Loop Diuretics

Mechanism of Action

Ion transport occurs in the nephron, the functional unit of the kidney, which performs three main functions: glomerular filtration, tubular reabsorption, and tubular secretion. These processes filter blood, remove waste via urine, and regulate ion and water levels in the body.

By Artwork by Holly Fischer - File:Kidney Nephron.png, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=150397160

Fig 1: structure of the nephron

The loop of Henle, part of the nephron, is responsible for approximately 25% of sodium reabsorption. It contains tubular cells with specific transporters:

• Na⁺/K⁺/Cl⁻ cotransporter: Reabsorbs sodium, potassium, and chloride from the tubular lumen into the cell in the ascending limb.
• Na⁺/K⁺ ATPase pump & chloride transporters: Move sodium and chloride from the tubular cell into the interstitial space.

This creates a high concentration of sodium and chloride in the interstitial space, drawing water from the descending limb. Calcium and magnesium are also reabsorbed via paracellular transport due to a positive charge gradient. These ions and water are then absorbed into the bloodstream.

Loop diuretics, like furosemide, inhibit the Na⁺/K⁺/Cl⁻ cotransporter in the ascending loop of Henle. This reduces sodium and chloride reabsorption, increases urinary excretion, and promotes distal potassium secretion. Calcium and magnesium excretion is also increased, making loop diuretics highly effective for inducing diuresis.

Other effects that furosemide elicits include:

• Reducing preload in heart failure by increasing venous capacitance
• Stimulating the renin-angiotensin-aldosterone system
• Upregulating endothelial prostaglandins

Furosemide lowers blood pressure via volume reduction, increased sodium excretion, and reduced vascular smooth muscle response to vasoconstrictors such as angiotensin II and noradrenaline. 

Kidney nephron molar transport diagram - File:Nephron-urine.svg - Wikipedia

Fig 2: Secretion and reabsorption of various substances throughout the nephron

Pharmacokinetics

Furosemide 40 mg is roughly equivalent to bumetanide 1 mg and both agents have similar pharmacokinetics. High-dose substitution should be avoided; it is preferrable to start at a lower dose and titrate gradually.

Loop diuretics are usually administered in the morning; if twice-daily dosing is needed, the second dose is given at lunchtime to avoid nocturia. The diuretic effect lasts 3–4 hours.

Loop diuretics are well absorbed orally, but furosemide can be used IV for rapid effect or if intestinal absorption is impaired, which can the case in patients with severe coronary heart failure with reduced intestinal perfusion.

*IM is only used in exceptional circumstances

Contraindications

Loop diuretics should not be initiated in patients with severe electrolyte disturbances, particularly marked hyponatraemia or hypokalaemia, as these agents can further exacerbate sodium and potassium depletion. Similarly, they are contraindicated in individuals with hypovolaemia or significant hypotension. In such cases, fluid and electrolyte imbalances must be corrected before treatment is started to avoid precipitating circulatory collapse or acute kidney injury.

Anuria represents an absolute contraindication, as loop diuretics require some residual renal function to exert their effect. Furosemide should also be avoided in patients with severe chronic kidney disease (eGFR <30 mL/min/1.73 m²) unless under specialist supervision. Loop diuretics are contraindicated in renal failure resulting from poisoning with nephrotoxic or hepatotoxic agents, and in hepatic cirrhosis associated with pre-coma or coma due to the risk of worsening hepatic encephalopathy.

Additional drug-specific contraindications must also be considered. Furosemide is contraindicated in patients with Addison’s disease and in those with digitalis toxicity, as electrolyte disturbances (particularly hypokalaemia and hypomagnesaemia) may increase the risk of arrhythmias.

Caution is warranted in patients with a known sulphonamide allergy (e.g. to co-trimoxazole or sulfasalazine), as cross-sensitivity reactions have been reported with furosemide and bumetanide. Furthermore, concomitant use of bumetanide with lithium salts is contraindicated due to the increased risk of lithium toxicity secondary to reduced renal clearance.

