Abstract

The anticonvulsant effect of acetazolamide and its congeners is mediated through carbonic anhydrase inhibition. The most active carbonic anhydrase inhibitors in vitro, acetazolamide and methazolamide, are among the three most active anticonvulsants in vivo. Variable anticonvulsant effect associated with little or no in vitro activity is most plausibly explained by the degree of metabolic conversion to active carbonic anhydrase inhibitors in vivo.

Inhibition of brain carbonic anhydrase appears to be the prime event in this anticonvulsant effect. The evidence in support of this belief is as follows: 1) measurement of inhibitor concentration in brain, plasma and red cells of mice after the intravenous administration of methazolamide and acetazolamide showed that brain concentration alone could be related to anticonvulsant activity; 2) the presence of renal carbonic anhydrase is not necessary for the anticonvulsant effect; 3) the 3- to 4-fold greater activity of methazolamide than acetazolamide in mice appears to be the direct result of its greater ability to penetrate into the central nervous system. In the rat, these carbonic anhydrase inhibitors are equivalent in anticonvulsant activity. The relation of brain inhibitor concentration to anticonvulsant effect in this species remains to be investigated.

Maximum concentration of inhibitor in brain precedes maximum anticonvulsant effect by one to two hours for both drugs. Among several possible reasons for this lack of direct correlation, an enhancing effect of acidosis consequent to systemic carbonic anhydrase inhibition was considered a definite possibility. Ammonium chloride acidosis augments the anticonvulsant activity of methazolamide. Inhibition of brain carbonic anhydrase is the prime event in the anti-convulsant activity of carbonic anhydrase inhibitors, but the available data do not exclude the sequelae of renal or red cell carbonic anhydrase inhibition as participants in the process.