Smarter Decisions,
Better Care

UpToDate synthesizes the most recent medical information into evidence-based practical recommendations clinicians trust to make the right point-of-care decisions.

  • Rigorous editorial process: Evidence-based treatment recommendations
  • World-Renowned physician authors: over 5,100 physician authors and editors around the globe
  • Innovative technology: integrates into the workflow; access from EMRs

Choose from the list below to learn more about subscriptions for a:


Subscribers log in here


Beta agonists in asthma: Acute administration and prophylactic use

INTRODUCTION

Beta adrenergic drugs are the most potent bronchodilators currently approved for clinical use in asthma and obstructive lung disease. Among the beta agonists, the individual agents vary in their rapidity of onset and duration of action. Inhaled, short-acting, selective beta-2 adrenergic agonists are the mainstay of acute asthma therapy, while inhaled, long-acting, selective beta-2 adrenergic agonists (in combination with inhaled glucocorticoids) play a role in long-term control of moderate to severe asthma.

The mechanism of action of beta adrenergic medications and their clinical use in the management of asthma will be reviewed here. The general approach to asthma management, the treatment of acute exacerbations of asthma, and an overview of the delivery of inhaled medications are discussed separately. (See "An overview of asthma management" and "Treatment of acute exacerbations of asthma in adults", section on 'Inhaled beta agonists' and "Delivery of inhaled medication in adults".)

MECHANISM OF ACTION

Beta agonists were developed through modifications of the epinephrine molecule to allow selective interaction with the beta-1 and beta-2 receptors (eg, isoproterenol), rather than the combined alpha and beta effects of epinephrine. Further modification allows selectivity for beta-2 receptors on bronchial smooth muscle to achieve bronchodilation without the tachycardia associated with activation of beta-1 receptors on cardiac muscle. Agents available by inhalation that are selective for the beta-2 adrenergic receptor (eg, albuterol, levalbuterol, salmeterol, formoterol) are preferred for asthma therapy compared with nonbeta-2 selective agents (eg, metaproterenol), because they provide equivalent bronchodilation with less cardiac stimulation [1]. Isoproterenol, a nonselective beta agonist, is no longer used to treat asthma exacerbations, due to the better safety and duration of action profiles of other available medications.

The beta-2 receptor is a G protein-coupled transmembrane receptor that activates the enzyme adenylyl cyclase [2]. Activation of adenylyl cyclase produces cyclic adenosine monophosphate (cAMP). The exact mechanism by which cAMP causes smooth muscle relaxation is not fully understood, but likely involves activation of protein kinase A and changes in intracellular calcium concentrations. Activation of the beta-2 receptor also affects potassium channels through a separate mechanism. The function of the beta-2 adrenergic receptor and the role of polymorphisms of the receptor in individual responses to beta agonists are discussed separately. (See "Beta-2 adrenergic receptor dysfunction and polymorphism in asthma".)

Variations in the molecular structure of beta agonists affect the onset and duration of bronchodilation. As an example, prolongation of the bronchodilator effect (relative to isoproterenol) is achieved by modifications that reduce susceptibility to degradation by catechol O-methyl transferase (COMT) and monoamine oxidase [1]. In addition, the long, lipophilic side chains of formoterol and salmeterol attach to the plasma membrane and increase the duration of binding of the drugs to the adrenergic receptor. The lipophilic side chain of salmeterol leads to incorporation of the drug into the cell membrane and activation of the beta adrenergic receptor through an alternate binding site, rather than the usual site in the aqueous surface of the cell membrane [2]. It is thought that accessing the alternate binding site deeper in the cell membrane slows the onset of action of salmeterol. In contrast, formoterol has a different lipophilic side chain and its onset of action is comparable to that of albuterol (also known as salbutamol).

