Furosemide
Clinical data
Pronunciation/fjʊˈroʊsəˌmaɪd/
Trade namesLasix, Furoscix, others
Other namesFurosemide
AHFS/Drugs.comMonograph
MedlinePlusa682858
License data
Pregnancy
category
  • AU: C
Routes of
administration		oral, intravenous, intramuscular, subcutaneous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: WARNING[1]Rx-only[2][3]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability43–69%
Protein binding91–99%
Metabolismliver and kidney glucuronidation
Onset of action30 to 60 min (PO), 5 min (IV)[4]
Elimination half-lifeup to 100 minutes
ExcretionKidneys (66%), bile (33%)
Identifiers
  • 4-Chloro-2-[(furan-2-ylmethyl)amino]-5-sulfamoylbenzoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.185
Chemical and physical data
FormulaC12H11ClN2O5S
Molar mass330.74 g·mol−1
3D model (JSmol)
  • o1cccc1CNc(cc2Cl)c(C(=O)O)cc2S(=O)(=O)N
  • InChI=1S/C12H11ClN2O5S/c13-9-5-10(15-6-7-2-1-3-20-7)8(12(16)17)4-11(9)21(14,18)19/h1-5,15H,6H2,(H,16,17)(H2,14,18,19) checkY
  • Key:ZZUFCTLCJUWOSV-UHFFFAOYSA-N checkY
  (verify)

Furosemide is a loop diuretic medication used to treat edema due to heart failure, liver scarring, or kidney disease.[4] It has had many trade names including Discoid, Frusemide, Lasix and Uremide. Furosemide may also be used for the treatment of high blood pressure.[4] It can be taken intravenously or orally.[4] When given intravenously, furosemide typically takes effect within five minutes; when taken orally, it typically metabolizes within an hour.[4]

Common side effects include orthostatic hypotension (decrease in blood pressure while standing, and associated lightheadedness), tinnitus (ringing in the ears), and photosensitivity (sensitivity to light).[4] Potentially serious side effects include electrolyte abnormalities, low blood pressure, and hearing loss.[4] It is recommended that serum electrolytes (especially potassium), serum CO2, creatinine and BUN levels are monitored for people taking furosemide, as well as monitoring of liver and kidney functioning. It is also recommended to be alert for the occurrence of any potential blood dyscrasias.[4] Furosemide is a type of loop diuretic that works by decreasing the reabsorption of sodium by the kidneys.[4] Common side effects of furosemide injection include hypokalemia (low potassium level), hypotension (low blood pressure), and dizziness.[5]

Furosemide was patented in 1959 and approved for medical use in 1964.[6] It is on the World Health Organization's List of Essential Medicines.[7] In the United States, it is available as a generic medication.[4] In 2020, it was the nineteenth most commonly prescribed medication in the United States, with more than 26 million prescriptions.[8][9] In 2020/21 it was the twentieth most prescribed medication in England.[10] It is on the World Anti-Doping Agency's banned drug list due to concerns that it may mask other drugs.[11] It has also been used in race horses for the treatment and prevention of exercise-induced pulmonary hemorrhage.[12][13]

Medical uses

Furosemide (Lasix) for injection.

Furosemide is primarily used for the treatment of edema, but also in some cases of hypertension (where there is also kidney or heart impairment).[14] It is often viewed as a first-line agent in most people with edema caused by congestive heart failure because of its anti-vasoconstrictor and diuretic effects.[15][4] Compared with furosemide, however, torasemide (aka "torsemide") has been demonstrated to show improvements to heart failure symptoms, possibly lowering the rates of rehospitalisation associated with heart failure, with no difference in risk of death. [16][17][18] Torsemide may also be safer than furosemide.[19][20] Providing self-administered subcutaneous furosemide has been found to reduce hospital admissions in people with heart failure, resulting in significant savings in healthcare costs.[21][22]

Furosemide is also used for liver cirrhosis, kidney impairment, nephrotic syndrome, in adjunct therapy for swelling of the brain or lungs where rapid diuresis is required (IV injection), and in the management of severe hypercalcemia in combination with adequate rehydration.[23]

Kidney disease

In chronic kidney diseases with hypoalbuminemia, furosemide is used along with albumin to increase diuresis.[24] It is also used along with albumin in nephrotic syndrome to reduce edema.[25]

Other information

Furosemide is mainly excreted by tubular secretion in the kidney. In kidney impairment, clearance is reduced, increasing the risk of adverse effects.[4] Lower initial doses are recommended in older patients (to minimize side-effects) and high doses may be needed in kidney failure.[26] It can also cause kidney damage; this is mainly by loss of excessive fluid (i.e., dehydration), and is usually reversible.

