Bit · Pharm/Tox
Diuretics by Tubular Site of Action
Five classes of diuretic, each blocking a different transporter at a different nephron segment. Side effects fall out of which ions move where.
Mechanism
The nephron is a sequence of transporters; each diuretic class hits a different segment:
- Proximal tubule — Acetazolamide (carbonic anhydrase inhibitor). Loses HCO₃⁻ in urine → metabolic acidosis. Used for altitude sickness, glaucoma, alkalosis correction. Weak diuretic.
- Thick ascending limb — Loop diuretics (furosemide, bumetanide, torsemide, ethacrynic acid). Block Na⁺-K⁺-2Cl⁻ cotransporter. Most potent diuretic class. Disrupt the medullary gradient → impairs concentrating ability. Lose: Na, K, Ca, Mg, H⁺. Cause hypokalemic metabolic alkalosis, ototoxicity (especially with aminoglycosides), gout.
- Distal convoluted tubule — Thiazides (HCTZ, chlorthalidone, metolazone). Block Na⁺-Cl⁻ cotransporter. Lose Na, K, H⁺. Retain Ca²⁺ (paradoxically — used for nephrolithiasis). HHHHU — Hyperglycemia, Hyperlipidemia, Hyperuricemia, Hypercalcemia, hypoNatremia, Hypokalemia (and metabolic alkalosis). Cause SIADH-like hyponatremia.
- Collecting duct — K⁺-sparing diuretics. Two subtypes: aldosterone antagonists (spironolactone, eplerenone) block aldo receptor; epithelial Na⁺ channel blockers (amiloride, triamterene) block ENaC. All retain K⁺ → hyperkalemia risk. Spironolactone: antiandrogen effects (gynecomastia, ED).
- Osmotic — Mannitol. Filtered freely but not reabsorbed; pulls water in tubules. Used for ↑ ICP, oliguria, rhabdo. Causes pulmonary edema if too aggressive.
Differentiator Table
| Class | Site | Transporter | Net effect | Major adverse effects |
|---|---|---|---|---|
| Carbonic anhydrase inhibitor | Proximal tubule | Carbonic anhydrase | ↑ HCO₃⁻ excretion | Metabolic acidosis, hypokalemia, paresthesia, sulfa allergy |
| Loop diuretic | Thick ascending limb | NKCC2 (Na-K-2Cl) | Massive Na/water loss; ↑ urinary Ca | Hypokalemia, metabolic alkalosis, ototoxicity, hyperuricemia, hyperglycemia, dehydration |
| Thiazide | DCT | NCC (Na-Cl) | Moderate Na/water loss; ↓ urinary Ca | HHHHU mnemonic; hyponatremia; sulfa allergy |
| Aldosterone antagonist | Collecting duct (cortical) | Aldosterone receptor | Retain K; spare Na | Hyperkalemia, gynecomastia (spironolactone), menstrual irregularities |
| ENaC blocker | Collecting duct | ENaC | Retain K; mild Na loss | Hyperkalemia |
| Osmotic | Mostly PT and loop | No transporter; osmotic | Pulls water without ion loss | Pulmonary edema, hypernatremia |
The Pivot
Two questions decide most exam scenarios:
- What is the patient's potassium doing on the drug? Down → loop or thiazide. Up → K-sparing.
- What about calcium? Loop diuretic wastes Ca²⁺ — used in acute hypercalcemia. Thiazide retains Ca²⁺ — used in hypercalciuric stones.
NBME-Style Stem
A 64-year-old man with severe heart failure is started on a diuretic. Two weeks later he develops painful gynecomastia and is found to have serum K⁺ 5.9 mEq/L. Which of the following diuretics is most likely responsible?
Concept Anchor
Five nephron segments, five diuretics, five predictable electrolyte patterns. Knowing which transporter the drug blocks tells you both what it pees out and what it holds in.