Analysis of Safety Margin of Lithium Carbonate Against Cardiovascular Adverse Events Assessed in the Halothane-Anesthetized Dogs

Abstract

Lithium is one of the classical drugs that have been widely used for treating bipolar disorder. However, several cardiac side effects including sick sinus syndrome, bundle branch block, ventricular tachycardia/fibrillation, non-specific T-wave abnormalities in addition to Brugada-type electrocardiographic changes have been noticed in patients who were given antidepressant, anticonvulsant, and/or antipsychotic drugs besides lithium. In this study, we assessed cardiohemodynamic and electrophysiological effects of lithium carbonate by itself to begin to analyze onset mechanisms of its cardiovascular side effects. Lithium carbonate in intravenous doses of 0.1, 1, and 10 mg/kg over 10 min was cumulatively administered with an interval of 20 min to the halothane-anesthetized beagle dogs (n = 4), which provided peak plasma Li⁺ concentrations of 0.02, 0.18, and 1.79 mEq/L, respectively, reflecting sub-therapeutic to toxic concentrations. The low and middle doses prolonged the ventricular effective refractory period at 30 min and for 5–30 min, respectively. The high dose decreased the heart rate for 45–60 min, delayed the intraventricular conduction for 15–20 min and the ventricular repolarization at 45 min, and prolonged the effective refractory period for 5–60 min. No significant change was detected in the other cardiovascular variables. Thus, lithium alone may have a wide safety margin against hemodynamic adverse events; however, it would directly and/or indirectly inhibit Na⁺ and K⁺ channels, which may synergistically increase the ventricular refractoriness from the sub-therapeutic concentration and decrease the heart rate at the supra-therapeutic one. These findings may partly explain its clinically observed various types of arrhythmias as well as electrocardiographic changes.