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Foundational Sciences · Pharmacology
Diuretics: Classes, Sites & Effects
A high-yield Step 1 walk down the nephron covering the five diuretic classes — their sites and molecular targets (carbonic anhydrase/PCT, NKCC2/loop, NCC/thiazide, aldosterone-receptor & ENaC/collecting duct, osmotic), signature toxicities, clinical uses, and the classic calcium and acid–base contrasts the boards test. Includes a full drug-comparison table, indication and toxicity vignettes, and the OH DANG / HyperGLUC mnemonics.
13 min readHigh yield
Overview: One Nephron, Five Classes
Diuretics are best learned as a walk down the nephron — each class reduces Na⁺ reabsorption at a specific segment, and the segment predicts both the potency and the signature electrolyte/acid–base derangement. From proximal to distal:
- Proximal convoluted tubule (PCT) — carbonic anhydrase inhibitors (acetazolamide) and, functionally, osmotic diuretics (mannitol).
- Thick ascending limb (TAL) — loop diuretics block the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2); the most powerful class.
- Early distal convoluted tubule (DCT) — thiazides block the Na⁺-Cl⁻ cotransporter (NCC).
- Cortical collecting duct — K⁺-sparing agents: aldosterone-receptor antagonists (spironolactone/eplerenone) and ENaC blockers (amiloride/triamterene).
Two unifying rules solve most Step 1 questions: (a) calcium — Loops Lose calcium, Thiazides reTain it; (b) acid–base — carbonic anhydrase inhibitors (proximal) and K⁺-sparing agents (collecting duct) cause a metabolic acidosis, while loops and thiazides cause a hypokalemic contraction alkalosis.
Must-Know Facts
- Acetazolamide — inhibits carbonic anhydrase in the PCT → loss of NaHCO₃⁻ → self-limited hyperchloremic (non-anion-gap) metabolic acidosis; also causes paresthesias.
- Loop diuretics (furosemide, bumetanide, torsemide) — block NKCC2 in the TAL; abolish the medullary concentration gradient and still work in renal failure. Signature toxicities: ototoxicity (worse with aminoglycosides), hypokalemic metabolic alkalosis, hypocalcemia/hypomagnesemia, and hyperuricemia/gout.
- Loops increase Ca²⁺ and Mg²⁺ excretion (loss of the lumen-positive potential) → used to treat hypercalcemia.
- Ethacrynic acid = the only non-sulfonamide loop → use in sulfa allergy, but it is more ototoxic.
- Thiazides (HCTZ, chlorthalidone) — block NCC in the early DCT; decrease Ca²⁺ excretion → used for calcium stones/idiopathic hypercalciuria and osteoporosis. Signature toxicities: hyponatremia, hypokalemic metabolic alkalosis, and "HyperGLUC" (↑glucose, ↑lipids, ↑uric acid, ↑calcium).
- Thiazides are paradoxically used in nephrogenic diabetes insipidus and lose efficacy at GFR < 30 (except metolazone).
- Spironolactone/eplerenone — competitive aldosterone-receptor antagonists; reduce mortality in HFrEF (spironolactone, RALES). Toxicity: hyperkalemia and, for spironolactone, gynecomastia/antiandrogen effects.
- Amiloride/triamterene — block the epithelial Na⁺ channel (ENaC); cause hyperkalemia; amiloride treats lithium-induced nephrogenic DI.
- Sulfa cross-reactivity: acetazolamide, loops (except ethacrynic acid), and thiazides.
- NSAIDs blunt diuretic efficacy by inhibiting prostaglandin-mediated renal blood flow.
