Cardio-respiratory toxicity of propoxyphene and norpropoxyphene in conscious rabbits

The toxic effects of alpha-d-propoxyphene (P) and its primary metabolite alpha-d-norpropoxyphene (NP) were compared to intravenous infusions (100 min.) of equimolar doses of P and NP (80 micronmol/kg equivalent to 30 mg/kg P HCl) in conscious rabbits. During P infusion severe respiratory depression and convulsions were seen in all animals, and six of the nine animals died. During NP infusion, however, only minimal respiratory depression was seen and all the animals survived. Considerable prolongation of the QRS complex and cardiac arrhythmias like intermittent A-V block and ventricular extrasystoles were seen in the ECG during both P and NP infusion, while the arterial blood pressure was unchanged. In P injection experiments (6 mg/kg P HCl), ECG changes preceded reduction in respiratory rate and during NP infusion only minor changes were seen in arterial blood gases, demonstrating that the ECG changes produced by P and NP are independent of respiratory depression. The ECG changes were found to be similar to those reported in quinidine intoxication. The QRS prolongation was markedly correlated with plasma concentrations during and after P and NP infusion. The results of the present investigation favour the hypothesis that the contribution of NP to the toxicity of oral P overdosage in man is ascribed to its cardiotoxic action whereas P is responsible for the CNS toxicity (respiratory depression and convulsions) as well as cardiotoxicity.