Furosemide acts within 1 hour of oral administration (after IV injection, the peak effect is within 30 minutes). Diuresis is usually complete within 6–8 hours of oral administration, but there is significant variation between individuals.[27]

Adverse effects

Furosemide also can lead to gout caused by hyperuricemia. Hyperglycemia is also a common side effect.[28][29][30]

The tendency, as for all loop diuretics, to cause low serum potassium concentration (hypokalemia) has given rise to combination products, either with potassium or with the potassium-sparing diuretic amiloride (Co-amilofruse). Other electrolyte abnormalities that can result from furosemide use include hyponatremia, hypochloremia, hypomagnesemia, and hypocalcemia.[31]

In the treatment of heart failure, many studies have shown that the long-term use of furosemide can cause varying degrees of thiamine deficiency, so thiamine supplementation is also suggested.[32]

Furosemide is a known ototoxic agent generally causing transient hearing loss but can be permanent. Reported cases of furosemide induced hearing loss appeared to be associated with rapid intravenous administration, high dosages, concomitant renal disease and coadministration with other ototoxic medication.[33][34] However, a recently reported longitudinal study showed that participants treated with loop diuretics over 10 years were 40% more likely to develop hearing loss and 33% more likely of progressive hearing loss compared to participants who did not use loop diuretics.[35] This suggests the long-term consequences of loop diuretics on hearing could be a more significant than previously thought and further research is required in this area.  

Other precautions include: nephrotoxicity, sulfonamide (sulfa) allergy, and increases free thyroid hormone effects with large doses.[36]

Interactions

Furosemide has potential interactions with these medications:[37]

Potentially hazardous interactions with other drugs:

Mechanism of action

Furosemide, like other loop diuretics, acts by inhibiting the luminal Na-K-Cl cotransporter in the thick ascending limb of the loop of Henle, by binding to the Na-K-2Cl transporter, thus causing more sodium, chloride, and potassium to be excreted in the urine.[38]

The action on the distal tubules is independent of any inhibitory effect on carbonic anhydrase or aldosterone; it also abolishes the corticomedullary osmotic gradient and blocks negative, as well as positive, free water clearance. Because of the large NaCl absorptive capacity of the loop of Henle, diuresis is not limited by development of acidosis, as it is with the carbonic anhydrase inhibitors.

Additionally, furosemide is a noncompetitive subtype-specific blocker of GABA-A receptors.[39][40][41] Furosemide has been reported to reversibly antagonize GABA-evoked currents of α6β2γ2 receptors at μM concentrations, but not α1β2γ2 receptors.[39][41] During development, the α6β2γ2 receptor increases in expression in cerebellar granule neurons, corresponding to increased sensitivity to furosemide.[40]

Pharmacokinetics

  • Molecular weight (daltons) 330.7
  •  % Bioavailability 47 – 70%
    • Bioavailability with end-stage renal disease 43 – 46%[42][43]
  •  % Protein binding 91 – 99[44]
  • Volume of distribution (L/kg) 0.07 – 0.2[45][46]
    • Volume of distribution may be higher in patients with cirrhosis or nephrotic syndrome[45]
  • Excretion
    •  % Excreted in urine (% of total dose) 60 – 90[45][46]
    •  % Excreted unchanged in urine (% of total dose) 53.1 – 58.8 [47]
    •  % Excreted in feces (% of total dose) 7 – 9[27]
    •  % Excreted in bile (% of total dose) 6 – 9[46]
  • Approximately 10% is metabolized by the liver in healthy individuals, but this percentage may be greater in individuals with severe kidney failure [46]
  • Renal clearance (mL/min/kg) 2.0[45]
  • Elimination half-life (hrs) 2[44]
    • Prolonged in congestive heart failure (mean 3.4 hrs)[45][48]
    • Prolonged in severe kidney failure (4 – 6 hrs)[49] and anephric patients (1.5 – 9 hrs)[46]
  • Time to peak concentration (hrs)
    • Intravenous administration 0.3[50]
    • Oral solution 0.83[44]
    • Oral tablet 1.45[44]

The pharmacokinetics of furosemide are apparently not significantly altered by food.[51]

No direct relationship has been found between furosemide concentration in the plasma and furosemide efficacy. Efficacy depends upon the concentration of furosemide in urine.[27]

Names

Furosemide is the INN and BAN.[52] The previous BAN was frusemide.

