Chlorpromazine

Chlorpromazine is a low-potency phenothiazine antipsychotic used for schizophrenia, mania, acute agitation, intractable hiccups and severe nausea and vomiting. It is widely available and inexpensive. It is strongly sedating with prominent hypotension and anticholinergic effects, and carries a risk of photosensitivity and cholestatic jaundice.

Classification. First-generation (typical) antipsychotic, aliphatic phenothiazine.

Mechanism. Dopamine D2 antagonism, with strong antagonism of histamine H1, muscarinic M1 and alpha-1 adrenergic receptors, and some 5-HT2 blockade.

Pharmacokinetics. Oral bioavailability about 30% because of first-pass metabolism; peak in 2 to 4 hours. Metabolised by CYP2D6 and others to many metabolites. Half-life about 30 hours.

Schizophrenia and other psychoses, adults (oral).

• Start 25 mg two to three times daily, or 75 mg at night.
• Titration: increase by 25 mg daily every 2 to 3 days based on response and tolerance.
• Usual 200 to 400 mg daily. Maximum 800 mg daily; up to 1000 mg daily in resistant illness under specialist care.
• Duration: at least 12 months after a first episode.

Acute agitation or mania (intramuscular). 25 to 50 mg deep intramuscular injection, repeated after 6 to 8 hours as needed. Keep the patient lying for 30 minutes and check blood pressure. Maximum 100 mg for a single injection.

Intractable hiccups. 25 to 50 mg orally three or four times daily; if oral treatment fails, 25 to 50 mg intramuscularly.

Severe nausea and vomiting. 10 to 25 mg orally every 4 to 6 hours; 25 mg intramuscularly then 25 to 50 mg every 3 to 4 hours if needed.

Older adults. Start one third to one half of the adult dose.

Children (specialist use only). About 0.5 mg/kg orally every 4 to 6 hours; usual maximum 40 mg daily under 5 years and 75 mg daily aged 5 to 12 years.

Contraindications. Coma or severe CNS depression, bone marrow suppression, liver impairment or cholestatic jaundice, phaeochromocytoma, known QT prolongation, narrow-angle glaucoma, urinary retention, hypersensitivity. Boxed-warning-level increase in mortality in older adults with dementia-related psychosis.

Serious adverse effects. Neuroleptic malignant syndrome, torsades de pointes, orthostatic hypotension and syncope, seizures, agranulocytosis (usually in the first 3 months), cholestatic jaundice, tardive dyskinesia, hyperprolactinaemia, hypothermia or hyperthermia, ocular and skin pigmentation with long-term use.

Common adverse effects. Sedation, dry mouth, constipation, blurred vision, nasal congestion, weight gain, photosensitivity, extrapyramidal symptoms (less than with haloperidol), galactorrhoea.

Interactions. Antihypertensives and nitrates add hypotension. Anticholinergics, tricyclics and antihistamines add anticholinergic effects. Alcohol, opioids and benzodiazepines add sedation. QT-prolonging drugs (macrolides, quinolones, quinine, artemether-lumefantrine, chloroquine, ondansetron) add risk. Antacids and kaolin reduce absorption. Levodopa is antagonised. Fluoxetine and paroxetine raise levels. It lowers the seizure threshold.

Common prescribing errors. Giving intramuscular doses to a standing patient; combining with other QT-prolonging drugs; ignoring jaundice or fever; failing to protect against sunlight.

Special groups.

• Pregnancy: use only if benefit outweighs risk; third-trimester exposure can cause neonatal extrapyramidal symptoms and withdrawal.
• Breastfeeding: excreted in milk and sedation reported; avoid or use with infant monitoring.
• Children: specialist use only; about 0.5 mg/kg orally every 4 to 6 hours.
• Older adults: lower doses; high risk of hypotension, falls, confusion and mortality in dementia.
• Kidney impairment: start low.
• Liver impairment: contraindicated.

Formulations. Tablets 25 mg, 50 mg and 100 mg; oral solution 25 mg/5 mL; injection 25 mg/mL. Avoid skin contact with liquid forms because of contact dermatitis.

Baseline. ECG, potassium and magnesium, blood pressure lying and standing, weight, fasting glucose or HbA1c, lipids, full blood count, liver tests, and a baseline rating of extrapyramidal symptoms.

Monitoring. Weight and waist at baseline, 4, 8 and 12 weeks, then annually; fasting glucose or HbA1c and lipids at baseline, 12 weeks, then annually. Full blood count in the first 3 months if fever or infection appears. Annual eye and skin review in long-term use. Repeat the ECG after dose increases; stop or reduce if QTc is over 500 ms.

Stopping. Reduce gradually over several weeks to limit relapse and rebound symptoms.

Referral and escalation. Refer to psychiatry for first-episode psychosis or treatment resistance. Fever with rigidity, jaundice, syncope or QTc over 500 ms needs emergency care.