Beta2-adrenergic agonist explained

Beta₂-adrenergic agonists, also known as adrenergic β₂ receptor agonists, are a class of drugs that act on the β₂ adrenergic receptor. Like other β adrenergic agonists, they cause smooth muscle relaxation. β₂ adrenergic agonists' effects on smooth muscle cause dilation of bronchial passages, vasodilation in muscle and liver, relaxation of uterine muscle, and release of insulin. They are primarily used to treat asthma and other pulmonary disorders. Bronchodilators are considered an important treatment regime for chronic obstructive pulmonary disease (COPD) and are usually used in combination with short acting medications and long acting medications in a combined inhaler.^{[1] [2]}

Mechanism of action

Activation of β adrenergic receptors leads to relaxation of smooth muscle in the lung, and dilation and opening of the airways.^[3]

β adrenergic receptors are coupled to a stimulatory G protein of adenylyl cyclase. This enzyme produces the second messenger cyclic adenosine monophosphate (cAMP). In the lung, cAMP decreases calcium concentrations within cells and activates protein kinase A. Both of these changes inactivate myosin light-chain kinase and activate myosin light-chain phosphatase. In addition, β₂ agonists open large conductance calcium-activated potassium channels and thereby tend to hyperpolarize airway smooth muscle cells. The combination of decreased intracellular calcium, increased membrane potassium conductance, and decreased myosin light chain kinase activity leads to smooth muscle relaxation and bronchodilation.^[3]

Adverse effects

Findings indicate that β₂ stimulants, especially in parenteral administration such as inhalation or injection, can induce adverse effects:

• Tachycardia secondary to peripheral vasodilation and cardiac stimulation (Such tachycardia may be accompanied by palpitations.)^[4]
• Tremor, excessive sweating, anxiety, insomnia, and agitation^[5]
• More severe effects include paradoxical bronchospasm, hypokalemia, and in rare cases a myocardial infarction. (More severe effects, such as pulmonary edema, myocardial ischemia, and cardiac arrhythmia, are exceptional.)^{[6] [7]}

Overuse of β₂ agonists and asthma treatment without proper inhaled corticosteroid use has been associated with an increased risk of asthma exacerbations and asthma-related hospitalizations.^[8] The excipients, in particular sulfite, could contribute to the adverse effects.

Delivery

All β₂ agonists are available in inhaler form, as either metered-dose inhalers which dispense an aerosolized drug and contains propellants, dry powder inhalers which dispense a powder to be inhaled, or soft mist inhalers which dispense a mist without use of propellants.^[9]

Salbutamol (INN) or albuterol (USAN) and some other β₂ agonists, such as formoterol, also are sold in a solution form for nebulization, which is more commonly used than inhalers in emergency rooms. Nebulizers continuously deliver aerosolized drug and salbutamol delivered through nebulizer was found to be more effective than IV administration.^[10]

Salbutamol and terbutaline are also both available in oral forms.^[11] In addition, several of these medications are available in intravenous forms, including both salbutamol and terbutaline. It can be used in this form in severe cases of asthma, but it is more commonly used to suppress premature labor because it also relaxes uterine muscle, thereby inhibiting contractions.^[12]

Risks

On 18 November 2005, the U.S. Food and Drug Administration (FDA) alerted healthcare professionals and patients that several long-acting bronchodilator medicines have been associated with possible increased risk of worsening wheezing in some people, and requested that manufacturers update warnings in their existing product labeling.

A 2006 meta-analysis found that "regularly inhaled β agonists (orciprenaline/metaproterenol [Alupent], formoterol [Foradil], fluticasone+salmeterol [Serevent, Advair], and salbutamol/albuterol [Proventil, Ventolin, Volmax, and others]) increased the risk of respiratory death more than two-fold, compared with a placebo," while used to treat chronic obstructive pulmonary disease.^[13] On 11 December 2008, a panel of experts convened by the FDA voted to ban drugs Serevent and Foradil from use in the treatment of asthma. When these two drugs are used without steroids, they increase the risks of more severe attacks. They said that two other, much more popular, asthma drugs containing long-acting β agonists—Advair and Symbicort—should continue to be used.^[14]

Types

They can be divided into short-acting, long-acting, and ultra-long-acting beta adrenoreceptor agonists:

Generic name—Trade name

Short-acting β₂ agonists (SABAs)

