Bumetanide

Last updated
Bumetanide
Bumetanide structure.svg
Bumetanide ball-and-stick.png
Clinical data
Trade names Bumex, Burinex, others
AHFS/Drugs.com Monograph
MedlinePlus a684051
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth, intravenous, intramuscular
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: WARNING [1] Rx-only
Pharmacokinetic data
Bioavailability Almost complete (~80%)
Protein binding 97%
Metabolism Liver
Elimination half-life ~0.8 hours
Excretion Kidney
Identifiers
  • 3-butylamino-4-phenoxy-5-sulfamoyl-benzoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.044.534 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H20N2O5S
Molar mass 364.42 g·mol−1
3D model (JSmol)
  • c1ccccc1Oc2c(NCCCC)cc(C(=O)O)cc2S(=O)(=O)N
  • InChI=1S/C17H20N2O5S/c1-2-3-9-19-14-10-12(17(20)21)11-15(25(18,22)23)16(14)24-13-7-5-4-6-8-13/h4-8,10-11,19H,2-3,9H2,1H3,(H,20,21)(H2,18,22,23) Yes check.svgY
  • Key:MAEIEVLCKWDQJH-UHFFFAOYSA-N Yes check.svgY
   (verify)

Bumetanide, sold under the brand name Bumex among others, is a medication used to treat swelling and high blood pressure. [2] This includes swelling as a result of heart failure, liver failure, or kidney problems. [2] It may work for swelling when other medications have not. [2] For high blood pressure it is not a preferred treatment. [2] It is taken by mouth, or by injection into a vein or muscle. [2] Effects generally begin within an hour and last for about six hours. [2]

Contents

Common side effects include dizziness, low blood pressure, low blood potassium, muscle cramps, and kidney problems. [2] Other serious side effects may include hearing loss and low blood platelets. [2] Blood tests are recommended regularly for those on treatment. [2] Safety during pregnancy and breastfeeding is unclear. [3] Bumetanide is a loop diuretic and works by decreasing the reabsorption of sodium by the kidneys. [4] [2]

Bumetanide was patented in 1968 and came into medical use in 1972. [5] It is on the World Health Organization's List of Essential Medicines. [6] It is available as a generic medication. [4] In 2020, it was the 270th most commonly prescribed medication in the United States, with more than 1 million prescriptions. [7] [8]

Medical uses

It is used to treat swelling and high blood pressure. [2] This includes swelling as a result of heart failure, liver failure, or kidney problems. [2] For high blood pressure it is not a preferred treatment. [2] It is taken by mouth, or by injection into a vein or muscle. [2]

Side effects

Common side effects include dizziness, low blood pressure, low blood potassium, muscle cramps, and kidney problems. [2] Other serious side effects may include hearing loss and low blood platelets. [2] A large observational study [9] concluded that people with a sulfonamide antibiotic allergy may be allergic to sulfonamide non-antibiotics, such as bumetanide, but this is likely due to certain people being at an increased risk in general to developing allergic reactions rather than cross-reactivity between sulfonamide-containing drugs. In smaller studies, the lack of cross-reactivity between sulfonamide antibiotics and sulfonamide non-antibiotics has been demonstrated. [10] [11]

Safety during pregnancy and breastfeeding is unclear. [3]

Pharmacology

Pharmacodynamics

Bumetanide is a loop diuretic and works by decreasing the reabsorption of sodium by the kidneys. The main difference between bumetanide and furosemide is in their bioavailability and potency. About 60% of furosemide is absorbed in the intestine, and there are substantial inter- and intraindividual differences in bioavailability (range 10-90%). About 80% of bumetanide is absorbed, and its absorption does not change when it is taken with food. It is said to be a more predictable diuretic, meaning that the predictable absorption is reflected in a more predictable effect. [12] Bumetanide is 40 times more potent than furosemide for people with normal renal function. [12]

Synthesis

Bumetanide is synthesized from 4-chlorobenzoic acid. [13] [14] [15] [16] In the first stage of synthesis, it undergoes sulfonylchlorination by chlorosulfonic acid, forming 4-chloro-3-chlorosulfonylbenzoic acid, which is further nitrated with nitric acid to 4-chloro-3-chlorosulfonyl-5-nitrobenzoic acid. Reacting this with ammonia gives 5-aminosulfonyl-4-chloro-3-nitrobenzoic acid, which when reacted with sodium phenolate is transformed into 5-amino-sulfonyl-3-nitro-5-phenoxybenzoic acid. Reduction of the nitro group in this product by hydrogen using a palladium on carbon catalyst gives 3-amino-5-aminosulfonyl-5-phenoxybenzoic acid. Finally, reacting this with butyl alcohol in the presence of sulfuric acid, followed by treatment with sodium hydroxide to hydrolyze the butyl ester, gives the desired bumetanide.

