Diuretics — Classification by Nephron Site, Adverse Effects and Uses

The most useful way to learn diuretics is by their site of action along the nephron. Each segment reabsorbs sodium with a different transporter, so each class blocks a different protein and produces a predictable set of electrolyte changes. If you know the transporter, you can work out most of the adverse effects instead of memorising them.

Loop diuretics compete with chloride for the Na-K-2Cl (NKCC2) cotransporter on the apical membrane of the thick ascending limb. Blocking it stops sodium and chloride reabsorption. Because potassium can no longer recycle back into the lumen, the lumen-positive voltage that drives paracellular reabsorption is lost, so calcium and magnesium are lost in the urine too. That is why loop diuretics cause hypocalcaemia and hypomagnesaemia, while thiazides do the opposite with calcium.

• Uses: oedema of congestive heart failure, cirrhosis and renal disease including nephrotic syndrome; acute pulmonary oedema; hypertension with renal disease.
• Bioavailability: furosemide about 50%; bumetanide and torsemide close to 80%.
• Still effective at low GFR — loop diuretics keep working below 30 mL/min/1.73 m², which is why they are preferred in chronic kidney disease.

Thiazides block the Na⁺/Cl⁻ cotransporter in the proximal part of the distal convoluted tubule. Only about 3–5% of filtered sodium is reabsorbed there, so they are weaker diuretics than loop drugs but excellent long-term antihypertensives. Thiazide-like agents (chlorthalidone, indapamide, metolazone) have a different structure but the same mechanism.

Blocking Na-Cl entry increases flow through the basolateral Na⁺/Ca²⁺ exchanger, so more calcium is reabsorbed — thiazides lower urine calcium and raise serum calcium. This one fact explains two uses (recurrent calcium stones with hypercalciuria, and a bone-sparing effect) and one adverse effect (hypercalcaemia).

• Uses: primary hypertension (a first-line class), oedema of heart failure and cirrhosis, nephrogenic diabetes insipidus, recurrent calcium stones with high urine calcium.
• Kidney function: thiazides lose effect as GFR falls; chlorthalidone, metolazone and indapamide keep working below 30 mL/min/1.73 m².
• Combination with a loop diuretic gives strong diuresis but risks AKI, hypokalaemia and hypomagnesaemia.

Potassium-sparing diuretics act in the late distal tubule and collecting duct, where aldosterone drives sodium reabsorption through ENaC in exchange for potassium secretion. They give only a modest diuresis but retain potassium, so they are paired with loop or thiazide drugs or used for their hormonal effects.

Carbonic anhydrase in the proximal tubule lets the tubule reclaim filtered bicarbonate. Acetazolamide blocks it, so bicarbonate, sodium and water stay in the urine. The diuresis is weak and short-lived, but the drug produces a mild metabolic acidosis — and that, plus reduced fluid secretion in the eye and brain, explains almost all its uses.

• Glaucoma — reduces aqueous humour secretion; topical dorzolamide and brinzolamide, systemic acetazolamide. See primary glaucoma.
• Idiopathic intracranial hypertension — reduces CSF production.
• Acute mountain sickness — the metabolic acidosis counters the respiratory alkalosis of hyperventilation.
• Urine alkalinisation — helps dissolve uric acid and cystine stones (but may promote calcium stones).
• Other: centrencephalic epilepsy, oedema of heart failure.

Mannitol is a six-carbon sugar that is freely filtered and poorly reabsorbed. It stays in the tubule and holds water with it by osmosis. Given intravenously, it also raises plasma osmolality and draws water out of brain and eye tissue — the basis of its two approved uses: reducing raised intracranial pressure from cerebral oedema and reducing intraocular pressure.

• Dose for ICP or IOP: 0.25–2 g/kg IV over 30–60 minutes.
• Onset: ICP falls 15–30 minutes after the dose; the effect lasts 1.5–6 hours.
• Adverse effects: dehydration, precipitation of heart failure from the initial fluid shift into the circulation, electrolyte disturbance, and osmotic tubular injury (acute tubular necrosis).

1. Ototoxicity belongs to loop diuretics, not thiazides — and the risk multiplies with aminoglycosides. Ethacrynic acid is the worst offender.
2. Calcium moves in opposite directions: loop diuretics waste calcium (hypocalcaemia), thiazides retain it (stones, osteoporosis benefit, hypercalcaemia as an adverse effect).
3. Acetazolamide causes acidosis, every other main class (loop, thiazide) causes alkalosis; potassium-sparing drugs push potassium up and can cause hyperchloraemic acidosis.
4. Gynaecomastia points to spironolactone because it also binds androgen and progesterone receptors.
5. Thiazides treat a polyuric state — nephrogenic diabetes insipidus — even though they are diuretics.
6. Triamterene can cause kidney stones and megaloblastic anaemia; it should be avoided in patients with previous stones.
7. Mannitol in anuria or pulmonary oedema is the classic wrong answer: the drug cannot leave the circulation and expands plasma volume.
8. Carbonic anhydrase inhibitors in cirrhosis are the classic contraindication: they carry a risk of fulminant hepatic necrosis.