title: CO2 retention as a basis for increased toxicity of salicylate with acetazolamide: avoidance of increased toxicity with benzolamide.
abstract: Two carbonic anhydrase inhibitors, acetazolamide and benzolamide, are capable of increasing the toxicity of sodium salicylate in mice. Beginning at about 2 mg/kg, each of the inhibitors, in combination with a fixed (400 mg/kg) dose of salicylate, generates a dose-mortality curve that reaches a plateau at about 60% deaths at 6 to 8 mg/kg. This effect can be duplicated by 8 to 10% inspired CO2. It appears that the respiratory acidosis secondary to the inhibition of red cell carbonic anhydrase is responsible for the increased toxicity; earlier work by others shows that acidosis increases the concentration of salicylate in the brain. In the treatment of salicylate poisoning by carbonic anhydrase inhibitors, the goal is to alkalinize the urine and increase the excretion of salicylate. With the newer inhibitor, benzolamide, it is possible to dissociate the respiratory acidosis from the renal effect. Maximal alkalinization of the urine is possible with a dose (about 1 mg/kg) below that which generates a respiratory acidosis. With this dose, there is no increase in the early toxicity of salicylate.
mesh_terms: D000086:Acetazolamide / Q000633:toxicity*; D000142:Acidosis, Respiratory / Q000503:physiopathology; D000468:Alkalies / Q000652:urine; D000818:Animals; D001574:Benzolamide / Q000494:pharmacology*; D002245:Carbon Dioxide / Q000378:metabolism* / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D012459:Salicylates / Q000633:toxicity*; D013830:Thiadiazoles / Q000494:pharmacology*
chemical_list: D000468:Alkalies; D012459:Salicylates; D013830:Thiadiazoles; D002245:Carbon Dioxide; D001574:Benzolamide; D000086:Acetazolamide