10-hydroxynortriptyline and Arrhythmias--Cardiac

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.

Topics: Aged; Aged, 80 and over; Arrhythmias, Cardiac; Clinical Trials as Topic; Depressive Disorder; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Male; Middle Aged; Nortriptyline

The potential cardiotoxicity of the hydroxymetabolites of nortriptyline (NT) has been raised by inferential data from clinical studies and by the experimentally demonstrated cardiac effects of 2-OH-imipramine. Cardiac output, arterial pressure, and a continuous electrocardiogram were assessed after intravenous de novo administration of NT or its hydroxymetabolites to 41 swine. NT at doses ranging from 3.5 to 7 mg base per kilogram caused significantly more arrhythmias than did E-10-hydroxynortriptyline (E-10-OH-NT) but was not significantly different from Z-10-hydroxynortriptyline (Z-10-OH-NT) in this effect. Z-10-OH-NT, in contrast, to its geometrical isomer caused marked bradycardia, and decrements in blood pressure and cardiac output. NT and Z-10-OH-NT, but not E-10-OH-NT, produced dose-correlated declines in cardiac output. The hydroxymetabolites had smaller volumes of distribution, shorter half-lives and larger free fractions compared with NT. The differing cardiotoxicity of the hydroxymetabolites could not be accounted for by differing pharmacokinetic properties.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Blood Proteins; Cardiac Output, Low; Chromatography, High Pressure Liquid; Dialysis; Electrocardiography; Half-Life; Heart Diseases; Isomerism; Nortriptyline; Protein Binding; Swine

Among 18 elderly depressed patients given ECGs before and during nortriptyline treatment, plasma E-10-hydroxynortriptyline and the sum of E-10-hydroxynortriptyline and nortriptyline distinguished the group with conduction/repolarization effects. Plasma nortriptyline, age, drug dose, and baseline cardiovascular status did not.

Topics: Age Factors; Aged; Arrhythmias, Cardiac; Depressive Disorder; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Male; Middle Aged; Nortriptyline