An analysis of antiarrhythmic action in a series of related compounds with reference to their selectivity for ischaemic tissue

Treatment with antiarrhythmic drugs has been largely ineffective with respect to reducing mortality in patients with myocardial infarction due to the paradoxical tendency of some antiarrhythmic drugs to have concommitant proarrhythmic effects. This phenomenon may arise when electrophysiologic effects in normal myocardium occur at doses similar to those that suppress arrhythmogenic substrates in ischaemic tissue. This thesis examines the actions of six structurally-related antiarrhythmic drugs to test the hypothesis that drugs which act selectively in ischaemic myocardium will be more effective antiarrhythmic agents than drugs which lack such selectivity. An isolated rat heart model was developed that allowed for simultaneous measurement of drug effects on optically-recorded action potentials in normal and ischaemic myocardium following coronary occlusion. This technique yielded quantitative indices of drug selectivity for ischaemic tissue with respect to effects on excitability (Vmax) and repolarisation (APD). These results were compared to the antiarrhythmic profiles of each drug as determined in separate rat models of non-ischaemic and ischaemic arrhythmias. In the latter experiments slope and goodness of fit (r²), which measure variability about the curve for antiarrhythmic protection, were interpreted as indices of selectivity for antiarrhythmic versus proarrhythmic effects. Potency for protection against ischaemic arrhythmias was inversely related to slope and goodness of fit to the antiarrhythmic dose-response curve. However, lack of potency did not compromise efficacy. Thus, effective protection against ischaemic arrhythmias was better defined by steep slopes and strong goodness of fit coefficients since these drugs showed maximum safety and efficacy, even though they tended to be less potent. Slope and goodness of fit correlated strongly with increased potency for prolonging repolarisation in ischaemic versus normal tissue, demonstrating that drugs which act selectively in ischaemic myocardium are more ideal therapeutic antiarrhythmic agents than drugs which lack such specificity.Medicine, Faculty ofAnesthesiology, Pharmacology and Therapeutics, Department ofGraduat