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

Explanation

## Loop Diuretics: Mechanism of Action **Key Point:** Loop diuretics (furosemide, bumetanide, torsemide, ethacrynic acid) are the most potent diuretics because they inhibit the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2) on the apical membrane of the thick ascending limb (TAL) of the loop of Henle. ### Why the Thick Ascending Limb? The TAL is responsible for reabsorbing approximately 20–25% of filtered sodium and chloride. Blocking this transporter prevents the positive charge gradient needed for paracellular reabsorption of Mg²⁺ and Ca²⁺, making loop diuretics the only diuretics that **increase urinary calcium excretion** (calciuria). ### Comparison of Diuretic Classes | Diuretic Class | Site of Action | Transporter Blocked | Potency | K⁺ Effect | |---|---|---|---|---| | **Loop diuretics** | Thick ascending limb | Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2) | **Highest** | **↓ K⁺** (hypokalemia) | | Thiazides | Distal convoluted tubule | Na⁺-Cl⁻ cotransporter (NCC) | Moderate | ↓ K⁺ (hypokalemia) | | K⁺-sparing | Collecting duct | ENaC / aldosterone | Low | ↑ K⁺ (hyperkalemia) | | Carbonic anhydrase inhibitors | Proximal convoluted tubule | Carbonic anhydrase | Low | ↑ K⁺ (hyperkalemia) | **High-Yield:** Loop diuretics are the **first-line** diuretics for acute pulmonary edema, acute decompensated heart failure, and renal impairment (GFR < 30 mL/min) because thiazides become ineffective in severe renal dysfunction. **Clinical Pearl:** Loop diuretics cause **hypokalemia, hypomagnesemia, hypocalcemia, and hyperuricemia** — remember the mnemonic **"LAHH"** (Loop diuretics cause hypokalemia, hypomagnesemia, hypocalcemia, and hyperuricemia). ### Why Furosemide Is Preferred Furosemide is the most commonly used loop diuretic in clinical practice due to: - Rapid onset (oral: 1 hour, IV: 5 minutes) - Predictable dose-response relationship - Availability in multiple formulations - Minimal protein binding (97%) [cite:KD Tripathi 8e Ch 12]