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[Physiology](https://durgical.com/en/physiology/) · [Renal, fluids and acid–base](https://durgical.com/en/physiology/#s-renal)

# Where and how diuretics act

- Mechanism
- Exam priority: high

Each diuretic blocks a salt transporter in one stretch of the nephron. Knowing where it acts predicts how much urine forms and which electrolytes are lost.

Updated 2026-11-01

Also called: Diuretic sites of action, Natriuretics

**See it in 3D:** [Kidneys](https://durgical.com/en/anatomy/kidney/)

## Key points

- Proximal: carbonic anhydrase inhibitors (acetazolamide) → lose HCO₃⁻: hyperchloremic metabolic acidosis; used in altitude sickness.
- Loop: furosemide and relatives block NKCC2 → the most potent; hypokalemia, alkalosis, hypomagnesemia, more urinary calcium.
- Distal: thiazides block NCC → hypokalemia, hyponatremia, less urinary calcium (mild hypercalcemia), high uric acid and glucose.
- Collecting duct: mineralocorticoid receptor antagonists (spironolactone) and ENaC blockers (amiloride) → spare K⁺: risk of hyperkalemia.
- Every diuretic acting before the collecting duct increases K⁺ and H⁺ loss (more Na⁺ and flow in the collecting duct).
- Mannitol (osmotic) holds water in the lumen; SGLT2 inhibitors cause glycosuria and mild natriuresis.

## What it is

Diuretics increase sodium excretion (and water with it) by blocking a transporter in a specific nephron segment. Their strength depends on how much Na⁺ that segment reabsorbs and on whether later segments can compensate. Their side effects follow from the transporter blocked and from what reaches the collecting duct.

## How it works, step by step

- The drug reaches the tubular lumen (most are secreted in the proximal tubule by organic anion or cation transporters).
- It blocks its segment's Na⁺ transporter, and that Na⁺ stays in the lumen with the water that goes with it.
- Later segments recover part of the extra Na⁺, which is why proximal agents are weak and loop agents strong.
- More Na⁺ and flow reach the collecting duct: ENaC reabsorbs more, the lumen becomes more negative and K⁺ and H⁺ secretion rise.
- Volume contraction activates renin and aldosterone, which reinforce K⁺ loss and alkalosis.
- With chronic use, distal segments hypertrophy and retain more Na⁺ (resistance); combining sites of action overcomes it.

### The nephron: segments, transporters and diuretics

**Na⁺ reabsorbed** ≈ 65–70% **Water reabsorbed** ≈ 65–70%

#### Proximal tubule

- **What it does:** Reabsorbs ≈ 65–70% of filtered Na⁺ and water (isosmotically), nearly all glucose and amino acids, ≈ 80% of HCO₃⁻ and most K⁺ and phosphate. Secretes organic acids and bases (many drugs) and makes NH₄⁺ from glutamine.
- **Transporters:** NHE3 (Na⁺/H⁺) with carbonic anhydrase; SGLT2 (early segment, ≈ 90% of glucose) and SGLT1; NaPi-2a (phosphate); basolateral Na⁺/K⁺-ATPase.
- **Hormones:** Ang II stimulates NHE3 (more Na⁺ and HCO₃⁻: contraction alkalosis); PTH inhibits NaPi-2a (phosphaturia) and activates 1α-hydroxylase (active vitamin D).
- **Drugs:** Carbonic anhydrase inhibitors (1), SGLT2 inhibitors (2) and osmotic diuretics (3, with the thin descending limb).
- **Disorders:** Fanconi syndrome (loses glucose, amino acids, phosphate and HCO₃⁻); type 2 (proximal) renal tubular acidosis; familial renal glucosuria (SGLT2).

- Glomerulus and arterioles
- Proximal tubule
- Thin descending limb
- Thin ascending limb
- Thick ascending limb
- Distal convoluted tubule
- Collecting tubule and duct
- Juxtaglomerular apparatus (macula densa)
- Cortex
- Medulla
- Interstitial osmolality (≈ 300 → 1200 mOsm/kg)
- Diuretic site of action (no.)

