[New aspects of frequency-dependent effect of class 1 anti-arrhythmia drugs. A critical analysis of useful...

The primary action of class-1-antiarrhythmic drugs is due to blockade of cardiac sodium channels and shows drug-specific frequency dependence, i.e., increasing blockade with increasing stimulation frequency. However, this increasing blockade saturates at higher rates. This behavior can be explained by a periodical binding and unbinding reaction of drug molecules with channel binding sites (periodical ligand binding). The analysis of the saturation behavior of frequency-dependent block of 12 class-1-antiarrhythmic drugs clusters into three groups (I-III), which do not coincide with the commonly used subclassification (1a-1c). However, from the saturation behavior of block and its onset-kinetics (rate of increase of block upon increasing the frequency) found with these groups, three different profiles of antiarrhythmic and proarrhythmic efficacy can be deduced. Thus, saturation in the frequency range above 120/min combined with slow onset-kinetics may create a higher risk of exercise-induced proarrhythmic effects, if agents with such characteristics are given at a concentration sufficiently high to suppress extrasystoles. Therefore, a subdivision of class-1-antiarrhythmic drugs according to the saturation behavior of frequency-dependent block and its onset-kinetics is proposed.