Diuretics compared by nephron segment — site, electrolytes and acid–base
Verified · Oct 2026Each diuretic blocks sodium reabsorption at one segment, and the segment predicts the drug: how strong it is, which electrolytes it wastes or keeps, and its signature adverse effects. Tolvaptan is the exception — it removes water, not sodium.
One nephron, five targets
The proximal tubule reabsorbs 60–70% of the filtered load, using NHE3 and carbonic anhydrase. The thick ascending limb reabsorbs 25–30% of filtered sodium through NKCC2. The distal convoluted tubule takes 5–10% through NCC, and ENaC in the collecting duct about 3%. Loops are the most potent diuretics because they block the largest share of sodium reabsorption; ENaC blockers and aldosterone antagonists are weak diuretics because their segment handles so little.
A large share does not guarantee a strong drug. Carbonic anhydrase inhibitors act on the proximal tubule, but distal segments reabsorb the extra sodium delivered to them, and the falling serum bicarbonate leaves less substrate for the enzyme, so the diuresis fades. Mannitol acts on no transporter: it is filtered and not reabsorbed, so it holds water in the tubule by osmosis.
Potassium follows the sodium delivered to the collecting duct. Loops and thiazides send more sodium there and activate renin–aldosterone, so the lumen-negative distal tubule traps potassium and H⁺ in the lumen, to be lost in the urine — hypokalemia and metabolic alkalosis. Potassium-sparing diuretics block ENaC or the aldosterone receptor, so potassium and H⁺ secretion fall — hyperkalemia and a hyperchloremic metabolic acidosis. Tolvaptan blocks the V2 receptor instead, increasing free-water excretion without significantly changing urinary sodium or potassium excretion.
Comparison
Site, target and strength
| Diuretic | Segment | Target | Share of filtered Na⁺ at that segment | Strength |
|---|---|---|---|---|
| Carbonic anhydrase inhibitors (acetazolamide) | Proximal tubule | Luminal and cellular carbonic anhydrase | 60–70% of the filtered load | Weak and self-limiting — distal segments compensate and bicarbonate substrate falls |
| Osmotic (mannitol) | Proximal tubule and thick ascending limb | No transporter: filtered, less than 10% reabsorbed | — | Osmotic water loss; also raises plasma osmolality |
| Loop (furosemide, bumetanide, torsemide) | Thick ascending limb | NKCC2 (chloride-binding site) | 25–30% | Most potent ("high-ceiling") |
| Thiazide (hydrochlorothiazide, chlorthalidone) | Distal convoluted tubule | NCC (chloride site) | 5–10% | Most lose effect at GFR below 30 (metolazone, chlorthalidone and indapamide keep it) |
| ENaC blockers (amiloride, triamterene) | Late distal tubule and collecting duct | ENaC (directly) | ~3% | Weak |
| Aldosterone antagonists (spironolactone, eplerenone) | Collecting duct principal cells | Cytoplasmic mineralocorticoid receptor (ENaC indirectly) | ~3% | Weak |
| Vaptan (tolvaptan) | Collecting duct | V2 receptor (aquaporin-2 not inserted) | — (water, not sodium) | Aquaresis: free-water excretion |
— = not applicable or not stated on the source pages.
Electrolytes and acid–base
| Diuretic | Serum K⁺ | Urinary Ca²⁺ | Mg²⁺ | Acid–base | Serum Na⁺ |
|---|---|---|---|---|---|
| Carbonic anhydrase inhibitors | ↓ (hypokalemia) | — | — | Hyperchloremic (normal anion gap) metabolic acidosis; alkaline urine | Hyponatremia possible |
| Mannitol | ↓ (hypokalemia) | — | — | — | Dilutional hyponatremia first, then hypernatremia with dehydration |
| Loop | ↓ (hypokalemia) | ↑ — calciuria (lumen-positive voltage lost) | ↓ (hypomagnesemia; cohort data question it) | Metabolic alkalosis (including contraction alkalosis) | Hyponatremia less common than with thiazides |
| Thiazide | ↓ (hypokalemia) | ↓ — calcium retained (up to 50% less in urine) | ↓ (NCC inhibition downregulates TRPM6) | Metabolic alkalosis | Hyponatremia more common (concentrating ability intact) |
| ENaC blockers | ↑ (hyperkalemia) | — | Amiloride reduces loop and thiazide magnesium loss | Hyperchloremic metabolic acidosis | — |
| Aldosterone antagonists | ↑ (hyperkalemia) | — | — | Hyperchloremic metabolic acidosis | — |
| Tolvaptan | Urinary K⁺ excretion not significantly changed; hyperkalemia can follow extracellular volume contraction | — | — | — | ↑ (free water removed) |
— = not stated on the source pages.
