The degree of potassium channel blockade and the risk of torsade de pointes: the truth, nothing but the truth, but not the whole truth

Abstract

This editorial refers to ‘Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death’† by M.L. De Bruin et al. , on page 590 Several anti-arrhythmic drugs, as well as medications not intended for cardiac indications, block a specific potassium channel named IKr (the rapid delayed rectifying potassium current). In the case of the anti-arrhythmic drugs, IKr channels are purposely targeted. By blocking potassium outflow currents, the anti-arrhythmic drugs prolong the action potential. This action (depicted in the electrocardiogram as prolongation of the QT interval) can be advantageous given that prolongation of the action potential also lengthens the refractory period, thereby suppressing common arrhythmias. Unfortunately, by a mechanism explained elsewhere,1 IKr blockade may lead to excessive QT prolongation and trigger a polymorphic ventricular tachyarrhythmia (torsade de pointes) that may degenerate into ventricular fibrillation. Furthermore, because of its unique three-dimensional characteristics,2 IKr channels are very easily blocked by the small molecules of numerous non-cardiac drugs. The result is that otherwise harmless and valuable drugs, like the non-sedative antihistamines and the quinolone-antibiotics, become potentially lethal pro-arrhythmic medications.3 An important study by De Bruin et al .4 suggests that a strong correlation exists between the strength of IKr blockade caused by a given drug and its pro-arrhythmic potential. The concept that stronger IKr blockers will lead not only to more QT prolongation but also to higher arrhythmic risk is so logical that the reader will be left wondering why this study was ever conducted, let alone published. In reality, however, this concept has been difficult to prove.5 Amiodarone, ranolazine, and verapamil illustrate that the correlation between IKr … *Corresponding author. Tel: +972 524266859; fax: +972 36974416. E-mail address : saviskin{at}tasmc.health.gov.il