Beta-2 agonist discussions in asthma and a review of current data

Güncel kılavuzlar doğrultusunda astım tedavisinde kontrol edici olarak ilk seçenek inhale steroidlerdir. Bununla birlikte özellikle hava yolu obstrüksiyonu bulunan pek çok hastada gerek semptom giderici olarak, gerekse ek kontrol edici ilaç olarak hava yolu düz kaslarında relaksasyona yol açan bronkodilatörlere ihtiyaç duyulmaktadır. Hem kısa etkili hem de uzun etkili beta-2 agonistler (SABA ve LABA) astımda kullanılan bronkodilatörler arasında ayrı bir öneme sahiptir. İyi bilinen yararlarına rağmen, son yıllarda LABA’ların güvenliliği üzerine artan sayıda makale yayınlanmıştır. Bununla beraber, LABA monoterapisi ile ilişkili olduğu bildirilen risk artışı, standart tedavi olarak LABA ile kombine inhale kortikosteroid alan hastalarda gözlenmemiştir. Astım mortalitesi dahil olmak üzere, riskler ile ilgili tartışma sürerken, inhale kortikosteroide LABA eklenmesinin yararları geniş şekilde dokümante edilmiştir. Farmakogenetik gelişmeler sayesinde, birçok çalışmada etkinlik ve güvenliliği gösterilmiş olan bu ilaçların bazı istenmeyen yan etkilerinin potansiyel genetik temeli olabileceğine de dikkat çekilmiştir. Sonuç olarak; LABA’lar inhale kortikosteroidler ile birlikte kullanıldığında, astımda semptomların giderilmesi ve akciğer fonksiyonlarının iyileştirilmesinde etkili ve güvenlidir; ancak, inhale kortikosteroid tedavisi yokluğunda LABA monoterapisi hiçbir şekilde uygulanmamalıdır. Uygun dozlarda inhale kortikosteroid kullanımına rağmen kurtarma tedavisine gereksinim duyan astım hastalarının tedavi rejimlerine düzenli bronkodilatör eklenmelidir.

Astımda beta-2 agonist tartışmaları ve mevcut verilere bakış

Current guidelines recommend inhaled steroids as the first line control medication in the treatment of asthma. However, many patients particularly with airway obstruction need bronchodilators either as a symptom reliever or control medication to provide relaxation of bronchiolar smooth muscles. Both short acting and long acting beta-2 agonists (SABA and LABA) are of particular importance among the bronchodilators used in asthma. Despite their well-known benefits, in the recent years, a growing body of publications has been published on the safety of LABAs. However, the increased risk reported to be related to LABA monotherapy was not observed in patients receiving inhaled corticosteroid as the standard treatment in combination with LABA. The benefits of adding LABAs to inhaled corticosteroid have been thoroughly documented, while the risks, including asthma mortality, are currently under debate. Pharmacogenetic advancements drew attention to a potential genetic explanation for certain side effects of these medications whose efficacy and safety have been proven in several studies. In conclusion, LABAs are effective in relieving symptoms and improving lung functions and safe when combined with inhaled corticosteroid in asthma; however, LABA monotherapy should never be administered in the absence of inhaled corticosteroid treatment. Asthma patients that lack control of disease despite adequate doses of inhaled corticosteroids need addition of a regular bronchodilator to their treatment regimen.