Illustrative schematic drawn by Durgical (a long-loop juxtamedullary nephron); proportions and percentages are approximate and not for clinical decisions.

### The nephron: segments, transporters and diuretics

**Na⁺ reabsorbed** ≈ 25% **Water reabsorbed** 0%

#### Thick ascending limb of the loop of Henle

- **What it does:** Reabsorbs ≈ 25% of filtered Na⁺ but is impermeable to water: the diluting segment (fluid leaves at ≈ 100 mOsm/kg) and the engine of the medullary gradient. The lumen-positive potential drives paracellular Ca²⁺ and Mg²⁺ reabsorption.
- **Transporters:** Apical NKCC2 (Na⁺-K⁺-2Cl⁻); ROMK recycles K⁺ to the lumen; basolateral ClC-Kb with barttin; claudins 16 and 19 (paracellular path); Ca²⁺-sensing receptor.
- **Hormones:** ADH (V2) increases NaCl reabsorption; PTH increases Ca²⁺ reabsorption.
- **Drugs:** Loop diuretics (4): block NKCC2; Na⁺, K⁺, Ca²⁺ and Mg²⁺ are lost (hypokalemia, metabolic alkalosis, hypercalciuria).
- **Disorders:** Bartter syndrome (like a loop diuretic: hypokalemic alkalosis, hypercalciuria, high renin and aldosterone).

- Glomerulus and arterioles
- Proximal tubule
- Thin descending limb
- Thin ascending limb
- Thick ascending limb
- Distal convoluted tubule
- Collecting tubule and duct
- Juxtaglomerular apparatus (macula densa)
- Cortex
- Medulla
- Interstitial osmolality (≈ 300 → 1200 mOsm/kg)

Illustrative schematic drawn by Durgical (a long-loop juxtamedullary nephron); proportions and percentages are approximate and not for clinical decisions.

### The nephron: segments, transporters and diuretics

**Na⁺ reabsorbed** ≈ 5% **Water reabsorbed** 0%

#### Distal convoluted tubule

- **What it does:** Reabsorbs ≈ 5% of Na⁺; impermeable to water (keeps diluting). Actively reabsorbs Ca²⁺, under PTH control, and Mg²⁺.
- **Transporters:** NCC (Na⁺-Cl⁻ cotransporter); TRPV5 (Ca²⁺) with the basolateral Na⁺/Ca²⁺ exchanger; TRPM6 (Mg²⁺).
- **Hormones:** PTH (more Ca²⁺ reabsorption); aldosterone and Ang II in the late part.
- **Drugs:** Thiazides (5): block NCC; lower Ca²⁺ excretion (hypocalciuria) and cause hypokalemia and hyponatremia.
- **Disorders:** Gitelman syndrome (like a thiazide: hypokalemic alkalosis, hypomagnesemia, hypocalciuria). Gordon syndrome (pseudohypoaldosteronism type 2): the opposite, hypertension with hyperkalemia.

- Glomerulus and arterioles
- Proximal tubule
- Thin descending limb
- Thin ascending limb
- Thick ascending limb
- Distal convoluted tubule
- Collecting tubule and duct
- Juxtaglomerular apparatus (macula densa)
- Cortex
- Medulla
- Interstitial osmolality (≈ 300 → 1200 mOsm/kg)

Illustrative schematic drawn by Durgical (a long-loop juxtamedullary nephron); proportions and percentages are approximate and not for clinical decisions.