Synthesis of bumetanide Bumetanide synthesis.svg
Synthesis of bumetanide

Society and culture

It 2008, ESPN reported that four NFL players were being suspended under the steroid policy as a result of taking bumetanide. [17]

Bumetanide was an undisclosed active ingredient in the over-the-counter weight loss supplement StarCaps, which was removed from the market after its presence was discovered by the United States Food and Drug Administration. [18]

Research

In the brain, bumetanide blocks the NKCC1 cation-chloride co-transporter, and thus decreases internal chloride concentration in neurons. In turn, this concentration change makes the action of GABA more hyperpolarizing, which may be useful for treatment of neonatal seizures, which quite often are not responsive to traditional GABA-targeted treatment, such as barbiturates. Bumetanide is therefore under evaluation as a prospective antiepileptic drug. [19]

The drug has also been studied as a treatment for autism. [20] [21]

Related Research Articles

<span class="mw-page-title-main">Acetazolamide</span> Chemical compound

Acetazolamide, sold under the trade name Diamox among others, is a medication used to treat glaucoma, epilepsy, acute mountain sickness, periodic paralysis, idiopathic intracranial hypertension, heart failure and to alkalinize urine. It may be used long term for the treatment of open angle glaucoma and short term for acute angle closure glaucoma until surgery can be carried out. It is taken by mouth or injection into a vein. Acetazolamide is a first generation carbonic anhydrase inhibitor and it decreases the ocular fluid and osmolality in the eye to decrease intraocular pressure.

<span class="mw-page-title-main">Furosemide</span> Loop diuretic medication

Furosemide is a loop diuretic medication used to treat edema due to heart failure, liver scarring, or kidney disease. It has had many trade names including Discoid, Frusemide, Lasix and Uremide. Furosemide may also be used for the treatment of high blood pressure. It can be taken intravenously or orally. When given intravenously, furosemide typically takes effect within five minutes; when taken orally, it typically metabolizes within an hour.

<span class="mw-page-title-main">Sulfonamide (medicine)</span> Molecular moiety or the drug class that uses it

Sulfonamide is a functional group that is the basis of several groups of drugs, which are called sulphonamides, sulfa drugs or sulpha drugs. The original antibacterial sulfonamides are synthetic (nonantibiotic) antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame. The sulfonylureas and thiazide diuretics are newer drug groups based upon the antibacterial sulfonamides.

<span class="mw-page-title-main">Hydrochlorothiazide</span> Diuretic medication

Hydrochlorothiazide, sold under the brand name Hydrodiuril among others, is a diuretic medication used to treat hypertension and swelling due to fluid build-up. Other uses include treating diabetes insipidus and renal tubular acidosis and to decrease the risk of kidney stones in those with a high calcium level in the urine. Hydrochlorothiazide is taken by mouth and may be combined with other blood pressure medications as a single pill to increase effectiveness. Hydrochlorothiazide is a thiazide medication which inhibits reabsorption of sodium and chloride ions from the distal convoluted tubules of the kidneys, causing a natriuresis. This initially increases urine volume and lowers blood volume. It is believed to reduce peripheral vascular resistance.

Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%, and can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists (ARBs), and beta blockers.

<span class="mw-page-title-main">Loop diuretic</span> Diuretics that act along the loop of Henle in the kidneys

Loop diuretics are diuretics that act on the Na-K-Cl cotransporter along the thick ascending limb of the loop of Henle in nephrons of the kidneys. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure or chronic kidney disease. While thiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function.

<span class="mw-page-title-main">Amiloride</span> Medication

Amiloride, sold under the trade name Midamor among others, is a medication typically used with other medications to treat high blood pressure or swelling due to heart failure or cirrhosis of the liver. Amiloride is classified as a potassium-sparing diuretic. Amiloride is often used together with another diuretic, such as a thiazide or loop diuretic. It is taken by mouth. Onset of action is about two hours and it lasts for about a day.

<span class="mw-page-title-main">Chlortalidone</span> Thiazide-like diuretic drug

Chlortalidone, also known as chlorthalidone, is a thiazide-like diuretic drug used to treat high blood pressure, swelling, diabetes insipidus, and renal tubular acidosis. Because chlortalidone is effective in most patients with high blood pressure, it is considered a preferred initial treatment. It is also used to prevent calcium-based kidney stones. It is taken by mouth. Effects generally begin within three hours and last for up to three days. Long-term treatment with chlortalidone is more effective than hydrochlorothiazide for prevention of heart attack or stroke.

