Potentiation of pyridoxine by depressants and anticonvulsants in the treatment of acute isoniazid intoxication in dogs

Abstract

Treatments for acute isoniazid (INH) intoxication have included, singly and in various combinations, a great variety of drugs. As a consequence it is difficult to evaluate the efficacy of these antidotes, except for pyridoxine, the most commonly recommended one. In some cases of INH poisoning evaluation is further complicated because of concurrent alcohol ingestion. The objectives of this investigation were to determine whether ethanol enhances the toxic effects of acute INH overdose, as suggested by some clinical reports, and to evaluate the antidotal efficacy of phenobarbital, pentobarbital, phenytoin, ethanol, or diazepam when each is administered in combination with pyridoxine. Male dogs were either pretreated with iv ethanol and challenged 1 hr later with po INH, 50 or 75 mg/kg, or they were given INH, 75 mg/kg, and injected iv 30 min later with the test drugs, alone or in combination with pyridoxine. Ethanol pretreatment not only did not enhance the toxicity of INH but, in fact, it reduced the severity of convulsions, although it did not change the mortality rate. In the antidotal study, none of the five CNS depressants or anticonvulsants protected against clonic-tonic seizures or death. Pyridoxine, however, reduced the severity of the seizures and prevented death, although it did not completely block convulsions. The combination antidotal treatments (pyridoxine plus each of the CNS drugs) were the most effective; they prevented both convulsions and lethality. It is suggested that pyridoxine is the basic antidote for treatment of acute INH poisoning, and that the addition of an anticonvulsant or a CNS depressant to the therapy enhances effectiveness.