### The nephron: segments, transporters and diuretics

**Na⁺ reabsorbed** ≈ 2–5% **Water reabsorbed** variable (ADH)

#### Collecting tubule and duct

- **What it does:** Fine tuning: reabsorbs ≈ 2–5% of Na⁺, secretes K⁺ and H⁺ and reabsorbs water as ADH allows (urine from ≈ 50 to ≈ 1200 mOsm/kg). Principal cells handle Na⁺, K⁺ and water; intercalated cells handle acid–base.
- **Transporters:** Principal: ENaC, ROMK and BK (K⁺ secretion; BK is flow-driven), apical AQP2 (ADH) and basolateral AQP3/4. α-intercalated: H⁺-ATPase and H⁺/K⁺-ATPase (secrete acid). β-intercalated: pendrin (secrete HCO₃⁻). Inner medulla: urea transporters (ADH).
- **Hormones:** Aldosterone (more ENaC, ROMK, Na⁺/K⁺-ATPase and H⁺-ATPase); ADH via the V2 receptor → cAMP → AQP2 insertion; atrial natriuretic peptide curbs Na⁺ reabsorption.
- **Drugs:** ENaC blockers (6) and mineralocorticoid receptor antagonists (7): K⁺-sparing (risk of hyperkalemia). V2 receptor antagonists (8, vaptans): aquaretics.
- **Disorders:** Liddle syndrome (overactive ENaC: hypertension, hypokalemia, low renin and aldosterone); nephrogenic diabetes insipidus (V2 or AQP2, lithium); type 1 distal renal tubular acidosis (H⁺ secretion fails: urine pH > 5.5, hypokalemia, stones) and type 4 (hypoaldosteronism: hyperkalemia); SIADH (excess ADH).

- Glomerulus and arterioles
- Proximal tubule
- Thin descending limb
- Thin ascending limb
- Thick ascending limb
- Distal convoluted tubule
- Collecting tubule and duct
- Juxtaglomerular apparatus (macula densa)
- Cortex
- Medulla
- Interstitial osmolality (≈ 300 → 1200 mOsm/kg)

Illustrative schematic drawn by Durgical (a long-loop juxtamedullary nephron); proportions and percentages are approximate and not for clinical decisions.

## Diuretics by segment

| Class | Segment and target | Filtered Na⁺ blocked | Expected effects |
| --- | --- | --- | --- |
| [Carbonic anhydrase inhibitors](https://durgical.com/en/conditions/metabolic-alkalosis/) | Proximal tubule (carbonic anhydrase) | ≈ 3–5% net | Hyperchloremic acidosis, hypokalemia; altitude sickness, glaucoma |
| Osmotic (mannitol) | Proximal tubule and descending limb (water) | Variable | Water diuresis; lowers intracranial pressure |
| [Loop diuretics](https://durgical.com/en/conditions/hypokalaemia/) | Thick ascending limb (NKCC2) | Up to ≈ 20–25% | Hypokalemia, alkalosis, hypomagnesemia, hypercalciuria, ototoxicity |
| [Thiazides](https://durgical.com/en/conditions/hyponatraemia/) | Distal tubule (NCC) | ≈ 3–5% | Hypokalemia, hyponatremia, hypocalciuria, hyperuricemia, hyperglycemia |
| [Mineralocorticoid receptor antagonists](https://durgical.com/en/conditions/hyperkalaemia/) | Collecting duct (aldosterone receptor) | ≈ 1–2% | Hyperkalemia, acidosis; gynecomastia with spironolactone |
| [ENaC blockers](https://durgical.com/en/conditions/hyperkalaemia/) | Collecting duct (ENaC) | ≈ 1–2% | Hyperkalemia |

## Clinical notes

- Congestive heart failure: loop diuretics relieve edema; spironolactone also blocks the aldosterone that remodels the heart.
- Hypertension: thiazides are first line; sodium and potassium need watching, especially in older adults.
- Cirrhosis with ascites: spironolactone is the backbone because aldosterone is very high.
- ACE inhibitors/ARBs + K⁺-sparing diuretics + kidney disease = a combination with high hyperkalemia risk.

## Memory aid

'Before the collecting duct, potassium goes; in the collecting duct, it stays': proximal, loop and thiazide diuretics lose K⁺; collecting duct agents spare it.

## Test yourself

Think of the answer, then tap the question to see it.

## Why are loop diuretics more potent than thiazides?

The thick limb reabsorbs ≈ 25% of filtered Na⁺ and later segments have little capacity to recover it; the distal tubule handles only ≈ 5%.

## Why can a thiazide cause hyponatremia while a loop diuretic rarely does?

The thiazide blocks the distal diluting segment but leaves the medullary gradient intact, so water is still reabsorbed with ADH. The loop diuretic destroys the gradient and reduces water reabsorption.