• bitolterol—Tornalate
• fenoterol—Berotec
• isoprenaline (INN) or isoproterenol (USAN)—Isuprel
• levosalbutamol (INN) or levalbuterol (USAN)—Xopenex
• orciprenaline (INN) or metaproterenol (USAN)—Alupent
• pirbuterol—Maxair
• procaterol
• ritodrine—Yutopar
• salbutamol (INN) or albuterol (USAN)—Ventolin
• terbutaline—Bricanyl

Long-acting β₂ agonists (LABAs)

• arformoterol—Brovana (some consider it to be an ultra-LABA)^[15]
• bambuterol—Bambec, Oxeol
• clenbuterol—Dilaterol, Spiropent
• formoterol—Foradil, Oxis, Perforomist
• salmeterol—Serevent

Ultra-long-acting β₂ agonists

• abediterol^[16]
• carmoterol
• indacaterol—Arcapta Neohaler (U.S.), Onbrez Breezhaler (EU, RU)
• olodaterol—Striverdi Respimat
• vilanterol
  • with umeclidinium bromide—Anoro Ellipta
  • with fluticasone furoate—Breo Ellipta (U.S.), Relvar Ellipta (EU, RU)
  • with fluticasone furoate and umeclidinium bromide—Trelegy Ellipta

^{[17] [18]}

Unknown duration of action

• isoxsuprine
• mabuterol
• zilpaterol—Zilmax

Research

New drugs in this class with more selective activity or that act simultaneously as muscarinic receptor antagonists are under development as of 2023.^[19]

Society and culture

β₂ agonists are used by athletes and bodybuilders as anabolic performance-enhancing drugs and their use has been banned by the World Anti-Doping Agency except for certain drugs that people with asthma may use; they are also used illegally to try to promote the growth of livestock.^[20] A 2011 meta-analysis found no evidence that inhaled β₂-agonists improve performance in healthy athletes and found that the evidence was too weak to assess whether systemic administration of β₂-agonists improved performance in healthy people.^[21]

