Comparative cardiotoxicity of nortriptyline and its isomeric 10-hydroxymetabolites by Pollock B G, Everett G, Perel J M in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (1992). PubMed

Abstract

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.

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