Skip to main content
SpringerLink
Log in

Recovery from bronchoconstriction and bronchodilator tolerance

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

Until recently, researchers believed that tolerance or tachyphylaxis to the bronchodilator effects of β-agonists did not occur. However, recent studies examining the recovery from bronchoconstriction have clearly shown that an impaired response to β-agonists occurs in patients who have been using regular β-agonist treatment. This tolerance develops with both long- and short-acting β-agonists and is not affected by treatment with inhaled steroids. It develops rapidly, reaching a maximum within 1 wk of starting β-agonists, and has been demonstrated after methacholine, hypertonic saline, mannitol, and exercise-induced bronchoconstriction. The observed reduction in the bronchodilator response is proportional to the severity of bronchoconstriction. Therefore, although individuals with stable asthma show little evidence of tolerance, those with severe bronchospasm have a markedly reduced bronchodilator response to β-agonists. Almost all asthmatics show evidence of tolerance when tested in the setting of bronchoconstriction, although the extent of this tolerance varies. The reasons for this interindividual variation are not understood.

Bronchodilator tolerance is difficult to study in the clinical setting because nearly every patient has used multiple doses of β-agonist before seeking medical attention. However, there is compelling evidence that the response to rescue β-agonist treatment is reduced in those who use regular long- or short-acting β-agonists. The extent to which this phenomenon contributes to asthma morbidity and mortality remains to be determined.

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

Similar content being viewed by others

References

  1. Jenne, J. W., (1982), Whither beta-adrenergic tachyphylaxis? J. Allergy Clin Immunol. 70, 413–416.

    Article  PubMed  CAS  Google Scholar 

  2. Nelson, H. S., Raine, D. Jr., Doner, H. C., and Posey, W. C. (1977), Subsensitivity to the bronchodilator action of albuterol produced by chronic administration. Am. Rev. Respir. Dis. 116, 871–878.

    PubMed  CAS  Google Scholar 

  3. Harvey, J. E. and Tattersfield, A. E., (1982), Airway response to salbutamol: effect of regular salbutamol inhalations in normal, atopic and asthmatic subjects. Thorax 37, 280–287.

    PubMed  CAS  Google Scholar 

  4. Lipworth, B. J., Struthers, A. D., and McDevitt, D. G. (1999), Tachphylaxis to systemic but not to airway responses during prolonged therapy with high dose inhaled salbutamol in asthmatics. Am. Rev. Respir. Dis. 140, 586–592.

    Google Scholar 

  5. Weber, R. W., Smith, J. A., and Nelson, H. S., (1982), Aerosolized terbutaline in asthmatics: development of subsensitivity with long-term administration. J. Allergy Clin. Immunol. 70, 417–422.

    Article  PubMed  CAS  Google Scholar 

  6. McFadden, E. R., (1995), Perspectives in β2-agonist therapy: Vox clamatis in deserto vellux in tenebris. J. Allergy Clin. Immunol. 95, 641–651.

    Article  PubMed  Google Scholar 

  7. Rabe, K. F. (2003), State of the art in beta2-agonist therapy: a safety review of long-acting agents. Intern. J. Clin. Practice 57, 689–697.

    CAS  Google Scholar 

  8. Larj, M. J. and Bleecker, E. R., (2002), Effects of beta2-agonists on airway tone and bronchial responsiveness. J. Allergy Clin. Immunol. 110, S304-S312.

    Article  PubMed  CAS  Google Scholar 

  9. Barnes, P. J. (1995), Beta-adrenergic receptors and their regulation. Am. J. Respir. Crit. Care Med. 152, 838–860.

    PubMed  CAS  Google Scholar 

  10. Tan, K. S., Grove, A., McLean, A., Gnosspelius, Y., Hall, I. P., and Lipworth, B. J., (1997), Association between β2-adrenocepter polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics. Am. J. Respir. Crit. Care Med. 156, 28–35.

    PubMed  CAS  Google Scholar 

  11. Newnham, D. M., Grove, A., McDevitt, D. G., and Lipworth, B. J. (1995), Subsensitivity of bronchodilator and systemic β2 adrenergic responses after regular twice daily treatment with eformeterol dry powder in asthmatic patients. Thorax 50, 497–504.

    PubMed  CAS  Google Scholar 

  12. Lipworth, B. J., Clark, R. A., Dhillon, D. P., and McDevitt, D. G. (1990), Subsensitivity of beta-adrenoceptor responses in asthmatic patients taking regular low dose inhaled salbutamol. Eur. J. Clin. Pharmacol. 38, 203–205.

    Article  PubMed  CAS  Google Scholar 

  13. Cockcroft, D. W. and Swystun, V. A. (1996), Functional antagonism: tolerance produced by inhaled β2 agonists. Thorax 51, 1051–1056.

    PubMed  CAS  Google Scholar 

  14. O'Connor, B. J., Aikman, S. L., and Barnes, P. J. (1992), Tolerance to the nonbronchodilator effects of inhaled beta-agonists in asthma. N. Engl. J. Med. 327, 1204–1208.

    Article  PubMed  Google Scholar 

  15. Cheung, D., Timmers, M.C., Zwinderman, A. H., GBel, E. H., Dijkman, J. H., and Sterk, P. J. (1992), Long-term effects of a long-acting β2-adrenocepter agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma. N. Engl. J. Med. 327, 1198–1203.

