Skip to main content
SpringerLink
Log in

Adverse Effects of β-Agonists

Are They Clinically Relevant?

  • Current Opinion
  • Published:
American Journal of Respiratory Medicine

Abstract

Inhaled β2-adrenoceptor agonists (β2-agonists) are the most commonly used asthma medications in many Western countries. Minor adverse effects such as palpitations, tremor, headache and metabolic effects are predictable and dose related. Time series studies suggested an association between the relatively nonselective β-agonist fenoterol and asthma deaths. Three case-control studies confirmed that among patients prescribed fenoterol, the risk of death was significantly elevated even after controlling for the severity of asthma. The Saskatchewan study not only found an increased risk of death among patients dispensed fenoterol, but also suggested this might be a class effect of β2-agonists. However, in subsequent studies, the long-acting β2-agonist salmeterol was not associated with increased asthma mortality. In a case-control study blood albuterol (salbutamol) concentrations were found to be 2.5 times higher among patients who died of asthma compared with controls. It is speculated that such toxic concentrations could cause tachyarrhythmias under conditions of hypoxia and hypokalemia.

The risk of asthma exacerbations and near-fatal attacks may also be increased among patients dispensed fenoterol, but this association may be largely due to confounding by severity. Although salmeterol does not appear to increase the risk of near-fatal attacks, there is a consistent association with the use of nebulized β2-agonists. Nebulized and oral β2-agonists are also associated with an increased risk of cardiovascular death, ischemic heart disease and cardiac failure. Caution should be exercised when first prescribing a β-agonist for patients with cardiovascular disease.

A potential mechanism for adverse effects with regular use of β2-agonists is tachyphylaxis. Tachyphylaxis to the bronchodilator effects of long-acting β2-agonists can occur, but has been consistently demonstrated only for formoterol (eformoterol) a full agonist, rather than salmeterol, a partial agonist. Tachyphylaxis to protection against induced bronchospasm occurs with both full and partial β2-agonists, and probably within a matter of days at most. Underlying airway responsiveness to directly acting bronchoconstricting agents is not increased when the bronchodilator effect of the regular β2-agonist has been allowed to wear off, although there may be an increase in responsiveness to indirectly acting agents. While there has been speculation that underlying airway inflammation in asthma may be made worse by regular use of short-acting β2-agonists, in contradistinction, a number of studies have shown that long-acting β2-agonists have positive anti-inflammatory effects.

An Australian Cochrane Airways Group systematic review of the randomized, controlled trials of short-acting β-agonists found only minimal and clinically unimportant differences between regular use and use as needed. Regular short-acting treatment was better than placebo. However, a subsequent systematic review has found that regular use of long-acting β-agonists had significant advantages over regular use of short-acting β-agonists. More studies and data are needed on the regular use of β2-agonists in patients not taking inhaled corticosteroids, and in potentially vulnerable groups, such as the elderly and those with particular genotypes for the β-receptor, who might be more prone to adverse effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I
Table II
Table III
Table IV

Similar content being viewed by others

References

  1. Burney P, Chinn D, Luczynska C, et al. Variations in the prevalence of respiratory symptoms, self-reported asthma attacks, and use of asthma medication in the European Community Respiratory Health Survey (ECRHS). EurRespir J 1996; 9(4): 687–95

    Google Scholar 

  2. ISAAC. Worldwide variations in the prevalence of asthma symptoms: the International Study of Asthma and Allergies in Childhood (ISAAC). Eur Respir J 1998; 12(2): 315–35

    Article  Google Scholar 

  3. Janson C, Chinn S, Jarvis D, et al. Physician-diagnosed asthma and drug utilization in the European Community Respiratory Health Survey. Eur Respir J 1997; 10(8): 1795–802

    Article  PubMed  CAS  Google Scholar 

  4. Wong CS, Pavord I, Williams J, et al. Bronchodilator, cardiovascular and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma. Lancet 1990; 336: 1396–9

    Article  PubMed  CAS  Google Scholar 

  5. Neville A, Palmer JB, Gaddie J, et al. Metabolic effects of salbutamol: comparison of aerosol and intravenous administration. BMJ 1977; 1(6058): 413–4

