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.

In 1937, it was proposed that the normal acidification of urine was caused by secretion of hydrogen ions by the tubular cells of the kidney. These ions were provided by the action of the enzyme carbonic anhydrase, which catalyzes the formation of carbonic acid (H2CO3) from carbon dioxide and water.
in a lesser exchange of hydrogen ions for sodium ions in the kidney tubule. Sodium ions, along with bicarbonate ions, and associated water molecules were then excreted, and a diuretic effect was noted. The large doses required and the side effects of sulfanilamide prompted a search for more effective carbonic anhydrase inhibitors as diuretic drugs.
It was soon learned that the sulfonamide portion of an active diuretic molecule could not be monosubstituted or disubstituted. It was reasoned that a more acidic sulfonamide would bind more tightly to the carbonic anhydrase enzyme. Synthesis of more acidic sulfonamides produced compounds more than 2,500-fold more active than sulfanilamide. Acetazolamide was introduced in 1953 as an orally effective diuretic drug. Before that time, the organic mercurials, which commonly required intramuscular injection, were the principal diuretics available.
An increased excretion of only 2 to 5% of the filtered load of sodium is seen with carbonic anhydrase inhibitors because of increased reabsorption of sodium ions by the ascending limb of the loop of Henle and more distal nephron segments.

With prolonged use of the carbonic anhydrase inhibitor diuretics, the urine becomes more alkaline, and the blood becomes more acidic. When acidosis occurs, the carbonic anhydrase inhibitors lose their effectiveness as diuretics. They remain ineffective until normal acid-base balance in the body has been regained. For this reason, this class of compounds is limited in its diuretic use. Today, they are most commonly used in the treatment of glaucoma, in which they reduce the rate of aqueous humor formation and, subsequently, reduce the intraocular pressure. These compounds also have found some limited use in the treatment of absence seizures, to alkalinize the urine, to treat familial periodic paralysis, to reduce metabolic alkalosis, and prophylactically, to reduce acute mountain sickness.