                  

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Mar 2014. | This topic last updated: Jan 16, 2014.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2014 UpToDate, Inc.
References
Top
  1. Sorkness CA. Beta-adrenergic Agonists. In: Middleton's Allergy: Principles and Practice, 7th ed, Adkinson NF, Bochner BS, Busse WW, et al (Eds), Mosby, Philadelphia 2009. p.1485-503.
  2. Johnson M. Beta2-adrenoceptors: mechanisms of action of beta2-agonists. Paediatr Respir Rev 2001; 2:57.
  3. Johnson M. Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol 2006; 117:18.
  4. National Asthma Education and Prevention Program: Expert panel report III: Guidelines for the diagnosis and management of asthma. Bethesda, MD: National Heart, Lung, and Blood Institute, 2007. (NIH publication no. 08-4051). www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm (Accessed on March 21, 2011).
  5. Tipton WR, Nelson HS. Frequent parenteral terbutaline in the treatment of status asthmaticus in children. Ann Allergy 1987; 58:252.
  6. Schuh S, Parkin P, Rajan A, et al. High-versus low-dose, frequently administered, nebulized albuterol in children with severe, acute asthma. Pediatrics 1989; 83:513.
  7. Colacone A, Afilalo M, Wolkove N, Kreisman H. A comparison of albuterol administered by metered dose inhaler (and holding chamber) or wet nebulizer in acute asthma. Chest 1993; 104:835.
  8. Idris AH, McDermott MF, Raucci JC, et al. Emergency department treatment of severe asthma. Metered-dose inhaler plus holding chamber is equivalent in effectiveness to nebulizer. Chest 1993; 103:665.
  9. Wolfe JD, Yamate M, Biedermann AA, Chu TJ. Comparison of the acute cardiopulmonary effects of oral albuterol, metaproterenol, and terbutaline in asthmatics. JAMA 1985; 253:2068.
  10. Fanta CH, Rossing TH, McFadden ER Jr. Treatment of acute asthma. Is combination therapy with sympathomimetics and methylxanthines indicated? Am J Med 1986; 80:5.
  11. Appel D, Karpel JP, Sherman M. Epinephrine improves expiratory flow rates in patients with asthma who do not respond to inhaled metaproterenol sulfate. J Allergy Clin Immunol 1989; 84:90.
  12. Williams S, Seaton A. Intravenous or inhaled salbutamol in severe acute asthma? Thorax 1977; 32:555.
  13. Pierce RJ, Payne CR, Williams SJ, et al. Comparison of intravenous and inhaled terbutaline in the treatment of asthma. Chest 1981; 79:506.
  14. Salmeron S, Brochard L, Mal H, et al. Nebulized versus intravenous albuterol in hypercapnic acute asthma. A multicenter, double-blind, randomized study. Am J Respir Crit Care Med 1994; 149:1466.
  15. Travers AH, Rowe BH, Barker S, et al. The effectiveness of IV beta-agonists in treating patients with acute asthma in the emergency department: a meta-analysis. Chest 2002; 122:1200.
  16. Travers A, Jones AP, Kelly K, et al. Intravenous beta2-agonists for acute asthma in the emergency department. Cochrane Database Syst Rev 2001; :CD002988.
  17. Maguire JF, O'Rourke PP, Colan SD, et al. Cardiotoxicity during treatment of severe childhood asthma. Pediatrics 1991; 88:1180.
  18. Ahrens R, Weinberger M. Levalbuterol and racemic albuterol: are there therapeutic differences? J Allergy Clin Immunol 2001; 108:681.
  19. Gawchik SM, Saccar CL, Noonan M, et al. The safety and efficacy of nebulized levalbuterol compared with racemic albuterol and placebo in the treatment of asthma in pediatric patients. J Allergy Clin Immunol 1999; 103:615.
  20. "Pharmaceutical Approvals Monthly" FDC Reports. Chevy Chase, MD. 2005; 10(3):11.
  21. Handley DA, Tinkelman D, Noonan M, et al. Dose-response evaluation of levalbuterol versus racemic albuterol in patients with asthma. J Asthma 2000; 37:319.
  22. Tripp K, McVicar WK, Nair P, et al. A cumulative dose study of levalbuterol and racemic albuterol administered by hydrofluoroalkane-134a metered-dose inhaler in asthmatic subjects. J Allergy Clin Immunol 2008; 122:544.
  23. Nelson HS, Bensch G, Pleskow WW, et al. Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. J Allergy Clin Immunol 1998; 102:943.