## Why can spironolactone cause hyperkalemia?

It blocks the aldosterone receptor in the principal cell: ENaC falls, the lumen becomes less negative and K⁺ secretion through ROMK decreases.

## Why does acetazolamide cause metabolic acidosis?

Inhibiting proximal carbonic anhydrase means filtered HCO₃⁻ is not reabsorbed and is lost in urine; plasma HCO₃⁻ falls and Cl⁻ replaces it.

[Add to my cards (4)](https://durgical.app/estudiar/?add=/en/physiology/where-and-how-diuretics-act/)

## See it in 3D

The structures of Durgical's 3D anatomy where it happens.

- [Kidneys](https://durgical.com/en/anatomy/kidney/)

## Related topics

- [Transport in the loop of Henle](https://durgical.com/en/physiology/transport-in-the-loop-of-henle/)
- [Distal tubule and collecting duct](https://durgical.com/en/physiology/distal-tubule-and-collecting-duct/)
- [Proximal tubule transport](https://durgical.com/en/physiology/proximal-tubule-transport/)
- [Potassium balance](https://durgical.com/en/physiology/potassium-balance/)
- [The countercurrent mechanism, urea recycling and urine concentration](https://durgical.com/en/physiology/the-countercurrent-mechanism-urea-recycling-and-urine-concentration/)
- [Heart failure physiology](https://durgical.com/en/physiology/heart-failure-physiology/)
- [Physiology of hypertension](https://durgical.com/en/physiology/physiology-of-hypertension/)

## Related conditions

- [Heart failure](https://durgical.com/en/conditions/heart-failure/)
- [Arterial hypertension](https://durgical.com/en/conditions/arterial-hypertension/)
- [Hypokalaemia](https://durgical.com/en/conditions/hypokalaemia/)
- [Hyperkalaemia](https://durgical.com/en/conditions/hyperkalaemia/)
- [Cirrhosis](https://durgical.com/en/conditions/cirrhosis/)
- [Metabolic alkalosis](https://durgical.com/en/conditions/metabolic-alkalosis/)
- [Hyponatraemia](https://durgical.com/en/conditions/hyponatraemia/)

## In Biochemistry

- [Aldosterone](https://durgical.com/en/biochemistry/molecules/aldosterone/)
- [Na⁺/K⁺-ATPase (sodium pump)](https://durgical.com/en/biochemistry/enzymes/na-k-atpase/)
- [Glucose](https://durgical.com/en/biochemistry/molecules/glucose/)

## In Pharmacology

- [ACE inhibitors](https://durgical.com/en/pharmacology/classes/ace-inhibitors/)
- [Angiotensin II receptor blockers (ARBs)](https://durgical.com/en/pharmacology/classes/angiotensin-ii-receptor-blockers/)

[← All of physiology](https://durgical.com/en/physiology/)

Educational physiology content; not a diagnostic or treatment guide and no substitute for a health professional's advice. Values are approximate references. No doses are given.

Sources: [25.6 Tubular Reabsorption](https://openstax.org/books/anatomy-and-physiology-2e/pages/25-6-tubular-reabsorption) (OpenStax (Rice University), 2022); [25.9 Regulation of Fluid Volume and Composition](https://openstax.org/books/anatomy-and-physiology-2e/pages/25-9-regulation-of-fluid-volume-and-composition) (OpenStax (Rice University), 2022); [Heart Failure (Congestive Heart Failure)](https://www.ncbi.nlm.nih.gov/books/NBK430873/) (StatPearls (NCBI Bookshelf), 2024); [Low blood potassium: MedlinePlus Medical Encyclopedia](https://medlineplus.gov/ency/article/000479.htm) (MedlinePlus, US National Library of Medicine, 2026); Hall JE. Guyton and Hall Textbook of Medical Physiology, 13th ed. (ch. 32). Reference book used to check facts; its text and figures are not reproduced (Elsevier, 2016).

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License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/physiology/where-and-how-diuretics-act/