β2 (beta2) adrenergic receptor 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, such as COPD.
Mechanism of action
Activation of β adrenergic receptors leads to relaxation of smooth muscle in the lung, and dilation and opening of the airways.
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.
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; tachycardia can be accompanied by palpitations
- Tremor, excessive sweating, anxiety, insomnia, and agitation
Asthma aggravation has been observed in patients using large doses of β2 agonists, but if it results from spontaneous course of the disease or adverse effect of the drugs is not known. The excipients, in particular sulfite, could contribute to the adverse effects. The possible loss of the bronchodilator activity of β2 mimetics could be attenuated by inhaled corticosteroid intake.
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. Salbutamol and terbutaline are also both available in oral forms. The nebulizer form is as effective as administering the drug intravenously.
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.
On November 18, 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.
On June 29, 2006, Cornell University and Stanford University researchers reported that a meta-analysis they conducted 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.
On December 11, 2008, a panel of experts convened by the FDA voted to ban the 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. The experts said that two other much more popular asthma drugs containing long-acting β agonists, Advair and Symbicort, should continue to be used.
Generic name—Trade name
Short-acting β2 agonists (SABAs)
- isoprenaline (INN) or isoproterenol (USAN)—Isuprel
- levosalbutamol (INN) or levalbuterol (USAN)—Xopenex
- orciprenaline (INN) or metaproterenol (USAN)—Alupent
- salbutamol (INN) or albuterol (USAN)—Ventolin
Long-acting β2 agonists (LABAs)
Society and culture
β2 agonists are abused 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. 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.
- Ramanujan K (June 29, 2006). "Common beta-agonist inhalers more than double death rate in COPD patients, Cornell and Stanford scientists assert". Cornell Chronicle. Retrieved June 30, 2006.
- Harris, Gardiner (December 11, 2008). "F.D.A. Panel Votes to Ban Asthma Drugs". The New York Times. Retrieved January 19, 2009.
- Matera, MG; Cazzola, M (2007). "Ultra-Long-Acting β2-Adrenoceptor Agonists: An Emerging Therapeutic Option for Asthma and COPD?". Drugs. 67 (4): 503–15. doi:10.2165/00003495-200767040-00002. PMID 17352511. Retrieved 7 March 2016.
- Cazzola, Mario; Matera, Maria Gabriella; Lötvall, Jan (15 July 2005). "Ultra long-acting β2-agonists in development for asthma and chronic obstructive pulmonary disease". Expert Opinion on Investigational Drugs. 14 (7): 775–83. doi:10.1517/13543718.104.22.1685. PMID 16022567.
- Cazzola, Mario; Calzetta, Luigino; Matera, Maria Gabriella (May 2011). "β2-adrenoceptor agonists: current and future direction". British Journal of Pharmacology. 163 (1): 4–17. doi:10.1111/j.1476-5381.2011.01216.x. PMC 3085864. PMID 21232045.
- Beier, J; Fuhr, R; Massana, E; Jiménez, E; Seoane, B; de Miquel, G; Ruiz, S (October 2014). "Abediterol (LAS100977), a novel long-acting β2-agonist: Efficacy, safety and tolerability in persistent asthma". Respiratory Medicine. 108 (10): 1424–1429. doi:10.1016/j.rmed.2014.08.005. PMID 25256258. Retrieved 25 March 2016.
- Drug Enforcement Administration. November 2013 Clenbuterol
- Pluim BM, de Hon O, Staal JB, Limpens J, Kuipers H, Overbeek SE, Zwinderman AH, Scholten RJ (Jan 2011). "β₂-Agonists and physical performance: a systematic review and meta-analysis of randomized controlled trials". Sports Med. 41 (1): 39–57. doi:10.2165/11537540-000000000-00000. PMID 21142283.
- beta-Adrenergic+Receptor+Agonists at the US National Library of Medicine Medical Subject Headings (MeSH)