Electrophysiological effects of desmethylimipramine and desmethyldoxepin on canine cardiac Purkinje fibers

Abstract Although the tricyclic antidepressant drugs imipramine and doxepin exert similar direct electrophysiological effects on cardiac cells, toxic cardiac arrhythmias and conduction disturbances are much more commonly associated with imipramine than doxepin in clinical use. To ascertain if this discrepancy could be due to different cellular electrophysiological actions of active metabolites of imipramine and doxepin, the effects of desmethylimipramine (DMI) and desmethyldoxepin (DMD) on isolated, superfused, canine cardiac Purkinje fibers were studied by glass microelectrodes and programmed stimulation. At a concentration of 50 ng/ml neither DMI nor DMD affected the resting membrane potential (RMP), action potential amplitude (Amp), maximum upstroke velocity of phase 0 (V max ), action potential duration to repolarization to 50 and 100% of the amplitude (APD50, APD100), effective refractory period (ERP), or conduction velocity (CV). At 250 ng/ml neither drug affected Amp, APD100, or CV; both compounds reduced APD50 by 10 to 15%; and DMD but not DMI caused small reductions of RMP, V max , and ERP. At 1000 ng/ml neither DMI nor DMD affected RMP but both caused more marked reductions of APD50 (31 to 35%) and ERP (21 to 23%). At this concentration both substances also reduced Amp by 6 to 7%, V max by 28 to 35%, APD100 by 7 to 12%, and CV by 15 to 25%. These effects of DMI and DMD are similar to those produced by the parent drugs. Differences in cardiotoxicity between imipramine and doxepin in clinical use are probably not due to different direct cellular electrophysiological effects of the circulating demethylated metabolites of these drugs.