furosemide

Furosemide
Systematic (IUPAC) name
4-chloro-2-(furan-2-ylmethylamino)- 5-sulfamoylbenzoic acid
Identifiers
CAS number	54-31-9
ATC code	C03CA01
PubChem	162482
DrugBank	APRD00608
ChemSpider	3322
Chemical data
Formula	C12H11ClN2O5S
Mol. mass	330.745 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	43-69%
Metabolism	hepatic and renal glucuronidation
Half life	up to 100 minutes
Excretion	renal 66%, biliary 33%
Therapeutic considerations
Licence data	US Daily Med:link
Pregnancy cat.	C(AU) C(US)
Legal status	℞ Prescription only
Routes	Oral, IV, IM
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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.

Mechanism of action

The name Lasix is derived from the phrase "lasts six (hours)" -- referring to its duration of action. Like other loop diuretics, furosemide acts by inhibiting the 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 and the fact that 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 ^[1][2][3]. Furosemide has been reported to reversibly antagonize GABA-evoked currents of alpha6 beta2 gamma2 receptors at microM concentrations, but not alpha1 beta2 gamma2 receptors ^[1][3]. During development, the alpha6 beta2 gamma2 receptor increases in expression in cerebellar granule neurons, corresponding to increased sensitivity to furosemide^[2].

Clinical use in humans

Furosemide, as a loop diuretic, is principally used in the following indications (Aventis, 1998):

• Edema associated with heart failure, hepatic cirrhosis, renal impairment, nephrotic syndrome
• Hypertension
• Adjunct in cerebral/pulmonary edema where rapid diuresis is required (IV injection)

It is also sometimes used in the management of severe hypercalcemia in combination with adequate rehydration ^[4].

Although disputed,^[5] it is considered ototoxic: "usually with large parenteral doses and rapid administration and in renal impairment"^[6]

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

Use in horses

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 that it increases circulation to the kidneys, it does not help kidney function, and is not recommended for kidney disease.

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 cause 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 detectible in urine 36-72 hours following injection. Its use is prohibited by most equestrian organizations.

Drug Interactions

Furosemide has potential interactions with the following medications:^[7]

• 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

Brand names

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

References

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.