Chemistry:Salbutamol

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Short description: Medication
Salbutamol
Salbutamol.svg
RS-salbutamol-from-xtal-3D-balls.png
Salbutamol (top),
(R)-(−)-salbutamol (center) and
(S)-(+)-salbutamol (bottom)
Clinical data
Trade namesVentolin, Proventil, ProAir, others[1]
Other namesAlbuterol (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa607004
License data
Pregnancy
category
Routes of
administration		By mouth, Inhalational, Intravenous
Drug classBeta2-adrenergic agonist
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismLiver
Onset of action<15 min (inhaled), <30 min (pill)[6]
Elimination half-life3.8–6 hrs (inhaled); 5–7.2 hrs (pill)[6]
Duration of action3–6 hrs (inhaled); up to 8 hrs (pill)[6]
ExcretionKidney
Identifiers
CAS Number
PubChem CID
PubChem SID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC13H21NO3
Molar mass239.315 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
 ☒N☑Y (what is this?)  (verify)

Salbutamol, also known as albuterol and sold under the brand name Ventolin among others,[1] is a medication that opens up the medium and large airways in the lungs.[6] It is a short-acting β2 adrenergic receptor agonist which works by causing relaxation of airway smooth muscle.[6] It is used to treat asthma, including asthma attacks and exercise-induced bronchoconstriction, as well as chronic obstructive pulmonary disease (COPD).[6] It may also be used to treat high blood potassium levels.[7] Salbutamol is usually used with an inhaler or nebulizer, but it is also available in a pill, liquid, and intravenous solution.[6][8] Onset of action of the inhaled version is typically within 15 minutes and lasts for two to six hours.[6]

Common side effects include shakiness, headache, fast heart rate, dizziness, and feeling anxious.[6] Serious side effects may include worsening bronchospasm, irregular heartbeat, and low blood potassium levels.[6] It can be used during pregnancy and breastfeeding, but safety is not entirely clear.[6][9]

Salbutamol was patented in 1966 in Britain and became commercially available in the UK in 1969.[10][11] It was approved for medical use in the United States in 1982.[6] It is on the World Health Organization's List of Essential Medicines.[12] Salbutamol is available as a generic medication.[6] In 2021, it was the seventh most commonly prescribed medication in the United States, with more than 61 million prescriptions.[13][14]

Medical uses

Salbutamol is typically used to treat bronchospasm (due to any cause—allergic asthma or exercise-induced), as well as chronic obstructive pulmonary disease.[6] It is also one of the most common medicines used in rescue inhalers (short-term bronchodilators to alleviate asthma attacks).[15]

As a β2 agonist, salbutamol also has use in obstetrics. Intravenous salbutamol can be used as a tocolytic to relax the uterine smooth muscle to delay premature labor. While preferred over agents such as atosiban and ritodrine, its role has largely been replaced by the calcium channel blocker nifedipine, which is more effective and better tolerated.[16]

Salbutamol has been used to treat acute hyperkalemia, as it stimulates potassium flow into cells, thus lowering the potassium in the blood.[7]

Adverse effects

The most common side effects are fine tremor, anxiety, headache, muscle cramps, dry mouth, and palpitation.[17] Other symptoms may include tachycardia, arrhythmia, flushing of the skin, myocardial ischemia (rare), and disturbances of sleep and behaviour.[17] Rarely occurring, but of importance, are allergic reactions of paradoxical bronchospasms, urticaria (hives), angioedema, hypotension, and collapse. High doses or prolonged use may cause hypokalemia, which is of concern especially in patients with kidney failure and those on certain diuretics and xanthine derivatives.[17]

Salbutamol metered dose inhalers have been described as the "single biggest source of carbon emissions from NHS medicines prescribing" due to the propellants used in the inhalers. Dry powder inhalers are recommended as a low-carbon alternative.[18]

