Which diuretic acts by inhibiting the Na⁺-K⁺-2Cl⁻ cotransporter in the thick ascending limb of the loop of Henle?

Explanation

## Mechanism of Loop Diuretics **Key Point:** Loop diuretics (furosemide, bumetanide, torsemide, ethacrynic acid) inhibit the Na⁺-K⁺-2Cl⁻ (NKCC2) cotransporter located on the apical membrane of thick ascending limb cells. ### Site and Mechanism The thick ascending limb of the loop of Henle is the segment responsible for generating the corticomedullary osmotic gradient. By blocking NKCC2, loop diuretics: 1. Prevent reabsorption of ~25–30% of filtered sodium 2. Abolish the positive lumen potential that drives paracellular cation reabsorption 3. Reduce medullary hypertonicity, impairing water reabsorption in the collecting duct **High-Yield:** Loop diuretics are the most potent class and cause the greatest natriuresis; they work even when GFR is low (unlike thiazides). ### Comparison Table | Diuretic Class | Site of Action | Target | Potency | Key Feature | |---|---|---|---|---| | **Loop** | Thick ascending limb | NKCC2 cotransporter | Highest | Works at low GFR | | **Thiazide** | Distal convoluted tubule | NCC cotransporter | Moderate | Metabolic alkalosis | | **K⁺-sparing** | Collecting duct | ENaC / aldosterone | Low | Hyperkalemia risk | | **Carbonic anhydrase inhibitor** | Proximal tubule | Carbonic anhydrase | Low | Metabolic acidosis | **Clinical Pearl:** Furosemide is the most commonly used loop diuretic in clinical practice due to rapid onset (1 hour oral, 1 min IV) and reliable absorption. [cite:KD Tripathi 8e Ch 18]