Rate dependence of the effect of antiarrhythmic drugs delaying cardiac repolarization: an overview

Prolongation of the cardiac action potential and refractoriness (class III effect) is a potentially beneficial electrophysiological mechanism of action. However, this effect may be diminished or eliminated at rapid heart rates, so-called 'reverse rate dependence' of prolongation of repolarization. Action potential duration normally shortens as heart rate increases, due to increases in outward repolarizing currents, and/or decreases in inward depolarizing currents. The assessment of the effect of drugs on action potential duration is complicated by inter-species differences in ionic currents mediating repolarization, heterogeneity within the heart in repolarizing currents, and differential effect of drugs in different species, during differing experimental conditions, and at different rates of stimulation. In general, most drugs which predominantly block the IKr repolarizing current exhibit reverse rate-dependent effects on cardiac repolarization. Drugs or combinations of drugs which produce multiple ionic channel blocks and possibly those which block the IKs current, may be less prone to this potentially undesirable effect.