Pharmacology

The tertiary butyl group in salbutamol makes it more selective for β2 receptors,[19] which are the predominant receptors on the bronchial smooth muscles. Activation of these receptors causes adenylyl cyclase to convert ATP to cAMP, beginning the signalling cascade that ends with the inhibition of myosin phosphorylation and lowering the intracellular concentration of calcium ions (myosin phosphorylation and calcium ions are necessary for muscle contractions). The increase in cAMP also inhibits inflammatory cells in the airway, such as basophils, eosinophils, and most especially mast cells, from releasing inflammatory mediators and cytokines.[20][21] Salbutamol and other β2 receptor agonists also increase the conductance of channels sensitive to calcium and potassium ions, leading to hyperpolarization and relaxation of bronchial smooth muscles.[22]

Salbutamol is either filtered out by the kidneys directly or is first metabolized into the 4′-O-sulfate, which is excreted in the urine.[8]

Chemistry

(R)-(−)-salbutamol (top) and (S)-(+)-salbutamol (bottom)

Salbutamol is sold as a racemic mixture. The (R)-(−)-enantiomer (CIP nomenclature) is shown in the image at right (top), and is responsible for the pharmacologic activity; the (S)-(+)-enantiomer (bottom) blocks metabolic pathways associated with elimination of itself and of the pharmacologically active enantiomer (R).[23] The slower metabolism of the (S)-(+)-enantiomer also causes it to accumulate in the lungs, which can cause airway hyperreactivity and inflammation.[24] Potential formulation of the R form as an enantiopure drug is complicated by the fact that the stereochemistry is not stable, but rather the compound undergoes racemization within a few days to weeks, depending on pH.[25]

The direct separation of Salbutamol enantiomers and the control of enantiomeric purity has been described by thin-layer chromatography.[26]

History

Salbutamol was discovered in 1966, by a team led by David Jack at the Allen and Hanburys laboratory (a subsidiary of Glaxo) in Ware, Hertfordshire, England, and was launched as Ventolin in 1969.[27]

The 1972 Munich Olympics were the first Olympics where anti-doping measures were deployed, and at that time β2 agonists were considered to be stimulants with high risk of abuse for doping. Inhaled salbutamol was banned from those games, but by 1986 was permitted (although oral β2 agonists were not). After a steep rise in the number of athletes taking β2 agonists for asthma in the 1990s, Olympic athletes were required to provide proof that they had asthma in order to be allowed to use inhaled β2 agonists.[28]

In February 2020, the U.S. Food and Drug Administration (FDA) approved the first generic of an albuterol sulfate inhalation aerosol for the treatment or prevention of bronchospasm in people four years of age and older with reversible obstructive airway disease and the prevention of exercise-induced bronchospasm in people four years of age and older.[29][30] The FDA granted approval of the generic albuterol sulfate inhalation aerosol to Perrigo Pharmaceutical.[29]

In April 2020, the FDA approved the first generic of Proventil HFA (albuterol sulfate) metered dose inhaler, 90 μg per inhalation, for the treatment or prevention of bronchospasm in patients four years of age and older who have reversible obstructive airway disease, as well as the prevention of exercise-induced bronchospasm in this age group.[31] The FDA granted approval of this generic albuterol sulfate inhalation aerosol to Cipla Limited.[31]

Society and culture

In 2020, generic versions were approved in the United States.[29][31]

Names

Ventolin 2 mg tablets made by GSK (Turkey)

Salbutamol is the international nonproprietary name (INN) while albuterol is the United States Adopted Name (USAN).[32] The drug is usually manufactured and distributed as the sulfate salt (salbutamol sulfate).

It was first sold by Allen & Hanburys (UK) under the brand name Ventolin, and has been used for the treatment of asthma ever since.[33] The drug is marketed under many names worldwide.[1]

Misuse

Albuterol and other beta-2 adrenergic agonists are used by some recreational bodybuilders.[34][35]

Doping

(As of 2011) there was no evidence that an increase in physical performance occurs after inhaling salbutamol, but there are various reports for benefit when delivered orally or intravenously.[36][37] In spite of this, salbutamol required "a declaration of Use in accordance with the International Standard for Therapeutic Use Exemptions" under the 2010 WADA prohibited list. This requirement was relaxed when the 2011 list was published to permit the use of "salbutamol (maximum 1600 micrograms over 24 hours) and salmeterol when taken by inhalation in accordance with the manufacturers' recommended therapeutic regimen."[38][39]

