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commonly used diuretic (trade name Lasix) used to treat hypertension and edema (同)Lasix

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/09/17 15:14:55」(JST)

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Furosemide (INN/BAN^[1]), previously 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.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.^[3]

1 Medical uses
2 Adverse effects
- 2.1 Interactions
3 Mechanism of action
4 Veterinary uses
- 4.1 Precautions, side effects, and administration for horses
5 Clinical use in kidney disease
- 5.1 Dose in normal renal function
- 5.2 Pharmacokinetics
- 5.3 Dose in renal impairment gfr (ml/min.)
- 5.4 Dose in patients undergoing renal replacement therapies
- 5.5 Important drug interactions
- 5.6 Route
- 5.7 Other information
6 Brand names
7 References
8 Further reading
9 External links

Medical uses

Furosemide is primarily used for the treatment of hypertension and edema.^[4] It is the first-line agent in most people with edema caused by congestive heart failure.^[4] 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.^[5]

Adverse effects

Although disputed,^[6] it is considered ototoxic: "usually with large parenteral doses and rapid administration and in renal impairment".^[7] 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:^[8]

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 a decrease in Mg²⁺ and Ca²⁺ reabsorption. 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.^[9]^[10]^[11] Furosemide has been reported to reversibly antagonize GABA-evoked currents of α₆β₂γ₂ receptors at µM concentrations, but not α₁β₂γ₂ receptors.^[9]^[11] During development, the α₆β₂γ₂ receptor increases in expression in cerebellar granule neurons, corresponding to increased sensitivity to furosemide.^[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. 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. Although 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

In chronic kidney diseases with hypoalbuminemia it is used along with albumin to increase diuresis. It is also used along with albumin in nephrotic syndrome to reduce edema. BMC Nephrol. 2012 Aug 29;13:92. doi: 10.1186/1471-2369-13-92. The added-up albumin enhances the diuretic effect of furosemide in patients with hypoalbuminemic chronic kidney disease: a randomized controlled study. Phakdeekitcharoen B1, Boonyawat K Ann Pharmacother. 2003 May;37(5):695-700. Combined furosemide and human albumin treatment for diuretic-resistant edema. Elwell RJ1, Spencer AP, Eisele G

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
Antiepileptics: 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 and should be administered with caution.
Furosemide acts within 1 hour of oral administration (after IV peak effect within 30 minutes); diuresis is 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, Furon, 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

^ http://www.mhra.gov.uk/Howweregulate/Medicines/Namingofmedicines/ChangestomedicinesnamesBANstorINNs/index.htm
^ [1]
^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.
^ ^a ^b "Furosemide". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
^ Rossi S, ed. (2004). Australian Medicines Handbook 2004 (5th ed.). Adelaide, S.A.: Australian Medicines Handbook Pty Ltd. ISBN 0-9578521-4-2.
^ 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.
^ BNF 45 March 2003
^ Brand name:Lasix - Generic name: Furosemide Prescription Drug Information, Side Effects - PDRHealth
^ ^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.
^ ^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.
^ ^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.

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

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. ループ利尿剤：最大有効量および主な副作用 loop diuretics maximum effective dose and major side effects
2. 利尿剤の作用機序 mechanism of action of diuretics
3. 小児におけるネフローゼ症候群の対症療法 symptomatic management of nephrotic syndrome in children
4. 線状IgA水疱性皮膚症 linear iga bullous dermatosis
5. 心不全患者における利尿剤の使用 use of diuretics in patients with heart failure

English Journal

Biorelevant solubility of poorly soluble drugs: Rivaroxaban, furosemide, papaverine and niflumic acid.

Takács-Novák K, Szőke V, Völgyi G, Horváth P, Ambrus R, Szabó-Révész P.SourceDepartment of Pharmaceutical Chemistry, Semmelweis University, H-1092 Hőgyes Endre street 9, Budapest, Hungary. Electronic address: novak.krisztina@pharma.semmelweis-univ.hu.
Journal of pharmaceutical and biomedical analysis.J Pharm Biomed Anal.2013 Sep;83:279-85. doi: 10.1016/j.jpba.2013.05.011. Epub 2013 May 18.
In this work the biorelevant solubility of four drugs representing different acid-base property, wide range of lipohilicity and low aqueous solubility was studied. The equilibrium solubility of rivaroxaban (non-ionizable), furosemide (acid), papaverine (base) and niflumic acid (ampholyte) was determ
PMID 23770783

Thorough investigation of the retention mechanisms and retention behavior of amides and sulfonamides on amino column in hydrophilic interaction liquid chromatography.