Signature adverse effects and uses
| Diuretic | Signature adverse effects | Main uses |
|---|---|---|
| Carbonic anhydrase inhibitors | Sulfonamide reactions; kidney stones (alkaline urine); hepatic encephalopathy in cirrhosis | Glaucoma, acute mountain sickness, idiopathic intracranial hypertension |
| Mannitol | Pulmonary edema in heart failure (volume expansion first); acute kidney injury | Raised intracranial or intraocular pressure (IV) |
| Loop | Ototoxicity; hyperuricemia; volume depletion | Heart failure and pulmonary edema; edema in CKD; symptomatic hypercalcemia |
| Thiazide | Hyponatremia; hyperglycemia; hyperuricemia | Hypertension; calcium stones with hypercalciuria; nephrogenic DI |
| ENaC blockers | Hyperkalemia; triamterene stones and folate antagonism | Diuretic-induced hypokalemia; Liddle syndrome |
| Aldosterone antagonists | Hyperkalemia; gynecomastia (spironolactone) | HFrEF; cirrhotic ascites; primary aldosteronism |
| Tolvaptan | Overly rapid sodium correction → osmotic demyelination; polyuria, nocturia and urinary frequency | Euvolemic or hypervolemic hyponatremia (not hypovolemic); ADPKD (Jynarque) |
High-yield
Practice questions
Q1A 68-year-old woman with hypertension and osteoporosis needs a diuretic. Her physician wants the class that lowers urinary calcium loss.
Which diuretic class and mechanism fit best?
- A.A loop diuretic, which blocks NKCC2 in the thick ascending limb
- B.A thiazide, which blocks NCC in the distal convoluted tubule
- C.An aldosterone antagonist, which blocks the mineralocorticoid receptor
- D.Acetazolamide, which blocks proximal-tubule carbonic anhydrase
- E.Mannitol, which raises tubular osmolarity
Show answer
B. A thiazide, which blocks NCC in the distal convoluted tubule — Thiazides block NCC and reduce urinary calcium by up to 50%: calcium is retained proximally after volume depletion and possibly distally. Loops do the opposite — blocking NKCC2 removes the lumen-positive voltage that drives paracellular calcium reabsorption, causing calciuria. Aldosterone antagonists act on the collecting duct and mainly spare potassium. Acetazolamide alkalinizes the urine, which favors kidney stones rather than protecting against calcium loss, and mannitol is an IV osmotic agent for raised intracranial or intraocular pressure, not a long-term antihypertensive.
Q2A 72-year-old man with heart failure takes furosemide and hydrochlorothiazide. His serum magnesium and potassium are both low despite supplements.
Adding which diuretic would also reduce his magnesium loss?
- A.Acetazolamide
- B.Bumetanide
- C.Mannitol
- D.Metolazone
- E.Amiloride
Show answer
E. Amiloride — Amiloride blocks ENaC in the late distal tubule and collecting duct, so less potassium and H⁺ are secreted, and it decreases the magnesium loss caused by thiazides and loops; ENaC blockers are used to correct diuretic hypokalemia and hypomagnesemia. Bumetanide is another loop diuretic and metolazone another thiazide-like drug, which would add to the losses; acetazolamide causes hypokalemia, and mannitol causes electrolyte losses of its own.
Q3A 70-year-old woman with heart failure is admitted with hyponatremia (serum sodium 123 mEq/L) and edema. The team wants a drug that removes free water without significantly changing urinary sodium and potassium excretion.
Which drug acts this way?
