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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