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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
Author(s) -
Campbell Terence J.
Publication year - 1983
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1983.tb11046.x
Subject(s) - chemistry , lipophilicity , depolarization , guinea pig , kinetics , stimulation , pharmacology , ventricle , sodium channel , sodium , biophysics , stereochemistry , medicine , biology , physics , organic chemistry , quantum mechanics
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.