Plasma concentrations and cardiotoxic effects of desipramine and protriptyline in the rat

1 Desipramine and protriptyline were administered to anaesthetized rats by two consecutive intravenous infusions in order to obtain a peak level (first infusion) followed by lower steady state concentrations (second infusion) (Wagner, 1974). Theoretical plasma level time courses were confirmed experimentally.2 Desipramine and protriptyline were measured in atria and ventricles. Increasing infusion rates led to proportional increases in plasma and atrial concentrations. The tissue/medium ratio ranged from 57 to 21 for desipramine and from 43 to 11 for protriptyline according to the time of determination during infusions.3 Heart rate changes, deviation of the electrical axis of the heart and prolongation of atrioventricular conduction were recorded at fixed times during infusion.4 Positive chronotropic effects were noted at plasma concentrations ranging from 0.035 to 0.1 mug/ml for desipramine and from 0.04 to 1.2 mug/ml for protriptyline. At higher plasma concentrations the positive chronotropic effect decreased and bradycardia developed. Both drugs induced right rotation of the electrical axis of the heart. Threshold plasma levels giving 40 degrees rotation were 1.35 mug/ml (desipramine) and 1.75 mug/ml (protriptyline). Atrioventricular conduction was prolonged at threshold plasma concentrations of 2.2 mug/ml for desipramine and 3.6 mug/ml for protriptyline.5 Desipramine is more cardiotoxic than protriptyline. This difference is discussed in relation to the plasma and heart concentration of the two drugs.