Abuse of the drug may be confirmed by detection of its presence in plasma or urine, typically exceeding 1,000 ng/mL. The window of detection for urine testing is on the order of just 24 hours, given the relatively short elimination half-life of the drug,[40][41][42] estimated at between 5 and 6 hours following oral administration of 4 mg.[20]

Research

Salbutamol has been studied in subtypes of congenital myasthenic syndrome associated with mutations in Dok-7.[43]

It has also been tested in a trial aimed at treatment of spinal muscular atrophy; it is speculated to modulate the alternative splicing of the SMN2 gene, increasing the amount of the SMN protein, the deficiency of which is regarded as a cause of the disease.[44][45]

Albuterol increases energy expenditure by 10-15 percent at a therapeutic dose for asthma and around 25 percent at a higher, oral dose. In several human studies, albuterol increased lean body mass, reduced fat mass, and caused lipolysis; it has been studied for use as an anti-obesity and anti-muscle wasting medication when taken orally.[46][47]

Veterinary use

Salbutamol's low toxicity makes it safe for other animals and thus is the medication of choice for treating acute airway obstruction in most species.[24] It is usually used to treat bronchospasm or coughs in cats and dogs and used as a bronchodilator in horses with recurrent airway obstruction; it can also be used in emergencies to treat asthmatic cats.[48][49]

Toxic effects require an extremely high dose, and most overdoses are due to dogs chewing on and puncturing an inhaler or nebulizer vial.[50]

