Convulsions as the etiology of lactic acidosis in acute isoniazid toxicity in dogs

Abstract

The mechanism by which acute isoniazid (INH) overdose causes lactic acidosis is unknown. This study examines the role of convulsion in the development of lactic acidosis in dogs given po lethal doses of INH (75 mg/kg). Following INH, dogs did not develop acidosis until after they had experienced clonic-tonic convulsions. Acidosis, which became more pronounced with successive convulsions, was associated with marked increase of serum lactate (immediate postconvulsive level, 12.3 meq/liter, compared to control of 1.83 meq/liter). Diazepam, 0.5 mg/kg, plus pyridoxine HCl, 150 mg/kg, injected iv immediately following po INH, prevented both convulsions and changes in pH and lactate. When the antidotes were administered after the second convulsion of INH toxicity no further convulsions occurred and blood pH and lactate returned to control levels in 2 hr. “Curarization” of INH-treated dogs prevented both motor seizures and marked increase of lactate. In animals treated with INH and allowed to convulse two times to develop severe acidosis, correction of the acidosis with NaHCO 3 failed to prevent further convulsions and death. Diazepam and pyridoxine combinations, in doses that were ineffective for terminating INH-induced convulsions, became effective when given after correction of acidosis with NaHCO 3. It is concluded that convulsion is the main cause of lactic acidosis in acute INH toxicity and that correction of acidosis does not terminate acute INH toxicity. Although correction of acidosis increases the antidotal effectiveness of diazepam plus pyridoxine, increasing the dose of either or both of these two drugs achieves the same antidotal advantage without the potential problems of metabolic alkalosis which may result from NaHCO 3 administration.