Carbonic anhydrase, present mainly in cells of the proximal tubule epithelium, is responsible for the excretion of hydrogen ions (H+). Inhibition of this excretion leads to decreased reabsorption of bicarbonate (HCO3) and sodium ions (Na+) and thus decreased reabsorption of water; increased water is excreted. However, because this mechanism occurs primarily in the proximal tubule, increased water is reabsorbed in the distal tubule in a compensatory manner, which reduces the effect of carbonic anhydrase inhibitors.
In addition, the increased loss of Na+ leads to increased retention of Cl- and increased excretion of K+. This results in hypokalemia and hyperchloremic metabolic acidosis, which leads to increased availability of H+ in the kidney and thus drastically reduces the effect of carbonic anhydrase.