References

  1. ↑ 1.0 1.1 1.2 "Salbutamol". https://www.drugs.com/international/salbutamol.html. 
  2. ↑ Thereaputic Goods Administration (19 December 2018). "Prescribing medicines in pregnancy database". Australian Government. https://www.tga.gov.au/prescribing-medicines-pregnancy-database. 
  3. ↑ "Albuterol Use During Pregnancy". 8 March 2019. https://www.drugs.com/pregnancy/albuterol.html. 
  4. ↑ Thereaputic Goods Administration. "Poisons Standard October 2017". Australian Government. https://www.legislation.gov.au/Details/F2017L01285/Html/Text#_Toc471222305. 
  5. ↑ "Prescription Drug List". Government of Canada. 23 October 2014. https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/prescription-drug-list/list.html. 
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 "Albuterol". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/albuterol.html. 
  7. ↑ 7.0 7.1 "Emergency interventions for hyperkalaemia". The Cochrane Database of Systematic Reviews 2005 (2): CD003235. April 2005. doi:10.1002/14651858.CD003235.pub2. PMID 15846652. 
  8. ↑ 8.0 8.1 "Intravenous salbutamol for childhood asthma: evidence-based medicine?". Archives of Disease in Childhood 99 (9): 873–7. September 2014. doi:10.1136/archdischild-2013-304467. PMID 24938536. https://derbyhospitals-nhs.archive.knowledgearc.net/bitstream/handle/123456789/297/%2814%29%20Arch%20Dis%20Child.pdf?sequence=1&isAllowed=y. 
  9. ↑ Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk (9th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. 2011. p. 32. ISBN 9781608317080. https://books.google.com/books?id=OIgTE4aynrMC&pg=PA32. 
  10. ↑ Pharmaceutical innovation: revolutionizing human health. Philadelphia: Chemical Heritage Press. 1999. p. 226. ISBN 9780941901215. https://books.google.com/books?id=IH4lPs6S1bMC&pg=PA226. 
  11. ↑ Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 542. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA542. 
  12. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  13. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  14. ↑ "Albuterol - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Albuterol. 
  15. ↑ "Asthma: The Rescue Inhaler -- Now a Cornerstone of Asthma Treatment". WebMD. http://www.webmd.com/asthma/features/asthma-rescue-inhaler-cornerstone-asthma-treatment. 
  16. ↑ Australian Medicines Handbook. AMH. 2004. ISBN 978-0-9578521-4-3. 
  17. ↑ 17.0 17.1 17.2 "3.1.1.1 Selective beta2 agonists – side effects". British National Formulary (57 ed.). London: BMJ Publishing Group Ltd and Royal Pharmaceutical Society Publishing. March 2008. ISBN 978-0-85369-778-7. https://archive.org/details/britishnationalf0000unse_k4e9. 
  18. ↑ "Primary care networks incentivised to switch patients to more environmentally friendly inhalers". Pharmaceutical Journal. 3 September 2021. https://pharmaceutical-journal.com/article/news/primary-care-networks-incentivised-to-switch-patients-to-more-environmentally-friendly-inhalers?. 
  19. ↑ Foye's Principles of Medicinal Chemistry. Philadelphia, PA: Lippincott Williams & Wilkins. 2013. pp. 1314–1320. ISBN 9781609133450. OCLC 748675182. https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA1315. 
  20. ↑ 20.0 20.1 "Albuterol Sulfate". Rx List: The Internet Drug Index. http://www.rxlist.com/albuterol-sulfate-drug/clinical-pharmacology.htm. 
  21. ↑ "Albuterol Sulfate". Saunders Handbook of Veterinary Drugs (2nd ed.). St. Louis, Mo: Saunders/Elsevier. 2007. pp. 10–11. ISBN 9781416028888. 
  22. ↑ "Albuterol - Medical Countermeasures Database". CHEMM. US Department of Health and Human Services. 28 April 2017. https://chemm.nlm.nih.gov/countermeasure_albuterol.htm. 
  23. ↑ "Medicinal Chemistry of the Peripheral Nervous System – Adrenergics and Cholinergics their Biosynthesis, Metabolism, and Structure Activity Relationships". http://pharmaxchange.info/notes/medicinal_chemistry/adrenergics_cholinergics.html. 
  24. ↑ 24.0 24.1 "Inhalation Therapy of Airway Disease". Merck Veterinary Manual. http://www.merckvetmanual.com/pharmacology/systemic-pharmacotherapeutics-of-the-respiratory-system/inhalation-therapy-of-airway-disease. 
  25. ↑ "Study of pH Stability of R-Salbutamol Sulfate Aerosol Solution and Its Antiasthmatic Effects in Guinea Pigs". Biol Pharm Bull 40 (9): 1374–1380. 1 September 2017. doi:10.1248/bpb.b17-00067. PMID 28652557. 
  26. ↑ Bhushan, R.; Tanwar, S. J. Chromatogr. A 2010, 1217, 1395–1398. (doi:10.1016/j.chroma.2009.12.071)
  27. ↑ "Sir David Jack, who has died aged 87, was the scientific brain behind the rise of the pharmaceuticals company Glaxo". The Telegraph. 17 November 2011. https://www.telegraph.co.uk/news/obituaries/finance-obituaries/8897458/Sir-David-Jack.html. 
