Importance of physico‐chemical properties in determining the kinetics of the effects of Class I antiarrhythmic drugs on maximum rate of depolarization in guinea‐pig ventricle

Abstract

1 The effects of Class I antiarrhythmic drugs on the maximum rate of depolarization of guinea-pig ventricular action potentials were studied by standard microelectrode techniques. 2 The ability of seven different drugs to depress in unstimulated tissue (‘resting block’) was found to correlate poorly with the lipophilicity (log P) of the compounds and only a little better with their molecular weights. 3 Depression of in stimulated tissue was studied for 11 drugs and found, in all cases, to increase with stimulation frequency (‘rate-dependent block’). 4 The rapidity of onset of rate-dependent block (at approximately equipotent concentrations) varied markedly between drugs. It correlated well with molecular weight (r = 0.83; P < 0.01). 5 The time constant of recovery from rate-dependent block (ire) also correlated very well with molecular weight (r = 0.94; P < 0.001) for the seven drugs thus studied. 6 A simplified model for the interaction of Class I drugs with the fast sodium channel is proposed in which the drugs all act as ‘inactivation enhancers’; (as suggested by other workers) but in which their molecular weight plays a central role in determining the kinetics of this interaction.