  24. Lötvall J, Palmqvist M, Arvidsson P, et al. The therapeutic ratio of R-albuterol is comparable with that of RS-albuterol in asthmatic patients. J Allergy Clin Immunol 2001; 108:726.
  25. Levalbuterol for asthma. Med Lett Drugs Ther 1999; 41:51.
  26. Datta D, Vitale A, Lahiri B, ZuWallack R. An evaluation of nebulized levalbuterol in stable COPD. Chest 2003; 124:844.
  27. Qureshi F, Zaritsky A, Welch C, et al. Clinical efficacy of racemic albuterol versus levalbuterol for the treatment of acute pediatric asthma. Ann Emerg Med 2005; 46:29.
  28. Hamilos DL, D'Urzo A, Levy RJ, et al. Long-term safety study of levalbuterol administered via metered-dose inhaler in patients with asthma. Ann Allergy Asthma Immunol 2007; 99:540.
  29. Carl JC, Myers TR, Kirchner HL, Kercsmar CM. Comparison of racemic albuterol and levalbuterol for treatment of acute asthma. J Pediatr 2003; 143:731.
  30. Truitt T, Witko J, Halpern M. Levalbuterol compared to racemic albuterol: efficacy and outcomes in patients hospitalized with COPD or asthma. Chest 2003; 123:128.
  31. Hardasmalani MD, DeBari V, Bithoney WG, Gold N. Levalbuterol versus racemic albuterol in the treatment of acute exacerbation of asthma in children. Pediatr Emerg Care 2005; 21:415.
  32. Agrawal DK, Ariyarathna K, Kelbe PW. (S)-Albuterol activates pro-constrictory and pro-inflammatory pathways in human bronchial smooth muscle cells. J Allergy Clin Immunol 2004; 113:503.
  33. Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2012. www.ginasthma.org (Accessed on March 12, 2013).
  34. Grembiale RD, Pelaia G, Naty S, et al. Comparison of the bronchodilating effects of inhaled formoterol, salmeterol and salbutamol in asthmatic patients. Pulm Pharmacol Ther 2002; 15:463.
  35. Kips JC, Pauwels RA. Long-acting inhaled beta(2)-agonist therapy in asthma. Am J Respir Crit Care Med 2001; 164:923.
  36. Cockcroft DW, Murdock KY. Comparative effects of inhaled salbutamol, sodium cromoglycate, and beclomethasone dipropionate on allergen-induced early asthmatic responses, late asthmatic responses, and increased bronchial responsiveness to histamine. J Allergy Clin Immunol 1987; 79:734.
  37. Howarth PH, Durham SR, Lee TH, et al. Influence of albuterol, cromolyn sodium and ipratropium bromide on the airway and circulating mediator responses to allergen bronchial provocation in asthma. Am Rev Respir Dis 1985; 132:986.
  38. Twentyman OP, Finnerty JP, Harris A, et al. Protection against allergen-induced asthma by salmeterol. Lancet 1990; 336:1338.
  39. Bundgaard A, Buch D, Schmidt A, Bach-Mortensen N. Pretreatment of exercise-induced asthma in children using disodium cromoglycate and fenoterol inhalation powder. Eur J Respir Dis Suppl 1983; 130:36.
  40. Rohr AS, Siegel SC, Katz RM, et al. A comparison of inhaled albuterol and cromolyn in the prophylaxis of exercise-induced bronchospasm. Ann Allergy 1987; 59:107.
  41. Boulet LP, Turcotte H, Tennina S. Comparative efficacy of salbutamol, ipratropium, and cromoglycate in the prevention of bronchospasm induced by exercise and hyperosmolar challenges. J Allergy Clin Immunol 1989; 83:882.
  42. McFadden ER Jr. Hypothesis: exercise-induced asthma as a vascular phenomenon. Lancet 1990; 335:880.
  43. Anderson SD, Daviskas E. The airway microvasculature and exercise induced asthma. Thorax 1992; 47:748.
  44. Spitzer WO, Suissa S, Ernst P, et al. The use of beta-agonists and the risk of death and near death from asthma. N Engl J Med 1992; 326:501.
  45. Sly RM, Heimlich EM, Ginsburg J, et al. Exercise-induced bronchospasm: evaluation of metaproterenol. Ann Allergy 1968; 26:253.
  46. Henriksen JM, Agertoft L, Pedersen S. Protective effect and duration of action of inhaled formoterol and salbutamol on exercise-induced asthma in children. J Allergy Clin Immunol 1992; 89:1176.
  47. Green CP, Price JF. Prevention of exercise induced asthma by inhaled salmeterol xinafoate. Arch Dis Child 1992; 67:1014.
  48. Ramage L, Lipworth BJ, Ingram CG, et al. Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respir Med 1994; 88:363.
