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 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.

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

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

Pharmacokinetics

Furosemide and bumetanide have similar pharmacokinetics. Furosemide 40 mg is roughly equivalent to bumetanide 1 mg. High-dose substitution should be avoided; 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.

Contraindications

Loop diuretics are contraindicated in: 

• Severe electrolyte disturbances* (hyponatraemia or hypokalaemia) 
• Hypovolaemia and hypotension* 
• Addison’s disease (furosemide)
• Digitalis toxicity (risk of worsening hypokalaemia/hypomagnesaemia)
• Anuria 
• CKD <30mL/min/1.73 m² (furosemide)
• Liver cirrhosis associated with comatose and pre-comatose state 
• Renal failure resulting from poisoning by nephrotoxic and/or hepatotoxic agents
• Sulphonamide allergy (such as to co-trimoxazole or sulfasalazine) – possible cross-sensitivity with budesonide and furosemide
• Budesonide is contraindicated in patients taking lithium salts 

*These disturbances should be corrected before loop diuretics are started

Cautions and side effects

Monitor urea, creatinine and electrolytes during treatment. Loop diuretics can cause: hyponatraemia, hypocalcaemia, hypomagnesemia, hypovolaemia, hypokalaemia, increased creatinine and blood urea.

Other cautions:

• Hypoproteinemia increases risk of ototoxicity and reduces efficacy with furosemide, therefore careful dose titration is required (e.g. in nephrotic syndrome, bioavailability is reduced by around 30%). Ototoxicity risk is due to higher concentrations of free furosemide (not bound to protein), whereas the reduced efficacy is due to intratubular albumin and decreased tubular secretion.
• Rapid IV furosemide can cause tinnitus/deafness; max rate 4 mg/min (2.5 mg/min in severe renal impairment)
• IM administration is reserved for exceptional circumstances
• Impaired hepatic/renal function – hypokalaemia associated with diuretic use can cause encephalopathy with impaired hepatic function
• Acute porphyria (furosemide)
• Diabetes mellitus – increased insulin requirements and can cause hyperglycemia
• Elderly – risk of hypotension, falls and renal impairment, increased risk of mortality when using furosemide with risperidone in the elderly
• Patients are risk of urinary retention e.g. in benign prostatic hypertrophy
• Gout – risk of hyperuricaemia
• Furosemide may inhibit lactation in breastfeeding mothers
• Exacerbation or activation of systemic lupus erythematosus (furosemide)
• Severe cutaneous reactions such as Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)

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 ↑ diuretic levels
• Phenobarbital ↓ diuretic levels
• Sucralfate reduces furosemide absorption (administer 2 hours apart)
• Lithium levels ↑ 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.