MECHANISM OF THE ANTICONVULSANT ACTION OF ACETAZOLEAMIDE, A CARBONIC ANHYDRASE INHIBITOR

¹ Department of Pharmacology, University of Utah College of Medicine, Salt Lake City, Utah

The anticonvulsant action of acetazoleamide, a carbonic anhydrase inhibitor, has been studied in mice, with the use of the maximal electroshock seizure test to determine anticonvulsant potency. Inhibition of carbonic anhydrase is related to the anticonvulsant activity of sulfonamides containing a free —SO₂NH₂ group; thus, acetazoleamide and sulfanilamide were found to be anticonvulsants and to inhibit brain carbonic anhydrase, whereas sulfathiazole, in which the —SO₂NH₂ moiety is substituted, is not an anticonvulsant and does not inhibit the enzyme. Such inhibition is not a property common to all antiepileptic compounds; for example, phenobarbital, diphenyhydantoin and trimethadione, in anticonvulsant doses, were found to have no significant effect on mouse-brain carbonic anhydrase.

Acetazoleamide has an anticonvulsant effect which was not abolished by nephrectomy, and which therefore is independent of the action of the drug on the kidney.

A direct relation between anticonvulsant effect and inhibition of brain carbonic anhydrase has been shown in mice by comparing the activity of acetazoleamide with that of sulfanilamide, a much less potent inhibitor. The maximum degree of enzyme inhibition by these two drugs corresponded with their time of peak anticonvulsant effect. Acetazoleamide was approximately twice as potent as sulfanilamide, both as an anticonvulsant and as an inhibitor of brain carbonic anhydrase. An anticonvulsant ED₅₀ of either drug inhibited the brain enzyme activity by about 98 per cent. The ratio of concentrations of acetazoleamide and sulfanilamide in mouse brain at the same dose level was approximately 1:50. Compared with that of sulfanilamide, the anticonvulsant potency of acetazoleamide (2:1 ratio) was therefore reconciled with its much higher potency of enzyme inhibition in vitro (approximately 100: 1 ratio). It is anticipated that if potent congeners of acetazoleamide are developed which can reach higher concentrations in the brain, they will exhibit more marked anticonvulsant activity and may have greater clinical value in the treatment of epilepsy.

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