Key Facts

Diuretics are fundamental drugs in the management of hypertension, heart failure, and fluid overload. Understanding their sites of action in the nephron, efficacy, and side effects is essential for safe prescribing.

Classification by Site of Action

• Loop diuretics: thick ascending limb (TAL) — Na/K/2Cl co-transporter (NKCC2); most potent
• Thiazides/thiazide-like: early distal convoluted tubule (DCT) — Na/Cl co-transporter (NCC)
• Potassium-sparing: collecting duct — aldosterone receptor (spironolactone, eplerenone) or ENaC (amiloride, triamterene)
• Carbonic anhydrase inhibitors: proximal tubule — acetazolamide
• Osmotic: entire nephron — mannitol

Pathophysiology

• Diuretics promote sodium and water excretion → ↓ intravascular volume → ↓ preload → ↓ BP/oedema
• Thiazides: additionally cause vasodilation (long-term mechanism for antihypertensive effect)
• Spironolactone: blocks aldosterone → prevents Na reabsorption, prevents K excretion
• Loop diuretics also impair concentrating ability → produce dilute, large-volume urine

Indications

• Hypertension: thiazide-like diuretics (Step 3 NICE NG136)
• Heart failure: loop diuretics (furosemide) for fluid overload; spironolactone for mortality benefit (RALES)
• Oedema: loop diuretics
• Ascites: spironolactone ± furosemide
• Resistant hypertension: spironolactone (PATHWAY-2)
• Nephrotic syndrome: furosemide + albumin for severe oedema
• Acute pulmonary oedema: IV furosemide 40–80 mg
• Raised ICP: mannitol 20% IV
• Glaucoma: acetazolamide

Side Effects

Loop diuretics:

• Hypokalaemia, hyponatraemia, hypomagnesaemia
• Dehydration, postural hypotension
• Ototoxicity (high-dose IV, especially with aminoglycosides)
• Hyperuricaemia → gout

Thiazides:

• Hypokalaemia, hyponatraemia (especially elderly — can cause confusion/seizures)
• Hyperuricaemia → gout
• Impaired glucose tolerance, hypercalcaemia, erectile dysfunction

Spironolactone:

• Hyperkalaemia (main risk — especially with ACE-i/ARB)
• Gynaecomastia, breast tenderness (anti-androgen effect — switch to eplerenone)
• Menstrual irregularity

Red Flags

• Severe hypokalaemia (<2.5 mmol/L) → arrhythmia risk → IV potassium replacement
• Severe hyponatraemia (<120 mmol/L) → confusion, seizures → fluid restrict, slow correction (risk of osmotic demyelination)
• Hyperkalaemia (>6.0 mmol/L) on spironolactone → ECG, stop K-retaining drugs, treat urgently
• AKI from dehydration → hold diuretic, IV fluids

Before Starting

• U&Es: baseline K+, Na+, creatinine — essential
• eGFR: thiazides less effective if eGFR <30 (switch to loop)
• Urate: if history of gout
• Glucose/HbA1c: if diabetic or at risk (thiazides)
• ECG: if on digoxin (hypokalaemia increases digoxin toxicity)

Monitoring

• U&Es: within 1–2 weeks of starting/changing; then 3–6 monthly
• Postural BP: in elderly — assess for dehydration/hypotension
• Weight: daily in heart failure — monitor fluid balance
• Fluid balance: input/output chart in inpatients

Special Tests

• Renin-aldosterone ratio: if resistant HTN — exclude primary aldosteronism before starting spironolactone
• Urine osmolality/sodium: if hyponatraemia — differentiate dilutional from depletional

Hypertension

• Indapamide 2.5 mg OD or chlortalidone 12.5–25 mg OD: Step 3 (NICE NG136)
• Preferred over bendroflumethiazide (more evidence, longer-acting)

Heart Failure

• Furosemide 20–80 mg OD-BD: for fluid overload; titrate to dry weight
• Spironolactone 25–50 mg OD: mortality benefit in HFrEF (RALES trial — 30% mortality reduction)
• Eplerenone 25–50 mg OD: alternative to spironolactone (less gynaecomastia); EPHESUS trial (post-MI HF)
• Metolazone 2.5–5 mg OD: added to loop diuretic for diuretic resistance — very potent; monitor closely

Ascites

• Spironolactone 100 mg OD (up to 400 mg): first-line — blocks aldosterone (secondary hyperaldosteronism in cirrhosis)
• Add furosemide 40 mg OD (up to 160 mg): if inadequate response
• Ratio: spironolactone:furosemide 100:40 mg — maintains K+ balance

Electrolyte Management

• Hypokalaemia prevention: co-prescribe K-sparing diuretic (amiloride) or oral potassium supplements with loop/thiazide
• Severe hypokalaemia: IV potassium (max 40 mmol/hour via central line; 10 mmol/hour peripheral)
• Hyponatraemia: restrict fluids; if drug-induced, consider switching/stopping thiazide

Referral Criteria

• Cardiology: heart failure management, diuretic resistance
• Nephrology: renal impairment, complex electrolyte disorders
• Endocrinology: suspected Conn's syndrome (primary aldosteronism)

• Thiazide diuretics in hypertension: reduce stroke by ~30%, MI by ~20% (ALLHAT)
• Spironolactone in HFrEF (RALES): 30% relative reduction in mortality
• Eplerenone post-MI with HF (EPHESUS): 15% relative mortality reduction
• Diuretic resistance in heart failure: combination therapy (loop + thiazide) can restore diuresis but carries high electrolyte risk
• Electrolyte disturbances: preventable with monitoring; can be fatal if unrecognised (hypokalaemia → arrhythmia)

Diuretic Comparison

Key Trials