Furosemide

Furosemide is the most widely used loop diuretic. It produces rapid, powerful diuresis and is used for acute pulmonary oedema, congestion in heart failure, oedema in liver and kidney disease, and sometimes hypertension in chronic kidney disease. It is cheap, available in oral and injectable forms in nearly every East African hospital, and is also used in cirrhosis with ascites and in nephrotic syndrome.

Classification. Loop diuretic (anthranilic acid derivative; sulphonamide).

Mechanism. Blocks the sodium potassium 2 chloride cotransporter in the thick ascending limb of the loop of Henle, reducing reabsorption of up to 25% of filtered sodium. It also increases venous capacitance within minutes of intravenous injection, which helps pulmonary oedema before diuresis starts.

Pharmacodynamics. IV onset within 5 minutes, peak at 30 minutes, duration 2 hours. Oral onset 30 to 60 minutes, peak at 1 to 2 hours, duration 6 to 8 hours. The dose response curve is steep: a minimum threshold dose is needed, and falling kidney function raises that threshold.

Pharmacokinetics. Oral bioavailability varies from 10 to 90% (average 50%), and falls in gut oedema. Half life about 1.5 hours (longer in kidney or heart failure, up to 9 hours). About 50% excreted unchanged in urine by tubular secretion, the rest by glucuronidation. Highly protein bound (over 95%).

Heart failure and chronic oedema, adult (oral).

• Start 20 to 40 mg once daily in the morning (40 mg if already on a diuretic).

• Increase by 20 to 40 mg every 1 to 2 days until the target weight is reached.

• Usual maintenance 40 to 80 mg daily; severe oedema up to 240 mg daily in 2 divided doses; maximum 600 mg daily under specialist care.

• Switch to twice daily dosing when a single dose gives rebound sodium retention.

Acute pulmonary oedema and acute decompensated heart failure, adult (IV).

• 40 mg IV slowly (not faster than 4 mg/minute); 80 mg if on long term loop diuretic or kidney impairment. For a patient already on oral furosemide, give an IV dose at least equal to the total oral daily dose.

• Repeat after 1 to 2 hours if the response is poor; double the dose each time to a maximum single dose of 200 mg.

• Continuous infusion: 5 to 10 mg/hour after a 40 mg loading dose, increased to 20 mg/hour; maximum 40 mg/hour; rate not above 4 mg/minute.

• Add a thiazide like diuretic (metolazone or hydrochlorothiazide) in resistance.

Ascites in cirrhosis (with spironolactone), adult. Furosemide 40 mg with spironolactone 100 mg once daily in the morning; adjust both together every 3 to 5 days in the same ratio, to a maximum of furosemide 160 mg and spironolactone 400 mg daily. Target weight loss 0.5 kg daily (1 kg daily with leg oedema).

Hypertension in kidney impairment, adult. 40 mg once or twice daily; twice daily dosing is needed because of the short duration.

Acute kidney injury with fluid overload, adult. 80 to 250 mg IV over 1 hour, then reassess at 6 hours; stop if there is no urine response.

Children. Oral 1 to 2 mg/kg for each dose, once or twice daily; maximum 6 mg/kg daily. IV 0.5 to 1 mg/kg for each dose every 6 to 12 hours; maximum 2 mg/kg for any single dose. Neonates: 0.5 to 1 mg/kg for each dose every 12 to 24 hours (longer intervals in preterm infants).

Contraindications. Anuria not responding to a test dose; severe hypovolaemia or dehydration; severe hypokalaemia or hyponatraemia; hepatic coma and precoma; hypersensitivity.

Warnings. Hypokalaemia, hyponatraemia, hypomagnesaemia, hypochloraemic alkalosis, hypocalcaemia, hyperuricaemia and gout, raised glucose. Hypovolaemia and acute kidney injury. Ototoxicity (tinnitus, deafness), mostly with rapid IV injection above 4 mg/minute, high doses, kidney impairment or other ototoxic drugs. Hepatic encephalopathy may be triggered in cirrhosis. Urinary retention in prostate enlargement. Nephrocalcinosis and patent ductus arteriosus in preterm infants.

Adverse effects. Hypokalaemia, hyponatraemia, hypotension, dehydration, dizziness, tinnitus, rash, photosensitivity, gout, rarely pancreatitis or blood dyscrasias.

Interactions.

• Aminoglycosides and cisplatin: more ototoxicity and nephrotoxicity.
• Digoxin: hypokalaemia raises toxicity.
• Lithium: raised levels.
• Non steroidal anti-inflammatory drugs: blunt diuretic effect and cause kidney injury.
• Angiotensin converting enzyme inhibitors and angiotensin receptor blockers: first dose hypotension and kidney injury in volume depleted patients.
• Corticosteroids, amphotericin B, and other diuretics: more potassium loss.
• Sucralfate reduces absorption (separate by 2 hours).
• QT prolonging drugs: hypokalaemia raises the risk of torsades.

Special groups.

• Pregnancy: avoid for hypertension or physiological oedema; may be used in pulmonary oedema or heart failure when needed; can reduce placental perfusion.

• Breastfeeding: small amounts in milk; may suppress lactation at high doses.

• Patients of African ancestry: no dose change; thiazide like diuretics are better for hypertension.

• Older adults: start at 20 mg; risk of dehydration, falls, hyponatraemia and urinary retention.

• Kidney impairment: higher doses are needed to reach the threshold (up to 250 mg IV); bolus rate must stay at or under 4 mg/minute; monitor hearing.

• Liver impairment: start low; correct potassium before and during use; combine with spironolactone to keep potassium up.

Formulations. Tablets 20, 40, 80 mg; oral solution 10 mg/mL; injection 10 mg/mL.

Administration. Oral in the morning (second dose early afternoon, not later than 16:00). IV: slow injection over 2 to 5 minutes (maximum 4 mg/minute); dilute in 0.9% sodium chloride for infusion; protect from light; do not mix with acidic solutions (precipitation); pH above 5.5 needed.

Baseline. Weight, blood pressure, volume status, sodium, potassium, magnesium, calcium, creatinine and eGFR, urate, glucose, hearing history.

Monitoring. Daily weight and fluid balance in hospital. Sodium, potassium, magnesium and creatinine 1 to 2 weeks after starting or each dose increase, then every 3 to 6 months. In acute use, check electrolytes and creatinine daily. Replace potassium when below 3.5 mmol/L (target 4.0 to 5.0 mmol/L). Stop or reduce if there is symptomatic hypotension, creatinine rise over 30%, or sodium below 125 mmol/L.

Stopping. Taper to the lowest dose that holds a stable weight. Hold on sick days with vomiting, diarrhoea or poor intake.

Common prescribing errors. Fast IV bolus above 4 mg/minute in kidney impairment (ototoxicity); starting too low in chronic loop diuretic users; giving without potassium monitoring; combining with an aminoglycoside without hearing monitoring; missing hypovolaemia; using furosemide alone for hypertension in preserved kidney function; mixing in glucose or acidic solutions.