First Generation Antipsychotics

First generation antipsychotics (haloperidol, chlorpromazine, fluphenazine, trifluoperazine, flupentixol, zuclopenthixol, perphenazine, sulpiride, pimozide) are dopamine D2 antagonists. They remain widely used where cost and access matter, in acute agitation, and as long-acting injections.

Mechanism. D2 receptor blockade in the mesolimbic system controls positive symptoms; blockade in the nigrostriatal system causes parkinsonism, and in the tuberoinfundibular system raises prolactin. Low-potency agents (chlorpromazine) also block histamine, muscarinic and alpha-1 receptors.

Pharmacokinetics. Hepatic metabolism; haloperidol half-life 18 to 24 hours, chlorpromazine 24 to 30 hours. Depot esters release over 2 to 4 weeks. Haloperidol is metabolised by CYP2D6 and CYP3A4.

Differences. High-potency agents (haloperidol, fluphenazine) cause more extrapyramidal effects and less sedation. Low-potency agents (chlorpromazine) cause more sedation, hypotension and anticholinergic effects. Thioridazine is withdrawn in most regions for QT prolongation. Sulpiride is renally cleared and raises prolactin.

• Schizophrenia: when second generation agents are unavailable, unaffordable or not tolerated, or by patient preference. Start low.
• Acute agitation: haloperidol 5 mg intramuscularly, with promethazine 25 to 50 mg intramuscularly to reduce dystonia, in many practice settings; monitor vital signs and give oxygen.
• Long-acting injections: fluphenazine, haloperidol or zuclopenthixol decanoate, with a test dose, and overlap oral drug for 1 to 2 weeks. Haloperidol decanoate is converted from the oral dose at 10 to 15 times the daily oral dose each month.
• Extrapyramidal effects: reduce the dose; treat dystonia with procyclidine 5 mg intramuscularly or benzatropine 1 to 2 mg; parkinsonism with oral procyclidine 2.5 to 5 mg three times daily; akathisia with propranolol 10 to 20 mg two to three times daily.
• Do not give routine prophylactic anticholinergics, which worsen tardive dyskinesia and cognition.

Special groups. Pregnancy: haloperidol and chlorpromazine have the most data. Breastfeeding: use the lowest dose; monitor the infant. Children: specialist use. Older adults: haloperidol 0.5 to 1 mg and avoid in dementia. Kidney impairment: reduce sulpiride. Liver impairment: avoid chlorpromazine. Regional: chlorpromazine, haloperidol and fluphenazine decanoate are on most essential lists; ECG access is limited, so avoid combining QT-prolonging drugs (quinine, lumefantrine, macrolides).

Adverse effects. Acute dystonia (hours to days), akathisia, parkinsonism, tardive dyskinesia, neuroleptic malignant syndrome, hyperprolactinaemia, sedation, hypotension, anticholinergic effects, photosensitivity and skin pigmentation (chlorpromazine), cholestatic jaundice, and QT prolongation.

Contraindications. Parkinson disease and Lewy body dementia, severe CNS depression or coma, QT prolongation, hypokalaemia, and narrow-angle glaucoma for anticholinergic agents.

Interactions. QT-prolonging drugs and electrolyte disturbance; carbamazepine and rifampicin lower haloperidol levels; ritonavir raises them; lithium with haloperidol has rare neurotoxicity.

Monitoring. Movement disorders at each visit, weight and metabolic checks, prolactin symptoms, ECG with risk factors, and electrolytes.

Referral and escalation. Neuroleptic malignant syndrome, severe dystonia not responding, torsades, or tardive dyskinesia.