  49. Greenstone IR, Ni Chroinin MN, Masse V, et al. Combination of inhaled long-acting beta2-agonists and inhaled steroids versus higher dose of inhaled steroids in children and adults with persistent asthma. Cochrane Database Syst Rev 2005; :CD005533.
  50. Ni Chroinin M, Greenstone IR, Danish A, et al. Long-acting beta2-agonists versus placebo in addition to inhaled corticosteroids in children and adults with chronic asthma. Cochrane Database Syst Rev 2005; :CD005535.
  51. O'Byrne PM, Bisgaard H, Godard PP, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005; 171:129.
  52. Lemanske RF Jr, Mauger DT, Sorkness CA, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med 2010; 362:975.
  53. Chowdhury BA, Dal Pan G. The FDA and safe use of long-acting beta-agonists in the treatment of asthma. N Engl J Med 2010; 362:1169.
  54. Lemanske RF Jr, Busse WW. The US Food and Drug Administration and long-acting beta2-agonists: the importance of striking the right balance between risks and benefits of therapy? J Allergy Clin Immunol 2010; 126:449.
  55. Hausdorff WP, Caron MG, Lefkowitz RJ. Turning off the signal: desensitization of beta-adrenergic receptor function. FASEB J 1990; 4:2881.
  56. Repsher LH, Anderson JA, Bush RK, et al. Assessment of tachyphylaxis following prolonged therapy of asthma with inhaled albuterol aerosol. Chest 1984; 85:34.
  57. Drazen JM, Israel E, Boushey HA, et al. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. Asthma Clinical Research Network. N Engl J Med 1996; 335:841.
  58. Dennis SM, Sharp SJ, Vickers MR, et al. Regular inhaled salbutamol and asthma control: the TRUST randomised trial. Therapy Working Group of the National Asthma Task Force and the MRC General Practice Research Framework. Lancet 2000; 355:1675.
  59. Pearlman DS, Chervinsky P, LaForce C, et al. A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N Engl J Med 1992; 327:1420.
  60. Cheung D, Timmers MC, Zwinderman AH, et al. Long-term effects of a long-acting beta 2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma. N Engl J Med 1992; 327:1198.
  61. Cockcroft DW, McParland CP, Britto SA, et al. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet 1993; 342:833.
  62. Haney S, Hancox RJ. Rapid onset of tolerance to beta-agonist bronchodilation. Respir Med 2005; 99:566.
  63. Dweik RA, Sorkness RL, Wenzel S, et al. Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma. Am J Respir Crit Care Med 2010; 181:1033.
  64. Bonini M, Permaul P, Kulkarni T, et al. Loss of salmeterol bronchoprotection against exercise in relation to ADRB2 Arg16Gly polymorphism and exhaled nitric oxide. Am J Respir Crit Care Med 2013; 188:1407.
  65. Nelson HS. Beta-adrenergic agonists. In: Middleton's Allergy: Principles and Practice, 6th Ed, Adkinson NF, Yunginger JW, Busse WW, et al (Eds), Mosby, St Louis 2003. p.803.
  66. Jenne JW, Valcarenghi G, Druz WS, et al. Comparison of tremor responses to orally administered albuterol and terbutaline. Am Rev Respir Dis 1986; 134:708.
  67. Kurisu S, Inoue I, Kawagoe T, et al. Assessment of medications in patients with tako-tsubo cardiomyopathy. Int J Cardiol 2009; 134:e120.
  68. Osuorji I, Williams C, Hessney J, et al. Acute stress cardiomyopathy following treatment of status asthmaticus. South Med J 2009; 102:301.
  69. Rennyson SL, Parker JM, Symanski JD, Littmann L. Recurrent, severe, and rapidly reversible apical ballooning syndrome in status asthmaticus. Heart Lung 2010; 39:537.
  70. Leslie D, Coats PM. Salbutamol-induced diabetic ketoacidosis. Br Med J 1977; 2:768.
  71. van den Berg BT, Louwerse RT, Luiken GJ, et al. Hypokalaemia in healthy volunteers after single and multiple doses of formoterol or salbutamol. Clin Drug Investig 1998; 15:523.
  72. Berger WE. The use of inhaled formoterol in the treatment of asthma. Ann Allergy Asthma Immunol 2006; 97:24.
  73. Guhan AR, Cooper S, Oborne J, et al. Systemic effects of formoterol and salmeterol: a dose-response comparison in healthy subjects. Thorax 2000; 55:650.