Pharmacokinetic factors may contribute to altered nortriptyline effects in the elderly. Plasma concentrations of nortriptyline's principal metabolite, E-10-hydroxynortriptyline, tend to be greater than nortriptyline, increase with age, and may contribute to cardiotoxicity. Electrocardiogram changes were evaluated in 21 ambulatory, elderly, depressed outpatients who were treated with therapeutic doses of nortriptyline. Resting electrocardiograms were obtained before and after 6 weeks of treatment. Plasma samples were assayed simultaneously for nortriptyline, E-, and Z-10-hydroxynortriptyline. Three subjects developed a first degree atrioventricular block and one developed a right bundle branch block during treatment. Mean daily nortriptyline dose and steady state plasma level in these subjects did not differ from those who did not develop conduction defects, but E-10-hydroxynortriptyline levels were significantly higher. Overall, there were significant correlations between changes in the PR interval and QRS duration with plasma concentrations of nortriptyline, E-10-hydroxynortriptyline, Z-10-hydroxynortriptyline, and the sum of nortriptyline and its 10-hydroxynortriptyline metabolites. Multiple regression analyses suggested that increases in PR interval were associated with increasing nortriptyline concentration, while increases in QRS duration and Q-Tc intervals were associated with increasing Z-10-hydroxynortriptyline concentration. E- and Z-10-hydroxynortriptyline may contribute substantially to the cardiac conduction effects of nortriptyline treatment and may be of particular importance in the elderly.
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