Salbutamol

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Salbutamol
Salbutamol.svg
RS-salbutamol-from-xtal-3D-balls.png
Salbutamol (top),
(R)-(−)-salbutamol (center) and
(S)-(+)-salbutamol (bottom)
Clinical data
Trade names Ventolin, Proventil, others[3]
Synonyms Albuterol (USAN US)
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • AU: A [1]
  • US: C (Risk not ruled out) [2]
Routes of
administration
by mouth, inhalational, IV
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Liver
Onset of action <15 min (inhaled), <30 min (pill)[6]
Elimination half-life 3.8–6 hours
Duration of action 2–6 hrs[6]
Excretion Kidney
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.038.552 Edit this at Wikidata
Chemical and physical data
Formula C13H21NO3
Molar mass 239.311 g/mol
3D model (JSmol)
Chirality Racemic mixture
 ☒N☑Y (what is this?)  (verify)

Salbutamol, also known as albuterol and marketed as Ventolin among other names,[3] is a medication that opens up the medium and large airways in the lungs.[6] It is used to treat asthma including asthma attacks, exercise-induced bronchoconstriction, and 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 is also available as a pill 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] It is a short-acting β2 adrenergic receptor agonist which works by causing airway smooth muscles to relax.[6]

Salbutamol was first made in 1967 in Britain and became commercially available in the UK in 1969.[10] 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, the most effective and safe medicines needed in a health system.[11] Salbutamol is available as a generic medication.[6] The wholesale cost in the developing world of an inhaler which contains 200 doses is between US$1.12 and US$2.64 as of 2014.[12] In the United States, it is between $25 and $50 for a typical month supply.[13]

Medical uses[edit]

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).[14]

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, better tolerated, and administered orally.[15]

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[edit]

The most common side effects are fine tremor, anxiety, headache, muscle cramps, dry mouth, and palpitation.[16] Other symptoms may include tachycardia, arrhythmia, flushing of the skin, myocardial ischemia (rare), and disturbances of sleep and behaviour.[16] 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 renal failure and those on certain diuretics and xanthine derivatives.[16]

Pharmacology[edit]

The tertiary butyl group in salbutamol makes it more selective for β2 receptors,[17] 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.[18][19] 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.[20]

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

Chemistry[edit]

Structure and activity[edit]

(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).[21] The slower metabolism of the (S)-(+)-enantiomer also causes it to accumulate in the lungs, which can cause airway hyperreactivity and inflammation.[22]

History[edit]

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.[23]

The 1972 Munich Olympics were the first Olympics where anti-doping measures were deployed, and at that time beta-2 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 beta-2 agonists were not). After a steep rise in the number of athletes taking beta-2 agonists for asthma in the 1990s, Olympic athletes were required to provide proof that they had asthma in order be allowed to use inhaled beta-2 agonists.[24]

Society and culture[edit]

Cost[edit]

International wholesale price of 200 doses of salbutamol[12]

The wholesale cost of a 200-dose inhaler is between US$1.12 and US$2.64 in the developing world as of 2014[12] and GB£1.50 in the United Kingdom as of 2015.[25] In the United States, a typical month supply is between $25 and $50.[13]

Names[edit]

Ventolin 2 mg tablets made by GSK (Turkey)

Salbutamol is the INN (international nonproprietary name) while albuterol is the USAN (United States adopted name). The drug is usually manufactured and distributed as the sulphate salt (salbutamol sulphate).

It was first sold by Allen & Hanburys (UK) under the brand name Ventolin, and has been used for the treatment of asthma ever since.[26] The drug is marketed under many names worldwide.[3]

Doping[edit]

As of 2011 there was no evidence that an increase in physical performance occurs after inhaling salbutamol, but various reports for benefit when delivered orally or intravenously.[27][28] 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."[29][30]

Abuse of the drug may be confirmed by detection of its presence in plasma or urine, typically exceeding 1000 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,[31][32][33] estimated at between 5 and 6 hours following oral administration of 4 mg.[18]

Research[edit]

Salbutamol has been studied in subtypes of congenital myasthenic syndrome associated with mutations in Dok-7.[34]

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 whose deficiency is regarded as a cause of the disease.[35][36]

Veterinary use[edit]

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.[22] 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.[37][38]

Toxic effects require an extremely high dose, and most overdoses are due to dogs chewing on and puncturing an inhaler or nebulizer vial.[39]

See also[edit]

References[edit]

