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.[4][15] 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]
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]
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.[citation needed]
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]
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 diureticamiloride (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]
Antihypertensives: enhanced hypotensive effect; increased risk of first dose hypotensive effect with alpha-blockers; increased risk of ventricular arrhythmias with sotalol if hypokalemia occurs
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.[citation needed]
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]
Approximately 10% is metabolized by the liver in healthy individuals, but this percentage may be greater in individuals with severe kidney failure [46]
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]
The diuretic effects are put to use most commonly in horses to prevent bleeding during a race. In the United States of America, pursuant to the racing rules of most states, horses that bleed from the nostrils (exercise-induced pulmonary hemorrhage) three times are permanently barred from racing. Sometime in the early 1970s, furosemide's ability to prevent, or at least greatly reduce, the incidence of bleeding by horses during races was discovered accidentally. 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.[citation needed]
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.
Furosemide is injected either intramuscularlyorintravenously, 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]
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^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.
^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. PMID25770069.
^Täger T, Fröhlich H, Seiz M, Katus HA, Frankenstein L (July 2019). "READY: relative efficacy of loop diuretics in patients with chronic systolic heart failure-a systematic review and network meta-analysis of randomised trials". Heart Failure Reviews. 24 (4): 461–472. doi:10.1007/s10741-019-09771-8. PMID30874955. S2CID77394851.
^Miles JA, Hanumanthu BK, Patel K, Chen M, Siegel RM, Kokkinidis DG (June 2019). "Torsemide versus furosemide and intermediate-term outcomes in patients with heart failure: an updated meta-analysis". Journal of Cardiovascular Medicine. 20 (6): 379–388. doi:10.2459/JCM.0000000000000794. PMID30950982. S2CID96436158.
^Abraham B, Megaly M, Sous M, Fransawyalkomos M, Saad M, Fraser R, et al. (January 2020). "Meta-Analysis Comparing Torsemide Versus Furosemide in Patients With Heart Failure". The American Journal of Cardiology. 125 (1): 92–99. doi:10.1016/j.amjcard.2019.09.039. PMID31699358. S2CID207937875.
^Kitsios GD, Mascari P, Ettunsi R, Gray AW (April 2014). "Co-administration of furosemide with albumin for overcoming diuretic resistance in patients with hypoalbuminemia: a meta-analysis". Journal of Critical Care. 29 (2): 253–259. doi:10.1016/j.jcrc.2013.10.004. PMID24268626.
^Favrelière S, Delaunay P, Lebreton JP, Rouby F, Atzenhoffer M, Lafay-Chebassier C, et al. (June 2020). "Drug-induced hearing loss: a case/non-case study in the French pharmacovigilance database". Fundamental & Clinical Pharmacology. 34 (3): 397–407. doi:10.1111/fcp.12533. PMID31912913. S2CID210087413.
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