Differential analysis of frequency-dependent effects of antiarrhythmic drugs: importance of the saturation behavior of frequency-dependent sodium-channel blockade.

Frequency-dependent effects of class I antiarrhythmic drugs on Vmax reported in the literature are analyzed with respect to periodical drug binding to sodium channels. The analysis reveals that class I action can be differentiated according to the onset kinetics as well as to the saturation behavior of frequency-dependent sodium-channel blockade at increasing frequencies. As will be shown, class I drugs even of the same subclass (Ic) may differ markedly from each other with respect to the saturation behavior of frequency-dependent block. These findings may be of interest in view of the Cardiac Arrhythmia Suppression Trial (CAST) because the results found with flecainide and encainide in this study are usually extrapolated to other Ic drugs. Additionally, the influence of postrepolarization refractoriness caused by a class I drug on the action potential shortening during repetitive premature stimulation is compared with the effects of prolongation of absolute refractoriness induced by a class III drug.