Furosemide

Furosemide

Systematic (IUPAC) name
4-chloro-2-(furan-2-ylmethylamino)- 5-sulfamoylbenzoic acid
Clinical data
Licence data	US Daily Med:link
Pregnancy cat.	C(AU) C(US)
Legal status	℞ Prescription only
Routes	Oral, IV, IM
Pharmacokinetic data
Bioavailability	43-69%
Metabolism	hepatic and renal glucuronidation
Half-life	up to 100 minutes
Excretion	renal 66%, biliary 33%
Identifiers
CAS number	54-31-9
ATC code	C03CA01
PubChem	CID 3440
DrugBank	APRD00608
ChemSpider	3322 Y
UNII	7LXU5N7ZO5 Y
KEGG	D00331 Y
ChEBI	CHEBI:47426 Y
ChEMBL	CHEMBL35 Y
Chemical data
Formula	C12H11ClN2O5S
Mol. mass	330.745 g/mol
SMILES	eMolecules & PubChem
InChI 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) Y Key:ZZUFCTLCJUWOSV-UHFFFAOYSA-N Y
Y(what is this?)  (verify)

Furosemide (INN) or frusemide (former BAN) is a loop diuretic used in the treatment of congestive heart failure and edema. It is most commonly marketed by Sanofi-Aventis under the brand name Lasix. It has also been used to prevent Thoroughbred and Standardbred race horses from bleeding through the nose during races.

Along with some other diuretics, furosemide is also included on the World Anti-Doping Agency's banned drug list due to its alleged use as a masking agent for other drugs.

Medical uses

Furosemide is primarily used for the treatment of two conditions: hypertension and edema.^[1] It is the first line agent in most people with edema due to congestive heart failure.^[1]

• Edema associated with heart failure, hepatic cirrhosis, renal impairment, nephrotic syndrome
• Hypertension
• Adjunct in cerebral/pulmonary edema where rapid diuresis, i.e. lowering body water content by inducing urination, is required (IV injection)

It is also sometimes used in the management of severe hypercalcemia in combination with adequate rehydration.^[2]

Adverse effects

Although disputed,^[3] it is considered ototoxic: "usually with large parenteral doses and rapid administration and in renal impairment"^[4] Furosemide also can lead to gout.

The tendency, as for all loop diuretics, to cause low potassium levels (hypokalemia) has given rise to combination products, either with potassium itself (e.g. Lasix-K) or with the potassium sparing diuretic of amiloride (Co-amilofruse).

Interactions

Furosemide has potential interactions with the following medications:^[5]

• Aminoglycoside antibiotics such as gentamicin
• Aspirin and other salicylates
• Other diuretics (e.g. ethacrynic acid, hydrochlorothiazide)
• Indomethacin
• Lithium
• Synergistic effects with other antihypertensives (e.g. doxazosin)
• Sucralfate

Mechanism of action

Main article: Loop diuretic

Furosemide, like other loop diuretics, acts by inhibiting NKCC2, the luminal Na-K-2Cl symporter in the thick ascending limb of the loop of Henle. 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.

Due to 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.

By inhibiting the transporter, the loop diuretics reduce the reabsorption of NaCl and also diminish the lumen-positive potential that derives from K⁺ recycling. This electrical potential normally drives divalent cation reabsorbtion in the loop, and by reducing this potential loop, diuretics cause an increase in Mg²⁺ and Ca²⁺ excretion. Prolonged use can cause significant hypomagnesemia in some patients. Since Ca²⁺ is actively reabsorbed in the distal convoluted tubule, loop diuretics do not generally cause hypocalcemia.

