Differential Analysis of the Frequency-Dependent Effects of Class 1 Antiarrhythmic Drugs According to Periodical Ligand Binding

Implications for Antiarrhythmic and Proarrhythmic Efficacy

Abstract

The frequency-dependent block of cardiac sodium channels by class 1 antiarrhythmic drugs can be described by a periodical ligand binding process between drug molecules and channel binding sites. This predicts a linear relation between onset-rate constant of frequency-dependent block and diastolic interval as well as saturation of block with high stimulation rates. From both relationships, the binding kinetics (time constant, T_on) and saturation level of block (bd_inf) can be estimated. This is examplified for the frequency-dependent block (reduction of the maximal upstroke velocity of action potentials) induced by prajmaline (10^-6M). In the same way, the frequency-dependent effects of 11 other class I drugs reported in the literature were analyzed and compared with each other. When the drugs are ranked with respect to their binding kinetics (T_on), there is a close relationship to the subclasses (la, lb, lc), with lb drugs exhibiting the fastest and lc drugs the slowest kinetics. However, differences also exist in the saturation behavior of frequency-dependent block even within the same subclasses (la and lc). Thus, the class 1 drugs can also be subdivided in three other groups exhibiting clearly separated bands of block-frequency relations, with half-maximal saturation occurring at different stimulation rates. Our findings may have differential implications for the antiarrhythmic and proarrhythmic efficacy of class 1 drugs.