Acute cocaine toxicity: Antagonism by agents interacting with adrenoceptors

Agents which interact with alpha- or beta-adrenoceptors were evaluated for efficacy in preventing seizures and death from a lethal dose of cocaine. Rats were first pretreated with the test drug(s), then subjected to an intraperitoneal LD₈₆ of cocaine (70 mg/kg). In this model, control vehicle-pretreated animals developed seizures within six minutes, followed by death within 10 minutes. Significant protection against death was afforded by pretreatment with clonidine (0.25 mg/kg), prazocin (5.0 to 20 mg/kg), propranolol (8.0 to 32 mg/kg), orlabetalol (49 mg/kg). Surviving animals still experienced seizures as judged through behavior and EEG recordings. Phentolamine did not affect the incidence of seizures or death. Two nonadrenoceptor agents were also studied: hydralazine reduced the incidence of death and seizures at 5.0 and 10 mg/kg, but reserpine did not alter the incidence of death or seizures. A combination of prazocin and propranolol did not provide additional protection compared to single agents. We conclude that the pathogenesis of acute cocaine death is complex, and that this toxicity can be antagonized by agents having either central or peripheral effects.