Carbonic Anhydrase Inhibitors

In the late 1930s, it was reported that sulfanilamide and other N-unsubstituted sulfonamides could induce diuresis characterized by excretion of an alkaline urine that is high in sodium bicarbonate. It was soon realized that these compounds inhibited carbonic anhydrase, an enzyme highly concentrated in renal tissue, and that this enzyme was important for the tubular reabsorption of bicarbonate. The common structural motif of carbonic anhydrase inhibitors is an unsubstituted sulfonamide moiety. These findings led to the synthesis of a series of compounds capable of inhibiting carbonic anhydrase, the most useful of which was acetazolamide (Diamox), which is considered the prototype of this class of diuretics. Although the clinical use of carbonic anhydrase inhibitors has greatly diminished since the 1960s, when their use was increasingly supplanted by the more potent thiazide diuretics (discussed later), they have been vitally important in helping to delineate the physiological role of carbonic anhydrase in electrolyte conservation and acid-base balance. Acetazolamide (Diamox), dichlorphenamide (Daranide), and methazolamide (Neptazane) are the carbonic anhydrase inhibitors available in the United States.

Inhibition of proximal tubule brush border carbonic anhydrase decreases bicarbonate reabsorption, and this accounts for their diuretic effect. In addition, carbonic anhydrase inhibitors affect both distal tubule and collecting duct H+ secretion by inhibiting intracellular carbonic anhydrase.

Renal excretion of Na+, K+, and HCO3" is increased by carbonic anhydrase inhibition. Diuresis following carbonic anhydrase inhibition consists primarily of Na+ and HCO3", with only a small increase of Clexcretion. This so-called bicarbonate diuresis is unique to carbonic anhydrase inhibitors. The fractional excretion of Na+ is generally limited to 5%, as a consequence of downstream compensatory Na+ reabsorption. Although distal nephron sites recapture much of the Na+, they possess only a limited ability to absorb HCO3". Fractional K+ excretion, however, can be as much as 70%. Potassium loss is particularly marked following carbonic anhydrase inhibition, both because of the presence of poorly reabsorbable HCO3" accompanying Na+ and because of the inhibition of the Na+-H+ exchange mechanism. Elevated urinary HCO3" excretion leads to the formation of alkaline urine and to metabolic acidosis as a result of both HCO3" loss and impaired H+ secretion.

The main therapeutic use of carbonic anhydrase inhibitors is not for the production of diuresis but in the treatment of glaucoma. This is true especially of the topically applied compound dorzolamide (Trusopt). Because the formation of aqueous humor in the eye depends on carbonic anhydrase, acetazolamide has proved to be a useful adjunct to the usual therapy for lowering intraocular pressure. Although acetazolamide has been used in the treatment of epilepsy, particularly absence epilepsy, it is not known whether the beneficial results are due to carbonic anhydrase inhibition or to the resulting acidosis. Oral carbonic anhydrase inhibitors are also useful in preventing or treating acute mountain sickness. Adverse reactions are minor; they include loss of appetite, drowsiness, confusion, and tingling in the extremities. Animal studies have shown some terato-genic potential, so the use of carbonic anhydrase inhibitors is not recommended during the first trimester of pregnancy.

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