Drug-induced arrhythmia: pharmacogenomic prescribing?

Abstract

Drug-induced Torsades de Pointes is a rare, unpredictable, and life-threatening serious adverse event. It can be caused by both cardiac and non-cardiac drugs and has become a major issue in novel drug development and for the regulatory authorities. This review describes the problem, predisposing factors, and the underlying genetic predisposition as it is understood currently. The future potential for pharmacogenomic-guided and personalized prescription to prevent drug-induced Torsades de Pointes is discussed. Database searches utilized reports from www.qtdrugs.org up to January 2012, case reports and articles from www.pubmed.com up to January 2012, and the British National Formulary edition at www.bnf.org.

Figure 1

An example of second-degree heart block (Mobitz type 2) with severe QT prolongation associated with sotalol therapy. A probable ventricular ectopic occurs (arrowed) with associated severe QT prolongation and a bizarre T-wave followed by a late coupled initiation of Torsades de Pointes.

Figure 2

The diagram illustrates the timing of the ventricular myocyte action potential and the surface ECG with associated inward and outward currents. Blockade of the rapid rectifier current (I_Kr) is the most common mechanism for drug-induced QT prolongation and Torsades de Pointes.