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. It is used to treat

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...

, including

asthma attacks Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, coug ...

exercise-induced bronchoconstriction Exercise-induced asthma, or E.I.A., occurs when the airways narrow as a result of exercise. The preferred term for this condition is exercise-induced bronchoconstriction (EIB). While exercise does not cause asthma, it is frequently an asthma trig ...

, and

chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by long-term respiratory symptoms and airflow limitation. The main symptoms include shortness of breath and a cough, which may or may not produce ...

(COPD). It may also be used to treat high blood potassium levels. Salbutamol is usually used with an

inhaler An inhaler (also known as a puffer, pump or allergy spray) is a medical device used for delivering medicines into the lungs through the work of a person's breathing. This allows medicines to be delivered to and absorbed in the lungs, which prov ...

nebulizer In medicine, a nebulizer (American English) or nebuliser (British English) is a drug delivery device used to administer medication in the form of a mist inhaled into the lungs. Nebulizers are commonly used for the treatment of asthma, cystic fibro ...

, but it is also available in a pill, liquid, 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 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 Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release (degranulation) of substances from mast cells or basophils under the influence of anaphylatoxins. It causes di ...

, irregular heartbeat, and low blood potassium levels. It can be used during

pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

and

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that br ...

, 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 The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. Salbutamol is available as a generic medication. 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

(due to any cause—allergic

or exercise-induced), as well as

. It is also one of the most common medicines used in rescue inhalers (short-term bronchodilators to alleviate

). As a β₂ agonist, salbutamol also has use in obstetrics. Intravenous salbutamol can be used as a

tocolytic Tocolytics (also called anti-contraction medications or labor suppressants) are medications used to suppress premature labor (from Greek τόκος ''tókos'', "childbirth", and λύσις ''lúsis'', "loosening"). Preterm birth accounts for 70% ...

to relax the

uterine The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...

smooth muscle to delay

premature labor Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is between ...

. While preferred over agents such as

atosiban Atosiban, sold under the brand name Tractocile among others, is an inhibitor of the hormones oxytocin and vasopressin. It is used as an intravenous medication as a labour repressant (tocolytic) to halt premature labor. It was developed by Ferri ...

and

ritodrine Ritodrine (trade name Yutopar) is a tocolytic drug used to stop premature labor. This drug has been removed from the US market, according to FDA Orange Book. It was available in oral tablets or as an injection and was typically used as the hyd ...

, its role has largely been replaced by the calcium channel blocker

nifedipine Nifedipine (3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate), sold under the brand name Adalat and Procardia, among others, is a calcium channel blocker medication used to manage angina, high blood pressure, Ra ...

, which is more effective and better tolerated. Salbutamol has been used to treat acute

hyperkalemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occasi ...

, as it stimulates potassium flow into cells, thus lowering the potassium in the blood.

Adverse effects

The most common side effects are fine tremor,

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

, headache,

muscle cramps A cramp is a sudden, involuntary, painful skeletal muscle contraction or overshortening associated with electrical activity; while generally temporary and non-damaging, they can cause significant pain and a paralysis-like immobility of the ...

dry mouth Xerostomia, also known as dry mouth, is dryness in the mouth, which may be associated with a change in the composition of saliva, or reduced salivary flow, or have no identifiable cause. This symptom is very common and is often seen as a side eff ...

, and

palpitation Palpitations are perceived abnormalities of the heartbeat characterized by awareness of cardiac muscle contractions in the chest, which is further characterized by the hard, fast and/or irregular beatings of the heart. Symptoms include a rapi ...

. Other symptoms may include

tachycardia 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 ( ...

, arrhythmia, flushing of the skin,

myocardial ischemia Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pla ...

(rare), and disturbances of sleep and behaviour. Rarely occurring, but of importance, are allergic reactions of

paradoxical A paradox is a logically self-contradictory statement or a statement that runs contrary to one's expectation. It is a statement that, despite apparently valid reasoning from true premises, leads to a seemingly self-contradictory or a logically u ...

bronchospasms,

urticaria Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-last ...