  1. ^ Thereaputic Goods Administration. "Prescribing medicines in pregnancy database". Australian Government. 
  2. ^ "HSDB:Albuterol". ToxNet. US National Library of Medicine. 
  3. ^ a b c "Salbutamol". Drugs.com. Archived from the original on 2016-03-30. Retrieved April 11, 2016. 
  4. ^ Thereaputic Goods Administration. "Poisons Standard October 2017". Australian Government. 
  5. ^ "Prescription Drug List". Government of Canada. 
  6. ^ a b c d e f g h i j k l m "Albuterol". Drugs.com. The American Society of Health-System Pharmacists. Archived from the original on 2015-12-08. Retrieved Dec 2, 2015. 
  7. ^ a b Mahoney, BA; Smith, WA; Lo, DS; Tsoi, K; Tonelli, M; Clase, CM (18 April 2005). "Emergency interventions for hyperkalaemia". The Cochrane Database of Systematic Reviews (2): CD003235. doi:10.1002/14651858.CD003235.pub2. PMID 15846652. 
  8. ^ a b Starkey, ES; Mulla, H; Sammons, HM; Pandya, HC (September 2014). "Intravenous salbutamol for childhood asthma: evidence-based medicine?" (PDF). Archives of Disease in Childhood. 99 (9): 873–7. doi:10.1136/archdischild-2013-304467. PMID 24938536. Archived from the original (PDF) on 2017-09-08. 
  9. ^ Yaffe, Sumner J. (2011). Drugs in pregnancy and lactation : a reference guide to fetal and neonatal risk (9th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 32. ISBN 9781608317080. Archived from the original on 2015-12-08. 
  10. ^ Landau, Ralph (1999). Pharmaceutical innovation : revolutionizing human health. Philadelphia: Chemical Heritage Press. p. 226. ISBN 9780941901215. Archived from the original on 2015-12-08. 
  11. ^ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016. 
  12. ^ a b c "Salbutamol". International Drug Price Indicator Guide. Retrieved 5 December 2015. 
  13. ^ a b Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 448. ISBN 9781284057560. 
  14. ^ Hatfield, Heather. "Asthma: The Rescue Inhaler -- Now a Cornerstone of Asthma Treatment". WebMD. Archived from the original on 2017-07-16. Retrieved 2017-06-27. 
  15. ^ Rossi, S (2004). Australian Medicines Handbook. AMH. ISBN 0-9578521-4-2. 
  16. ^ a b c "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 0-85369-778-7. 
  17. ^ Lemke, T.L.; Williams, D.A.; Roche, V.F.; Zito, S.W. (2013). Foye's Principles of Medicinal Chemistry. Philadelphia, PA: Lippincott Williams & Wilkins. pp. 1314–1320. ISBN 9781609133450. OCLC 748675182. Archived from the original on 2017-09-08. 
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  19. ^ Papich, Mark G. (2007). "Albuterol Sulfate". Saunders Handbook of Veterinary Drugs (2nd ed.). St. Louis, Mo: Saunders/Elsevier. pp. 10–11. ISBN 9781416028888. 
  20. ^ US Department of Health and Human Services (2017-04-28). "Albuterol - Medical Countermeasures Database". CHEMM. Archived from the original on 2017-08-03. Retrieved 2017-06-23. 
  21. ^ Mehta, Akul. "Medicinal Chemistry of the Peripheral Nervous System – Adrenergics and Cholinergics their Biosynthesis, Metabolism, and Structure Activity Relationships". Archived from the original on 2010-11-04. Retrieved 2010-10-20. 
  22. ^ a b "Inhalation Therapy of Airway Disease". Merck Veterinary Manual. Archived from the original on 2017-06-25. Retrieved 2017-06-22. 
  23. ^ "Sir David Jack, who has died aged 87, was the scientific brain behind the rise of the pharmaceuticals company Glaxo". The Telegraph. Nov 17, 2011. Archived from the original on 2011-11-25. 
  24. ^ Fitch, KD (2006). "beta2-Agonists at the Olympic Games". Clinical reviews in allergy & immunology. 31 (2–3): 259–68. doi:10.1385/CRIAI:31:2:259. PMID 17085798. 
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  29. ^ "The 2010 Prohibited List International Standard" (PDF). WADA. Archived from the original (PDF) on 2013-09-11. Retrieved 2010-10-20. 
  30. ^ "The 2011 Prohibited List International Standard" (PDF). WADA. Archived (PDF) from the original on 2012-05-13. Retrieved 2012-05-22. 
  31. ^ Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Biomedical Publications. pp. 33–35. ISBN 0-9626523-6-9. 
  32. ^ Berges, Rosa; S; V; F; M; F; M; D (2000). "Discrimination of Prohibited Oral Use of Salbutamol from Authorized Inhaled Asthma Treatment". Clinical Chemistry. 46 (9): 1365–75. PMID 10973867. Archived from the original on 2011-07-17. 
  33. ^ Schweizer, C; Saugy, M; Kamber, M (2004). "Doping test reveals high concentrations of salbutamol in a Swiss track and field athlete". Clin. J. Sport Med. 14 (5): 312–315. doi:10.1097/00042752-200409000-00018. PMID 15377972. Archived from the original on 2012-10-05. closed access publication – behind paywall
  34. ^ Liewluck, Teerin; Selcen, Duygu; Engel, Andrew G. (November 2011). "Beneficial effects of albuterol in congenital endplate acetylcholinesterase deficiency and Dok-7 myasthenia". Muscle & Nerve. 44 (5): 789–794. doi:10.1002/mus.22176. PMC 3196786Freely accessible. PMID 21952943. Archived from the original on 2015-12-08. 
  35. ^ Van Meerbeke, J. P.; Sumner, C. J. (2011). "Progress and promise: The current status of spinal muscular atrophy therapeutics". Discovery medicine. 12 (65): 291–305. PMID 22031667. 
  36. ^ Lewelt, A.; Newcomb, T. M.; Swoboda, K. J. (2011). "New Therapeutic Approaches to Spinal Muscular Atrophy". Current Neurology and Neuroscience Reports. 12 (1): 42–53. doi:10.1007/s11910-011-0240-9. PMC 3260050Freely accessible. PMID 22134788. 
  37. ^ Plumb, Donald C. (2011). "Albuterol Sulfate". Plumb's Veterinary Drug Handbook (7th ed.). Stockholm, Wisconsin; Ames, Iowa: Wiley. pp. 24–25. ISBN 9780470959640. 
  38. ^ Clarke, Kathy W.; Trim, Cynthia M. (2013-06-28). Veterinary Anaesthesia E-Book. Elsevier Health Sciences. p. 612. ISBN 9780702054235. Archived from the original on 2017-09-08. 
  39. ^ Cote, Etienne (2014-12-09). "Albuterol Toxicosis". Clinical Veterinary Advisor - E-Book: Dogs and Cats. Elsevier Health Sciences. pp. 45–46. ISBN 9780323240741. Archived from the original on 2017-09-08. 

External links[edit]