Metoclopramide

Metoclopramide is a dopamine D2 receptor antagonist with 5-HT4 agonist and weak 5-HT3 antagonist activity that acts as a central antiemetic and an upper gastrointestinal prokinetic. It crosses the blood brain barrier, so extrapyramidal reactions, including acute dystonia and irreversible tardive dyskinesia, are its main hazards.

Classification. Substituted benzamide; antiemetic; prokinetic.

Mechanism. D2 blockade in the chemoreceptor trigger zone reduces nausea. Peripheral D2 blockade and 5-HT4 agonism enhance acetylcholine release from the myenteric plexus, increasing oesophageal sphincter tone, gastric emptying and small bowel transit without affecting colonic motility.

Pharmacodynamics. Prokinetic effect needs intact vagal and enteric neurons and is reduced by anticholinergics and opioids. Prolactin rises through D2 blockade at pituitary level.

Pharmacokinetics. Oral bioavailability about 80% with considerable first-pass variation. Onset oral 30 to 60 minutes, IM 10 to 15 minutes, IV 1 to 3 minutes. Half-life 5 to 6 hours, prolonged in kidney impairment.

Metabolism. Hepatic via CYP2D6 with minor CYP1A2 and CYP3A4 involvement. About 20% to 30% of a dose is excreted unchanged in urine. Poor CYP2D6 metabolisers and CYP2D6 inhibitors raise exposure.

Adult doses unless stated. The most widely used approach limits dose and duration; a boxed warning on tardive dyskinesia advises against treatment over 12 weeks.

Nausea and vomiting, general.

• 10 mg orally, IM or slow IV up to three times daily.

• Maximum 30 mg daily (or 0.5 mg/kg daily).

• Maximum 5 days.

• Minimum 6 hours between doses.

Diabetic gastroparesis (alternative regimen). 10 mg orally 30 minutes before meals and at bedtime (up to four times daily), maximum 40 mg daily, for 2 to 8 weeks. Use of over 12 weeks is not advised. Because of tardive dyskinesia risk, many clinicians restrict this indication.

Postoperative nausea and vomiting. Prevention or treatment 10 mg IV at the end of surgery.

Chemotherapy-induced nausea and vomiting. Second-line or breakthrough 10 mg orally or IV every 8 hours. The older high-dose regimens (1 to 2 mg/kg IV) are not advised because of dystonia.

Acute migraine adjunct. 10 mg IV or orally with an analgesic, improving absorption and relieving nausea.

Small bowel intubation and radiology. 10 mg IV single dose over 1 to 2 minutes (5 mg in children 6 to 14 years; 2.5 mg under 6 years).

Paediatric dosing (age 1 to 18 years; second-line, short use only).

Maximum 0.5 mg/kg daily and 5 days. Contraindicated under 1 year.

Kidney and liver adjustment.

• CrCl 15 to 60 mL/min: reduce the dose by 50%.

• CrCl under 15 mL/min: reduce the dose by 75%.

• Severe liver impairment (Child-Pugh C): reduce the dose by 50%.

• Older adults: use 5 mg for each dose and adjust to kidney function.

• Known CYP2D6 poor metabolisers: reduce dose.

Contraindications.

• Gastrointestinal haemorrhage, obstruction or perforation; within 3 to 4 days of gastrointestinal surgery.

• Phaeochromocytoma (hypertensive crisis).

• Epilepsy; Parkinson disease; history of tardive dyskinesia or neuroleptic malignant syndrome.

• Prolactin-dependent tumour.

• History of methaemoglobinaemia or NADH cytochrome b5 reductase deficiency.

• Children under 1 year.

Common adverse effects. Drowsiness, restlessness, diarrhoea, fatigue and depression.

Serious adverse effects.

• Acute dystonia (oculogyric crisis, torticollis, trismus, opisthotonus), most often in young women, children and after IV dosing; may be mistaken for seizures or tetanus.

• Akathisia and drug-induced parkinsonism.

• Tardive dyskinesia: risk rises with dose, duration, older age and diabetes; often irreversible.

• Neuroleptic malignant syndrome and serotonin syndrome.

• Hyperprolactinaemia: galactorrhoea, gynaecomastia and amenorrhoea.

• Methaemoglobinaemia (especially neonates), hypertension, bradycardia, QT prolongation and rare cardiac arrest with rapid IV 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.

• Diphenhydramine 25 to 50 mg IV or IM is an alternative.

• Continue an oral antimuscarinic for 1 to 2 days and stop metoclopramide.

Major interactions.

• Antipsychotics, other antiemetic dopamine antagonists and serotonergic drugs: additive extrapyramidal and neuroleptic malignant syndrome risk.

• Levodopa and dopamine agonists: pharmacological antagonism.

• CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine): raised metoclopramide levels.

• Antimuscarinics and opioids: oppose the prokinetic effect.

• Faster absorption of paracetamol, ciclosporin, tacrolimus and alcohol; reduced digoxin absorption.

• MAOIs: hypertensive reaction.

• Increased sedation with CNS depressants.

Special groups.

• Pregnancy: large cohort data show no consistent malformation risk; used for hyperemesis after first-line options.

• Breastfeeding: small amounts enter milk; raises prolactin and is sometimes used to increase supply; monitor infant for sedation and diarrhoea.

• Children: dystonia risk is high; restrict to second-line, short courses.

• Older adults: lower dose and shorter use; higher risk of parkinsonism and tardive dyskinesia.

• Diabetes: variable absorption in gastroparesis; monitor glucose.

• Regional: widely available and often used without prescription for abdominal pain and vomiting in young women and children, who then present with dystonia misdiagnosed as seizures, tetanus or hysteria.

Formulations. Tablets 10 mg; oral solution 5 mg in 5 mL; injection 10 mg in 2 mL; some markets have suppositories.

Oral administration. Take 30 minutes before meals.

IV administration.

• Injection: give undiluted over at least 3 minutes; rapid injection causes intense anxiety and restlessness (akathisia) followed by drowsiness.

• Infusion: dilute 10 mg in 50 mL sodium chloride 0.9% or glucose 5% and infuse over 15 to 30 minutes.

• Protect diluted solutions from light and use within 24 hours.

• Avoid IV injection of doses over 10 mg.

Baseline. Neurological history including movement disorders, kidney function and medication review for dopamine antagonists and CYP2D6 inhibitors.

Monitoring.

• Examine for movement disorders before starting and at every review, and stop at the first sign.

• Review need at 5 days and limit continuous use to 12 weeks.

• Kidney function when doses are repeated.

• Blood pressure in hypertension, and methaemoglobin if cyanosis develops.

• Mood in those with depression.

Therapeutic drug monitoring. Not applicable.

Stopping. No taper is needed. Stop at once for dystonia, parkinsonism, dyskinesia, neuroleptic malignant syndrome or serotonin syndrome.

Referral and escalation. Seek neurological review for persisting movement disorders after stopping. Admit for neuroleptic malignant syndrome with fever, rigidity, autonomic instability and raised creatine kinase.