Review article: cardiac adverse effects of gastrointestinal prokinetics

Gastrointestinal prokinetics, such as metoclopramide, cisapride and levosul piride, are widely used for the management of functional gut disorders. Rec ently, several studies have shown that cisapride (a partial 5-HT4 receptor agonist) can induce dose-dependent cardiac adverse effects, including lengt hening of the electrocardiographic QT interval, syncopal episodes and ventr icular dysrhythmias. Until recently, it was not clear whether these effects were dependent on 5- HT4 receptor activation or related to peculiar characteristics in the molec ular structure of single agents within the benzamide class. Experimental ev idence now favours the second hypothesis: cisapride possesses Class III ant iarrhythmic properties and prolongs the action potential duration through b lockade of distinct voltage-dependent K+ channels, thus delaying cardiac re polarization and prolonging the QT interval. Patients at risk of cardiac adverse effects are children, subjects with idi opathic, congenital or acquired long QT syndrome and, in particular, those receiving concomitant medication with Class III antiarrhythmic agents, some H-1-receptor antagonists (e.g. terfenadine), or drugs such as azole antifu ngals (e.g. ketoconazole, itraconazole, miconazole and fluconazole) and mac rolide antibacterials (e.g. erythromycin, clarithrod-mycin and troleandomyc in), which can inhibit cisapride metabolism by interfering with the CYP3A4 isoenzyme.