A 68-year-old man with acute decompensated heart failure and pulmonary edema is admitted to the ICU. He is started on intravenous furosemide. The segment marked **B** in the nephron diagram is the primary site of action of this drug. Which of the following best describes the mechanism and clinical consequence of loop diuretic action at this site?

Explanation

## Why "Inhibition of Na+/K+/2Cl− cotransporter (NKCC2) leading to maximum urinary sodium loss and potassium depletion" is right Loop diuretics (furosemide, torsemide, bumetanide) act on the thick ascending limb of the loop of Henle (**segment B**) by inhibiting the Na+/K+/2Cl− cotransporter (NKCC2). This is the rate-limiting step for sodium reabsorption in the nephron, making loop diuretics the most potent class of diuretics. The inhibition of NKCC2 prevents reabsorption of sodium, potassium, and chloride, leading to massive urinary losses of sodium and secondary potassium depletion (hypokalemia). This mechanism is the foundation of their clinical efficacy in acute pulmonary edema and CHF, as described in Guyton & Hall 14e Ch 32 and KD Tripathi 9e Ch 41. ## Why each distractor is wrong - **"Inhibition of Na+/Cl− cotransporter in the distal convoluted tubule causing mild diuresis with calcium retention"**: This describes the mechanism of thiazide diuretics, which act on the DCT (segment C), not the thick ascending limb. Thiazides cause mild diuresis and paradoxically *increase* calcium reabsorption (hypercalcemia risk), opposite to loop diuretics. - **"Inhibition of aquaporin-2 channels in the collecting duct resulting in nephrogenic diabetes insipidus"**: This describes the mechanism of vasopressin antagonists (vaptans), not loop diuretics. Loop diuretics do not directly target aquaporin-2 channels. - **"Inhibition of H+/Na+ exchanger in the proximal convoluted tubule causing bicarbonate wasting and metabolic acidosis"**: This is not the mechanism of loop diuretics. The proximal tubule (segment A) reabsorbs sodium via the Na+/H+ exchanger, but loop diuretics do not act here; they act on segment B. **High-Yield:** Loop diuretics inhibit NKCC2 in the thick ascending limb → maximum natriuresis + hypokalemia + hypercalcemia risk (opposite of thiazides) + ototoxicity at high IV doses. [cite: Guyton & Hall 14e Ch 32; KD Tripathi 9e Ch 41]