    Article  PubMed  CAS  Google Scholar 

  6. Burggraaf J, Westendorp RG, in’t Veen JC, et al. Cardiovascular side effects of inhaled salbutamol in hypoxic asthmatic patients. Thorax 2001; 56(7): 567–9

    Article  PubMed  CAS  Google Scholar 

  7. Williams AJ, Weiner C, Reiff D, et al. Comparison of the effect of inhaled selective and non-selective adrenergic agonists on cardiorespiratory parameters in chronic stable asthma. Pulm Pharmacol 1994; 7(4): 235–41

    Article  PubMed  CAS  Google Scholar 

  8. Walters E, Cockroft A, Griffiths T, et al. Optimal dose of salbutamol respiratory solution: comparison of three doses with plasma levels. Thorax 1981; 36: 625–58

    Article  PubMed  CAS  Google Scholar 

  9. Newnham DM. Asthma medications and their potential adverse effects in the elderly: recommendations for prescribing. Drug Saf 2001; 24(14): 1065–80

    Article  PubMed  CAS  Google Scholar 

  10. Pearce N, Beasley R, Crane J, et al. End of the New Zealand asthma mortality epidemic. Lancet 1995; 345(8941): 41–4

    Article  PubMed  CAS  Google Scholar 

  11. Suissa S, Ernst P. Optical illusions from visual data analysis: example of the New Zealand asthma mortality epidemic. J Clin Epidemiol 1997; 50(10): 1079–88

    Article  PubMed  CAS  Google Scholar 

  12. Lanes SF, Birmann B, Raiford D, et al. International trends in sales of inhaled fenoterol, all inhaled beta-agonists, and asthma mortality, 1970–1992. J Clin Epidemiol 1997; 50(3): 321–8

    Article  PubMed  CAS  Google Scholar 

  13. Romano F, Recchia G, Staniscia T, et al. Rise and fall of asthma-related mortality in Italy and sales of beta2-agonists, 1980–1994. Eur J Epidemiol 2000; 16(9): 783–7

    Article  PubMed  CAS  Google Scholar 

  14. Crane J, Pearce N, Flatt A, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981–83: case-control study. Lancet 1989; I(8644): 917–22

    Article  Google Scholar 

  15. Crane J, Pearce N, Burgess C, et al. Asthma and the beta agonist debate. Thorax 1995; 50Suppl. 1: S5–10

    Article  PubMed  Google Scholar 

  16. Pearce N, Grainger J, Atkinson M, et al. Case-control study of prescribed fenoterol and death from asthma in New Zealand, 1977–81. Thorax 1990; 45(3): 170–5

    Article  PubMed  CAS  Google Scholar 

  17. Grainger J, Woodman K, Pearce N, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981–7: a further case-control study. Thorax 1991; 46(2): 105–11

    Article  PubMed  CAS  Google Scholar 

  18. 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: 501–6

    Article  PubMed  CAS  Google Scholar 

  19. Suissa S, Ernst P, Bolvin JF. A cohort analysis of excess mortality in asthma and the use of inhaled beta agonists. Am J Respir Crit Care Med 1994; 149: 604–10

    PubMed  CAS  Google Scholar 

  20. Abramson M, Bailey M, Couper F, et al. Are asthma medications and management related to deaths from asthma?. Am J Respir Crit Care Med 2001; 163(1): 12–8

    PubMed  CAS  Google Scholar 

  21. Rea HH, Scragg R, Jackson R, et al. A case-control study of deaths from asthma. Thorax 1986; 41(11): 833–9

    Article  PubMed  CAS  Google Scholar 

  22. Beasley R, Burgess C, Pearce N, et al. Confounding by severity does not explain the association between fenoterol and asthma death. Clin Exp Allergy 1994; 24(7): 660–8

    Article  PubMed  CAS  Google Scholar 

  23. Blais L, Ernst P, Suissa S. Confounding by indication and channeling over time: the risks of beta 2-agonists. Am J Epidemiol 1996; 144(12): 1161–9

    Article  PubMed  CAS  Google Scholar 

  24. Ernst P, Spitzer WO, Suissa S, et al. Risk of fatal and near-fatal asthma in relation to inhaled corticosteroid use. JAMA 1992; 268(24): 3462–4

