A patient is taking spironolactone for heart failure. Its mechanism of action is best described as:

• A Blockade of the Na-K-2Cl cotransporter (NKCC2) in the thick ascending limb
• B Inhibition of the Na-Cl cotransporter in the distal convoluted tubule
• C Direct blockade of epithelial sodium channels (ENaC) independent of aldosterone
• D Competitive inhibition of aldosterone at cytosolic mineralocorticoid receptors in the principal cells of the collecting duct, preventing ENaC and ROMK expression ✓

Explanation

Spironolactone and eplerenone are aldosterone receptor antagonists that competitively block mineralocorticoid receptors in the principal cells of the collecting duct. Aldosterone normally drives transcription of ENaC (apical sodium channel) and ROMK (apical K+ channel) and Na+/K+-ATPase (basolateral), promoting sodium retention and potassium excretion. Blocking this causes natriuresis and potassium retention (hyperkalemia risk). In heart failure, RAAS overactivation makes aldosterone blockade particularly effective. Amiloride blocks ENaC directly.

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

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Written and medically reviewed by the StethoPrep medical team.