Long-acting beta-adrenoceptor agonist

"LABA" redirects here. For other uses, see Laba (disambiguation).

Long-acting β adrenoceptor agonists (LABAs) are beta-adrenergic agonists usually prescribed for moderate-to-severe persistent asthma and chronic obstructive pulmonary disease (COPD). They are designed to reduce the need for shorter-acting β₂ agonists such as salbutamol (albuterol), as they have a duration of action of approximately 12 hours in comparison with the 4-to-6-hour duration of salbutamol, making them candidates for sparing high doses of corticosteroids^{[citation needed]} or treating nocturnal asthma and providing symptomatic improvement in patients with COPD. With the exception of formoterol, long-acting β₂ agonists are not recommended for the treatment of acute asthma exacerbations because of their slower onset of action compared to salbutamol. Their long duration of action is due to the addition of a long, lipophilic side-chain that binds to an exosite on adrenergic receptors. This allows the active portion of the molecule to continuously bind and unbind at β₂ receptors in the smooth muscle in the lungs.

Long-acting beta-adrenoceptor agonist
Drug class
Salmeterol—an example of long-acting β2 adrenoreceptor agonist
Legal status
In Wikidata

Medical uses

When combined with inhaled steroids, β adrenoceptor agonists can improve symptoms.^[1][2] In children this benefit is uncertain and they may be potentially harmful.^[2] They should not be used without an accompanying steroid due to an increased risk of severe symptoms, including exacerbation in both children and adults.^[3] A 2018 meta-analysis was unable to determine whether an increase serious adverse events reported in the previous meta-analysis on regular salmeterol alone is abolished by the additional use of regular inhaled corticosteroid.^[4] Large surveillance studies are ongoing to provide more information. There were no asthma-related deaths and few asthma-related serious adverse events when salmeterol is used with an inhaled steroid.^[5][6] At least with formoterol, an increased risk appears to be present even when steroids are used^[7] and this risk has not been ruled out for salmeterol.^[8]

Agents

Some of the currently available long-acting β₂ adrenoceptor agonists include:
International nonproprietary name (INN): Trade (brand) name

• arformoterol: Brovana (some consider it to be an ultra-LABA)^[9]
• bambuterol: Bambec, Oxeol
• clenbuterol: Dilaterol, Spiropent
• formoterol: Foradil, Oxis, Perforomist
• salmeterol: Serevent
• protokylol: Ventaire

Ultra-LABAs

Several long-acting β adrenoreceptor agonists have a duration of action of 24 hours, allowing for once-daily dosing. They are considered to be ultra-long-acting β adrenoreceptor agonists (ultra-LABAs)^[10] and are now approved.

• indacaterol: approved by the European Medicines Agency (EMA) on November 30, 2009,^[11] and by Russian FDA-equivalent under the trade name Onbrez Breezhaler. In the United States. it was approved by the Food and Drug Administration (FDA) under the trade name Arcapta Neohaler on July 1, 2011)^[12]
• olodaterol: approved in some European countries and Russia, and by the U.S. Food and Drug Administration (FDA) on July 31, 2014, under Striverdi Respimat^[13]
• vilanterol is the ultra-LABA not available by itself but only as a component of combination drugs:
  • with fluticasone furoate: Breo Ellipta (U.S.), Relvar Ellipta (EU, RU). This second medication in this combination is the synthetic inhaled corticosteroid fluticasone furoate. This product was approved by the FDA in May 2013 as once-daily inhaled therapy for the treatment of chronic obstructive pulmonary disease (COPD)
  • with umeclidinium bromide: Anoro Ellipta. Umeclidinium bromide is a long-acting muscarinic antagonist.^[14] This combination was approved by the FDA on December 18, 2013^[15] for the long-term maintenance treatment of COPD. On March 28, 2014, it was approved in European countries^[16] and in Russia^[17] under the same trade name.

Ultra-LABAs under development

• abediterol (codenamed LAS100977)^[18][19]
• salmefamol (salbutamol and para-methoxyamphetamine (PMA) hybrid)^{[citation needed]}

Failed agents

• carmoterol (formerly TA-2005):^[19] development terminated^[20]
• PF-610355: development terminated^[21]

Concerns

A meta-analysis study from 2006 (pooled results of 19 trials, 33,826 participants) raised concerns that Salmeterol may increase the risk of death in asthmatics, and that the additional risk was not reduced with the adjunctive use of inhaled steroids (e.g., as with the combination product fluticasone/salmeterol).^[22] The proposed mechanism is that while LABAs relieve asthma symptoms, they can also promote bronchial inflammation and sensitivity without warning.^[23] On February 18, 2011, the FDA issued a safety alert for long-acting β agonists.^[24] Following new clinical safety trials however, the FDA issued updated guidance on 20 December 2017, that there is no significant increased risk of serious asthma outcomes with LABAs when used together with inhaled corticosteroids.^[25]

