Diuretics

Diuretics increase urine output by inhibiting solute (mainly Na⁺) reabsorption along the nephron, dragging water with it. They are the backbone of therapy in hypertension, oedematous states (heart failure, cirrhosis, nephrotic syndrome) and several niche conditions (glaucoma, idiopathic intracranial hypertension, nephrolithiasis). For NEET PG, the single most rewarding strategy is to anchor every drug to its nephron site of action, then predict its electrolyte and acid–base footprint from that site.

Classification by nephron site

Sodium is reabsorbed sequentially: ~65% in the proximal convoluted tubule (PCT), ~25% in the thick ascending limb of Henle (TAL), ~5–7% in the distal convoluted tubule (DCT) and ~2–3% in the collecting duct (CD). The more proximal the block, the greater the theoretical natriuresis — but downstream segments compensate. This is why loop diuretics (TAL, the "high-ceiling" agents) are the most powerful, not the proximally acting carbonic anhydrase inhibitors.

Class	Site	Molecular target	Diuretic potency	Prototype
Carbonic anhydrase inhibitors	PCT	Carbonic anhydrase	Weak	Acetazolamide
Osmotic diuretics	PCT, descending limb	Osmotic effect (no transporter)	Moderate	Mannitol
Loop ("high-ceiling")	TAL	Na⁺-K⁺-2Cl⁻ (NKCC2) cotransporter	Highest	Furosemide
Thiazides / thiazide-like	DCT	Na⁺-Cl⁻ (NCC) cotransporter	Moderate	Hydrochlorothiazide
K⁺-sparing — aldosterone antagonists	CD principal cell	Mineralocorticoid receptor	Weak	Spironolactone
K⁺-sparing — ENaC blockers	CD principal cell	Epithelial Na⁺ channel (ENaC)	Weak	Amiloride, triamterene
ADH antagonists (aquaretics)	CD	V2 receptor	Water only	Tolvaptan
SGLT2 inhibitors (newer)	PCT	SGLT2 (Na⁺-glucose)	Mild osmotic/natriuretic	Dapagliflozin

High-yield: Loop diuretics are "high-ceiling" because their dose–response curve keeps rising — they can excrete up to ~25% of filtered Na⁺. Thiazides have a low ceiling (max ~5%), so escalating the dose mainly increases toxicity, not effect.

Loop diuretics

Drugs: furosemide, torsemide, bumetanide, ethacrynic acid. Mechanism: Inhibit the NKCC2 cotransporter on the luminal membrane of the TAL → abolish Na⁺, K⁺, Cl⁻ reabsorption. By dissipating the lumen-positive transepithelial potential (normally driven by K⁺ back-leak through ROMK), they also abolish the paracellular reabsorption of Ca²⁺ and Mg²⁺.

Net effects: Loss of Na⁺, K⁺, Cl⁻, Ca²⁺ and Mg²⁺, plus H⁺ → hypokalaemic, hypochloraemic metabolic alkalosis with hypocalcaemia and hypomagnesaemia. They also impair the medullary concentration gradient, reducing urinary concentrating ability.

High-yield: Loops are the diuretic of choice in acute pulmonary oedema. IV furosemide also produces immediate venodilation (prostaglandin-mediated) that reduces preload before the diuretic effect begins — which is why NSAIDs blunt furosemide's action.

Pharmacokinetics: Heavily protein-bound; reach the lumen via organic anion transporters (OAT) in the PCT — so they act from the luminal side. Bioavailability of oral furosemide is erratic (~50%); torsemide and bumetanide have superior, more predictable absorption.