See also

• Discovery and development of β₂ agonists
• β3-adrenergic agonist

Notes and References

1. Book: Hsu E, Bajaj T . Beta 2 Agonists . StatPearls . Treasure Island (FL) . StatPearls Publishing . 2022 . 31194406 . https://www.ncbi.nlm.nih.gov/books/NBK542249/ . 2022-04-05 . .
2. van Geffen . Wouter H. . Tan . Daniel J. . Walters . Julia Ae . Walters . E. Haydn . 2023-12-06 . Inhaled corticosteroids with combination inhaled long-acting beta2-agonists and long-acting muscarinic antagonists for chronic obstructive pulmonary disease . The Cochrane Database of Systematic Reviews . 12 . 12 . CD011600 . 10.1002/14651858.CD011600.pub3 . 1469-493X . 10698842 . 38054551.
3. Proskocil BJ, Fryer AD . Beta2-agonist and anticholinergic drugs in the treatment of lung disease . Proceedings of the American Thoracic Society . 2 . 4 . 305–310 . 2005-11-01 . 16267353 . 10.1513/pats.200504-038SR . 22198277 .
4. Book: Almadhoun K, Sharma S . Bronchodilators . 2020 . http://www.ncbi.nlm.nih.gov/books/NBK519028/ . StatPearls. StatPearls Publishing. 30085570. 2020-03-16 .
5. Billington CK, Penn RB, Hall IP . β₂ Agonists . Handbook of Experimental Pharmacology . 237 . 23–40 . 2016 . 27878470 . 5480238 . 10.1007/164_2016_64 . 978-3-319-52173-2 .
6. Lulich KM, Goldie RG, Ryan G, Paterson JW . Adverse reactions to beta 2-agonist bronchodilators . Medical Toxicology . 1 . 4 . 286–299 . July 1986 . 2878344 . 10.1007/bf03259844 . 58394547 .
7. Book: McCoshen JA, Fernandes PA, Boroditsky ML, Allardice JG . Determinants of Reproductive Mortality and Preterm Childbirth . January 1996 . Bittar EE, Zakar T . Advances in Organ Biology . 195–223 . Elsevier. en. 1: Pregnancy and Parturition . 10.1016/S1569-2590(08)60073-7 . 978-1-55938-639-5 .
8. Reddel HK, Bacharier LB, Bateman ED, Brightling CE, Brusselle GG, Buhl R, Cruz AA, Duijts L, Drazen JM, FitzGerald JM, Fleming LJ, Inoue H, Ko FW, Krishnan JA, Levy ML, Lin J, Mortimer K, Pitrez PM, Sheikh A, Yorgancioglu AA, Boulet LP . 6 . Global Initiative for Asthma Strategy 2021: executive summary and rationale for key changes . The European Respiratory Journal . 59 . 1 . 2102730 . January 2022 . 34667060 . 8719459 . 10.1183/13993003.02730-2021 .
9. Sorino C, Negri S, Spanevello A, Visca D, Scichilone N . Inhalation therapy devices for the treatment of obstructive lung diseases: the history of inhalers towards the ideal inhaler . English . European Journal of Internal Medicine . 75 . 15–18 . May 2020 . 32113944 . 10.1016/j.ejim.2020.02.023 . 211727980 .
10. Encyclopedia: Gad SE . Albuterol . 2014 . https://linkinghub.elsevier.com/retrieve/pii/B9780123864543008095 . Encyclopedia of Toxicology . 112–115 . 2023-04-24 . Elsevier . en . 10.1016/b978-0-12-386454-3.00809-5 . 978-0-12-386455-0.
11. Book: Paediatric Cardiology . 2010 . 199–218 . https://www.sciencedirect.com/science/article/pii/B9780702030642000126 . CHAPTER 12 - Pharmacological and Interventional Fetal Cardiovascular Treatment. 10.1016/B978-0-7020-3064-2.00012-6 . Third . Jaeggi ET, Tulzer G . Churchill Livingstone . 978-0-7020-3064-2 .
12. Motazedian S, Ghaffarpasand F, Mojtahedi K, Asadi N . Terbutaline versus salbutamol for suppression of preterm labor: a randomized clinical trial . Annals of Saudi Medicine . 30 . 5 . 370–375 . 2010 . 20697169 . 2941249 . 10.4103/0256-4947.67079 . free .
13. Salpeter SR, Buckley NS, Salpeter EE . Meta-analysis: anticholinergics, but not beta-agonists, reduce severe exacerbations and respiratory mortality in COPD . Journal of General Internal Medicine . 21 . 10 . 1011–1019 . October 2006 . 16970553 . 1831628 . 10.1111/j.1525-1497.2006.00507.x .
14. News: F.D.A. Panel Votes to Ban Asthma Drugs . Harris G . 11 December 2008 . . 19 January 2009 .
15. Matera MG, Cazzola M . ultra-long-acting beta2-adrenoceptor agonists: an emerging therapeutic option for asthma and COPD? . Drugs . 67 . 4 . 503–515 . 2007 . 17352511 . 10.2165/00003495-200767040-00002 . 46976912 .
16. Beier J, Fuhr R, Massana E, Jiménez E, Seoane B, de Miquel G, Ruiz S . Abediterol (LAS100977), a novel long-acting β2-agonist: efficacy, safety and tolerability in persistent asthma . Respiratory Medicine . 108 . 10 . 1424–1429 . October 2014 . 25256258 . 10.1016/j.rmed.2014.08.005 . free .
17. Cazzola M, Matera MG, Lötvall J . Ultra long-acting beta 2-agonists in development for asthma and chronic obstructive pulmonary disease . Expert Opinion on Investigational Drugs . 14 . 7 . 775–783 . July 2005 . 16022567 . 10.1517/13543784.14.7.775 . 11930383 .
18. Cazzola M, Calzetta L, Matera MG . β(2) -adrenoceptor agonists: current and future direction . British Journal of Pharmacology . 163 . 1 . 4–17 . May 2011 . 21232045 . 3085864 . 10.1111/j.1476-5381.2011.01216.x . free .
19. Matera MG, Rinaldi B, Calzetta L, Rogliani P, Cazzola M . Advances in adrenergic receptors for the treatment of chronic obstructive pulmonary disease: 2023 update . Expert Opinion on Pharmacotherapy . 1–10 . November 2023 . 37955136 . 10.1080/14656566.2023.2282673 . 265148154 .
20. Web site: Drug Enforcement Administration . November 2013 . Clenbuterol . https://web.archive.org/web/20191017084433/https://www.deadiversion.usdoj.gov/drug_chem_info/clenbuterol.pdf . 17 October 2019 .
21. Pluim BM, de Hon O, Staal JB, Limpens J, Kuipers H, Overbeek SE, Zwinderman AH, Scholten RJ . 6 . β₂-Agonists and physical performance: a systematic review and meta-analysis of randomized controlled trials . Sports Medicine . 41 . 1 . 39–57 . January 2011 . 21142283 . 10.2165/11537540-000000000-00000 . 189906919 .