Acetazolamide causes a self-limiting diuresis because:

• A It is rapidly excreted by the kidney, losing its effect after a few doses
• B Aldosterone compensates by upregulating ENaC in the collecting duct
• C Tolerance develops through carbonic anhydrase enzyme upregulation
• D Bicarbonate depletion from proximal tubular inhibition leads to metabolic acidosis, reducing the substrate available for carbonic anhydrase and diminishing the bicarbonaturia driving diuresis ✓

Explanation

Acetazolamide inhibits carbonic anhydrase in the proximal tubule, preventing HCO3− reabsorption and causing bicarbonaturia with cation (Na+, K+) loss. However, as plasma bicarbonate falls (metabolic acidosis develops), less bicarbonate is filtered; once the tubular fluid is bicarbonate-depleted, there is no more substrate for the inhibited enzyme to process and the diuretic effect wanes. This is why acetazolamide is self-limiting and tachyphylaxis develops within 2-3 days of continuous use.

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

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