Adverse effects (mnemonic "OH DANG"):

• Ototoxicity (dose-related, usually reversible; worse with aminoglycosides; ethacrynic acid is the most ototoxic)
• Hypokalaemia / Hypomagnesaemia / Hypocalcaemia
• Dehydration / hypovolaemia, prerenal azotaemia
• Allergy / sulfa cross-reactivity (use ethacrynic acid in true sulfa allergy — it is the only non-sulfonamide loop)
• Nephritis (interstitial), Nocturia
• Gout (hyperuricaemia from competition at OAT) + hyperGlycaemia + hyperlipidaemia

Indications: acute pulmonary oedema, chronic heart failure with congestion, oedema of CKD/nephrotic syndrome (high doses needed), cirrhotic ascites (with spironolactone), hypertension in renal impairment, and hypercalcaemia ("loops lose calcium" — furosemide + saline).

Thiazides and thiazide-like diuretics

Drugs: hydrochlorothiazide, chlorthalidone, indapamide, metolazone (thiazide-like). Mechanism: Block the NCC (Na⁺-Cl⁻) cotransporter in the early DCT.

Electrolyte signature — the mirror image of loops for calcium:

• Hypokalaemia, hyponatraemia, hypochloraemic metabolic alkalosis, hypomagnesaemia
• Hypercalcaemia (enhanced distal Ca²⁺ reabsorption + volume contraction)
• Hyperuricaemia, hyperglycaemia, hyperlipidaemia, hypercalcaemia → the classic "hyper-GLUC" (Glucose, Lipids, Uric acid, Calcium) plus the "hypos" of Na/K.

Calcium contrast (very heavily tested): Loops → hypoCalcaemia (Ca lost in urine) → used to treat hypercalcaemia. Thiazides → hyperCalcaemia (Ca retained) → used to prevent recurrent calcium stones and in idiopathic hypercalciuria.

High-yield: Thiazides become ineffective when GFR falls below ~30 mL/min — switch to a loop diuretic in advanced CKD. Exception: metolazone retains efficacy in renal impairment and is used synergistically with a loop in diuretic-resistant oedema ("sequential nephron blockade").

High-yield: Thiazides are first-line for essential hypertension and reduce urinary calcium — hence useful in osteoporosis-prone, stone-forming patients. They also paradoxically reduce urine volume in nephrogenic diabetes insipidus (by inducing mild volume contraction and enhancing proximal reabsorption).

Indications: hypertension (preferred chlorthalidone/indapamide for longer action and outcome data), mild heart failure oedema, recurrent calcium nephrolithiasis, idiopathic hypercalciuria, and nephrogenic DI.

Potassium-sparing diuretics

These act on the cortical collecting duct principal cell and are weak diuretics but valuable for limiting K⁺ loss and blocking aldosterone.

1. Aldosterone (mineralocorticoid receptor) antagonists — spironolactone, eplerenone. Competitively block the intracellular MR → reduced synthesis of ENaC and Na⁺/K⁺-ATPase → mild natriuresis with K⁺ and H⁺ retention.

• Spironolactone is non-selective → gynaecomastia, menstrual irregularity, impotence (anti-androgenic). Eplerenone is selective → fewer endocrine effects.
• Mortality benefit in HFrEF (RALES, EPHESUS, EMPHASIS-HF trials).
• DOC for primary hyperaldosteronism (Conn syndrome) and for cirrhotic ascites (high circulating aldosterone makes it the first-line diuretic here).

2. ENaC blockers — amiloride, triamterene. Directly block the luminal ENaC, independent of aldosterone.

• Amiloride is used in Liddle syndrome (gain-of-function ENaC mutation), lithium-induced nephrogenic DI, and to offset thiazide-induced hypokalaemia.
• Triamterene can cause renal stones and a benign blue-green fluorescent urine.

High-yield: The dreaded shared toxicity of all K⁺-sparing agents is hyperkalaemia and hyperchloraemic metabolic acidosis — dangerous when combined with ACE inhibitors/ARBs, NSAIDs, or in renal failure. Spironolactone's classic exam toxicity is gynaecomastia.

Carbonic anhydrase inhibitors

Drug: acetazolamide (also dorzolamide/brinzolamide topically for glaucoma). Mechanism: Inhibit carbonic anhydrase in the PCT → reduced H⁺ generation → reduced Na⁺/H⁺ exchange → loss of HCO₃⁻, Na⁺ and K⁺ in urine.

