau, for first episode continue t/t for 1-2

year and for second and subsequent episodes t/t may be required for 5 years to indefinite.

Reduces symptoms of acute psychotic mania, but not proved as mood stabilizer.

Before starting drug evaluate BMI, if found high then measure blood sugar levels and lipid profile. Monitor BMI, BP and prolactin levels during the t/t.

S/E:-Low potency drug so less neurological side effects but more anticholinergic and other s/e.

Life threatening s/e may be NMS jaundice agranulocytosis, seizures(rarely).

Wait gain is common while sedation is problematic.

What to do about side effects:-For sedation give drug at night time, For motor symptoms anticholinergics as benzatropine or THP may be added. Reduce the dose or switch over to atypical antipsychotics if required.

Dosing:-200-800 mg/day Low dosing has been used to provide short term relief of day

time agitation and anxiety. High doses may induce or worsen negative symptoms of schiz.

Overdosing may cause EPS, sedation, hypotension, coma and respiratory depression.

Half life 8-33 hrs. Drug interactions:- May decrease the effect of levodopa. May

increase effect of antihypertensive. Increases the metabolism of phenytoin.

Use cautiously in alcohol withdrawal and convulsive disorders. Use cautiously in renal, hepatic, cardiac impairment, in elderly

and children.

FLUPHENAZINE A REVIEW:- High potency and long acting antipsychotic. Piperazine derivative of phenothiazines. Uses and precautions are similar to the chlorpromazine. Dose:-Oral dose is1-20 mg/day and 1/3 to ½ of oral dose

when used i.m Fluphenazine decanoate 50 mg/2ml given i.m or s.c.

given at interval no longer then 4 weeks. Notable side effects:- neuroleptic induced deficit

syndrome, akathisia, priapism, EPS, tardive dyskinesia. Half life of oral drug is about 15 hrs while for i.m

formulation 6.8-9.6 days In children safety and efficacy not established. Decanoate

and enanthate formulations are C/I under 12 yrs of age. Generally consider atypical antipsychotics in them.

HALOPERIDOL A REVIEW:- Belongs to Butyrophenone group of antipsychotics. Commonly prescribed for:-Manifestations of psychotic disorders. Tics and vocal utterances of tourett’s disorder. bipolar disorder. Second line t/t of severe behaviour problems in children of hyper

excitability. Prolonged parenteral anti psychotic therapy (decanoate i.m.) Mechanism:-Block D2 receptors reducing positive symptoms of

psychosis, improve tics in tourett’s disorder. However most schizophrenics do not have remission but rather

reduction of symptoms. Reduces psychotic symptoms of mania but not proven mood

stabilizer. Tests :-Weigh all the patients, If overweight look for diabetes or

dyslipidemia. Monitor BMI, BP, prolactin levels during t/t Side effects:- Motor side effects, hyperprolactinemia, worsening of

Negative symptoms, dizziness, sedation, hypotension, weight gain. Rarely NMS seizures agranulocytosis. To reduce s/e:-Give dose at night, reduce the dose, give

anticholinergics or switch to atypical ones. Dose:-Oral dose1-40 mg/day. Immediate release inj 2-5 mg/dose. Decanoate inj 10-20 times of previous oral daily dose, max up to

100 mg. Administer total dose every 4 weeks. Over dosing causes EPS, hypotension, sedation, respiratory

depression, shock like state. Rapid discontinuation may lead to rebound psychosis, so taper down

slowly. Half life:- Oral half life about 12-38 hrs, decanoate about 3 weeks. Interactions:- decreases effect of levo dopa. Increases the effect of antihypertensive. Additive to CNS depressants. Reduces effect of anticoagulants.

Haloperidol + Anticholinergics may raise intraocular pressure.

Haloperidol + Epinephrine may decrease BP. Warnings:-caution in respiratory depression, parkinsonism. Manic pts may turn to rapid depression. Avoid extreme heat exposure. Pt with hyperthyroidism may experience neurotoxicity. Elderly may be more susceptible to hypotension, respiratory

depression. Do not use in comatose, Parkinson's and allergic to the drug. Not intended to use under age of 3 yrs. Potential advantage:- Intramuscular formulation for

emergency use. Low cost, effective t/t. Depot formulation for noncompliance.

