Diuretics

Diuretics increase urinary sodium and water excretion and are used to remove excess fluid and lower blood pressure. They treat heart failure, cirrhosis, nephrotic syndrome, kidney disease and hypertension, and have specific uses in hypercalcaemia, hyperkalaemia, raised intracranial pressure, glaucoma and altitude illness.

Classification by site. Proximal tubule: carbonic anhydrase inhibitors and osmotic diuretics. Thick ascending limb: loop diuretics. Distal convoluted tubule: thiazide and thiazide-like diuretics. Collecting duct: potassium-sparing diuretics and mineralocorticoid receptor antagonists. Vasopressin receptor antagonists act as aquaretics.

Sodium handling. About 65% of filtered sodium is reabsorbed in the proximal tubule, 25% in the thick ascending limb, 5% in the distal convoluted tubule and 3% to 5% in the collecting duct. Loop diuretics therefore have the greatest ceiling effect.

Delivery to the site of action. Loop diuretics and thiazides are bound to protein and reach the tubule lumen through organic anion transporters, so low filtration and competition from NSAIDs and uraemic anions reduce effect.

Compensatory responses. After a dose, sodium retention rises (post-diuretic retention), the renin-angiotensin-aldosterone system and sympathetic system activate, and distal tubule cells hypertrophy. These explain the braking phenomenon and diuretic resistance.

Diuretic resistance. Causes: non-adherence, high sodium intake, NSAIDs, low glomerular filtration, gut oedema reducing absorption of oral drugs, and hypoalbuminaemia in nephrotic syndrome. Responses: switch to intravenous dosing, use bumetanide or torasemide for better bioavailability, raise the dose to reach the threshold, add a thiazide-like drug (sequential nephron blockade), or give a continuous infusion.

• Loop diuretics: furosemide 20 to 80 mg, bumetanide 0.5 to 2 mg, torasemide 5 to 20 mg daily.
• Thiazides and thiazide-like: hydrochlorothiazide 12.5 to 25 mg, chlortalidone 12.5 to 25 mg, indapamide 1.5 to 2.5 mg daily; metolazone 2.5 to 10 mg for sequential blockade.
• Potassium-sparing: amiloride 5 to 10 mg, triamterene 150 to 250 mg daily.
• Mineralocorticoid receptor antagonists: spironolactone 25 to 100 mg, eplerenone 25 to 50 mg daily.
• Carbonic anhydrase inhibitors: acetazolamide 250 to 500 mg.
• Osmotic: mannitol 0.25 to 1 g/kg intravenously.

• Heart failure congestion: loop diuretic titrated to euvolaemia, with an MRA and SGLT2 inhibitor added for prognosis.
• Hypertension: thiazide-like diuretic as first or second step. Loop diuretic when eGFR is under 30 mL/min/1.73 m2.
• Cirrhosis with ascites: spironolactone first, with furosemide added, in a ratio of 100 mg to 40 mg.
• Nephrotic syndrome and kidney disease: loop diuretic, with a thiazide-like drug for resistance, and albumin infusion in selected severe cases.
• Hypercalcaemia: only after rehydration, with furosemide 20 to 40 mg intravenously if volume overloaded.
• Hyperkalaemia with volume overload: furosemide 40 to 80 mg intravenously.
• Kidney stones with hypercalciuria: thiazide.
• Nephrogenic diabetes insipidus: thiazide or amiloride.
• Selection: pick by clinical question: volume removal (loop), long-term blood pressure (thiazide-like), potassium conservation (potassium-sparing or MRA), brain or eye pressure (osmotic or carbonic anhydrase inhibitor).

Contraindications. Anuria, severe hypovolaemia, hepatic coma, and severe electrolyte disturbance. Do not use diuretics to treat oedema of pre-eclampsia.

Adverse effects. Hypovolaemia and hypotension, acute kidney injury, hypokalaemia (loop and thiazide), hyperkalaemia (potassium-sparing and MRAs), hyponatraemia, hypomagnesaemia, hypocalcaemia (loop) or hypercalcaemia (thiazide), metabolic alkalosis, hyperuricaemia and gout, hyperglycaemia, and ototoxicity with loop diuretics.

Interactions. NSAIDs reduce effect and add kidney injury risk. ACE inhibitors, angiotensin receptor blockers and diuretics with an NSAID cause acute kidney injury. Lithium levels rise with thiazides. Hypokalaemia increases digoxin toxicity and QT-related arrhythmia. Aminoglycosides add oto- and nephrotoxicity.

Monitoring. Daily weight and fluid balance, blood pressure, sodium, potassium, magnesium, creatinine and urea 1 to 2 weeks after starting or changing the dose, then every 3 to 6 months.

Sick day rule. Withhold during vomiting, diarrhoea or dehydrating illness and restart when eating and drinking normally.

Special groups. Pregnancy: avoid routine use. Older adults: start low because of hyponatraemia, falls and hypovolaemia. Cirrhosis: limit weight loss to 0.5 kg daily without oedema and 1 kg daily with oedema. Neonates: prolonged half-life.