A patient with hypertension on hydrochlorothiazide develops hypokalemia and metabolic alkalosis. The mechanism of thiazide-induced hypokalemia is:

• A Increased sodium delivery to the distal nephron activates aldosterone-driven Na+/K+ exchange in principal cells, increasing K+ secretion; thiazides also directly activate ROMK channels ✓
• B Thiazides directly block the K+ channel in principal cells of the collecting duct
• C Thiazides inhibit carbonic anhydrase, causing bicarbonaturia and obligate K+ loss
• D Volume depletion from thiazides causes SIADH with dilutional hypokalemia

Explanation

Thiazides block the NCC (Na+/Cl- cotransporter) in the distal convoluted tubule, reducing sodium reabsorption at that site. This increased sodium delivery to the aldosterone-sensitive principal cells of the cortical collecting duct enhances the electrogenic sodium reabsorption via ENaC, creating a lumen-negative potential difference that drives potassium secretion through ROMK channels. Additionally, volume depletion from thiazide use activates RAAS, raising aldosterone levels that further stimulate ENaC and ROMK, compounding K+ loss. Metabolic alkalosis accompanies hypokalemia because intracellular K+ depletion is balanced by intracellular H+ uptake and extracellular H+ loss.

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

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Written and medically reviewed by the StethoPrep medical team.