Effects: Alkaline diuresis with hyperchloraemic metabolic acidosis; self-limiting natriuresis (tolerance develops within days as bicarbonate is depleted).

Indications (mnemonic "GAMA"): Glaucoma (reduces aqueous humour), Altitude (mountain) sickness prophylaxis (the metabolic acidosis stimulates ventilation), Metabolic alkalosis correction, and Alkalinisation of urine (for weak-acid overdose, e.g., aspirin, and to prevent uric-acid/cystine stones). Also useful in idiopathic intracranial hypertension and some periodic paralyses.

High-yield: Acetazolamide causes a normal anion gap (hyperchloraemic) metabolic acidosis, paraesthesias, renal stones (alkaline urine + reduced citrate) and may precipitate hepatic encephalopathy by alkalinising urine and increasing NH₃ reabsorption. It is a sulfonamide — avoid in sulfa allergy.

Osmotic diuretics

Drug: mannitol. Mechanism: Freely filtered, poorly reabsorbed solute that holds water osmotically in the tubule (and expands plasma volume acutely). Indications: raised intracranial pressure, acute glaucoma, prevention of oliguric acute kidney injury / rhabdomyolysis, and to promote excretion in some poisonings. Caution: Initial volume expansion can precipitate pulmonary oedema in heart failure — mannitol is contraindicated in established anuria and decompensated cardiac failure.

ADH antagonists and SGLT2 inhibitors

• Vaptans (tolvaptan, conivaptan): V2-receptor antagonists producing pure water diuresis ("aquaresis"); used in euvolaemic/hypervolaemic hyponatraemia (e.g., SIADH) and ADPKD. Risk: overly rapid sodium correction → osmotic demyelination.
• SGLT2 inhibitors (dapagliflozin, empagliflozin): block proximal glucose-coupled Na⁺ reabsorption → osmotic diuresis/natriuresis; landmark cardiovascular and renal protection in heart failure and CKD, now part of mainstream HF therapy.

Comparative electrolyte and acid–base table

Parameter	Loop	Thiazide	K⁺-sparing	CA inhibitor
Urinary Na⁺	↑↑↑	↑↑	↑	↑
Serum K⁺	↓	↓	↑	↓
Serum Ca²⁺	↓	↑	– / ↑	–
Serum Mg²⁺	↓	↓	↑	–
Uric acid	↑	↑	–	–
Acid–base	Metabolic alkalosis	Metabolic alkalosis	Metabolic acidosis (hyperchloraemic)	Metabolic acidosis (hyperchloraemic)
Urinary Ca²⁺	↑	↓	–	↑

Clinical use — choosing the right agent

A stepwise approach to the oedematous/hypertensive patient:

Essential hypertension → thiazide (chlorthalidone/indapamide preferred) → add ACEi/ARB or CCB → if resistant, add spironolactone (DOC for resistant hypertension).

Acute pulmonary oedema → IV loop (furosemide) for venodilation + diuresis → add oxygen, nitrates.

Chronic HFrEF → loop for symptom relief → add MRA (spironolactone/eplerenone) for mortality benefit → SGLT2 inhibitor + ARNI + beta-blocker.

Cirrhotic ascites → spironolactone first (counters secondary hyperaldosteronism) → add furosemide in ~100:40 (spironolactone:furosemide) ratio if inadequate.

Diuretic-resistant oedema → combine loop + metolazone (sequential nephron blockade); watch for profound hypokalaemia.

High-yield: In cirrhosis, spironolactone is preferred over a loop as the initial single agent because aldosterone is high; in heart failure, a loop is the symptomatic first choice but the MRA is added for survival benefit.

Drug interactions and resistance

• NSAIDs inhibit renal prostaglandins → blunt the action of loops and thiazides and worsen K⁺-sparing hyperkalaemia.
• Aminoglycosides + loops → additive ototoxicity and nephrotoxicity.
• Digoxin + K⁺-wasting diuretics → hypokalaemia potentiates digoxin toxicity.
• Lithium: thiazides reduce lithium clearance → toxicity; amiloride is the safe diuretic in lithium-induced nephrogenic DI.
• Diuretic braking/resistance: chronic loop use causes distal nephron hypertrophy and avid Na⁺ reabsorption; overcome with a thiazide-type add-on or continuous infusion.

