Biological Functions
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.
Mechanism of action
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.
Clinical Use
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.