Brand names under which furosemide is marketed include: Aisemide, Apo-Furosemide, Beronald, Desdemin, Discoid, Diural, Diurapid, Dryptal, Durafurid, Edemid, Errolon, Eutensin, Flusapex, Frudix, Frusemide, Frusetic, Frusid, Fulsix, Fuluvamide, Furesis, Furix, Furo-Puren, Furon, Furosedon, Fusid.frusone, Hydro-rapid, Impugan, Katlex, Lasilix, Lasix, Lodix, Lowpston, Macasirool, Mirfat, Nicorol, Odemase, Oedemex, Profemin, Rosemide, Rusyde, Salix, Seguril, Teva-Furosemide, Trofurit, Uremide, and Urex.

Veterinary uses

The diuretic effects are put to use most commonly in horses to prevent bleeding during a race. Sometime in the early 1970s, furosemide's ability to prevent, or at least greatly reduce, the incidence of bleeding (exercise-induced pulmonary hemorrhage) by horses during races was discovered accidentally. In the United States of America, pursuant to the racing rules of most states, horses that bleed from the nostrils three times are permanently barred from racing. Clinical trials followed, and by decade's end, racing commissions in some states in the USA began legalizing its use on race horses. In 1995, New York became the last state in the United States to approve such use, after years of refusing to consider doing so.[53] Some states allow its use for all racehorses; some allow it only for confirmed "bleeders". Its use for this purpose is still prohibited in many other countries.

Furosemide is also used in horses for pulmonary edema, congestive heart failure (in combination with other drugs), and allergic reactions. Although it increases circulation to the kidneys, it does not help kidney function, and is not recommended for kidney disease.[54]

It is also used to treat congestive heart failure (pulmonary edema, pleural effusion, and/or ascites) in cats and dogs.[55] It can also be used in an attempt to promote urine production in anuric or oliguric acute kidney failure.

Horses

Furosemide is injected either intramuscularly or intravenously, usually 0.5-1.0 mg/kg twice/day, although less before a horse is raced. As with many diuretics, it can cause dehydration and electrolyte imbalance, including loss of potassium, calcium, sodium, and magnesium. Excessive use of furosemide will most likely lead to a metabolic alkalosis due to hypochloremia and hypokalemia. The drug should, therefore, not be used in horses that are dehydrated or experiencing kidney failure. It should be used with caution in horses with liver problems or electrolyte abnormalities. Overdose may lead to dehydration, change in drinking patterns and urination, seizures, gastrointestinal problems, kidney damage, lethargy, collapse, and coma.

Furosemide should be used with caution when combined with corticosteroids (as this increases the risk of electrolyte imbalance), aminoglycoside antibiotics (increases risk of kidney or ear damage), and trimethoprim sulfa (causes decreased platelet count). It may also cause interactions with anesthetics, so its use should be related to the veterinarian if the animal is going into surgery, and it decreases the kidneys' ability to excrete aspirin, so dosages will need to be adjusted if combined with that drug.

Furosemide may increase the risk of digoxin toxicity due to hypokalemia.

The drug is best not used during pregnancy or in a lactating mare, as it has been shown to be passed through the placenta and milk in studies with other species. It should not be used in horses with pituitary pars intermedia dysfunction (Cushings).

Furosemide is detectable in urine 36–72 hours following injection. Its use is restricted by most equestrian organizations.

In April 2019, it was announced that Lasix would be banned from use at US racetracks within 24 hours of a horse racing starting in 2021.[56]

