Comparative cardiotoxicity of nortriptyline and its isomeric 10-hydroxymetabolites.
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.
Pollock
B G
BG
Department of Psychiatry, University of Pittsburgh, School of Medicine, Pennsylvania.
Everett
G
G
Perel
J M
JM
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D002303:Cardiac Output, Low / Q000139:chemically induced; D002851:Chromatography, High Pressure Liquid; D003956:Dialysis; D004562:Electrocardiography; D006207:Half-Life; D006331:Heart Diseases / Q000139:chemically induced*; D007536:Isomerism; D009661:Nortriptyline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*; D011485:Protein Binding; D013552:Swine
D001798:Blood Proteins; C013567:10-hydroxynortriptyline; D009661:Nortriptyline