Antiemetics for PONV — 5-HT3 antagonists, dexamethasone, droperidol, NK1 antagonists

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Red flags

• Ondansetron and the other 5-HT3 antagonists PROLONG THE QT INTERVAL in a dose-dependent fashion, and the risk of torsades de pointes is real in the patient with pre-existing long-QT syndrome, electrolyte disturbance (hypokalaemia, hypomagnesaemia), hepatic impairment, or concurrent administration of other QT-prolonging drugs (droperidol, haloperidol, macrolides, fluoroquinolones, methadone). Avoid or reduce the dose in the long-QT patient and correct hypokalaemia and hypomagnesaemia before giving a 5-HT3 antagonist at the top of its dose range.
• Droperidol carries a FOOD AND DRUG ADMINISTRATION BLACK-BOX WARNING for QT prolongation and torsades de pointes, issued and leading to a dramatic fall in its use, with the warning partially relaxed in 2024 but the caution remaining. It is contraindicated in known or congenital long-QT syndrome and must be used with caution in the elderly, in cardiac disease, and with other QT-prolonging drugs — and NEVER combined with ondansetron without an explicit assessment of the QT risk, because both prolong the QT and the combination is the single most commonly encountered double-QT scenario in PONV prophylaxis.
• Rescue treatment of breakthrough PONV MUST use a drug from a DIFFERENT class than the prophylaxis. Giving a second dose of the same agent used for prophylaxis (for example, more ondansetron after ondansetron prophylaxis) is largely ineffective, because the receptor is already occupied; reaching for a different class (droperidol after ondansetron, or an NK1 antagonist after dexamethasone) is the evidence-based and the mechanistically rational response.
• Prophylaxis is NOT for everyone. Routine prophylaxis in every patient is neither cost-effective nor safe, because the low-risk patient (Apfel 0 or 1) has a baseline incidence under 20 per cent and is exposed to the adverse effects and cost of an agent they did not need. Risk-stratify with the Apfel score first and reserve combination prophylaxis for the moderate and high-risk patient.
• The NK1 antagonist aprepitant is a moderate inhibitor of CYP3A4 and can increase the plasma concentration and the effect of co-administered CYP3A4 substrates, including some chemotherapeutic agents, midazolam, and the steroids. In the perioperative setting the interaction with dexamethasone is clinically relevant — aprepitant can roughly double dexamethasone exposure — and the dexamethasone dose should be considered when the two are combined.