Acetazolamide: It is a carbonic anhydrase inhibitor. It inhibits the renal enzyme Carbonic Anhydrase (CA). This enzyme normally functions to reabsorb the bicarbonate in the kidneys. So acetazolamide depletes the body of bicarbonates, expedites its excretion, and causes temporary metabolic acidosis. For understanding the mechanism of Diamox, studying the physiology of carbonic anhydrase enzymes is important.

The physiological role of carbonic anhydrase enzyme:

In the lumen of the proximal convoluted tubule (PCT) are the epithelial cells. The apical membrane of the epithelial cell contains the Na+- H+ exchanger. It means Na+ is secreted from the lumen into the cell. In exchange, H+ is secreted into the lumen. In the lumen, bicarbonate  (HCO3) is filtered at the glomerulus. This  H+ and HC03  ions react to form carbonic acid (H2C03). This H2C03 then decomposes to form C02 and H20. This reaction is catalyzed by a carbonic anhydrase enzyme (type IV) found on the luminal membrane of the epithelial cell.

In the cytoplasm, this reaction is catalyzed by carbonic anhydrase (type II). This H2C03 ionizes spontaneously to form H+ and HC03 ions. The HC03 and Na+ are transported into the interstitium by Na+ bicarbonate symporter, from there it reaches the blood. This H+ is reutilized for exchange with Na+. The end result of this entire process is the reabsorption of bicarbonate and sodium from the lumen into the blood. This is how carbonic anhydrase contributes to the reabsorption of HC03 and Na+.

Mode of action of acetazolamide:

Due to CA inhibition, the reabsorption of bicarbonate decreases, and more is lost in the urine. Inhibition of CA in the cytoplasm results in the decreased formation of H+. Without enough H+ to exchange with Na+, the activity of the exchanger is also decreased. So Na+ reabsorption is also decreased. So, acetazolamide decreases Na+ and HC03 reabsorption in PCT.

• Effect of acetazolamide on urinary excretion:

Effect on pH: Due to increased excretion and reduced reabsorption of HCO3 (base). The pH of urine is increased.

Effect on Na+: Due to decreased reabsorption of Na+ at PCT, the amount of Na+ leaving the PCT is increased. However, the ascending limb of Henle’s loop has a very high capacity of reabsorbing this Na+. So Na+ excretion is comparatively less (5%). Hence, diuresis is mild in this case.

Effect on K+: In contrast to the Na+ excretion, the fractional excretion of K+ is as high as 70%. Moreover, the increased reabsorption in the collecting tubule (CT) of the nephrons, leads to increased electronegativity. This in turn increases the secretion of K+ into the lumen. Na+ is being exchanged with K+ and H+. As acetazolamide decreases Na+ reabsorption in the PCT, more Na+ reaches the collecting duct and is reabsorbed there. Increased Na reabsorption in the collecting duct increases the electronegativity in the lumen. This in turn causes increased secretion of K+. Acetazolamide decreases the formation of H+ in the collecting duct. Without H+, the Na+ exchange takes place only with K+. So more

K+ is excreted to cover the loss of H+. This loss causes a marked increase in K+ excretion and results in hypokalemia (a condition characterized by low levels of potassium in the blood).

• Self-limiting action of acetazolamide: With continued loss of HC03 in urine, blood bicarbonate levels decrease, so less bicarbonate is filtered at the glomerulus. Eventually, a point comes when the uncatalyzed reaction of C02 and H20 is sufficient to reabsorb filtered HC03. Thus acetazolamide has self-limiting action.
• Action on GFR: Acetazolamide decreases Glomerular filtration rate (GFR). It is an inducer of electrolytic imbalance and associated abnormalities. It also leads to the development of kidney stones (calcium phosphate and oxalate stones) due to decreased secretion of magnesium and citrate.
• Adverse effects of acetazolamide: It causes sulfa allergy, ammonia toxicity, and metabolic acidosis (toxic build-up of acid in the blood due to underlying kidney disease).

For the aforementioned reasons, Acetazolamide is not recommended for patients with underlying kidney disease or CKD.