(hives),

angioedema Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are ...

hypotension Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dia ...

, and collapse. High doses or prolonged use may cause

hypokalemia Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abno ...

, which is of concern especially in patients with

kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

and those on certain

diuretics A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics i ...

and

xanthine Xanthine ( or ; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffeine ...

derivatives. Salbutamol metered dose inhalers have been described as the "single biggest source of carbon emissions from

NHS The National Health Service (NHS) is the umbrella term for the publicly funded healthcare systems of the United Kingdom (UK). Since 1948, they have been funded out of general taxation. There are three systems which are referred to using the " ...

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, g ...

in salbutamol makes it more selective for β₂ receptors, which are the predominant receptors on the bronchial smooth muscles. Activation of these receptors causes

adenylyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

to convert ATP to cAMP, beginning the

signalling cascade A biochemical cascade, also known as a signaling cascade or signaling pathway, is a series of chemical reactions that occur within a biological cell when initiated by a stimulus. This stimulus, known as a first messenger, acts on a receptor that ...

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

basophil Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammator ...

eosinophil Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...

s, and most especially

mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...

s, 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. 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''). 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 An enantiopure drug is a pharmaceutical that is available in one specific enantiomeric form. Most biological molecules (proteins, sugars, etc.) are present in only one of many chiral forms, so different enantiomers of a chiral drug molecule bind d ...

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 enantiomers and the control of enantiomeric purity has been described by

thin-layer chromatography Thin-layer chromatography (TLC) is a chromatography technique used to separate non-volatile mixtures. Thin-layer chromatography is performed on a sheet of an inert substrate such as glass, plastic, or aluminium foil, which is coated with a t ...

History

Salbutamol was discovered in 1966, by a team led by David Jack at the

Allen and Hanburys Allen and Hanburys Ltd was a British pharmaceutical manufacturer, absorbed by Glaxo Laboratories in 1958. GlaxoSmithKline, its successor company, used the Allen and Hanburys name for the specialist respiratory division until beginning to phase ...

laboratory (a subsidiary of

Glaxo GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the tent ...

) in

Ware, Hertfordshire Ware is a town in Hertfordshire, England close to the county town of Hertford. It is also a civil parish in East Hertfordshire district. Location The town lies on the north–south A10 road which is partly shared with the east–west A414 (fo ...

, 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 The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(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 A United States Adopted Name (USAN) is a unique nonproprietary name assigned to a medication marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association (AMA), the United Sta ...

(USAN). The drug is usually manufactured and distributed as the

sulfate The sulfate or sulphate ion is a polyatomic anion with the empirical formula . Salts, acid derivatives, and peroxides of sulfate are widely used in industry. Sulfates occur widely in everyday life. Sulfates are salts of sulfuric acid and many ...

salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quant ...

(salbutamol sulfate). It was first sold by

Allen & Hanburys Allen and Hanburys Ltd was a British pharmaceutical manufacturer, absorbed by Glaxo Laboratories in 1958. GlaxoSmithKline, its successor company, used the Allen and Hanburys name for the specialist respiratory division until beginning to phase ...

(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 Congenital myasthenic syndrome (CMS) is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction. The effects of the disease are similar to Lambert-Eaton Syndrome and myasthenia gravis, the difference ...

associated with mutations in ''

Dok-7 Dok-7 is a non-catalytic cytoplasmic adaptor protein that is expressed specifically in muscle and is essential for the formation of neuromuscular synapses. Further, Dok-7 contains pleckstrin homology (PH) and phosphotyrosine-binding (PTB) domains ...

''. 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 Survival of motor neuron 2 (''SMN2'') is a gene that encodes the SMN protein (full and truncated) in humans. Gene The ''SMN2'' gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four ge ...

'' 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 Recurrent airway obstruction, also known as broken wind, heaves, wind-broke horse, or sometimes by the term usually reserved for humans, chronic obstructive pulmonary disease or disorder (COPD) – it is a respiratory disease or chronic conditio ...

; 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 ''

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