The cardiotoxicity of macrolides: the role of interactions

Drug-induced long QT syndrome (LQTS) is characterized by prolongation of the QT interval and the risk of syncope and sudden cardiac death due to torsades de pointes (TdP) ventricular tachycardia upon exposure to certain antiarrhythmic and non-cardiovascular drug therapy. Most of the drugs responsible for LQTS can also block the rapid delayed rectifier K current, IKr in ventricular cardiomyocytes. The present review addresses the intrinsic proarrhythmogenic effect of macrolides and the role of interactions in their cardiotoxicity. Among macrolides, erythromycin and clarithromycin have the greatest potential for causing QT interval prolongation and TdP. Furthermore, macrolides can potentiate cardiotoxicity of other proarrhythmic agents applied concomitantly due to drug interactions. Pharmacodynamic interactions occur when macrolides are coadministered with other drugs with IKr blocking potential. On the other hand, pharmacokinetic interactions of macrolides arising from inhibition of cytochrome P450 3A4 (CYP3A4) isoenzyme and/or P-glycoprotein transport system may also increase the risk of cardiotoxicity. The awareness of this potentially lethal side effect of macrolide antibiotics is fundamental for health professionals. Simultaneous therapy with macrolides and other QT interval prolonging drugs, especially those metabolized by CYP3A4, should be avoided.