Acetazolamide, a carbonic anhydrase inhibitor, causes metabolic acidosis as an adverse effect. Which biochemical mechanism explains this?

• A Carbonic anhydrase inhibition in red blood cells impairs CO2 transport from tissues
• B Acetazolamide inhibits renal H+/K+-ATPase in the collecting duct causing potassium retention
• C Inhibition of gastric carbonic anhydrase reduces acid secretion causing alkalotic reflex compensation
• D Inhibition of proximal tubule carbonic anhydrase prevents H+ secretion and HCO3- reabsorption; urinary bicarbonate wasting causes hyperchloremic non-anion-gap metabolic acidosis ✓

Explanation

In the proximal tubule, carbonic anhydrase (specifically CA-IV on the luminal membrane and CA-II intracellularly) catalyzes the formation of H+ and HCO3- from CO2 and water. Secreted H+ combines with filtered HCO3- in the tubular lumen to form H2CO3, which is dehydrated back to CO2 and water by luminal CA-IV — enabling bicarbonate reabsorption. Acetazolamide inhibits both CA-II and CA-IV, dramatically reducing proximal bicarbonate reabsorption. The resulting urinary bicarbonate loss (bicarbonaturia) depletes serum HCO3-, while Cl- is retained to maintain electroneutrality, producing hyperchloremic (normal anion gap) metabolic acidosis. This is why acetazolamide is used therapeutically for metabolic alkalosis correction.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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