RATE-DEPENDENCE OF CLASS-III ACTIONS IN THE HEART

The pharmacodynamics of many antiarrhythmic drugs are altered by heart mte. The ability of sodium channel blockers to decrease conduction velocity (class I action) is more pronounced with rapid heart rates. Drugs with class III action increase action potential duration and refractoriness in the heart. Most drugs with class III actions, currently being developed, produce their action by blocking one or several of the potassium channels responsible for repolarization. In vitro and in vivo studies have shown that their ability to increase repolarization time is less pronounced, or even disappears, at rapid pacing or heart rates. This so called 'inverse' rate-dependence of class III action is a characteristic of all drugs currently used in man except amiodarone, for which prolongation of repolarization time persists to a limited extent with rapid heart rates. It has been suggested that one possible mechanism of the inverse rate-dependence of class III action is related to the preferential binding of drugs to the potassium channels in the closed, polarized state. An inverse rate-dependence of class III action has also been found on prolongation of refractoriness. However, preliminary studies suggest that the positive inotropism of class III drugs not only persists but may increase with rapid heart rates. The clinical consequences of this phenomenon remain unclear, especially in view of the fact that the rate-dependence of class III action on dispersion of repolarization has not been specifically studied and that class III actions tend to decrease in ischemic tissues. However, the increase of action prolongation at slow heart rates may contribute to the bradycardia-dependent development of torsades de pointes arrhythmias. Moreover, the rate-dependence of class III actions needs to be taken into account when studying the relationship between plasma concentrations of new drugs with class III activity and the prolongation of repolarization time they induce.