Quantitative structure/activity relations based on use-dependent block and repriming kinetics in myocardium.

Different class 1 antiarrhythmic drugs have differing capabilities for producing a rate-dependent modulation of cardiac excitability. Structural hypotheses regarding these drug actions, both in terms of their widely differing abilities for blocking myocardial sodium channels during individual action potentials and their associated repriming kinetics, have been proposed. Recent studies on the channel blocking actions of these drugs, assessed using maximum upstroke velocities of intracellularly recorded actions potentials (APs), are reviewed in order to test these hypotheses. The size/solubility hypothesis, which says that smaller antiarrhythmic drugs with good lipid distribution capabilities provide more rapid repriming kinetics, is supported by results on 36 of 40 drugs having molecular weights up to 350. Blocking abilities during individual APs are also examined, with lipid distribution coefficients describing this blocking capability within selected classes of drug structures. However overall "potency" must include consideration of drug repriming kinetics which allows for accumulation of excitability block. Evidence which suggests that the kinetically slower drugs may be more cardiotoxic (arrhythmogenic) is presented. A model for the steep size dependence of drug recovery times is provided by a cylindrical pore having a radius of 4.1 Angstroms. Finally the different drug pools that drive the hypothesized hydrophilic and hydrophobic pathways to the receptor are considered in order to explain why drug lipid distribution characteristics might play a role in recovery kinetics.