Block of sodium currents by antiarrhythmic agents: analysis of the electrophysiologic effects of propafenone in heart muscle.

Antiarrhythmic efficacy may result from the ability of class I drugs to depress cardiac sodium currents (INa). Drug interaction with sodium channels could underlie INa blockade and can be defined in terms of the law of mass action which is modulated by many experimental conditions. As exemplified by propafenone, INa blockade occurs in 2 forms: tonic and phasic inhibition. Steady-state phasic (or use-dependent) INa blockade is determined by the interstimulus interval and reflects a labile equilibrium between drug occupancy of and dissociation from a channel-associated binding site. The drug-specific kinetics of the latter process together with the duration of the diastole determine the accumulation of blocked, that is, nonconductive, channels. Several lines of evidence suggest that tonic and phasic INa blockade are not 2 different manifestations of the same molecular event. Decreasing resting potential or reducing extracellular Na+ concentration strongly accentuates tonic blockade, whereas phasic blockade is comparatively less affected by these interventions. Consistent with this special susceptibility are individual concentration-response relations characterized by different apparent dissociation constants and Hill (nH) coefficients. Cardiac sodium channels presumably possess less drug affinity under resting conditions. Their binding of drugs no longer seems to be an allosteric process during repetitive stimulation, but could be characterized by 1:1 stoichiometry.