This document provides a summary of typical antipsychotic drugs. It discusses the history of antipsychotics beginning with phenothiazines in the 1950s. It then classifies typical antipsychotics and describes their pharmacokinetics, mechanisms of action, indications, precautions, adverse reactions, and reviews several individual drugs including chlorpromazine, fluphenazine, haloperidol, and zuclopenthixol.

1. TYPICAL ANTIPSYCHOTICS
By : Dr. Gajanand Verma
Dr. Anant kr. Rathi
Dr. khushboo Bairwa

2. 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.

3. 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

4. CONTINUED:-
 D) DIPHENYLBUTYLPIPERIDINES:-
 PIMOZIDE
 E) INDOLE DERIVATIVES:-
 MOLINDONE
 F) DIBENZOXAZEPINES:-
 LOXAPINE

5. 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.

6. 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.)

7.  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.

8. 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.

9. 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.

10.  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.

11.  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.

12.  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.

13. 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.

14.  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.

15. 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.


16. 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

17.  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.

18.  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.

19. 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.

20. 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.

21.  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.

22. 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.

23. 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.

24. 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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 THANKS