PDF

___

1. Global Initiative for Asthma (GINA) Report. Global Strategy for Asthma Management And Prevention. Updated 2008.
2. Kelly HW. Risk versus benefit considerations for the β2-agonists. Pharmacotherapy 2006; 26: 164-74.
3. Price AH, Clissold SP. Salbutamol in the 1980s. A reappraisal of its clinical efficacy. Drugs 1989; 38: 77-122.
4. Stolley PD, Schirinar R. Association between asthma mortality and isoproterenol aerosols: a review. Prev Med 1978; 7: 519-38.
5. Speizer FE, Doll R, Heaf P. Observations on recent increase in mortality from asthma. BMJ 1968; 1: 335-9.
6. Sears MR, O'Donnell TV, Rea HH. Asthma mortality and socioeconomic status. N Z Med J 1985; 98: 765.
7. Sears MR, Rea HH, Beaglehole R, Gillies AJ, Holst PE, O'Donnell TV, et al. Asthma mortality in New Zealand: a two year national study. N Z Med J 1985; 98: 271-5.
8. Crane J, Pearce N, Flatt A, Burgess C, Jackson R, Kwong T, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-83: case-control study. Lancet 1989; 1: 917-22.
9. Pearce N, Grainger J, Atkinson M, Crane J, Burgess C, Culling C, et al. Case-control study of prescribed fenoterol and death from asthma in New Zealand, 1977-81. Thorax 1990; 45: 170-5.
10. Grainger J, Woodman K, Pearce N, Crane J, Burgess C, Keane A, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-7: a further case-control study. Thorax 1991; 46: 105-11.
11. Spitzer WO, Suissa S, Ernst P, Horwitz RI, Habbick B, Cockcroft D, et al. The use of beta-agonists and the risk of death and near death from asthma. N Engl J Med 1992; 326: 501-6.
12. Sears MR, Taylor DR, Print CG, Lake DC, Li QQ, Flannery EM, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990; 336: 1391-6.
13. Taylor DR, Sears MR, Herbison GP, Flannery EM, Print CG, Lake DC, et al. Regular inhaled beta agonist in asthma: effects on exacerbations and lung function. Thorax 1993; 48: 134-8.
14. Suissa S, Assimes T, Ernst P. Inhaled short acting β-agonist use in COPD and the risk of acute myocardial infarction. Thorax 2003; 58: 43-6.
15. Moore RH, Khan A, Dickey BF. Long-acting inhaled β2-agonists in asthma therapy. Chest 1998; 113: 1095-108.
16. Löfdahl CG, Svedmyr N. Formoterol fumarate, a new beta2 adrenoreceptor agonist: acute studies of selectivity and duration of effect after inhaled and oral administration. Allergy 1989; 44: 264-71.
17. Mak JC, Grandordy B, Barnes PJ. High affinity [3H] formoterol binding sites in lung: characterization and autoradiographic mapping. Eur J Pharmacol 1994; 269: 35-41.
18. Naline E, Zhang Y, Qian Y, Mairon N, Anderson GP, Grandordy B, et al. Relaxant effects and durations of action of formoterol and salmeterol on the isolated human bronchus. Eur Respir J 1994; 7: 914-20.
19. Palmqvist M, Persson G, Lazer L, Rosenborg J, Larsson P, Lötvall J. Inhaled dry-powder formoterol and salmeterol in asthmatic patients: onset of action, duration of effect and potency. Eur Respir J 1997; 10: 2484-9.
20. Lipworth BJ. Airway subsensitivity with long-acting beta2- agonists: is there cause for concern? Drug Saf 1997; 16: 295- 308.
21. Palmqvist M, Ibsen T, Mellén A, Lötvall J. Comparison of the relative efficacy of formoterol and salmeterol in asthmatic patients. Am J Respir Crit Care Med 1999; 160: 244-9.
22. Dougherty JA, Didur BL, Aboussouan LS. Long-acting inhaled β2-agonists for stable COPD. Ann Pharmacother 2003; 37: 1247-55.
23. Jaeschke R, Guyatt GH, Cook D, Morris J, Willan A, McIlroy W, et al. The effect of increasing doses of beta-agonists on airflow in patients with chronic airflow limitation. Respir Med 1993; 87: 433-8.
24. Merriam-Webster’s Collegate Dictionary 10th ed. Springfield, MA: Merriam-Webster, 1999: 864.
25. Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 1993; 306: 1034-7.
26. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM; SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006; 129: 15-26. Erratum in: Chest 2006; 129: 1393.
27. Wechsler ME, Lehman E, Lazarus SC, Lemanske RF Jr, Boushey HA, Deykin A, et al; National Heart, Lung, and Blood Institute's Asthma Clinical Research Network. Beta-adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 2006; 173: 519-26. Epub 2005 Dec 1.
28. Mcivor RA, Pizzichini E, Turner MO, Hussack P, Hargreave FE, Sears MR. Potential masking effects of salmeterol on airway inflammation in asthma. Am J Respir Crit Care Med 1998; 158: 924-30.
29. Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Metaanalysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med 2006; 144: 904-12.
30. Rodrigo GJ, Moral VP, Marcos LG, Castro-Rodriguez JA. Safety of regular use of long-acting beta agonists as monotherapy or added to inhaled corticosteroids in asthma. A systematic review. Pulm Pharmacol Ther 2009; 22: 9-19.
31. Anderson HR, Ayres JG, Sturdy PM, Bland JM, Butland BK, Peckitt C, et al. Bronchodilator treatment and deaths from asthma: case-control study. BMJ 2005; 330: 117. Epub 2004 Dec 23.
32. Maringe C, Rickard K, DiSantostefano R, et al. Concomitant use of long-acting β-agonists with inhaled corticosteroids among asthma patients in the UK primary care. Eur Respir J 2007; 30(Suppl 51): P3698.
33. Pauwels RA, Löfdahl CG, Postma DS, Tattersfield AE, O'Byrne P, Barnes PJ, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997; 337: 1405-11. Erratum in: N Engl J Med 1998; 338: 139.
34. Sears MR, Ottosson A, Radner F, Suissa S. Long-acting β- agonists: a review of formoterol safety data from asthma clinical trials. Eur Respir J 2009; 33: 21-32.
35. Jaeschke R, O'Byrne PM, Mejza F, et al. The safety of long acting beta agonists among patients with asthma using inhaled corticosteroids. Systematic review and meta-analysis. Am J Respir Clin Care Med 2008; 178: 1009-16.
36. Kramer JM. Balancing and benefits and risks of inhaled longacting beta-agonists. N Engl J Med 2009; 360: 1592-5.
37. Levenson M. Long-acting beta agonists and adverse asthma events meta-analysis: statistical briefing package for joint meeting of the Pulmonary-Allergy Drugs Advisory Committee, Drug Safety and Risk Management Advisory Committee and Pediatric Advisory Committee, December 10-11, 2008. Available at: http://www.fda.gov/ohrms/dockets/ac/cder08. html# PulmonaryAllergy. Accessed June 19, 2009
38. Sears MR. Safety of long-acting β-agonists are new data really required? Chest 2009; 136: 604-7.
39. Taylor R. The β-agonist saga and Its clinical relevance: on and on it goes. Clinical commentary. Am J Respir Crit Care Med 2009; 179: 976-8.
40. Nelson HS. Long-acting beta-agonists in adult asthma: evidence that these drugs are safe. Primary Care Respir J 2006; 15: 271-7.
41. Vassiliou V, Zipitis CS. Long-acting bronchodilators: time for a re-think. JR Soc Med 2006; 99: 382-3.
42. Aaron SD. Rebuttal: should we avoid beta-agonists for moderate and severe chronic obstructive pulmonary disease? Can Fam Physician 2007; 53: 1429-32.
43. Rodrigo GJ, Nannini LJ, Rodriguez-Roisin R. Safety of longacting beta2-agonists in stable COPD: a systematic review. Chest 2008; 133: 1079-87.