  28. ↑ "beta2-Agonists at the Olympic Games". Clinical Reviews in Allergy & Immunology 31 (2–3): 259–68. 2006. doi:10.1385/CRIAI:31:2:259. PMID 17085798. 
  29. ↑ 29.0 29.1 29.2 "FDA approves first generic of ProAir HFA". U.S. Food and Drug Administration (FDA) (Press release). 24 February 2020. Retrieved 24 February 2020. This article incorporates text from this source, which is in the public domain.
  30. ↑ "Albuterol Sulfate: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=203760. 
  31. ↑ 31.0 31.1 31.2 "FDA Approves First Generic of a Commonly Used Albuterol Inhaler to Treat and Prevent Bronchospasm". U.S. Food and Drug Administration (FDA) (Press release). 8 April 2020. Retrieved 10 April 2020. This article incorporates text from this source, which is in the public domain.
  32. ↑ "Salbutamol". PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/Salbutamol#section=Pharmacology. 
  33. ↑ "Ventolin remains a breath of fresh air for asthma sufferers, after 40 years". The Pharmaceutical Journal 279 (7473): 404–405. http://www.pharmj.com/pdf/articles/pj_20071013_landmarkdrugs01.pdf. 
  34. ↑ "β2-Adrenergic agonist salbutamol augments hypertrophy in MHCIIa fibers and sprint mean power output but not muscle force during 11 weeks of resistance training in young men". Journal of Applied Physiology 130 (3): 617–626. March 2021. doi:10.1152/japplphysiol.00553.2020. PMID 33357007. https://findresearcher.sdu.dk/ws/files/178570378/japplphysiol.00553.2020.pdf. 
  35. ↑ "Anabolic steroid users' misuse of non-traditional prescription drugs". Research in Social & Administrative Pharmacy 15 (8): 949–952. August 2019. doi:10.1016/j.sapharm.2018.07.003. PMID 31303195. 
  36. ↑ "β₂-Agonists and physical performance: a systematic review and meta-analysis of randomized controlled trials". Sports Medicine 41 (1): 39–57. January 2011. doi:10.2165/11537540-000000000-00000. PMID 21142283. 
  37. ↑ "The rush to adrenaline: drugs in sport acting on the beta-adrenergic system". British Journal of Pharmacology 154 (3): 584–97. June 2008. doi:10.1038/bjp.2008.164. PMID 18500380. 
  38. ↑ "The 2010 Prohibited List International Standard". WADA. http://www.wada-ama.org/Documents/World_Anti-Doping_Program/WADP-Prohibited-list/WADA_Prohibited_List_2010_EN.pdf. 
  39. ↑ "The 2011 Prohibited List International Standard". WADA. http://www.wada-ama.org/Documents/World_Anti-Doping_Program/WADP-Prohibited-list/To_be_effective/WADA_Prohibited_List_2011_EN.pdf. 
  40. ↑ Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Biomedical Publications. 2008. pp. 33–35. ISBN 978-0-9626523-6-3. 
  41. ↑ "Discrimination of prohibited oral use of salbutamol from authorized inhaled asthma treatment". Clinical Chemistry 46 (9): 1365–75. September 2000. doi:10.1093/clinchem/46.9.1365. PMID 10973867. http://www.clinchem.org/cgi/content/abstract/46/9/1365. 
  42. ↑ "Doping test reveals high concentrations of salbutamol in a Swiss track and field athlete". Clinical Journal of Sport Medicine 14 (5): 312–5. September 2004. doi:10.1097/00042752-200409000-00018. PMID 15377972. closed access
  43. ↑ "Beneficial effects of albuterol in congenital endplate acetylcholinesterase deficiency and Dok-7 myasthenia". Muscle & Nerve 44 (5): 789–94. November 2011. doi:10.1002/mus.22176. PMID 21952943. 
  44. ↑ "Progress and promise: the current status of spinal muscular atrophy therapeutics". Discovery Medicine 12 (65): 291–305. October 2011. PMID 22031667. http://www.discoverymedicine.com/James-P-Van-Meerbeke/2011/10/12/progress-and-promise-the-current-status-of-spinal-muscular-atrophy-therapeutics/. 
  45. ↑ "New therapeutic approaches to spinal muscular atrophy". Current Neurology and Neuroscience Reports 12 (1): 42–53. February 2012. doi:10.1007/s11910-011-0240-9. PMID 22134788. 
  46. ↑ "The beta2 -adrenergic receptor - a re-emerging target to combat obesity and induce leanness?". The Journal of Physiology 600 (5): 1209–1227. March 2022. doi:10.1113/JP281819. PMID 34676534. 
  47. ↑ "Anabolic and lipolytic actions of beta2 -agonists in humans and antidoping challenges". Drug Testing and Analysis 12 (5): 597–609. May 2020. doi:10.1002/dta.2728. PMID 31960603. 
  48. ↑ "Albuterol Sulfate". Plumb's Veterinary Drug Handbook (7th ed.). Stockholm, Wisconsin; Ames, Iowa: Wiley. 2011. pp. 24–25. ISBN 9780470959640. 
  49. ↑ Veterinary Anaesthesia E-Book. Elsevier Health Sciences. 28 June 2013. p. 612. ISBN 9780702054235. https://books.google.com/books?id=hZh5AAAAQBAJ&pg=PA612. 
  50. ↑ "Albuterol Toxicosis". Clinical Veterinary Advisor - E-Book: Dogs and Cats. Elsevier Health Sciences. 9 December 2014. pp. 45–46. ISBN 9780323240741. https://books.google.com/books?id=NmziBQAAQBAJ&pg=PR120. 

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