Prochlorperazine

Prochlorperazine is a piperazine phenothiazine that blocks dopamine D2 receptors in the chemoreceptor trigger zone and has weaker antihistamine, antimuscarinic and alpha adrenergic activity. It is an inexpensive, widely used antiemetic and treatment for vertigo, but acute dystonia and sedation limit its use, particularly in young adults and children.

Classification. Phenothiazine antiemetic and antipsychotic.

Mechanism. D2 blockade in the chemoreceptor trigger zone reduces nausea. Antagonism of histamine H1 and muscarinic receptors in the vestibular nuclei contributes to its effect in vertigo. Alpha adrenergic blockade causes hypotension.

Pharmacodynamics. Onset: oral 30 to 40 minutes, IM 10 to 20 minutes, buccal 30 minutes. Duration 4 to 6 hours (up to 12 hours buccal).

Pharmacokinetics. Oral bioavailability only about 12% to 20% because of first-pass metabolism. Buccal and rectal routes bypass first-pass effects. Half-life 6 to 8 hours after oral dosing. Highly protein bound (over 90%).

Metabolism. Hepatic via CYP2D6 and CYP1A2 and by conjugation. It crosses the placenta and enters milk.

Adult doses unless stated. This article covers antiemetic and vestibular use; antipsychotic dosing is outside its scope.

Severe nausea and vomiting.

• Oral: 20 mg stat, then 10 mg after 2 hours if needed.

• IM: 12.5 mg stat, followed by oral dosing after 6 hours.

• Maximum 40 mg daily for antiemetic use.

Prevention of nausea and vomiting (such as with chemotherapy or radiotherapy). 5 to 10 mg orally two or three times daily. Buccal tablet 3 mg twice daily (maximum 6 mg twice daily). Rectal 25 mg twice daily where available.

Postoperative nausea and vomiting. 5 to 10 mg IM 1 to 2 hours before induction, or 5 to 10 mg IV 15 to 30 minutes before induction. Treatment 5 to 10 mg IV or IM, with a maximum single dose of 10 mg.

Vertigo, Meniere disease and labyrinthine disorders. 5 mg orally three times daily, increased to a maximum of 30 mg daily in divided doses. Buccal 3 mg twice daily. Review at 4 weeks and stop if no response.

Acute migraine adjunct. 10 mg IV or IM with a fluid bolus if hypotension is a risk, often combined with diphenhydramine 25 mg to prevent dystonia.

Paediatric dosing (not for children under 2 years or under 10 kg; second-line, short courses).

• Age 2 to 5 years: 1.25 mg two to three times daily.

• Age 6 to 11 years: 2.5 mg two to three times daily.

• Age 12 to 17 years: 5 mg two to three times daily.

• Treatment duration should be as short as possible.

Kidney and liver adjustment. Avoid in severe liver impairment. In kidney impairment use lower doses and extend intervals.

Contraindications.

• Hypersensitivity to phenothiazines; CNS depression or coma.

• Bone marrow suppression; severe liver disease; phaeochromocytoma.

• Children under 2 years or under 10 kg.

• Narrow-angle glaucoma, urinary retention, prolactinoma.

• Parkinson disease (worsens motor symptoms).

Common adverse effects. Drowsiness, dizziness, dry mouth, constipation, blurred vision, urinary retention and postural hypotension.

Serious adverse effects.

• Acute dystonia (oculogyric crisis, torticollis, trismus), akathisia and drug-induced parkinsonism; dystonia is most common in young adults, women and children, often after the first doses.

• Tardive dyskinesia with prolonged use.

• Neuroleptic malignant syndrome.

• QT prolongation and torsades de pointes.

• Agranulocytosis, cholestatic jaundice, photosensitivity and hyperprolactinaemia.

• Lowering of the seizure threshold.

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

• Hypotension with IV or IM injection.

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 prochlorperazine.

Major interactions.

• Metoclopramide 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): avoid or monitor ECG.

• CNS depressants, alcohol and opioids: increased sedation.

• Antihypertensives: additive hypotension.

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

• Lithium: neurotoxicity risk.

• CYP2D6 inhibitors: higher levels.

Special groups.

• Pregnancy: avoid in the third trimester if possible, because of neonatal extrapyramidal signs and withdrawal; may be used if the benefit outweighs risk.

• Breastfeeding: low transfer; avoid prolonged use because of infant sedation.

• Children: high risk of dystonia; avoid where alternatives exist.

• Older adults: start at lower doses, with greater risk of hypotension, sedation, falls, confusion and parkinsonism.

• Kidney impairment: lower dose and monitor.

• Liver impairment: avoid in severe impairment.

• Regional: widely used and sold without prescription in many settings; acute dystonia may be mistaken for tetanus, seizure or meningism, so ask about recent antiemetic use.

Formulations. Tablets 5 mg; buccal tablets 3 mg; injection 12.5 mg in 1 mL; suppositories 25 mg; oral syrup.

Oral and buccal administration. Swallow tablets with water. Place buccal tablets high between the upper lip and gum and allow them to dissolve over 1 to 2 hours; do not swallow or chew.

Injection. Give IM deep into the upper outer buttock. IV use is in hospital only, given slowly at no more than 5 mg/min and never as a bolus; patient lying down for at least 30 minutes afterwards to reduce hypotension.

Baseline. Medication review for dopamine antagonists, QT prolonging drugs and Parkinson disease. ECG if cardiac risk. Blood pressure lying and standing.

Monitoring.

• Movement disorders at each dose review; stop at the first sign of dystonia.

• Blood pressure during IV or IM use.

• Full blood count if fever or sore throat develops.

• Liver enzymes if jaundice appears.

• ECG with other QT prolonging drugs.

Therapeutic drug monitoring. Not applicable.

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. Neurology review for persisting dyskinesia. Evaluate persistent vomiting for obstruction, raised intracranial pressure, metabolic causes and pregnancy.