    Article  PubMed  CAS  Google Scholar 

  25. Mann RD, Kubota K, Pearce G, et al. Salmeterol: a study by prescription-event monitoring in a UK cohort of 15,407 patients. J Clin Epidemiol 1996; 49(2): 247–50

    Article  PubMed  CAS  Google Scholar 

  26. Meier CR, Jick H. Drug use and pulmonary death rates in increasingly symptomatic asthma patients in the UK. Thorax 1997; 52(7): 612–7

    Article  PubMed  CAS  Google Scholar 

  27. Campbell DA, McLennan G, Coates JR, et al. A comparison of asthma deaths and near-fatal asthma attacks in South Australia. Eur Respir J 1994; 7(3): 490–7

    Article  PubMed  CAS  Google Scholar 

  28. Garrett JE, Lanes SF, Kolbe J, et al. Risk of severe life threatening asthma and beta agonist type: an example of confounding by severity. Thorax 1996; 51(11): 1093–9

    Article  PubMed  CAS  Google Scholar 

  29. Pearce N, Hensley MJ. Epidemiologic studies of beta agonists and asthma deaths. Epidemiol Rev 1998; 20(2): 173–86

    Article  PubMed  CAS  Google Scholar 

  30. Van Ganse E, van der Linden PD, Leufkens HG, et al. Asthma medications and disease exacerbations: an epidemiological study as a method for asthma surveillance. Eur Respir J 1995; 8(11): 1856–60

    Article  PubMed  Google Scholar 

  31. Van der Merwe L, Plaatjes M, Van Schalwyk E, et al. Risk factors for near-fatal and fatal asthma in a third world population [abstract]. Respirology 2002; 7 Suppl.: A26

    Google Scholar 

  32. Williams C, Crossland L, Finnerty J, et al. Case-control study of salmeterol and near-fatal attacks of asthma. Thorax 1998; 53(1): 7–13

    Article  PubMed  CAS  Google Scholar 

  33. Suissa S, Hemmelgarn B, Biais L, et al. Bronchodilators and acute cardiac death. Am J Respir Crit Care Med 1996; 154(6 Pt 1): 1598–602

    PubMed  CAS  Google Scholar 

  34. Martin RM, Dunn NR, Freemantle SN, et al. Risk of non-fatal cardiac failure and ischaemic heart disease with long acting beta 2 agonists. Thorax 1998; 53(7): 558–62

    Article  PubMed  CAS  Google Scholar 

  35. Au DH, Curtis JR, Psaty BM. Risk of myocardial ischaemia and beta-adrenoceptor agonists. Ann Med 2001; 33(5): 287–90

    Article  PubMed  CAS  Google Scholar 

  36. Holgate ST, Baldwin CJ, Tattersfield AE. Beta-adrenergic agonist resistance in normal human airways. Lancet 1977; II(8034): 375–7

    Article  Google Scholar 

  37. Harvey JE, Baldwin CJ, Wood PJ, et al. Airway and metabolic responsiveness to intravenous salbutamol in asthma: effect of regular inhaled salbutamol. Clin Sci (Lond) 1981; 60(5): 579–85

    CAS  Google Scholar 

  38. Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990; 336: 1391–6

    Article  PubMed  CAS  Google Scholar 

  39. Newnham D, Grove A, McDevitt D, et al. Subsensitivity of bronchodilator and systemic beta 2 adrenoceptor responses after regular twice daily treatment with eformoterol dry powder in asthmatic patients. Thorax 1995; 50: 475–504

    Article  Google Scholar 

  40. O’Connor BJ, Fuller RW, Barnes PJ. Nonbronchodilator effects of inhaled beta 2 agonists: greater protection against adenosine monophosphate- than methacholine-induced bronchoconstriction in asthma. Am J Respir Crit Care Med 1994; 150(2): 381–7

    PubMed  Google Scholar 

  41. Beach JR, Young CL, Harkawat R, et al. Effect on airway responsiveness of six weeks treatment with salmeterol. Pulm Pharmacol 1993; 6: 155–7

    Article  PubMed  CAS  Google Scholar 

  42. Booth H, Bish R, Walters J, et al. Salmeterol tachyphylaxis in steroid treated asthmatic subjects. Thorax 1996; 51: 1100–4