<span class="mw-page-title-main">Potassium-sparing diuretic</span> Drugs that cause diuresis without causing potassium loss in the urine and leading to hyperkalemia

Potassium-sparing diuretics refers to drugs that cause diuresis without causing potassium loss in the urine. They are typically used as an adjunct in management of hypertension, cirrhosis, and congestive heart failure. The steroidal aldosterone antagonists can also be used for treatment of primary hyperaldosteronism. Spironolactone, a steroidal aldosterone antagonist, is also used in management of female hirsutism and acne from PCOS or other causes.

<span class="mw-page-title-main">Triamterene</span> Chemical compound

Triamterene is a potassium-sparing diuretic often used in combination with thiazide diuretics for the treatment of high blood pressure or swelling. The combination with hydrochlorothiazide, is known as hydrochlorothiazide/triamterene.

<span class="mw-page-title-main">Losartan</span> Blood pressure medication

Losartan, sold under the brand name Cozaar among others, is a medication used to treat high blood pressure (hypertension). It is in the angiotensin receptor blocker (ARB) family of medication, and is considered protective of the kidneys. Besides hypertension, it is also used in diabetic kidney disease, heart failure, and left ventricular enlargement. It comes as a tablet that is taken by mouth. It may be used alone or in addition to other blood pressure medication. Up to six weeks may be required for the full effects to occur.

<span class="mw-page-title-main">Tizanidine</span> Muscle relaxant medication

Tizanidine, sold under the brand name Zanaflex among others, is an alpha-2 (α2) adrenergic receptor agonist, similar to clonidine, that is used to treat muscle spasticity due to spinal cord injury, multiple sclerosis, and spastic cerebral palsy. Effectiveness appears similar to baclofen or diazepam. It is taken by mouth.

<span class="mw-page-title-main">Metolazone</span> Chemical compound

Metolazone is a thiazide-like diuretic marketed under the brand names Zytanix, Metoz, Zaroxolyn, and Mykrox. It is primarily used to treat congestive heart failure and high blood pressure. Metolazone indirectly decreases the amount of water reabsorbed into the bloodstream by the kidney, so that blood volume decreases and urine volume increases. This lowers blood pressure and prevents excess fluid accumulation in heart failure. Metolazone is sometimes used together with loop diuretics such as furosemide or bumetanide, but these highly effective combinations can lead to dehydration and electrolyte abnormalities.

<span class="mw-page-title-main">Torasemide</span> Diuretic medication

Torasemide, also known as torsemide, is a diuretic medication used to treat fluid overload due to heart failure, kidney disease, and liver disease. It is a less preferred treatment for high blood pressure. It is taken by mouth or by injection into a vein.

The Na–K–Cl cotransporter (NKCC) is a transport protein that aids in the secondary active transport of sodium, potassium, and chloride into cells. In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two different genes. Two isoforms of the NKCC1/Slc12a2 gene result from keeping or skipping exon 21 in the final gene product.

<span class="mw-page-title-main">Carbonic anhydrase inhibitor</span> Class of pharmaceuticals

Carbonic anhydrase inhibitors are a class of pharmaceuticals that suppress the activity of carbonic anhydrase. Their clinical use has been established as anti-glaucoma agents, diuretics, antiepileptics, in the management of mountain sickness, gastric and duodenal ulcers, idiopathic intracranial hypertension, neurological disorders, or osteoporosis.

<span class="mw-page-title-main">NCAA banned substances</span>

In the United States the National Collegiate Athletic Association (NCAA), has since the 1970s been patrolling the usage of illegal drugs and substances for student-athletes attending universities and colleges. In 1999, NCAA Drug Committee published a list containing substances banned for the usage to student-athletes. Year after year it is updated and given to those students participating in college sports. If any student is caught taking any of the substances, they are subjected to suspension or even banned from participating in NCAA sports and possibly attending the university.

<span class="mw-page-title-main">Diuretic</span> Substance that promotes the production of urine

A diuretic is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics increase the excretion of water from the body, through the kidneys. There exist several classes of diuretic, and each works in a distinct way. Alternatively, an antidiuretic, such as vasopressin, is an agent or drug which reduces the excretion of water in urine.

<span class="mw-page-title-main">Ototoxic medication</span>

Ototoxicity is defined as the toxic effect on the functioning of the inner ear, which may lead to temporary or permanent hearing loss (cochleotoxic) and balancing problems (vestibulotoxic). Drugs or pharmaceutical agents inducing ototoxicity are regarded as ototoxic medications.