Cautions and Adverse Effects

Loop diuretics can cause: hyponatraemia, hypocalcaemia, hypomagnesemia, hypovolaemia, hypokalaemia, increased creatinine and blood urea, therefore it is important to monitor urea, creatinine and electrolytes during treatment. 

In patients with hypoproteinaemia, such as those with nephrotic syndrome, the exposure to furosemide may be reduced by approximately 30% due to decreased tubular secretion of furosemide due to binding to intratubular albumin. At the same time, reduced protein binding increases the concentration of free (unbound) furosemide in plasma, heightening the risk of ototoxicity. Careful dose titration and monitoring are therefore essential in this population.

Ototoxicity is a recognised adverse effect of loop diuretics, particularly with rapid intravenous administration of furosemide. Tinnitus and, in rare cases, irreversible deafness may occur. To minimise risk, intravenous furosemide should not be administered at a rate exceeding 4 mg per minute (or 2.5 mg per minute in severe renal impairment). Intramuscular administration is generally discouraged and reserved only for exceptional circumstances.

Caution is also required in patients with hepatic or renal impairment. In individuals with liver disease, diuretic-induced hypokalaemia may precipitate hepatic encephalopathy. Furosemide should be used cautiously in acute porphyria and may exacerbate or activate systemic lupus erythematosus. In patients with diabetes mellitus, loop diuretics may increase blood glucose levels and insulin requirements.

Elderly patients are particularly vulnerable to adverse effects, including hypotension, dehydration, falls, and worsening renal function. An increased risk of mortality has been reported when furosemide is used concomitantly with risperidone in older adults. Additional caution is warranted in patients at risk of urinary retention (such as those with benign prostatic hypertrophy), as increased urine output may precipitate acute retention.

Metabolic complications include hyperuricaemia, which may precipitate gout. Furosemide may also inhibit lactation in breastfeeding mothers. Rare but serious hypersensitivity reactions, including severe cutaneous adverse reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported and require immediate discontinuation of therapy.

Interactions

Loop diuretics can interact with drugs that:

Enhance hypotension:

• Antihypertensives, phenothiazines, MAOIs, TCAs

Increase risk of hypokalemia:

• Other diuretics, antipsychotics, amphotericin, salbutamol, tacrolimus, corticosteroids

Increase risk of cardiac toxicity in hypokalemia:

• Amiodarone, disopyramide, flecainide, sotalol, digoxin

Increase nephrotoxicity:

• NSAIDs, cisplatin

Increase ototoxicity:

• Aminoglycosides, vancomycin, cisplatin

Alter drug plasma concentrations:

• Ritonavir increases diuretic levels
• Phenobarbital reduces diuretic levels
• Sucralfate reduces furosemide absorption (administer 2 hours apart)
• Lithium levels increased by loop diuretics
• Furosemide undergoes significant renal tubular secretion so furosemide exposure may be affected by other drugs (or affect serum levels of these drugs) also undergoing this, such as methotrexate and probenecid. 

Other:

• Ciclosporin ↑ risk of hyperuricemia/gout

References

1. Diuretics | Treatment summaries | BNF | NICE accessed 24/2/25
2. Furosemide 40 mg tablets – Summary of Product Characteristics (SmPC) – (emc) last updated on emc: 04 Mar 2021. Accessed 24/2/25
3. Furosemide 10 mg/ml Solution for Injection – Summary of Product Characteristics (SmPC) – (emc) last updated on emc: 16 Oct 2024. Accessed 24/2/25
4. Diuretics | Prescribing information | Heart failure – chronic | CKS | NICE Last revised in August 2024. Accessed 24/2/25.
5. Bumetanide 5 mg Tablets – Summary of Product Characteristics (SmPC) – (emc) Last updated on emc: 29 Nov 2024. Accessed 24/2/25.
6. Bumetanide | Drugs | BNF | NICE accessed 25/2/25.
7. Furosemide | Drugs | BNF | NICE accessed 25/2/25.