Additionally, furosemide is a noncompetitive subtype-specific blocker of GABA-A receptors.^[6][7][8] Furosemide has been reported to reversibly antagonize GABA-evoked currents of α₆β₂γ₂ receptors at µM concentrations, but not α₁β₂γ₂ receptors.^[6][8] During development, the α₆β₂γ₂ receptor increases in expression in cerebellar granule neurons, corresponding to increased sensitivity to furosemide.^[7]

Brand names

Some of the brand names under which furosemide is marketed include: Aisemide, Apo-Furosemide, Beronald, Desdemin, Discoid, Diural, Diurapid, Dryptal, Durafurid, Edemid, Errolon, Eutensin, Flusapex, Frudix, Frusetic, Frusid, Fulsix, Fuluvamide, Furesis, Furix, Furo-Puren, Furosedon, Fusid.frusone, Hydro-rapid, Impugan, Katlex, Lasilix, Lasix, Lodix, Lowpston, Macasirool, Mirfat, Nicorol, Odemase, Oedemex, Profemin, Rosemide, Rusyde, Salix, Trofurit, Uremide and Urex. The name Lasix is derived from the phrase "lasts six (hours)"  — referring to its duration of action.^[9] Intravenous and oral Lasix lasts two to four hours. ^[10]

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 (EIPH) by horses during races was discovered accidentally. Pursuant to the racing rules of most states, horses that bleed from the nostrils three times are permanently barred from racing (for their own protection). Clinical trials followed, and by decade's end, racing commissions in some states began legalizing its use on race horses. On September 1, 1995, New York became the last state in the United States to approve such use, after years of refusing to consider doing so. Some states allow its use for all racehorses; some allow it only for confirmed "bleeders." However, its use for this purpose is still prohibited in many other countries, and veterinarians dispute its use for this problem.

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

It is also used to treat congestive heart failure in canines (who expereince fluid on the lungs) due to complications from heartworms. It can be used in conjunction with an antibiotic and anti-inflamitory to treat this condition.

Precautions, side effects, and administration

Furosemide is injected either intramuscularly (IM) or intravenously (IV), usually 0.5-1.0 mg/kg 2x/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. It is especially important to prevent potassium loss. 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, GI 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 anesthesics, so its use should be related to the veterinarian if the animal is going into surgery, and it decreases the kidney's 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 prohibited by most equestrian organizations.

References

1. ^ ^{a b} "Furosemide". The American Society of Health-System Pharmacists. http://www.drugs.com/monograph/furosemide.html. Retrieved 3 April 2011. 
2. ^ Rossi S, ed (2004). Australian Medicines Handbook 2004 (5th ed.). Adelaide, S.A.: Australian Medicines Handbook Pty Ltd. ISBN 0-9578521-4-2. http://www.amh.net.au/. 
3. ^ Rais-Bahrami K, Majd M, Veszelovszky E, Short B (2004). "Use of furosemide and hearing loss in neonatal intensive care survivors". Am J Perinatol 21 (6): 329–32. doi:10.1055/s-2004-831887. PMID 15311369. 
4. ^ BNF 45 March 2003
5. ^ Brand name:Lasix - Generic name: Furosemide Prescription Drug Information, Side Effects - PDRHealth
6. ^ ^{a b} Korpi ER, Kuner T, Seeburg PH, Lüddens H (1995). "Selective antagonist for the cerebellar granule cell-specific gamma-aminobutyric acid type A receptor". Mol. Pharmacology. 47 (2): 283–9. PMID 7870036. 
7. ^ ^{a b} Tia S, Wang JF, Kotchabhakdi N, Vicini S (1996). "Developmental changes of inhibitory synaptic currents in cerebellar granule neurons: role of GABA(A) receptor alpha 6 subunit". J. Neurosci. 16 (11): 3630–40. PMID 8642407. http://www.jneurosci.org/cgi/content/full/16/11/3630. 
8. ^ ^{a b} Wafford KA, Thompson SA, Thomas D, Sikela J, Wilcox AS, Whiting PJ (1996). "Functional characterization of human gamma-aminobutyric acidA receptors containing the alpha 4 subunit". Mol. Pharmacol. 50 (3): 670–8. PMID 8794909. 
9. ^ Sadava, David E.; Heller, H. Craig; Orians, Gordon H. (2006). Life, the science of biology (8th ed.). p. 1105. ISBN 9780716776710. 
10. ^ (Basic & Clinical Pharmacology, 11e Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor )

Further reading

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

External links

• Lasix and horse bleeding
• Furosemide in the Horse (Wind Publications)
• "Diuretics and other masking agents" (PDF) – Part S5 of the World Anti-Doping Agency's 2005 Prohibited List. International Standard.
• U.S. National Library of Medicine: Drug Information Portal - Furosemide