References

  1. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 "Bumetanide Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 8 April 2019.
  3. 1 2 "Bumetanide (Bumex) Use During Pregnancy". Drugs.com. Retrieved 8 April 2019.
  4. 1 2 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 225–226. ISBN   978-0-85711-338-2.
  5. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 458. ISBN   978-3-527-60749-5.
  6. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl: 10665/345533 . WHO/MHP/HPS/EML/2021.02.
  7. ↑ "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  8. ↑ "Bumetanide - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  9. ↑ Strom BL, Schinnar R, Apter AJ, Margolis DJ, Lautenbach E, Hennessy S, et al. (October 2003). "Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics". The New England Journal of Medicine. 349 (17): 1628–1635. doi: 10.1056/NEJMoa022963 . PMID   14573734.
  10. ↑ Hemstreet BA, Page RL (April 2006). "Sulfonamide allergies and outcomes related to use of potentially cross-reactive drugs in hospitalized patients". Pharmacotherapy. 26 (4): 551–557. doi:10.1592/phco.26.4.551. PMID   16553515. S2CID   21612858.
  11. ↑ Tornero P, De Barrio M, Baeza ML, Herrero T (August 2004). "Cross-reactivity among p-amino group compounds in sulfonamide fixed drug eruption: diagnostic value of patch testing". Contact Dermatitis. 51 (2): 57–62. doi:10.1111/j.0105-1873.2004.00274.x. PMID   15373844. S2CID   10908796.
  12. 1 2 Brunton L, Lazo JS, Parker KL, eds. (2006). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. pp. 749–753. ISBN   0-07-142280-3.
  13. ↑ DE 1964504,Feit PW,"Arzneimittelzubereitung mit einem Gehalt an 3-Butylamino-4-phenoxy-5-sulfamyl-benzoesaeure und deren Salzen",issued 9 July 1970, assigned to Leo Pharma Products, Ltd.
  14. ↑ Feit PW (May 1971). "Aminobenzoic acid diuretics. 2. 4-Substituted-3-amino-5-sulfamylbenzoic acid derivatives". Journal of Medicinal Chemistry. 14 (5): 432–9. doi:10.1021/jm00287a014. PMID   5117690.
  15. ↑ US 3634583,Feit PW,"Pharmaceutical composition for the treatment of oedematous conditions and hypertension",issued 11 January 1972, assigned to Leo Pharmaceutical Products Ltd AS
  16. ↑ US 4082851,Feit PW, Nielsen OB, Bruun H, Bretting CA,"Sulphonamides, compositions containing the same and methods for using the same in the treatment of hypertension or odemeas",issued 4 April 1978, assigned to Leo Pharmaceutical Products Ltd AS
  17. ↑ "McAllister, Smith, Grant, Texans' Pittman among players testing positive". ESPN.com. ESPN. October 26, 2008. Retrieved June 6, 2017.
  18. ↑ Food and Drug Administration Office of Criminal Investigations (March 26, 2014). "Pills Sold Throughout the United States Contained an Undisclosed Prescription Drug Banned By the National Football League". U.S. Department of Justice Press Release. United States Food and Drug Administration. Retrieved June 6, 2017.
  19. ↑ Löscher W, Puskarjov M, Kaila K (June 2013). "Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments". Neuropharmacology. 69: 62–74. doi:10.1016/j.neuropharm.2012.05.045. PMID   22705273. S2CID   22267675.
  20. ↑ Sprengers JJ, van Andel DM, Zuithoff NP, Keijzer-Veen MG, Schulp AJ, Scheepers FE, et al. (July 2020). "Bumetanide for Core Symptoms of Autism Spectrum Disorder (BAMBI): A Single Center, Double-Blinded, Participant-Randomized, Placebo-Controlled, Phase-2 Superiority Trial". Journal of the American Academy of Child and Adolescent Psychiatry. 60 (7): 865–876. doi: 10.1016/j.jaac.2020.07.888 . PMID   32730977. Recent trials have indicated positive effects of bumetanide in autism spectrum disorder (ASD).
  21. ↑ Zhang L, Huang CC, Dai Y, Luo Q, Ji Y, Wang K, et al. (January 2020). "Symptom improvement in children with autism spectrum disorder following bumetanide administration is associated with decreased GABA/glutamate ratios". Translational Psychiatry. 10 (1): 9. doi: 10.1038/s41398-020-0692-2 . PMC   7026137 . PMID   32066666.

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