Arrhythmia Risk of Antiemetic Agents

To the Editor:—

The recent strengthening of the US Food and Drug Administration (FDA) warning *on the proarrhythmic effects of droperidol follows 100 or so reported cases of droperidol-related arrhythmias. As clinicians implement the advised restrictions on use of droperidol, †increased use of the 5-HT³serotonin antagonists for management of postoperative nausea and vomiting (PONV) can be expected. Practitioners may be unaware that the 5-HT³antagonists are among a large group of drugs that can also prolong the QT interval and may theoretically contribute to the development of torsades de pointes. 1 

Although there appear to be no published clinical reports of ventricular tachycardia directly associated with 5-HT³antagonists, current prescribing information for dolasetron (Anzemet®; Aventis Pharmaceuticals, Kansas City, MO) 2includes a specific warning about the potential for QT interval prolongation and serious arrhythmia in at-risk patients. QT prolongation is thought to be due to hydrodolasetron, the active metabolite of dolasetron, and has been observed in healthy volunteers and in controlled clinical trials. 3The magnitude and frequency of the electrocardiographic changes increases with dose and may last as long as 24 h. The product insert also mentions three reported cardiac events, one fatal, in patients given doses of 100– 200 mg, although none was confirmed as torsades. 2 

The prescribing information for ondansetron 3(Zofran®; GlaxoSmithKline, Research Triangle Park, NC) does not contain a similar warning, although there are case reports of arrhythmias that occurred when ondansetron was combined with metoclopramide. 4 

The electrophysiological mechanisms responsible for drug-induced torsades de pointes are not completely understood. Potent block of the rapid component of the delayed rectifier potassium current by droperidol probably underlies QT prolongation observed in patients treated at therapeutic plasma concentrations (10–400 nm) of the drug. 55-HT³antagonists have been shown to block human cardiac Na⁺channels, 6and this may lead to clinically relevant Na⁺channel blockade, especially when high heart rates or depolarized/ischemic tissue is present. 6Na⁺channel blockade is associated with QRS widening. Ondansetron possesses submicromolar affinity for the HERG K⁺channel, which may cause prolongation of repolarization. However, none of the 5-HT³antagonists tested produces greater than 30% block of the slow delayed rectifier K⁺channel thought to be particularly important in the genesis of torsades de pointes. 6 

The potential for serious adverse events during perioperative use of antiemetic agents must be balanced against their benefit. Only two FDA-reported events occurred after administration of low doses (≤1 mg) of droperidol, and although droperidol has definite effects on prolongation of the QTc interval, extensive clinical experience suggests a rather small incidence of serious arrhythmia 7with prophylaxis or treatment of PONV. Compared to the extensive clinical and laboratory experience with droperidol, relatively little is known about the arrhythmia risk of 5-HT³antagonists. There is a lack of comparative data on the frequency of adverse cardiac events for droperidol on the one hand and the 5-HT³antagonists on the other. Unfortunately, in the absence of such data, the risk–benefit ratio is hard to assess, and the decision to restrict the prescribing of useful antiemetic agents is a difficult one.