References

  1. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  2. ↑ "Lasix- furosemide tablet". DailyMed. 26 January 2021. Retrieved 18 November 2022.
  3. ↑ "Furoscix- furosemide injection 80 mg/ 10 ml injection". DailyMed. 21 October 2022. Retrieved 18 November 2022.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 "Furosemide". The American Society of Health-System Pharmacists. Archived from the original on 19 November 2015. Retrieved 23 October 2015.
  5. ↑ "Coronavirus (COVID-19) Update: December 22, 2020". U.S. Food and Drug Administration (Press release). 22 December 2020. Retrieved 22 December 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  6. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 458. ISBN 9783527607495.
  7. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  8. ↑ "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
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  10. ↑ "PCA England". nhsbsa-opendata.s3.eu-west-2.amazonaws.com. Retrieved 8 August 2022.
  11. ↑ "WORLD ANTI-DOPING CODE INTERNATIONAL STANDARD PROHIBITED LIST 2022" (PDF). 2022. p. 12. Archived (PDF) from the original on 10 July 2022. Retrieved 27 July 2022.
  12. ↑ Sullivan S, Hinchcliff K (April 2015). "Update on exercise-induced pulmonary hemorrhage". The Veterinary Clinics of North America. Equine Practice. 31 (1): 187–198. doi:10.1016/j.cveq.2014.11.011. PMID 25770069.
  13. ↑ Hinchcliff KW, Couetil LL, Knight PK, Morley PS, Robinson NE, Sweeney CR, van Erck E (2015). "Exercise induced pulmonary hemorrhage in horses: American College of Veterinary Internal Medicine consensus statement". Journal of Veterinary Internal Medicine. 29 (3): 743–758. doi:10.1111/jvim.12593. PMC 4895427. PMID 25996660.
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  23. ↑ Rossi S, ed. (2004). Australian Medicines Handbook 2004 (5th ed.). Adelaide, S.A.: Australian Medicines Handbook Pty Ltd. ISBN 978-0-9578521-4-3.
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  25. ↑ Duffy M, Jain S, Harrell N, Kothari N, Reddi AS (October 2015). "Albumin and Furosemide Combination for Management of Edema in Nephrotic Syndrome: A Review of Clinical Studies". Cells. 4 (4): 622–630. doi:10.3390/cells4040622. PMC 4695849. PMID 26457719.
  26. ↑ "British National Formulary". Retrieved 9 November 2018.
  27. 1 2 3 Ponto LL, Schoenwald RD (May 1990). "Furosemide (frusemide). A pharmacokinetic/pharmacodynamic review (Part I)". Clinical Pharmacokinetics. 18 (5): 381–408. doi:10.2165/00003088-199018050-00004. PMID 2185908. S2CID 32352501.
  28. ↑ Li Q, Li X, Kwong JS, Chen H, Sun X, Tian H, Li S (June 2017). "Diagnosis and treatment for hyperuricaemia and gout: a protocol for a systematic review of clinical practice guidelines and consensus statements". BMJ Open. 7 (6): e014928. doi:10.1136/bmjopen-2016-014928. PMC 5623447. PMID 28645962.
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  30. ↑ Han Y, Cao Y, Han X, Di H, Yin Y, Wu J, Zhang Y, Zeng X (July 2023). "Hyperuricemia and gout increased the risk of long-term mortality in patients with heart failure: insights from the National Health and Nutrition Examination Survey". J Transl Med. 21 (1): 463. doi:10.1186/s12967-023-04307-z. PMC 10339518. PMID 37438830.
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  35. ↑ Joo Y, Cruickshanks KJ, Klein BE, Klein R, Hong O, Wallhagen MI (February 2020). Newman A (ed.). "The Contribution of Ototoxic Medications to Hearing Loss Among Older Adults". The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 75 (3): 561–566. doi:10.1093/gerona/glz166. PMC 7328195. PMID 31282945.
  36. ↑ "UpToDate". www.uptodate.com. Retrieved 6 November 2018.
  37. ↑ Brand name:Lasix - Generic name: Furosemide Prescription Drug Information, Side Effects - PDRHealth
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  44. 1 2 3 4 "Product Information: Lasix(R), furosemide" (PDF). Aventis Pharmaceuticals, Bridgewater, NJ. U.S. Food and Drug Administration. 2004.
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  48. ↑ Chaturvedi PR, O'Donnell JP, Nicholas JM, Shoenthal DR, Waters DH, Gwilt PR (March 1987). "Steady state absorption kinetics and pharmacodynamics of furosemide in congestive heart failure". International Journal of Clinical Pharmacology, Therapy, and Toxicology. 25 (3): 123–128. PMID 3557737.
  49. ↑ Brater DC (1991). "Clinical pharmacology of loop diuretics". Drugs. 41 (Supplement 3): 14–22. doi:10.2165/00003495-199100413-00004. PMID 1712712. S2CID 41247401.
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  51. ↑ AHFS Drug Information 2004. McEvoy GK, ed. Furosemide. American Society of Health-System Pharmacists; 2004: 2260-4.
  52. ↑ "Naming human medicines". Archived from the original on 27 April 2010. Retrieved 18 November 2009.
  53. ↑ "COMMENTARY : New York Buckles and Allows Lasix Use". Los Angeles Times. 28 May 1995. Retrieved 22 January 2022.
  54. ↑ Hinchcliff KW, Muir WW (January 2022). "Pharmacology of furosemide in the horse: a review". Journal of Veterinary Internal Medicine. 5 (4): 211–218. doi:10.1111/j.1939-1676.1991.tb00951.x. PMID 1941755.
  55. ↑ Kittleson M, Kienle R (1998). Small Animal Cardiovascular Medicine. Mosby. ISBN 978-0-8151-5140-1.
  56. ↑ "U.S. Racetracks to ban race-day Lasix in 2021". 18 April 2019.

Further reading

  • Aventis Pharma (1998). Lasix Approved Product Information. Lane Cove: Aventis Pharma Pty Ltd.
  • Forney B (2007). Understanding Equine Medications, Revised Edition (Horse Health Care Library). Eclipse Press. ISBN 978-1-58150-151-3.
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