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

1The effects of Class I antiarrhythmic drugs on the maximum rate of depolarization (Vmax) of guinea-pig ventricular action potentials were studied by standard microelectrode techniques. 2 The ability of seven different drugs to depress V'max 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 Vmax 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). 5The time constant of recovery from rate-dependent block (Tre) 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.

Resting, and rate‐dependent depression of of guinea‐pig ventricular action potentials by amiodarone and desethylamiodarone

“…over a clinically relet ing drive rates (Figure 3). (Campbell, 1983b). Such fast onset kinetics are consistent with the finding that amiodarone binds strongly and selectively to inactivated sodium chan-800 1000 1200 nels (Mason et al, 1984).…”

“…Such fast onset kinetics are consistent with the finding that amiodarone binds strongly and selectively to inactivated sodium chan-800 1000 1200 nels (Mason et al, 1984). Courtney, 1980a;Campbell, 1983b) and for the Ta drugs quinidine, disopyramide and procainamide (Tre = 2.3-12.2 s; Courtney, 1980a;Grant et al, 1982;Campbell, 1983a (Courtney, 1980a,b,c;Campbell, 1983b) (Varro et al, 1985). They are able to prolong action potential duration (Class III effect) and they have Class I effects with fast onset and offset kinetics so they respond rapidly to step increases in heart rate with an increased degree of depression of V. Thus in therapeutic concentrations, they have minimal influence on V.., and hence conduction at normal heart rates (Finerman et al, 1982;Zipes et al, 1984) but are able to respond to a premature beat or tachycardia with a rapid decrease in V,, (Campbell, 1983a).…”

“…While the ability to produce resting depression of V correlates well with lipophilicity for relatively low molecular weight drugs (Sada & Ban, 1981), this relationship does not hold for antiarrhythmic drugs with molecular weights above about 350 (Campbell, 1983b). For these compounds it has been suggested that their physical size somehow limits access to the resting sodium channel (Courtney, 1980a).…”

Electrophysiological effects of OPC‐88117, a new antiarrhythmic agent on papillary muscles and single ventricular myocytes isolated from guinea‐pig hearts

“…The recovery time constant (456 ms) was comparable to those obtained for lignocaine, mexiletine and tocainide (200-500ms) (Campbell 1980;1983a (Grant et al, 1984). Recently, we have shown that Class I antiarrhythmic drugs can be subdivided into two groups in terms of their sodium channel blocking phase during the conditioning clamp pulse to OmV; one 'transient' and one maintained (Kodama et al, 1987a;Courtney, 1988).…”

Depression of maximum rate of depolarization of guinea‐pig ventricular action potentials by metabolites of encainide

“…Elharrar & Zipes did not study the ability of ODE or MODE to reduce 1, in the absence of stimulation ('resting block' of the sodium channel). The ability to produce resting depression of P, correlates well with lipophilicity for class 1 agents of relatively low molecular weight (Sada & Ban, 1981), but this relationship breaks down for drugs with molecular weights above about 350 (Campbell, 1983c;Courtney, 1987). Encainide which has a relatively high molecular weight (352) and is relatively lipid insoluble, shows a similar inability to produce resting block (Campbell, 1983b).…”