DEVELOPMENT OF CLASS-III ANTIARRHYTHMIC AGENTS

Currently available antiarrhythmic agents that act by lengthening the action potential duration and refractory period exert most of their effect during bradycardia (class III(B)). Unfortunately, when these agents are most needed, i.e., during tachycardia, they lose most of their effect. In my opinion, ideally, antiarrhythmic agents need not change the electrophysiology of the normal sinus beat, but should lengthen refractoriness upon acceleration (class III(A)) of the heart until the refractory period exceeds the cycle length of the tachycardia. Three examples of how such class III(A) effects can be achieved are: (i) an upstroke-dependent activator of inward currents could form a universal class III(A) agent, (ii) a use-dependent blocker of i(TO) could be a great class III(A) agent in the atria, and (iii) a frequency-dependent blocker of late repolarizing currents (e.g., i(Ks)) could be a good target for a ventricular agent.