THE ANTICONVULSANT ACTIONS OF METHAZOLAMIDE (A CARBONIC ANHYDRASE INHIBITOR) AND DIPHENYLHYDANTOIN

¹ Experimental Therapeutics Research Section, Research Division, American Cyanamid Company, Pearl River, New York

The anticonvulsant actions of the carbonic anhydrase inhibitor, methazolamide, and diphenylhydantoin show the following similarities: both 1) cause abolition of the tonic extensor component of the maximal electroshock seizure; 2) cause elevation of the CS₅₀ for such seizures in normal and hyponatremic mice; 3) show enhancement and prolongation of their anticonvulsant effect against maximal electroshock seizures by ammonium chloride; 4) show reduction of anticonvulsant activity by sodium chloride; 5) show lack of effect against "minimal" pentylenetetrazol and "psychomotor" seizures in mice. The important differences found to date are: 1) reserpine has marked ability to antagonize the anticonvulsant effect of methazolamide but only a relatively weak antagonistic action on that of chiphenylhydantoin; 2) methazolamide inhibits carbonic anhydrase while sodium diphenylhydantoin has no such action; 3) methazolamide is more potent in rats than in mice; the reverse is true of sodium diphenylhydantoin.

The absence of parallelism between the dose-effect curves of the two agents against maximal electroshock seizures makes quantitative comparisons difficult. At the ED₅₀ level of response in mice, the two drugs are about equipotent; at the ED₉₅ level, sodium diphenylhydantoin is about two and one-half times more active. The potency of methazolamide is about ten times that of sodium diphenylhuydantoin its rats. Combinations of the two drugs appear to have an additive effect against maximal electroshock seizures in mice. In ability to elevate the CS₅₀ for maximal electroshock seizures in normal and hyponatremic mice, sodium diphenylhdantoin is the far more effective agent. Methazolamide is three to four times more potent than acetazolamide against maximal electroshock seizures its mice; it is about twice as active in rats.

Rats do not develop a tolerance to the anticonvulsant effect of methazolamide. The anticonvulsant effectiveness of methazolamide, acetazolamide and sodium diphenylhydantoin is reduced to an equal degree in mice treated with the drugs, starch, or receiving no treatment at all. This reduction its the anticonvulsant effect of these drugs in mice does not appear to be due to the development of tolerance since it appears to be independent of prior drug treatment.

Methazolamide is well absorbed from the gastrointestinal tract of the mouse; following intravenous administration, maximum concentration of inhibitor in the brains of mice is achieved within 5 minutes.

From the marked ability of reserpine to antagonize the anticonvulsant action of methazolamide, it is inferred that the anticonvulsant action of carbonic anhydrase inhibition differs from that of diphenylhydantoin in having a comparatively weak effect on seizure spread.