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Classify antipsychotic drugs. Describe the dopamine pathways, extrapyramidal syndromes and adverse effects.

Pharmacology · 2nd Professional — Para-Clinical

Classification

Antipsychotics (neuroleptics) relieve the symptoms of psychosis, principally by blocking dopamine D2 receptors in the mesolimbic pathway.

Group	Drugs	Features
Typical (first generation) — high potency	Haloperidol, fluphenazine, trifluoperazine, pimozide	Strong D2 blockade; more extrapyramidal effects, less sedation and hypotension
Typical — low potency	Chlorpromazine, thioridazine	More sedation, antimuscarinic effects and postural hypotension; fewer extrapyramidal effects
Atypical (second generation)	Risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, clozapine	D2 and 5-HT2A blockade; fewer extrapyramidal effects; better for negative symptoms; but more metabolic adverse effects
Depot preparations	Fluphenazine decanoate, haloperidol decanoate, risperidone and paliperidone long-acting injections	Given every 2–4 weeks; transform adherence, which is the commonest cause of relapse

Dopamine Pathways — Effects of Blockade

Pathway	Normal function	Consequence of D2 blockade
Mesolimbic	Reward, emotional salience	Antipsychotic benefit — relief of positive symptoms (delusions, hallucinations); the therapeutic target
Mesocortical	Cognition, motivation	Worsening of negative symptoms and cognition — blockade here is harmful
Nigrostriatal	Motor control	Extrapyramidal side effects
Tuberoinfundibular	Dopamine tonically inhibits prolactin release	Hyperprolactinaemia — galactorrhoea, amenorrhoea, gynaecomastia, infertility, reduced bone density

CLINICAL PEARL

The same receptor blockade produces the benefit and most of the harm, in four different places. There is no way to block mesolimbic D2 without affecting the nigrostriatal and tuberoinfundibular pathways with a non-selective drug — which is why extrapyramidal effects and hyperprolactinaemia were inseparable from treatment until atypical agents, with their added 5-HT2A blockade, partly uncoupled them.

Extrapyramidal Syndromes

Syndrome	Timing	Features	Treatment
Acute dystonia	Hours to days	Torticollis, oculogyric crisis, trismus, opisthotonus; frightening and often mistaken for hysteria or tetanus	Intravenous or intramuscular antimuscarinic — promethazine or benztropine; response is rapid and dramatic
Akathisia	Days to weeks	Inner restlessness and an irresistible urge to move; strongly associated with distress and suicide, and frequently misread as agitation from the psychosis	Reduce the dose; propranolol; benzodiazepine
Parkinsonism	Weeks to months	Rigidity, bradykinesia, tremor	Reduce the dose, switch to an atypical, or add an antimuscarinic; levodopa is not used, as it worsens psychosis
Tardive dyskinesia	Months to years	Involuntary orofacial and limb movements — chewing, lip-smacking, tongue protrusion; from receptor UP-regulation; often irreversible	Prevention is everything; stop or reduce the drug (movements may transiently worsen); switch to clozapine; valbenazine or tetrabenazine. Antimuscarinics make it worse

Other Adverse Effects

Metabolic — the chief problem with atypicals: weight gain, diabetes and dyslipidaemia, worst with olanzapine and clozapine; these shorten life more than the psychosis does, and require active monitoring
Neuroleptic malignant syndrome — hyperthermia, lead-pipe rigidity, autonomic instability, altered consciousness and a markedly raised creatine kinase; evolves over days; mortality about 10%. Treated by stopping the drug, cooling, supportive care and dantrolene or bromocriptine
Cardiac — QT prolongation and torsades, especially with thioridazine, pimozide and haloperidol
Antimuscarinic and antiadrenergic — dry mouth, blurred vision, constipation, retention, postural hypotension (chlorpromazine)
Clozapine — uniquely effective in treatment-resistant schizophrenia and reduces suicide, but causes agranulocytosis in about 1%, requiring mandatory regular blood count monitoring; also myocarditis, seizures, hypersalivation and severe constipation
Others — photosensitivity and greyish skin pigmentation (chlorpromazine), corneal and lens deposits, cholestatic jaundice, seizures, sexual dysfunction

Typical and Atypical Antipsychotics Compared

Feature	Typical	Atypical
Receptor profile	Predominantly D2	D2 plus 5-HT2A; looser D2 binding
Positive symptoms	Effective	Equally effective
Negative symptoms	Little benefit, may worsen	Some benefit
Extrapyramidal effects	Common	Much less (though risperidone at higher dose behaves typically)
Tardive dyskinesia	Higher risk	Lower risk
Prolactin	Markedly raised	Less raised (but risperidone raises it most of all)
Metabolic effects	Less	Marked — weight gain, diabetes, dyslipidaemia; worst with olanzapine and clozapine
Cost	Low	Higher, though generics have narrowed the gap

The trade is one set of adverse effects for another — movement disorders for metabolic disease. Large pragmatic trials found little difference in overall effectiveness, so the choice rests on which adverse effects the individual patient can least afford

Uses and Applied Aspects

Schizophrenia and other psychoses; mania and bipolar disorder; adjunct in resistant depression; delirium (haloperidol in low dose)
Non-psychiatric uses — antiemesis (prochlorperazine, haloperidol, metoclopramide), intractable hiccup (chlorpromazine), Tourette syndrome, Huntington chorea
Monitor weight, waist circumference, glucose and lipids at baseline and regularly on any atypical — metabolic disease is now the leading cause of premature death in schizophrenia
Antipsychotics in elderly patients with dementia increase mortality and stroke; they should be used only for severe distress or risk, at the lowest dose, and reviewed constantly
Depot preparations are invaluable where adherence is poor, and in India where follow-up may be irregular and family supervision is often the practical alternative
Distinguish neuroleptic malignant syndrome from serotonin syndrome — the former evolves over days with lead-pipe rigidity and hyporeflexia; the latter over hours with clonus and hyperreflexia
Clozapine is reserved for treatment-resistant illness — defined as failure of two adequate trials of other antipsychotics — and is under-used, partly because the monitoring requirement deters prescribers
An ECG is worth doing before starting where QT-prolonging drugs are used or the patient has cardiac risk factors
Acute dystonia responds within minutes to a parenteral antimuscarinic, and recognising it prevents a frightening episode being mistaken for tetanus, hysteria or a seizure
Do not add an antimuscarinic routinely to prevent extrapyramidal effects; it adds anticholinergic burden, worsens tardive dyskinesia and impairs cognition
Negative symptoms and cognitive impairment, not the positive symptoms, determine long-term function — and they respond least well to drugs, which is why rehabilitation and family support matter so much
Continue treatment for at least 1 to 2 years after a first episode, and indefinitely after relapses; stopping is the commonest cause of readmission
Duration of untreated psychosis predicts outcome, so early detection and prompt treatment matter as much as the choice of drug
Antipsychotics do not treat dementia, and their use for behavioural symptoms should follow non-pharmacological measures, be time-limited and be reviewed at every visit
Rapid tranquillisation of an acutely disturbed patient uses an intramuscular benzodiazepine with or without haloperidol, with monitoring of consciousness, respiration and blood pressure afterwards
Never give intravenous haloperidol without ECG monitoring, because of the risk of torsades de pointes
Involve the family in India, where they usually supervise medication and are the earliest to detect relapse; family psychoeducation measurably reduces readmission

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