Acetazolamide - Mechanism of Action

Mechanism of Action

Acetazolamide is a carbonic anhydrase inhibitor. Medically it may be used to treat conditions of moderate to severe metabolic or respiratory alkalosis. It does this by interfering with bicarbonate (HCO₃-) reabsorption in the kidneys, thereby re-acidifying the blood (and thus alkalinizing the urine).

Carbonic anhydrase (CA) catalyzes the first part of the following reversible reaction (the second half happens spontaneously, favouring production of H+ + HCO₃-), in which carbon dioxide (CO₂) and water (H₂O) are converted to carbonic acid (H₂CO₃) and vice-versa:

CO₂ + H₂O <--CA--> H₂CO₃ <--> H+ + HCO₃-

In the kidney tubules, locally secreted hydrogen ions normally combine with filtered bicarbonate (HCO₃-) to form carbonic acid (H₂CO₃). Carbonic acid in turn is normally acted upon by carbonic anhydrase, leading to formation of CO₂. As CO₂ rapidly leaves the tubules by diffusing across cell membranes, the above reaction normally runs shifted strongly to the left (i.e. reversed), and more bicarbonate can be continuously reabsorbed from the preurine. However, in the presence of acetazolamide, carbonic anhydrase is inhibited and carbonic acid levels build up. The inhibition of carbonic anhydrase in turn leads to a slowing of the reverse reaction and a decrease in the body's ability to reabsorb serum bicarbonate, resulting in urinary bicarbonate wasting. This leads to a decreased ability to exchange Na+ for H+ in the presence of acetazolamide (in proximal convoluted tubules of kidney) resulting in a mild diuresis. By contrast, the H+ that is also present in the lumen is reabsorbed via an alternative pathway along with Cl-; it then passes into the bloodstream, leading to hyperchloremic metabolic acidosis. This effect can also be used for therapeutic correction of alkalosis seen in altitude sickness or other forms of respiratory alkalosis.