Salbutamol

Salbutamol (top), (R)-(−)-salbutamol (center) and (S)-(+)-salbutamol (bottom)
Systematic (IUPAC) name
(RS)-4-[2-(tert-Butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol
Clinical data
Trade names	Ventolin, Proventil, others
AHFS/Drugs.com	monograph
Licence data	US FDA:link
Pregnancy category	AU: A US: C (Risk not ruled out)
Legal status	AU: S3 (Pharmacist only) CA: F (prescription) UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral, inhalational, IV
Pharmacokinetic data
Metabolism	Liver
Onset of action	<15 min (inhaled), <30 min (pill)
Biological half-life	3.8–6 hours
Duration of action	2–6 hrs
Excretion	Kidney
Identifiers
CAS Number	18559-94-9 Y
ATC code	R03AC02 (WHO) R03CC02
PubChem	CID: 2083
IUPHAR/BPS	558
DrugBank	DB01001 Y
ChemSpider	1999 Y
UNII	QF8SVZ843E Y
KEGG	D02147 Y
ChEBI	CHEBI:2549 Y
ChEMBL	CHEMBL714 Y
Chemical data
Formula	C13H21NO3
Molecular mass	239.311 g/mol
SMILES OCc1cc(ccc1O)C(O)CNC(C)(C)C
InChI InChI=1S/C13H21NO3/c1-13(2,3)14-7-12(17)9-4-5-11(16)10(6-9)8-15/h4-6,12,14-17H,7-8H2,1-3H3 Y Key:NDAUXUAQIAJITI-UHFFFAOYSA-N Y
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Salbutamol, also known as albuterol and marketed as Ventolin among other names, is a medication that opens up the medium and large airways in the lungs. It is used to treat asthma, exercise-induced bronchospasm, and chronic obstructive pulmonary disease (COPD). It may also be used to treat high blood potassium levels. It is usually used by inhaler or nebulizer but is also available as a pill and intravenous solution. Onset of action of the inhaled version is typically within 15 minutes and lasts for two to six hours.

Common side effects include shakiness, headache, fast heart rate, dizziness, and feeling anxious. Serious side effects may include worsening bronchospasm, irregular heartbeat, and low blood potassium levels. It can be used during pregnancy and breastfeeding, but safety is not entirely clear. Salbutamol is a short-acting β₂ adrenergic receptor agonist which works by causing airway smooth muscles to relax.

Salbutamol was first made in 1967 in Britain. It was approved for medical use in the United States in 1982. It is on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system. It is available as a generic medication. The wholesale cost of an inhaler which contains 200 doses is between $1.12 and $2.64 (USD) in the developing world as of 2014. In the United States it is between $25 and $50 for a typical month supply.

Medical uses

Salbutamol is typically used to treat bronchospasm (due to any cause, allergen asthma or exercise-induced), as well as chronic obstructive pulmonary disease.

As a β₂ agonist, salbutamol also finds 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 orally administered.

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

Adverse effects

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

Chemistry

Structure and activity

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

This drug 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 both of it and of the pharmacologically active enantiomer.

With regard to structure-activity relationships, the tertiary butyl group in albuterol/salbutamol makes it more selective for β₂ receptors.

Detection after dosing

Salbutamol may be quantified in blood or plasma; practical needs for this include to confirm a diagnosis of poisoning in hospitalized patients, or to aid in a forensic investigation. As well, urinary salbutamol concentrations are frequently measured in competitive sports programs, for which a level in excess of 1000 μg/L is considered to represent abuse.

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, estimated at between 5 and 6 hours following oral administration of 4 mg.

Society and culture

Cost

Compliance with the Montreal Protocol, which requires the banning of the use of ozone-layer depleting CFCs, has caused the price of inhalers to increase as much as ten-fold, as generics have been forced off the market from 2009 to 2013 by new patents obtained by pharmaceutical companies for non-CFC delivery systems.

Names

Ventolin 2 mg tablets made by GSK (Turkey)

Salbutamol is the INN while albuterol is the USAN. 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. The drug is marketed under many names worldwide.

Doping

Clinical studies show no compelling evidence that salbutamol and other β₂ agonists can increase performance in healthy athletes. 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."

According to two small and limited studies, performed on eight and 16 subjects, respectively, salbutamol increases performance on endurance exercise even for a person without asthma.

Another study contradicts the above findings, however. The double blind, randomised test conducted on 12 non-asthmatic athletes concluded that salbutamol had a negligible effect on endurance performance. Nevertheless, the study also showed that the drug's bronchodilating effect may have improved respiratory adaptation at the beginning of exercise.

Salbutamol has been shown to improve muscle weight in rats and anecdotal reports hypothesise that it might be an alternative to clenbuterol for purposes of fat burning and muscle gain, with multiple studies supporting this claim. Abuse of the drug may be confirmed by detection of its presence in plasma or urine, typically exceeding 1000 µg/L.

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. In 2015, the US FDA approved a generic form under the name Proair Respiclick for Teva Pharmaceuticals.

Research

Salbutamol 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.

It has been studied in subtypes of congenital myasthenic syndrome associated with mutations in Dok-7.

See also

• Levosalbutamol — the (R)-(−)-enantiomer
• Ipratropium/salbutamol

External links

• U.S. National Library of Medicine: Drug Information Portal – Albuterol
• Side Effects
• Salbutamol at The Periodic Table of Videos