Loop Diuretics

Loop diuretics block the sodium-potassium-chloride cotransporter in the thick ascending limb of the loop of Henle, producing the strongest diuresis of any class. They are used for congestion in heart failure, cirrhosis, nephrotic syndrome and kidney disease, for acute pulmonary oedema, and as short-term adjuncts in hypercalcaemia and hyperkalaemia.

Members. Furosemide, bumetanide, torasemide and ethacrynic acid (the only non-sulphonamide loop diuretic).

Mechanism. Blockade of the luminal cotransporter prevents reabsorption of up to 25% of filtered sodium, reduces the lumen-positive potential that drives calcium and magnesium reabsorption, and impairs urinary concentration. Intravenous furosemide also dilates veins within minutes, reducing preload before diuresis starts. Prostaglandin synthesis supports their effect, which NSAIDs blunt.

Delivery to the tubule. Drugs are highly protein bound and reach the lumen through organic anion transporters. The threshold dose rises with falling eGFR, so patients with kidney disease need higher doses. Beyond the ceiling dose there is no extra effect, only more toxicity.

Pharmacokinetics. Furosemide oral bioavailability is 10% to 90% (average about 50%) and falls with gut oedema, with a half-life of 1 to 2 hours. Bumetanide and torasemide have bioavailability of 80% to 100%. Torasemide has a longer duration of action. About 40 mg of oral furosemide is equivalent to 20 mg of torasemide or 1 mg of bumetanide.

• Furosemide: most widely used; oral and intravenous.
• Bumetanide: about 40 times more potent by weight; predictable absorption.
• Torasemide: predictable absorption and longer action; also weak aldosterone-antagonist effect.
• Ethacrynic acid: for sulphonamide allergy; greater ototoxicity.

• Acute pulmonary oedema: furosemide 40 mg intravenously (or 1 to 2.5 times the home oral dose), at no more than 4 mg/minute, with oxygen and, if blood pressure allows, nitrates. Check response within 2 hours: urine sodium over 50 to 70 mmol/L and urine output over 100 to 150 mL/hour in the first 6 hours. If inadequate, double the dose, then consider an infusion of 5 to 40 mg/hour.
• Chronic heart failure congestion: furosemide 20 to 80 mg daily or twice daily, torasemide 5 to 20 mg daily, bumetanide 0.5 to 2 mg daily (maximum 10 mg daily). Use the lowest dose that keeps euvolaemia.
• Chronic kidney disease with oedema: furosemide 40 to 80 mg or more orally, titrated to response. Add metolazone or a thiazide-like drug for resistance.
• Cirrhotic ascites: furosemide 40 mg daily with spironolactone 100 mg daily, scaled to a maximum of 160 mg and 400 mg.
• Hyperkalaemia with volume overload: furosemide 40 to 80 mg intravenously.
• Hypercalcaemia: after rehydration, 20 to 40 mg intravenously if volume overloaded.
• Selection: prefer torasemide or bumetanide when gut oedema makes furosemide absorption unreliable. Use ethacrynic acid for confirmed severe sulphonamide allergy.

Contraindications. Anuria, severe hypovolaemia, severe hypokalaemia or hyponatraemia, hepatic coma, and allergy to the drug.

Adverse effects. Volume depletion and hypotension, hypokalaemia, hypomagnesaemia, hyponatraemia, hypocalcaemia, metabolic alkalosis, hyperuricaemia and gout, glucose intolerance, rash and interstitial nephritis. Ototoxicity (tinnitus, deafness) occurs with rapid intravenous doses, renal impairment, high doses and aminoglycoside co-treatment, and is greatest with ethacrynic acid. In premature infants, loop diuretics cause nephrocalcinosis and keep the ductus arteriosus open.

Interactions. Aminoglycosides and cisplatin (ototoxicity and nephrotoxicity), NSAIDs and probenecid (reduced delivery), lithium (raised levels), digoxin (hypokalaemia toxicity), ACE inhibitors and angiotensin receptor blockers (first-dose hypotension and kidney injury), sucralfate (reduced absorption), and corticosteroids (potassium loss).

Monitoring. Daily weight, fluid balance, blood pressure, sodium, potassium, magnesium, creatinine and urea. A weight loss goal of 0.5 to 1 kg daily in oedema.

Referral and escalation. Failure to respond to doubled intravenous doses, rising creatinine with refractory congestion, or severe electrolyte disturbance needs senior review and consideration of ultrafiltration.

Special groups. Pregnancy: avoid unless pulmonary oedema. Children: furosemide 1 to 2 mg/kg intravenously. Neonates: 1 mg/kg with extended dosing intervals. Older adults: start low. Renal impairment: higher doses needed. Cirrhosis: avoid excessive diuresis because of encephalopathy and hepatorenal syndrome.