5HT3 Receptor Antagonist Antiemetics

5HT3 receptor antagonists block serotonin-gated ion channels on vagal afferents and in the chemoreceptor trigger zone. They are the most widely used antiemetics for chemotherapy-induced, radiotherapy-induced and postoperative nausea and vomiting.

Pharmacokinetics. Ondansetron is cleared mainly by CYP3A4, CYP1A2 and CYP2D6, with a half life of about 3 to 6 hours. Granisetron half life is about 9 hours; palonosetron about 40 hours.

• Ondansetron 4 to 8 mg orally or intravenously every 8 hours; single intravenous dose not over 16 mg; daily maximum 24 mg.
• Granisetron 1 mg intravenously or 2 mg orally once daily.
• Palonosetron 0.25 mg intravenously once, or 0.5 mg orally.
• Tropisetron 5 mg once daily.

Differences. Palonosetron binds longer and covers delayed emesis. Ondansetron and dolasetron are more strongly associated with QT prolongation.

• Chemotherapy: give before treatment with dexamethasone; palonosetron preferred for moderate risk.
• Postoperative: ondansetron 4 mg intravenously at the end of surgery.
• Gastroenteritis in children: ondansetron about 0.15 mg/kg, up to 8 mg; by weight bands 2 mg for 8 to 15 kg, 4 mg for 15 to 30 kg and 8 mg over 30 kg.
• Hyperemesis: after other drugs have failed.

Selection. Ineffective for motion sickness.

Contraindications. Congenital long QT syndrome; apomorphine (profound hypotension).

Adverse effects. Headache, constipation, flushing, dose-related QT prolongation, serotonin syndrome (rare), hypersensitivity, and masking of ileus.

Interactions. Rifampicin, phenytoin and carbamazepine lower ondansetron levels through CYP3A4 induction, which matters in patients on tuberculosis treatment. Additive QT effects with macrolides, fluoroquinolones, haloperidol and antiarrhythmics.

Special groups.

• Liver impairment: ondansetron not over 8 mg daily in severe impairment.
• Kidney impairment: no adjustment.
• Pregnancy: ondansetron may carry a small first-trimester risk of oral clefts; reserve for failure of first-line drugs.
• Breastfeeding: acceptable.
• Older adults: avoid single intravenous doses over 8 mg because of QT risk.

Monitoring. ECG and potassium and magnesium in patients with heart disease, electrolyte disturbance or other QT drugs.

Referral and escalation. Persistent vomiting despite two drugs from different classes needs a search for obstruction, raised intracranial pressure or metabolic cause.