Loop diuretics (furosemide) cause hypokalaemic metabolic alkalosis. Which mechanism BEST explains the metabolic alkalosis?

• A Furosemide directly inhibits renal H+/K+ ATPase in the collecting duct
• B Volume contraction raises aldosterone, which increases principal cell Na+ reabsorption; the resulting electronegativity of the tubular lumen drives H+ and K+ secretion by intercalated cells and principal cells respectively (contraction alkalosis + secondary hyperaldosteronism) ✓
• C Furosemide inhibits NKCC2, directly increasing bicarbonate reabsorption in the thick ascending limb
• D Loss of Cl– in urine allows a 1:1 gain of HCO3– in plasma to maintain electroneutrality

Explanation

Furosemide inhibits NKCC2 in the thick ascending limb, causing urinary loss of Na+, K+, Cl–, and water. The resulting volume contraction activates the RAAS; elevated aldosterone stimulates principal cells to reabsorb Na+ (with water following) and drives K+ and H+ secretion (via ROMK and H+-ATPase/H+,K+-ATPase in alpha-intercalated cells). This combination of H+ loss in urine and HCO3– retention produces contraction (metabolic) alkalosis with hypokalaemia. The chloride-depletion mechanism (option D) also contributes but is secondary to the RAAS activation.

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

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