Salbutamol

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| _other_data=(RS)-4-[2-(tert-Butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol

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Salbutamol, also known as albuterol and sold under the brand name Ventolin among others,<ref name=brands/> is a medication that opens up the medium and large airways in the lungs.<ref name=AHFS2015>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is a short-acting β₂ adrenergic receptor agonist that causes relaxation of airway smooth muscle.<ref name="AHFS2015" /> It is used to treat asthma, including asthma attacks and exercise-induced bronchoconstriction, as well as chronic obstructive pulmonary disease (COPD).<ref name=AHFS2015/> It may also be used to treat high blood potassium levels.<ref name=Mah2005>Template:Cite journal</ref> Salbutamol is usually used with an inhaler or nebulizer, but it is also available in a pill, liquid, and intravenous solution.<ref name=AHFS2015/><ref name=starkey>Template:Cite journal</ref> Onset of action of the inhaled version is typically within 15 minutes and lasts for two to six hours.<ref name=AHFS2015/>

Common side effects include shakiness, headache, fast heart rate, dizziness, and feeling anxious.<ref name="AHFS2015" /> Serious side effects may include worsening bronchospasm, irregular heartbeat, and low blood potassium levels.<ref name=AHFS2015/> It can be used during pregnancy and breastfeeding, but safety is not entirely clear.<ref name=AHFS2015/><ref>Template:Cite book</ref>

Salbutamol was patented in 1966 in Britain and became commercially available in the UK in 1969.<ref>Template:Cite book</ref><ref name=Fis2006>Template:Cite book</ref> It was approved for medical use in the United States in 1982.<ref name=AHFS2015/> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">Template:Cite book</ref> Salbutamol is available as a generic medication.<ref name=AHFS2015/> In 2022, it was the seventh most commonly prescribed medication in the United States, with more than 59Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name=AHFS2015 /> It is also one of the most common medicines used in rescue inhalers (short-term bronchodilators to alleviate asthma attacks).<ref name=webmd>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="rossi">Template:Cite book</ref>

Salbutamol has been used to treat acute hyperkalemia, as it stimulates potassium flow into cells, thus lowering the potassium in the blood.<ref name=Mah2005/>

Two recent studies have suggested that salbutamol reduces the symptoms of newborns and adolescents with myasthenia gravis and transient neonatal myasthenia gravis.<ref name="pmid26791147">Template:Cite journal</ref><ref name="pmid37186601">Template:Cite journal</ref>

Adverse effects

The most common side effects are fine tremor, anxiety, headache, muscle cramps, dry mouth, and palpitation.<ref name=BNF57>Template:Cite book</ref> Other symptoms may include tachycardia, arrhythmia, flushing of the skin, myocardial ischemia (rare), and disturbances of sleep and behaviour.<ref name=BNF57/> 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.<ref name=BNF57/>

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.<ref>Template:Cite news</ref>

Pharmacology

The tertiary butyl group in salbutamol makes it more selective for β₂ receptors,<ref name="Lemke2013">Template:Cite book</ref> 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.<ref name=rxlist /><ref>Template:Cite book</ref> 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.<ref name=chemm>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Salbutamol is either filtered out by the kidneys directly or is first metabolized into the 4′-O-sulfate, which is excreted in the urine.<ref name=starkey />

Chemistry

File:(R)- and (S)-salbutamol.svg

(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).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The slower metabolism of the (S)-(+)-enantiomer also causes it to accumulate in the lungs, which can cause airway hyperreactivity and inflammation.<ref name=merck>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite journal</ref>

The direct separation of Salbutamol enantiomers and the control of enantiomeric purity has been described by thin-layer chromatography.<ref name="pmid20074739">Template:Cite journal</ref>

History

Salbutamol was discovered in 1966, by a research team led by David Jack at the Allen and Hanburys laboratory (now a subsidiary of Glaxo) in Ware, Hertfordshire, England, and was launched as Ventolin in 1969.<ref name=SirDavidJack_telegraph> Template:Cite news</ref>

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.<ref name=Fitch2006>Template:Cite journal</ref>

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.<ref name="FDA Albuterol PR">Template:Cite press release Template:PD-notice</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}Template:Dead linkTemplate:Cbignore</ref> The FDA granted approval of the generic albuterol sulfate inhalation aerosol to Perrigo Pharmaceutical.<ref name="FDA Albuterol PR" />

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.<ref name="FDA Proventil PR">Template:Cite press releaseTemplate:Dead linkTemplate:Cbignore Template:PD-notice</ref> The FDA granted approval of this generic albuterol sulfate inhalation aerosol to Cipla Limited.<ref name="FDA Proventil PR" />

Society and culture

In 2020, generic versions were approved in the United States.<ref name="FDA Albuterol PR" /><ref name="FDA Proventil PR" />

Names

File:Ventolin 2mg.JPG

Ventolin 2 mg tablets made by GSK (Turkey)

Salbutamol is the international nonproprietary name (INN) while albuterol is the United States Adopted Name (USAN).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>Template:Cite journal</ref> The drug is marketed under many names worldwide.<ref name="brands">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Misuse

Albuterol and other beta-2 adrenergic agonists are used by some recreational bodybuilders.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Doping

Template:As of 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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."<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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,<ref name="R. Baselt, 2008, pp. 33-35">Template:Cite book</ref><ref>Template:Cite journal</ref><ref>Template:Cite journalTemplate:Closed access</ref> estimated at between 5 and 6 hours following oral administration of 4 mg.<ref name=rxlist>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Research

Salbutamol has been studied in subtypes of congenital myasthenic syndrome associated with mutations in Dok-7.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Albuterol increases energy expenditure by 10 to 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref name=merck /> 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.<ref>Template:Cite book</ref><ref>Template:Cite book</ref>

Toxic effects require an extremely high dose, and most overdoses are due to dogs chewing on and puncturing an inhaler or nebulizer vial.<ref>Template:Cite book</ref>

References

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