Jovanović M, Stojanović BJ.SourceUniversity of Belgrade, Faculty of Pharmacy, Department of Drug Analysis, Vojvode Stepe 450, Belgrade, Serbia.
Journal of chromatography. A.J Chromatogr A.2013 Aug 2;1301:27-37. doi: 10.1016/j.chroma.2013.05.034. Epub 2013 Jun 3.
In this paper detailed analysis of a mixture of four amides (tropicamide, nicotinamide, tiracetam, and piracetam) and six sulfonamides (sulfanilamide, sulfacetamide, sulfamethoxazole, sulfafurazole, furosemide, and bumetanide) on aminopropyl column in hydrophilic interaction chromatography (HILIC) w
PMID 23791449

Attenuation of lithium-induced natriuresis and kaliuresis in P2Y2 receptor knockout mice.

Zhang Y, Li L, Kohan DE, Ecelbarger CM, Kishore BK.SourceNephrology Research (151M VA SLC Health Care System, 500 Foothill Drive, Salt Lake City, UT 84148. BK.Kishore@hsc.utah.edu.
American journal of physiology. Renal physiology.Am J Physiol Renal Physiol.2013 Aug;305(3):F407-16. doi: 10.1152/ajprenal.00464.2012. Epub 2013 Jun 5.
Whole body knockout (KO) of the P2Y2 receptor (P2Y2R) results in enhanced vasopressin V2 receptor activity and increased renal Na(+) conservation. We hypothesized that P2Y2R KO mice would be less sensitive to lithium-induced natriuresis and kaliuresis due to attenuated downregulation of one or more
PMID 23739592

Japanese Journal

慢性腎臓病患者における長時間作用型と短時間作用型ループ利尿薬の効果と安全性の検討

駒田敬則,吉田泉,佐久間由紀,森穂波,雨宮守正,中里優一,田部井薫
自治医科大学紀要 33, 79-90, 2011-03-01
現在ループ利尿薬を服用している血清Cr値1.5mg/dl以上の外来患者を対象とし,文書にて同意を得られた34名を対象とした。投与薬剤の順番をランダム化して,アゾセミドまたはフロセミドを,1-2ヶ月毎に交互に投与した。その結果,アゾセミド60mgとフロセミド40mgを同等力価と考えて交互に投与した場合,血圧,体重,尿量,尿中Na排泄量に差はなく,血液検査データ,尿中電解質などにも差は無かった。尿蛋白 …
NAID 110008506955

Inheritance of an Autosomal Recessive Disorder, Gitelmans Syndrome, Across Two Generations in One Family

Yagi Hiroki,Yahata Kensei,Usui Takeshi,Hasegawa Chinatsu,Seta Koichi,Sugawara Akira
Internal Medicine 50(11), 1211-1214, 2011
… Clinically, he was diagnosed as GS because of diuretic responsiveness to furosemide but not thiazide. …
NAID 130000770474

Related Pictures

★リンクテーブル★

リンク元	「利尿薬」「急性尿細管間質性腎炎」「フロセミド」
拡張検索	「furosemide renography」「furosemide renogram」「furosemide loading test followed by walking」

「利尿薬」

Furosemide
Systematic (IUPAC) name
	4-chloro-2-(furan-2-ylmethylamino)- 5-sulfamoylbenzoic acid
Clinical data
AHFS/Drugs.com	monograph
Licence data	US Daily Med:link
Pregnancy cat.	AU: C; US: C;
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	DB00695
ChemSpider	3322
UNII	7LXU5N7ZO5
KEGG	D00331
ChEBI	CHEBI:47426
ChEMBL	CHEMBL35
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) ; Key:ZZUFCTLCJUWOSV-UHFFFAOYSA-N ;
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