- A.Furosemide
- B.Hydrochlorothiazide
- C.Spironolactone
- D.Tolvaptan
- E.Acetazolamide
Show answer
D. Tolvaptan — Tolvaptan blocks the V2 receptor, so aquaporin-2 is not inserted: urine water excretion and free-water clearance rise and serum sodium increases, while urinary sodium and potassium excretion are not significantly changed; it is used for hypervolemic and euvolemic hyponatremia such as heart failure. Furosemide and hydrochlorothiazide are natriuretic and cause hypokalemia — thiazides are a common cause of hyponatremia — spironolactone retains potassium, and acetazolamide causes bicarbonate loss.
Q4A 64-year-old man is recovering in the ICU after cardiac surgery. After several days of aggressive loop diuresis he is still edematous, and his serum bicarbonate is 38 mEq/L with a chloride of 88 mEq/L.
Adding which diuretic would also lower his serum bicarbonate?
- A.Acetazolamide
- B.Hydrochlorothiazide
- C.Mannitol
- D.Tolvaptan
Show answer
A. Acetazolamide — Acetazolamide blocks proximal-tubule carbonic anhydrase, so bicarbonate is lost in the urine and serum bicarbonate falls — the logic behind its use to reverse metabolic alkalosis — and it also overcomes proximal reabsorption when a loop diuretic is not enough. A thiazide, like the loop, sends more sodium to the collecting duct and causes metabolic alkalosis. Mannitol expands the circulation before it is excreted and can precipitate pulmonary edema in heart failure, and tolvaptan removes free water without significantly changing urinary sodium or potassium excretion.
Sources
- Therapeutic Uses of Diuretic Agents — StatPearls (NCBI)
- Carbonic Anhydrase Inhibitors — StatPearls (NCBI)
- Acetazolamide — StatPearls (NCBI)
- Acetazolamide Tablets — FDA label — FDA / DailyMed
- Osmitrol (mannitol injection) — FDA label — FDA / DailyMed
- Thiazide Diuretics — StatPearls (NCBI)
- Hypercalciuria — StatPearls (NCBI)
- Metolazone tablets — FDA label — FDA / DailyMed
- Eplerenone — StatPearls (NCBI)
- Dyrenium (triamterene) — FDA label — FDA / DailyMed
- Physiology, Renin Angiotensin System — StatPearls (NCBI)
- Liddle Syndrome — StatPearls (NCBI)
- Hyponatremia — StatPearls (NCBI)
- Samsca (tolvaptan) — FDA label — FDA / DailyMed
- Jynarque (tolvaptan) — FDA label — FDA / DailyMed
- Methazolamide tablets — FDA label — FDA / DailyMed
- Mannitol — StatPearls (NCBI)
- Loop Diuretics — StatPearls (NCBI)
- Edecrin (ethacrynic acid) — FDA label — FDA / DailyMed
- Lasix (furosemide) — FDA label — FDA / DailyMed
- Ethacrynic Acid — StatPearls (NCBI)
- Resistant Hypercalcemia — StatPearls (NCBI)
- Hydrochlorothiazide — StatPearls (NCBI)
- Hydrochlorothiazide capsules — FDA label — FDA / DailyMed
- Thalitone (chlorthalidone) — FDA label — FDA / DailyMed
- Spironolactone — StatPearls (NCBI)
- Aldactone (spironolactone) — FDA label — FDA / DailyMed
- Inspra (eplerenone) — FDA label — FDA / DailyMed
- Amiloride — StatPearls (NCBI)
- Amiloride HCl tablets — FDA label — FDA / DailyMed
- Triamterene — StatPearls (NCBI)
- Hyperkalemia — StatPearls (NCBI)
- Desmopressin — StatPearls (NCBI)
- Physiology, Vasopressin — StatPearls (NCBI)
- Syndrome of Inappropriate Antidiuretic Hormone Secretion — StatPearls (NCBI)
- Vaprisol (conivaptan) — FDA label — FDA / DailyMed
Each class page compared lists its full sources; this page reuses facts verified there.
By LearnDrugs
Educational summary for medical students. Always verify against current prescribing information and guidelines. Not medical advice.