    Article  PubMed  CAS  Google Scholar 

  43. Cockcroft DW, Swystun VA. Functional antagonism produced by inhaled beta agonists. Thorax 1996; 51: 1051–6

    Article  PubMed  CAS  Google Scholar 

  44. Aldridge RE, Hancox RJ, Robin Taylor D, et al. Effects of terbutaline and budesonide on sputum cells and bronchial hyperresponsiveness in asthma. Am J Respir Crit Care Med 2000; 161(5): 1459–64

    PubMed  CAS  Google Scholar 

  45. Mclvor RA, Pizzichini E, Turner MO, et al. Potential masking effects of salmeterol on airway inflammation in asthma. Am J Respir Crit Care Med 1998; 158: 924–30

    Google Scholar 

  46. Page CP. An explanation of the asthma paradox. Am Rev Resp Dis 1993; 147: S29–33

    PubMed  CAS  Google Scholar 

  47. Li X, Ward C, Thien F, et al. An antiinflammatory effect of salmeterol, a long-acting beta2 agonist, assessed in airway biopsies and bronchoalveolar lavage in asthma. Am J Respir Crit Care Med 1999; 160: 1493–9

    PubMed  CAS  Google Scholar 

  48. Walters EH, Bjermer L, Faurschou P, et al. The anti-inflammatory profile of inhaled corticosteroids combined with salmeterol in asthmatic patients. Respir Med 2000; 94Suppl. F: S26–31

    Article  PubMed  Google Scholar 

  49. Wallin A, Sandstrom T, Soderberg M, et al. The effects of regular inhaled formoterol, budesonide, and placebo on mucosal inflammation and clinical indices in mild asthma. Am J Respir Crit Care Med 1999; 159(1): 79–86

    PubMed  CAS  Google Scholar 

  50. Eickelberg O, Roth M, Lorx R, et al. Ligand-independent activation of the glucocorticoid receptor by beta2-adrenergic receptor agonists in primary human lung fibroblasts and vascular smooth muscle cells. J Biol Chem 1999; 274(2): 1005–10

    Article  PubMed  CAS  Google Scholar 

  51. Orsida BE, Ward C, Li X, et al. Effect of a long-acting beta2-agonist over three months on airway wall vascular remodeling in asthma. Am J Respir Crit Care Med 2001; 164(1): 117–21

    PubMed  CAS  Google Scholar 

  52. Walters EH, Walters JA. A genetic twist to the beta-agonist ‘debate’. Clin Sci (Lond) 1999; 96(3): 219–20

    Article  CAS  Google Scholar 

  53. Walters E, Walters J. Inhaled short acting beta-2 agonist use in asthma: regular versus as-needed treatment. Available in The Cochrane Library [database on disk and CD ROM]. Updated quarterly. The Cochrane Collaboration; issue. Oxford: Oxford Update Software, 2000; Issue 3

    Google Scholar 

  54. Walters EH, Walters JA, Gibson PW. Regular treatment with long acting beta agonists versus daily regular treatment with short acting beta-agoinists in adults and children with stable asthma. Cochrane Database Syst Rev 2003; (1)

  55. Wooltorton E. Salmeterol (Severent) asthma trial halted early. CMAJ 2003; 168(6): 738

    PubMed  Google Scholar 

Download references

Acknowledgements

The Victorian Asthma Mortality Study was supported by the National Health & Medical Research Council of Australia. The Australian Airways Network is supported by a grant from the Commonwealth Department of Health and Aged Care. We thank Neil Pearce for permission to reproduce Fig1

Author information

Authors and Affiliations

  1. Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Australia

    Michael J. Abramson

  2. Department of Clinical Sciences, University of Tasmania Medical School, Hobart, Australia

    Julia Walters & E. Haydn Walters

Authors
  1. Michael J. Abramson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julia Walters
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Haydn Walters
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael J. Abramson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abramson, M.J., Walters, J. & Walters, E.H. Adverse Effects of β-Agonists. Am J Respir Med 2, 287–297 (2003). https://doi.org/10.1007/BF03256657

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03256657

Keywords

Search

Navigation