An investigation was conducted to study whether animals with experimental cardiovascular disorders were more sensitive to the cardiotoxic effects of nortriptyline (NT) than normal animals. Since increased toxicity might be due to hypersensitivity of the target organ (the heart) and/or to increased blood levels of the drug, NT blood levels and an electrocardiogram (ECG) were simultaneously recorded in unanesthetized rabbits during NT intravenous infusion. Nortriptyline induced marked ECG alterations such as tachycardia, arrhythmias, impaired conduction, ST and T wave abnormalities, although only the increase in PQ and QRS intervals were directly correlated with NT blood levels (p <0.01). A one-compartment model described the pharmacokinetics and pharmacodynamics of NT disappearance. Nortriptyline blood levels of about 0.5 μg ml caused a 10% increase in PQ and QRS. A 20% complex widening occurred at 1 μg ml. The pharmacokinetics and cardiac effects of NT did not significantly differ in rabbits with experimental myocardial infarction (isoprenaline 50 mg kg × 2 days), hyperthyroid rabbits (triiodothyronine 0.1 mg kg × 15 days), or controls.
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