Predicting drug-induced QT prolongation and torsades de Pointes

Abstract

Drugs used to treat cardiovascular disease as well as those used in the treatment of multiple other conditions can occasionally produce exaggerated prolongation of the QT interval on the electrocardiogram and the morphologically distinctive polymorphic ventricular tachycardia ("torsades de pointes"). This syndrome of drug-induced long QT syndrome has moved from an interesting academic exercise to become a key element in the development of any new drug entity. The prevailing view, that has driven both clinical care as well as drug regulation, holds that cardiac repolarisation represents a balance between inward currents (primarily through calcium and sodium channels) and outward currents (primarily through rapid and slowed delayed rectifier potassium channels) and that block of the rapid delayed rectifier (I_Kr) is the primary mechanism whereby drugs prolong individual action potentials, manifest on the surface electrocardiogram as QT interval prolongation. Such marked action potential prolongation in individual cardiac cells, in turn, is accompanied by arrhythmogenic afterdepolarisations thought to trigger torsades de pointes. This review will describe the evidence in support of this construct, and will describe the way in which clinical and whole heart experiments have informed molecular mechanisms and vice-versa. New data that challenge these views and that may, as a result, lead to new clinical care and drug screening paradigms, are discussed.

This article is protected by copyright. All rights reserved

from #Medicine via ola Kala on Inoreader http://ift.tt/1Qoi5UD
via IFTTT