loop diuretic

Mechanism: Loop diuretics block the NKCC2 transporter on the apical membrane of the thick ascending limb of the loop of Henle, preventing reabsorption of Na+, K+, and Cl-. This disrupts the countercurrent multiplier system, impairing the kidney's ability to concentrate urine, and results in significant loss of Na+, K+, Cl-, Ca2+, and Mg2+ in the urine. Because Ca2+ and Mg2+ reabsorption in this segment is driven by the lumen-positive potential generated by K+ recycling (via ROMK channels), loop diuretics cause hypocalcemia and hypomagnesemia—contrasting with thiazides which cause hypercalcemia.

Clinical uses: Acute decompensated heart failure and pulmonary edema (rapid preload reduction via venodilation plus diuresis), edema from cirrhosis or nephrotic syndrome, hypertension (less first-line than thiazides), hyperkalemia (increased K+ excretion), and hypercalcemia (increased Ca2+ excretion, useful in malignancy-associated hypercalcemia).

Adverse effects (mnemonic: OH DANG): Ototoxicity (especially with aminoglycosides or ethacrynic acid), Hypokalemia, Dehydration, Allergy (sulfa allergy cross-reactivity, except ethacrynic acid), Nephritis (interstitial), Gout (hyperuricemia due to competition for uric acid secretion), and metabolic alkalosis (contraction alkalosis plus increased H+ secretion in collecting duct due to hyperaldosteronism from volume depletion).

Pharmacokinetics: Loop diuretics act on the luminal side and require secretion into the tubule via organic anion transporters; their efficacy is reduced in renal failure due to competition with uremic toxins, often requiring higher doses. Ethacrynic acid is a non-sulfonamide alternative for patients with sulfa allergies.

Key associations: Loop diuretics are the most potent diuretics because the thick ascending limb reabsorbs about 20-25% of filtered Na+ (compared to ~5% for the distal tubule where thiazides act). Torsemide has more predictable oral bioavailability than furosemide. Furosemide can cause a sulfonamide-like allergic reaction. Bartter syndrome mimics chronic loop diuretic use due to a genetic NKCC2 mutation.