Drug interactions affecting analgesic toxicity.

Most reports of interactions involving analgesics deal with their effects on the actions of other drugs rather than vice versa. Aspirin and ethanol have synergistic effects on the development of gastritis, gastrointestinal bleeding, and chronic gastric ulcer. This must be the most common and most important interaction affecting analgesic toxicity. Combined overdosage of aspirin with central nervous system depressants may be particularly hazardous because suppression of the salicylate-induced respiratory stimulation further shifts the disordered acid-base balance towards acidosis. The toxicity of acetaminophen (paracetamol) depends primarily on the balance between the rate of formation of the hepatotoxic metabolite and the rate of glutathione synthesis in the liver. In animals, prolonged pretreatment with ethanol increases the metabolic activation and acute toxicity of acetaminophen, and there is some evidence that chronic alcoholics are more susceptible to hepatotoxicity following acute overdosage. It has been assumed that this sensitivity in chronic alcoholics is due to microsomal enzyme induction with enhanced metabolic activation of acetaminophen. However, the metabolic activation of acetaminophen, as judged by the urinary excretion of its cysteine and mercapturic acid conjugates, is not increased in heavy drinkers or in patients induced by long-term treatment with anticonvulsants or rifampicin. Microsomal enzyme induction is complex. There are important species differences and different agents may selectively induce different variants of the multiple forms of cytochrome P-450. The acute administration of ethanol greatly reduces the metabolic activation of acetaminophen in heavy drinkers with more than a 50 percent decrease in cysteine and mercapturic acid conjugate production. Thus ingestion of ethanol should reduce the risk of liver damage following acetaminophen overdosage. Cimetidine, which inhibits the oxidative metabolism of some drugs, reduces the hepatotoxicity and increases the dose of acetaminophen in mice required to kill 50 percent of the animals. However, contrary to expectations, cimetidine does not inhibit the oxidative metabolism of acetaminophen in man. Salicylamide competes with acetaminophen for sulphate conjugation but is unlikely to potentiate toxicity following overdosage since sulphate conjugation is rapidly saturated anyway. Animal studies suggest that the hepatotoxicity of acetaminophen after overdosage may be increased by other agents which deplete glutathione, but there is no information on this point in man.