Chlorpromazine for Nausea

Chlorpromazine is an aliphatic phenothiazine with D2 antagonist activity and strong antihistamine, antimuscarinic and alpha adrenergic effects. At low doses it is a broad-spectrum antiemetic for severe, refractory or palliative nausea, but sedation, hypotension and QT prolongation are greater than with prochlorperazine. This article covers antiemetic use only.

Classification. Phenothiazine antipsychotic used as an antiemetic.

Mechanism. D2 blockade in the chemoreceptor trigger zone, with additional H1, muscarinic, alpha-1 and 5-HT2 blockade that contributes to its effect on vestibular, vagal and central pathways of vomiting.

Pharmacodynamics. Onset: IM 15 to 30 minutes; oral 30 to 60 minutes. Antiemetic effects occur at doses far lower than antipsychotic doses.

Pharmacokinetics. Oral bioavailability 10% to 30% from first-pass metabolism; IM and rectal routes give higher exposure. Highly protein bound (over 90%). Half-life 20 to 30 hours with active metabolites.

Metabolism. Hepatic via CYP2D6, CYP1A2 and CYP3A4 and conjugation, with active metabolites. Excreted in urine and faeces.

Adult doses unless stated. Use the lowest effective dose and review at 48 to 72 hours.

Nausea and vomiting, general.

• Oral: 10 to 25 mg every 4 to 6 hours.

• IM: 25 mg initially, then 25 to 50 mg every 3 to 4 hours until vomiting stops, then oral dosing.

• Rectal: 100 mg every 6 to 8 hours where suppositories are available.

• Usual antiemetic total 50 to 100 mg daily; doses in the antipsychotic range are not needed.

Postoperative nausea and vomiting. 12.5 mg IM during surgery or after, repeated once after 30 minutes if needed. IV use is limited to hospital with dilution and slow rate.

Nausea in palliative care. 12.5 to 25 mg orally at night or twice daily. Subcutaneous bolus 12.5 to 25 mg, or continuous subcutaneous infusion 25 to 75 mg over 24 hours with specialist advice. It is useful for opioid-induced nausea and bowel obstruction when other antiemetics fail.

Paediatric dosing (age 6 months and over; second-line).

• Oral or rectal 0.55 mg/kg every 4 to 6 hours.

• IM 0.55 mg/kg every 6 to 8 hours.

• Maximum 40 mg daily up to 5 years (22.7 kg), and 75 mg daily for age 5 to 12 years.

• Contraindicated under 6 months. Avoid in suspected Reye syndrome.

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

Kidney and liver adjustment. Use lower doses and longer intervals in kidney impairment. Avoid in severe liver disease and in hepatic encephalopathy.

Contraindications.

• Hypersensitivity to phenothiazines; coma and severe CNS depression, including alcohol, barbiturate and opioid intoxication.

• Bone marrow suppression; severe liver disease; phaeochromocytoma.

• Children under 6 months; suspected Reye syndrome.

• Narrow-angle glaucoma, urinary retention, prolactinoma.

• QT prolongation or congenital long QT.

Common adverse effects. Sedation, postural hypotension, dry mouth, constipation, blurred vision, urinary retention and weight gain with long use.

Serious adverse effects.

• Acute dystonia, akathisia, parkinsonism and tardive dyskinesia.

• Neuroleptic malignant syndrome.

• QT prolongation and torsades de pointes.

• Neutropenia and agranulocytosis, usually in the first 3 months.

• Cholestatic jaundice, photosensitivity, skin pigmentation, and corneal or lens deposits with prolonged use.

• Lowering of the seizure threshold.

• Marked hypotension, particularly with IV or IM injection.

• Increased mortality in elderly patients with dementia-related psychosis.

Management of acute dystonia. Procyclidine 5 to 10 mg IV or IM, or biperiden 2.5 to 5 mg slow IV or IM, repeated after 20 to 30 minutes if needed. Stop chlorpromazine.

Management of hypotension. Lie the patient flat, give IV sodium chloride 0.9%, and use noradrenaline if a vasopressor is needed. Avoid adrenaline, which may cause paradoxical vasodilation.

Major interactions.

• Metoclopramide, prochlorperazine and other dopamine antagonists, and antipsychotics: additive extrapyramidal and QT risk.

• Levodopa and dopamine agonists: antagonism.

• QT prolonging drugs (antimalarials such as artemether-lumefantrine, quinine, chloroquine; macrolides; fluoroquinolones; citalopram; methadone; ondansetron): avoid or monitor ECG.

• CNS depressants, alcohol and opioids: additive sedation and respiratory depression.

• Antihypertensives and nitrates: additive hypotension.

• Lithium: neurotoxicity.

• Antacids and anticholinergics: reduced absorption; separate by 2 hours.

• Anticonvulsants: seizure threshold lowered, and carbamazepine toxicity.

Special groups.

• Pregnancy: avoid if possible; third trimester use causes neonatal extrapyramidal signs and withdrawal.

• Breastfeeding: enters milk; avoid or monitor the infant for sedation.

• Children: second-line only, with a high dystonia risk.

• Older adults: increased sensitivity; use reduced doses.

• Kidney impairment: use lower doses.

• Liver impairment: avoid in severe impairment; sedation can precipitate hepatic encephalopathy.

• Regional: widely available in East Africa at low cost; watch for combinations of QT prolonging antimalarials and other antiemetics.

Formulations. Tablets 25 mg, 50 mg and 100 mg; oral syrup 25 mg in 5 mL; injection 25 mg in 1 mL (and 50 mg in 2 mL); suppositories 100 mg in some markets.

Oral administration. With or without food. Avoid skin contact with liquid or injection because of contact dermatitis.

IM administration. Deep into the upper outer buttock, undiluted. Lie the patient flat for at least 30 minutes afterwards and check blood pressure.

IV administration. Not routine. If used in hospital, dilute 25 mg to 1 mg/mL with sodium chloride 0.9% and give slowly, not faster than 1 mg/min, with continuous blood pressure monitoring.

Subcutaneous use. May cause local irritation; use dilute solutions and rotate sites, or avoid.

Protect from light. Discoloured solutions should be discarded.

Baseline. Lying and standing blood pressure; ECG in heart disease or QT-prolonging coprescription; potassium and magnesium; full blood count if prolonged use is planned; liver function.

Monitoring.

• Blood pressure and sedation after each parenteral dose.

• Movement disorders at each review.

• ECG with interacting drugs.

• Full blood count if fever or sore throat develops, and at intervals for the first 3 months of regular use.

• Liver enzymes if jaundice appears.

• Eyes and skin in long-term use.

Therapeutic drug monitoring. Not used for antiemetic dosing.

Stopping. After short use, no taper is needed. After more than a few weeks of regular use, taper over 1 to 2 weeks to limit withdrawal dyskinesia and rebound nausea.

Referral and escalation. Admit for neuroleptic malignant syndrome, torsades or severe hypotension. Palliative care review for refractory nausea. Evaluate persistent vomiting for obstruction, raised intracranial pressure, metabolic causes and pregnancy.