Drug-by-Drug Comparison
| Drug (class) | MOA / site | Main clinical use | Key toxicity |
|---|---|---|---|
| Acetazolamide (carbonic anhydrase inhibitor) | Blocks carbonic anhydrase in PCT → ↓HCO₃⁻ reabsorption | Glaucoma, altitude/mountain sickness, idiopathic intracranial HTN (pseudotumor cerebri), metabolic alkalosis, urine alkalinization | Hyperchloremic metabolic acidosis (type 2 RTA–like), paresthesias, Ca–phosphate stones, sulfa allergy |
| Furosemide / bumetanide / torsemide (loop) | Block NKCC2 in thick ascending limb | Acute pulmonary edema, CHF/edema, HTN, hypercalcemia | Ototoxicity, Hypokalemia, hypocalcemia, hypomagnesemia, metabolic alkalosis, hyperuricemia/gout, sulfa allergy, interstitial nephritis |
| Ethacrynic acid (loop, non-sulfa) | Blocks NKCC2 (non-sulfonamide) | Loop diuresis in sulfa allergy | Same as loops but markedly more ototoxic |
| Hydrochlorothiazide / chlorthalidone (thiazide) | Block NCC in early DCT | HTN, CHF, calcium stones, nephrogenic DI, osteoporosis | HyperGLUC (↑Glucose, ↑Lipids, ↑Uric acid, ↑Calcium), hypokalemia, hyponatremia, metabolic alkalosis, sulfa allergy |
| Spironolactone / eplerenone (K⁺-sparing) | Aldosterone-receptor antagonist, collecting duct | Hyperaldosteronism (Conn), HFrEF (↓mortality), cirrhotic ascites | Hyperkalemia, metabolic acidosis, gynecomastia/antiandrogen (spironolactone) |
| Amiloride / triamterene (K⁺-sparing) | Block ENaC in collecting duct | K⁺-sparing add-on; Li⁺-induced nephrogenic DI (amiloride) | Hyperkalemia, metabolic acidosis |
| Mannitol (osmotic) | ↑Tubular fluid osmolarity (PCT + thin descending limb) | ↑ICP/cerebral edema, acute glaucoma | Pulmonary edema/volume overload, dehydration; contraindicated in anuria & CHF |
Indication Vignettes → Drug
- A trekker at 4,000 m develops headache, nausea, and dyspnea; a prophylactic agent that also causes finger tingling and a bicarbonate-wasting acidosis → acetazolamide.
- A patient with acute decompensated heart failure has bibasilar crackles and pink frothy sputum; the IV diuretic of choice for rapid decongestion/preload reduction → furosemide (loop).
- A woman with recurrent calcium oxalate stones and hypercalciuria needs a diuretic that lowers urinary calcium → thiazide (HCTZ).
- A cirrhotic with tense ascites and secondary hyperaldosteronism needs the first-line diuretic that also spares potassium → spironolactone.
- A comatose patient with a traumatic brain injury and rising intracranial pressure → mannitol.
- A bipolar patient on lithium develops polyuria and dilute urine unresponsive to ADH; add an ENaC blocker → amiloride.
Toxicity Vignettes → Drug
- An elderly CHF patient given a high-dose IV diuretic develops acute hearing loss/tinnitus — think loop diuretic (worst with ethacrynic acid or when combined with aminoglycosides).
- A hypertensive man on chronic therapy develops tender bilateral breast enlargement and decreased libido → spironolactone (antiandrogen effect).
- A patient started on an antihypertensive develops hyperglycemia, a gout flare, and hyponatremia → thiazide.
- A patient on a "potassium-sparing" agent has peaked T waves and a serum K⁺ of 6.5 → K⁺-sparing diuretic (spironolactone / amiloride) causing hyperkalemia.
- A glaucoma patient develops perioral/finger paresthesias and a non-anion-gap metabolic acidosis → acetazolamide.
The Classics (Worth Memorizing)
- Loop toxicity — "OH DANG!": Ototoxicity · Hypokalemia · Dehydration · Allergy (sulfa) · Nephritis (interstitial) · Gout (hyperuricemia).
- Thiazide toxicity — "HyperGLUC": hyperGlycemia · hyperLipidemia · hyperUricemia · hyperCalcemia.
- Calcium handling: "Loops Lose calcium, Thiazides reTain calcium."
- Ethacrynic acid = the loop for the sulfa-allergic patient (only non-sulfonamide loop).
Synthesis & Exam Pearls
Anchor every question on site → consequence:
- Potency tracks proximity to the TAL: loops are strongest because they hit the segment that reabsorbs ~25% of filtered Na⁺ and builds the medullary gradient.
- Calcium is the classic distractor: a patient with hypercalcemia gets a loop (Ca-wasting); a patient with calcium stones/osteoporosis gets a thiazide (Ca-retaining).
- Acid–base: acetazolamide and K⁺-sparing agents → metabolic acidosis; loops and thiazides → hypokalemic metabolic alkalosis.
- Potassium splits the field: loops and thiazides waste K⁺ (→ hypokalemia, consider adding a K⁺-sparing agent), whereas spironolactone/amiloride/triamterene retain K⁺ (→ hyperkalemia — dangerous with ACE inhibitors/ARBs).
- Special reversals: thiazides treat nephrogenic DI; amiloride treats lithium-induced nephrogenic DI; spironolactone/eplerenone improve survival in heart failure.
- Renal function: loops still work in advanced CKD; thiazides fail once GFR < 30 (except metolazone).
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