Complications to recognise quickly

• Hyponatraemia — most classically with thiazides (impaired free-water excretion in elderly women).
• Hypokalaemia — loops and thiazides; precipitates arrhythmia, digoxin toxicity, hepatic encephalopathy.
• Hyperkalaemia — K⁺-sparing agents, especially with RAAS blockers.
• Metabolic alkalosis (contraction alkalosis) with loops/thiazides; metabolic acidosis with CA inhibitors and K⁺-sparing drugs.
• Hypovolaemia / prerenal AKI, ototoxicity (loops), gout flare, dysglycaemia.

Key differentials / "which diuretic" discriminators

• Hypercalcaemia treatment → loop (+ saline). Hypercalciuria/stone prevention → thiazide.
• Sulfa allergy needing a loop → ethacrynic acid.
• Metabolic alkalosis in a diuresing patient → acetazolamide can help correct it.
• Hyponatraemia from SIADH → tolvaptan (or fluid restriction), never a thiazide.
• Gynaecomastia in a man on diuretics → spironolactone → switch to eplerenone or amiloride.

Recently asked / exam angle

NEET PG and INI-CET commonly test:

• Site of action matching ("furosemide acts on…" → NKCC2 of TAL; thiazide → NCC of DCT).
• Calcium handling: loop → hypocalcaemia/hypercalciuria vs thiazide → hypercalcaemia/hypocalciuria. This single contrast appears almost every year.
• Acid–base pairing: which diuretic causes hyperchloraemic metabolic acidosis (acetazolamide, K⁺-sparing) vs metabolic alkalosis (loops, thiazides).
• Sulfa-free loop = ethacrynic acid; most ototoxic = ethacrynic acid.
• Spironolactone as DOC in Conn syndrome, resistant hypertension and cirrhotic ascites; its mortality benefit in HFrEF; gynaecomastia.
• Acetazolamide for acute mountain sickness and glaucoma; mechanism of alkaline diuresis.
• Amiloride in Liddle syndrome and lithium-induced nephrogenic DI.
• Mannitol mechanism and contraindication in pulmonary oedema/anuria.
• Metolazone retaining efficacy in renal failure and synergy with loops.
• Image/diagram questions on the nephron asking to label the transporter blocked by each class.

Rapid revision

1. Loop = NKCC2 (TAL); thiazide = NCC (DCT); K⁺-sparing = ENaC/MR (CD); acetazolamide = carbonic anhydrase (PCT).
2. Loops are high-ceiling (excrete up to 25% filtered Na⁺); thiazides are low-ceiling.
3. Loops → lose calcium (treat hypercalcaemia); thiazides → retain calcium (prevent Ca stones).
4. Loops and thiazides → hypokalaemic, hypochloraemic metabolic alkalosis; both cause hyperGLUC (glucose, lipids, uric acid + Ca for thiazides).
5. K⁺-sparing agents and acetazolamide → hyperchloraemic metabolic acidosis.
6. Ethacrynic acid = only non-sulfa loop and the most ototoxic.
7. Spironolactone: DOC for Conn syndrome, cirrhotic ascites, resistant hypertension; causes gynaecomastia; HFrEF mortality benefit (RALES).
8. Acetazolamide: glaucoma, altitude sickness, urine alkalinisation, metabolic alkalosis correction.
9. Amiloride: Liddle syndrome and lithium-induced nephrogenic DI.
10. Metolazone works in renal failure and synergises with loops (sequential nephron blockade).
11. Thiazide first-line for essential hypertension; ineffective when GFR <30 → use a loop.
12. Mannitol contraindicated in pulmonary oedema and anuria; tolvaptan (V2 antagonist) for SIADH hyponatraemia.