Salbutamol, also known as albuterol and sold under the brand name Ventolin among others, is a medication that opens up the medium and large airways in the lungs. It is a short-acting β₂ adrenergic receptor agonist which works by causing relaxation of airway

smooth muscle Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...

. It is used to treat asthma, including asthma attacks, exercise-induced bronchoconstriction, and chronic obstructive pulmonary disease (COPD). It may also be used to treat high blood potassium levels. Salbutamol is usually used with an inhaler or nebulizer, but it is also available in a pill, liquid, and

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

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 Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...

, dizziness, and feeling anxious. Serious side effects may include worsening bronchospasm,

irregular heartbeat Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...

, and low blood potassium levels. It can be used during pregnancy and breastfeeding, but safety is not entirely clear. Salbutamol was patented in 1966 in Britain and became commercially available in the UK in 1969. It was approved for medical use in the United States in 1982. It is on the World Health Organization's List of Essential Medicines. Salbutamol is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

. In 2020, it was the seventh most commonly prescribed medication in the United States, with more than 61million prescriptions.

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. It is also one of the most common medicines used in rescue inhalers (short-term bronchodilators to alleviate asthma attacks). As a β₂ agonist, salbutamol also has use in

obstetrics Obstetrics is the field of study concentrated on pregnancy, childbirth and the postpartum period. As a medical specialty, obstetrics is combined with gynecology under the discipline known as obstetrics and gynecology (OB/GYN), which is a surgi ...

. Intravenous salbutamol can be used as a tocolytic to relax the uterine

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

Adverse effects

The most common side effects are fine

tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, fa ...

, anxiety,

headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...

, muscle cramps, dry mouth, and palpitation. Other symptoms may include tachycardia,

arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults ...

, flushing of the skin, myocardial ischemia (rare), and disturbances of sleep and behaviour. 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. 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.

Pharmacology

The tertiary

butyl group In organic chemistry, butyl is a four-carbon alkyl radical or substituent group with general chemical formula , derived from either of the two isomers (''n''-butane and isobutane) of butane. The isomer ''n''-butane can connect in two ways, givi ...

in salbutamol makes it more selective for β₂ receptors, which are the predominant receptors on the bronchial

s. Activation of these receptors causes adenylyl cyclase to convert ATP to

cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...

, beginning the signalling cascade that ends with the inhibition of

myosin Myosins () are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility. The first 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. 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. Salbutamol is either filtered out by the kidneys directly or is first metabolized into the 4′-''O''-sulfate, which is excreted in the urine.

Chemistry

Salbutamol is sold as a

racemic mixture In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...

. The (''R'')-(−)-

enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...

( 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''). The slower metabolism of the (''S'')-(+)-enantiomer also causes it to accumulate in the lungs, which can cause airway hyperreactivity and inflammation. 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. The direct separation of Salbutamol

s and the control of enantiomeric purity has been described by thin-layer chromatography.

History

Salbutamol was discovered in 1966, by a team led by

David Jack David Bone Nightingale Jack (3 April 1898 – 10 September 1958) was an English footballer who played as an inside forward. He scored 267 goals from 490 appearances in the Football League playing for Plymouth Argyle, Bolton Wanderers and Arsena ...

at the Allen and Hanburys laboratory (a subsidiary of Glaxo) in Ware, Hertfordshire, England, and was launched as Ventolin in 1969. The

1972 Munich Olympics The 1972 Summer Olympics (), officially known as the Games of the XX Olympiad () and commonly known as Munich 1972 (german: München 1972), was an international multi-sport event held in Munich, West Germany, from 26 August to 11 September 1972. ...

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. 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. The FDA granted approval of the generic albuterol sulfate inhalation aerosol to Perrigo Pharmaceutical. 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. The FDA granted approval of this generic albuterol sulfate inhalation aerosol to Cipla Limited.

Society and culture

In 2020, generic versions were approved in the United States.

Names

Salbutamol is the international nonproprietary name (INN) while albuterol is the United States Adopted Name (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

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

Research

Salbutamol has been studied in subtypes of congenital myasthenic syndrome associated with mutations in '' Dok-7''. It has also been tested in a trial aimed at treatment of

spinal muscular atrophy Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic ...

; it is speculated to modulate the

alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...

of the '' SMN2'' gene, increasing the amount of the SMN protein, the deficiency of which is regarded as a cause of the disease.

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

References

External links

*
Salbutamol
at '' The Periodic Table of Videos'' {{Portal bar, Medicine Antiasthmatic drugs Beta-adrenergic agonists Chemical substances for emergency medicine GSK plc brands Merck & Co. brands Phenols Phenylethanolamines Racemic mixtures Sympathomimetic amines Tert-butyl compounds World Health Organization essential medicines Wikipedia medicine articles ready to translate