ZUCLOPENTHIXOL A REVIEW:- Thioxanthine group of conventional antipsychotic. Dose ranging:- oral 20-60 mg/day, half life is 20 hrs. Acetate 50-150 mg every 2-3 days. Onset of action within 2-

4 hrs. Half life 32 hrs. Should not be used for more then 2 weeks.

Decanoate 150-300 mg every 2-4 weeks. Peak action usually 4-9 days. Half life 17-21 days.

Potential advantage:-Emergency use and non compliant pt. Can combine acute inj. with depot preparation for rapid

onset and long duration of action.

THIORIDAZINE A REVIEW:- Piperidine derivative of phenothiazine. Used in t/t of schizophrenic patients who fail to respond with other

antipsychotics. Augmentation of thioridazine can be dangerous specially with drugs that

prolong QTc or raise thioridazine plasma levels such as bupropion sertaline citalpram paroxetin duloxetine fluoxetine propranolol)

Tests:-Baseline ECG and serum K+ levels with periodic assessments during the t/t.

Monitor weight, BMI, BP. S/E:- pigmentary retinopathy at dose above recommended maximum. Weight gain and sedation are common. Life threatening effect may be ventricular arrhythmias, torsades de

pointes and sudden death. Maximum anticholinergic activity among typical antipsychotics. Dose 200-800 mg/day in divided doses. QTc prolongation is dose dependant. So start low and go slow carefully

monitoring the ECG. Interactions:- Additive bradycardia with propranolol, calcium channel

blockers, clonidine, digitalis.

Additive hypokalemia with diuretics, stimulants laxatives, glucocorticoids.

Avoid in patient of recent myocardial infarction and uncompensated heart failure.

Elderly pt may be more sensitive to S/E. Safety not established under age of 2 yrs. Generally benefits of thioridazines do not outweigh its risks

for most of the patients.

PIMOZIDE:- Diphenylbutylpiperidine derivative. Most potent antipsychotic. Indicated per oral in schiz and chronic psychosis. Special

indication for tourette syndrome and resistant tics. Has also been used in delusional disorder, delusional

parasitosis and listeria monocytogenes inhibitor. Pharmacodynamics:- extreme strong D2 blocker; strong

alpha1, D3, 5HT2A blocker; weak mAch ,H1 blocker. It also inhibit dopamine transporter accounting for stimulant

property of drug so can be used in ADHD. S/E :-High EPS chances including tardive dyskinesia and rabbit

syndrome. In particular akathisia is common. Significant sedative but sometime behaves as stimulant so

night time dose may cause insomnia, excitatation irritability agitation.

Drug may also cause depression, may result in suicide.

CONTINUE:-

High incidence of long QT, VT, VF, Torsades de pointes.

May rarely cause seizures.

Dosing:- long half life so OD dose given at morning.

For acute psychotic disorder 2 -12 mg starting with low doses, max dose 20 mg.

For chronic psychotic disorder 6 mg is usual dose.

For tics 1-16 mg.

For reactive depression 1-2 mg.

C/I and Precautions:- with drugs prolonging QT as citalopram, pt with prominent agitation anxiety, depression, Parkinson's, epilepsy, intoxication of alcohol opiates or psychoactive drugs as BZD, antidepressants.

LOXAPINE:- Dibenzoxazepine group of typical antipsychotic

structurally similar to clozapine, may behave as an atypical antipsychotic.

Indicated in treatment of schiz, control aggressive behaviour and restlessness, reduce hallucinations and delusions.

May be metabolized by N demethylation to amoxapine a tetra cyclic antidepressant

Dosing:- starting dose 10 mg BD, Dose range 30-50 mg BD. Max dose 250 mg/day.

S/E:- excessive salivation and indifference to surrounding are most significant. Other S/E includes EPS, NMS, gynecomastia, tremors, sedation.

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