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 Y
ATC code	C03CA01
PubChem	CID 3440
DrugBank	DB00695
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 O=S(=O)(N)c1c(Cl)cc(c(C(=O)O)c1)NCc2occc2
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/BAN^[1]) 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 under the brand name Lasix, and also under the brand names Fusid and Frumex.^[2] 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 hypertension and edema.^[3] It is the first-line agent in most people with edema caused by congestive heart failure.^[3] It is also used for hepatic cirrhosis, renal impairment, nephrotic syndrome, in adjunct therapy for cerebral/pulmonary edema where rapid diuresis is required (IV injection), and in the management of severe hypercalcemia in combination with adequate rehydration.^[4]

Adverse effects

Although disputed,^[5] it is considered ototoxic: "usually with large parenteral doses and rapid administration and in renal impairment".^[6] Furosemide also can lead to gout caused by hyperuricemia. Hyperglycemia is also a common side effect.

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 amiloride (Co-amilofruse).

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

Mechanism of action

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.

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.

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 reabsorption 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 generally do not cause hypocalcemia.

Additionally, furosemide is a noncompetitive subtype-specific blocker of GABA-A receptors.^[8][9][10] Furosemide has been reported to reversibly antagonize GABA-evoked currents of α₆β₂γ₂ receptors at µM concentrations, but not α₁β₂γ₂ receptors.^[8][10] During development, the α₆β₂γ₂ receptor increases in expression in cerebellar granule neurons, corresponding to increased sensitivity to furosemide.^[9]

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. 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 (for their own protection), these rules do not apply in all countries. Clinical trials followed, and by decade's end, racing commissions in some states in the USA 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 (which experience fluid on the lungs,and complications from heartworm. It can be used in conjunction with an antibiotic and anti-inflammatory to treat this condition It can also be used in an attempt to promote diuresis in anuric or oliguric acute renal failure

Precautions, side effects, and administration for horses

Furosemide is injected either intramuscularly (IM) or intravenously (IV), 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 anesthesics, 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 prohibited by most equestrian organizations.

Clinical use in kidney disease

Loop diuretic

Dose in normal renal function

• Oral: 20 mg – 1 g daily
• IV: 20 mg – 1.5 g daily

Doses titrated to response.

Pharmacokinetics

• Molecular weight (daltons) 330.7
• % Protein binding 91–99
• % Excreted unchanged in urine 80–90
• Volume of distribution (L/kg) 0.07–0.2
• half-life – normal/ESRF (h rs) 0.5–2/9.7

Dose in renal impairment gfr (ml/min.)

• 20–50 Dose as in normal renal function
• 10–20 Dose as in normal renal function; increased doses may be required
• <10 Dose as in normal renal function; increased doses may be required

Dose in patients undergoing renal replacement therapies

• cAPD Not dialysed. Dose as in GFR < 10 ml/min.
• HD Dialysed. Dose as in GFR < 10 ml/min.
• HDF/high flux Dialysed. Dose as in GFR < 10 ml/min.
• CAV/VVHD Not dialysed. Dose as in GFR = 10–20 ml/min.

Important drug interactions

Potentially hazardous interactions with other drugs:

• Analgesics: increased risk of nephrotoxicity with NSAIDs; antagonism of diuretic effect with NSAIDs
• Anti-arrhythmics: risk of cardiac toxicity with anti-arrhythmics if hypokalaemia occurs; effects of lidocaine and mexiletine antagonised
• Antibacterials: increased risk of ototoxicity with aminoglycosides, polymyxins and vancomycin; avoid concomitant use with lymecycline
• Antidepressants: increased risk of hypokalaemia with reboxetine; enhanced hypotensive effect with MAOIs; increased risk of postural hypotension with tricyclics
• Anti-epileptics: increased risk of hyponatraemia with carbamazepine
• Antifungals: increased risk of hypokalaemia with amphotericin
• Antihypertensives: enhanced hypotensive effect; increased risk of first dose hypotensive effect with alpha-blockers; increased risk of ventricular arrhythmias with sotalol if hypokalaemia occurs
• Antipsychotics: increased risk of ventricular arrhythmias with amisulpiride, sertindole or pimozide (avoid with pimozide) if hypokalaemia occurs; enhanced hypotensive effect with phenothiazines
• Atomoxetine: hypokalaemia increases risk of ventricular arrhythmias
• Cardiac glycosides: increased toxicity if hypokalaemia occurs
• Ciclosporin: variable reports of increased nephrotoxicity, ototoxicity and hepatotoxicity
• Lithium: risk of toxicity

Route

• IV peripherally or centrally, IM, oral RATE of ADMINISTRATION
• 1 hour; not greater than 4 mg/minute COMMENTS
• 250 mg to 50 ML sodium chloride 0.9% or undiluted via CRIP
• Increased danger of ototoxicity and nephrotoxicity if infused at faster rate than approximately 4 mg/min.
• Protect from light

Other information

• 500 mg orally ≡ 250 mg IV
• Excreted by tubular secretion, therefore in severe renal impairment (GFR 5–10 mL/min) lower doses are required due to accumulation in the body. It also can cause further renal damage so you want to give it cautiously.
• Furosemide acts within 1 hour of oral administration, (after IV peak effect within 30 minutes) diuresis complete within 6 hours

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, Teva-Furosemide, Trofurit, Uremide and Urex.

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.
• U.S. National Library of Medicine: Drug Information Portal - Furosemide
• Furosemide-A Practical Manual of Renal Medicine