Reversal of propranolol and verapamil toxicity by calcium.
Because of the increasing use of propranolol and verapamil in combination, a study of their interaction was conducted. In rabbits, propranolol given IV at 1 mg/kg followed by an IV infusion of verapamil at 0.1 mg/kg/min for 15 min caused profound hypotension, bradycardia, A-V block, and death in less than 1 h in each of 30 animals. In rabbits treated with propranolol and verapamil as above, calcium chloride (300 mg/kg) given IV immediately after verapamil infusion restored blood pressure and cardiac conduction to normal but the heart rate remained slow; all 12 animals survived. In miniature swine under sodium pentobarbital anesthesia, propranolol (0.5 mg/kg) and verapamil (0.5 mg/kg) IV produced the same physiological changes and death within 15 min in each of eight animals. Calcium chloride given at 150 mg/kg to miniature swine after propranolol and verapamil injections prevented death of each of the five animals; blood pressure and the electrocardiogram were restored to normal, although bradycardia persisted. In mice, the IP LD50 value of propranolol HCl, which is 80 +/- 2.7 mg/kg, was decreased to 10 mg/kg when the drug was given in combination with verapamil HCl at an IP dose of 3 mg/kg, which is less than 1/10 of its LD50. Deaths occurred within minutes and were preceded by convulsions. Pretreatment of mice with calcium chloride (600 mg/kg, IV) prevented death due to the combination of propranolol and verapamil. The data indicate that verapamil enhances the toxicity of propranolol and that calcium can antagonize this effect.