References

1. Higashi, AS; Zhu S; Stafford RS; Alexander GC (2011). "National trends in outpatient asthma treatment, 1997-2009". Journal of General Internal Medicine. 26 (12): 1465–70. doi:10.1007/s11606-011-1796-4. PMC 3235617. PMID 21769507.
2. Ducharme, Francine M; Ni Chroinin, Muireann; Greenstone, Ilana; Lasserson, Toby J (12 May 2010). "Addition of long-acting beta2-agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children". The Cochrane Database of Systematic Reviews (5): CD005535. doi:10.1002/14651858.CD005535.pub2. PMC 4169792. PMID 20464739.
3. Fanta CH (March 2009). "Asthma". New England Journal of Medicine. 360 (10): 1002–14. doi:10.1056/NEJMra0804579. PMID 19264689.
4. Cates, Christopher J.; Schmidt, Stefanie; Ferrer, Montse; Sayer, Ben; Waterson, Samuel (3 December 2018). "Inhaled steroids with and without regular salmeterol for asthma: serious adverse events". The Cochrane Database of Systematic Reviews. 2018 (12): CD006922. doi:10.1002/14651858.CD006922.pub4. ISSN 1469-493X. PMC 6524619. PMID 30521673.
5. Cates CJ, Cates MJ (2008). Cates, Christopher J (ed.). "Regular treatment with salmeterol for chronic asthma: serious adverse events". Cochrane Database Syst Rev (3): CD006363. doi:10.1002/14651858.CD006363.pub2. PMC 4015854. PMID 18646149.
6. . U.S. Food and Drug Administration (FDA). Feb 2010. Archived from the original on 2017-11-02. Retrieved 2019-12-16. Based on the available information, FDA concludes there is an increased risk for severe exacerbation of asthma symptoms, leading to hospitalizations in pediatric and adult patients as well as death in some patients using LABAs for the treatment of asthma. The agency is requiring the REMS and class-labeling changes to improve the safe use of these products.
7. Cates, CJ; Cates, MJ (Apr 18, 2012). "Regular treatment with formoterol for chronic asthma: serious adverse events". Cochrane Database of Systematic Reviews. 4 (4): CD006923. doi:10.1002/14651858.CD006923.pub3. PMC 4017186. PMID 22513944.
8. Cates, CJ; Cates, MJ (Jul 16, 2008). "Regular treatment with salmeterol for chronic asthma: serious adverse events". Cochrane Database of Systematic Reviews (3): CD006363. doi:10.1002/14651858.CD006363.pub2. PMC 4015854. PMID 18646149.
9. 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. S2CID 46976912. Retrieved 7 March 2016.
10. Cazzola M, Matera MG, Lötvall J (July 2005). "Ultra long-acting beta 2-agonists in development for asthma and chronic obstructive pulmonary disease". Expert Opin Investig Drugs. 14 (7): 775–83. doi:10.1517/13543784.14.7.775. PMID 16022567. S2CID 11930383.
11. European Public Assessment Report for Onbrez Breezhaler 2010-01-16 at the Wayback Machine
12. (Press release). U.S. Food and Drug Administration (FDA). 2011-07-01. Archived from the original on 2011-07-03. Retrieved 2011-07-02.
13. "New once-daily Striverdi (olodaterol) Respimat gains approval in first EU countries". Boehringer-Ingelheim. 18 October 2013.
14. (PDF). GlaxoSmithKline, Research Triangle Park, NC 27709. Archived from the original (PDF) on 10 July 2018. Retrieved 22 February 2016.
15. . U.S. Food and Drug Administration (FDA). Archived from the original on 24 March 2016. Retrieved 25 March 2016.
16. "Assessment report: Anoro. INN: umeclidinium bromide/vilanterol" (PDF). European Medicines Agency. Retrieved 25 March 2016.
17. "State Register of Nedicines: Anoro Ellipta (vilanterol + umeclidinium bromide)". Russian State Register of Medicinal Products (in Russian). Retrieved 25 March 2016.
18. 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.
19. Cazzola, Mario; Luigino Calzetta; Maria Gabriella Matera3 (May 2011). "β2-adrenoceptor agonists: current and future direction". Br J Pharmacol. 163 (1): 4–17. doi:10.1111/j.1476-5381.2011.01216.x. PMC 3085864. PMID 21232045.{{cite journal}}: CS1 maint: numeric names: authors list (link)
20. "Chiesi: Annual Report 2010" (PDF). Chiesi Farmaceutici S.p.A. p. 20. Retrieved 27 March 2016.
21. "AdisInsight: PF 610355". Springer International Publishing AG. Retrieved 25 March 2016.
22. Salpeter S, Buckley N, Ormiston T, Salpeter E (2006). "Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths". Ann Intern Med. 144 (12): 904–12. doi:10.7326/0003-4819-144-12-200606200-00126. PMID 16754916. S2CID 30648411.
23. Krishna Ramanujan (June 9, 2006). "Common asthma inhalers cause up to 80 percent of asthma-related deaths, Cornell and Stanford researchers assert". ChronicalOnline - Cornell University.
24. . U.S. Food and Drug Administration (FDA). Archived from the original on 22 March 2016. Retrieved 25 March 2016.
25. "FDA Drug Safety Communication: FDA review finds no significant increase in risk of serious asthma outcomes with long-acting beta agonists (LABAs) used in combination with inhaled corticosteroids (ICS)". U.S. Food and Drug Administration (FDA). 9 February 2019.