    Article  PubMed  CAS  Google Scholar 

  16. Yates, D. H., Sussman, H. S., Shaw, M. J., Barnes, P. J., and Chung, K. F. (1995), Regular formoterol treatment in mild asthma. Effect on bronchial responsiveness during and after treatment. Am. J. Respir. Crit. Care Med. 152, 1170–1174.

    PubMed  CAS  Google Scholar 

  17. Inman, M. D. and O'Byrne, P. M. (1996), The effect of regular inhaled albuterol on exercise-induced bronchoconstriction. Am. J. Respir. Crit. Care Med. 153, 65–69.

    PubMed  CAS  Google Scholar 

  18. Cockcroft, D. W., McParland, C. M., Britto, S. A., Swystun, V. A., and Rutherford, B. C. (1993), Regular inhaled salbutamol and airway responsiveness to allergen. Lancet 342, 833–837.

    Article  PubMed  CAS  Google Scholar 

  19. Johnson, M. (1998), The β-adrenoceptor. Am. J. Respir. Crit. Care Med. 158, S146-S153.

    PubMed  CAS  Google Scholar 

  20. Storms, W. W., Chervinsky, P., Ghannam, A., Bird, S., Hustad, C. M., and Edelman, J. M. (2004), A comparison of the effects of oral montelukast and inhaled salmeterol on response to resuce bronchodilation after challenge. Respir. Med. 98, 1051–1062.

    Article  PubMed  Google Scholar 

  21. Fishwick, D., Bradshaw, L., MacDonald, C., et al. (2001), Cumulative and single-dose design to assess the bronchodilator effects of β2-agonists in individuals with asthma. Am. J. Respir. Crit. Care Med. 163, 474–477.

    PubMed  CAS  Google Scholar 

  22. Hendeles, L., Beaty, R., Ahrens, R., Stevens, G., and Harman, E. M. (2004), Response to inhaled albuterol during nocturnal asthma. J. Allergy Clin. Immunol. 113, 1058–1062.

    Article  PubMed  CAS  Google Scholar 

  23. Hancox, R. J., Aldridge, R. E., Cowan, J. O., et al. (1999), Tolerance to beta agonists during acute bronchoconstriction. Eur. Respir. J. 14, 283–287.

    Article  PubMed  CAS  Google Scholar 

  24. Hancox, R. J., Cowan, J. O., Flannery, E. M., Herbison, G. P., McLachlan, C.R., and Taylor, D. R. (2000), Bronchodilator tolerance and rebound bronchoconstriction during regular inhaled betaagonist treatment. Respir. Med. 94, 767–771.

    Article  PubMed  CAS  Google Scholar 

  25. Jones, S. L., Cowan, J. O., Flannery, E. M., Hancox, R. J., Herbison, G. P., and Taylor, D. R. (2001), Reversing acute bronchoconstriction in asthma: the effect of bronchodilator tolerance. Eur. Respir. J. 17, 368–373.

    Article  PubMed  CAS  Google Scholar 

  26. Wraight, J. M., Hancox, R. J., Herbison, G. P., Cowan, J. O., Flannery, E. M., and Taylor, D. R. (2003), Bronchodilator tolerance: the impact of increasing bronchoconstriction. Eur. Respir. J. 21, 810–815.

    Article  PubMed  CAS  Google Scholar 

  27. Lee, D. K. C., Jackson, C. M., Bates, C. E., and Lipworth, B. J. (2004), Cross tolerance to salbutamol occurs independently of β2 adrenoceptor genotype-16 in asthmatic patients receiving regular formoterol or salmeterol. Thorax 59, 662–667.

    Article  PubMed  CAS  Google Scholar 

  28. Van der Woude, H. J., Winter, T. H., and Aalbers, R. (2001), Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting β2 agonists. Thorax 56, 529–535.

    Article  PubMed  Google Scholar 

  29. Haney, S. and Hancox, R. J. (2005), Tolerance to bronchodilation during treatment with long-acting beta-agonists, a randomised controlled trial. Respir. Res. 6, 107.

    Article  PubMed  CAS  Google Scholar 

  30. Haney, S. and Hancox, R. J. (2005), Rapid onset of tolerance to beta-agonist bronchodilation. Respir. Med. 99, 566–571.

    Article  PubMed  Google Scholar 

  31. Taylor, D. R., Town, G. I., Herbison, G. P., et al. (1998), Asthma control during long-term treatment with regular inhaled salbutamol and salmeterol. Thorax 53, 744–752.

    PubMed  CAS  Google Scholar 

  32. Hancox, R. J., Cowan, J. O., Flannery, E. M., et al. (1999), Randomised trial of an inhaled beta2 agonist, inhaled corticosteroid and their combination in the treatment of asthma. Thorax 54, 482–487.

    Article  PubMed  CAS  Google Scholar 

  33. Lee, D. K. C., Jackson, C. M., Currie, G. P., Cockburn W. J., and Lipworth, B. J. (2003), Comparison of combination inhalers vs inhaled corticosteroids alone in moderate persistent asthma. Br. J. Clin. Pharmacol. 56, 494–500.

    Article  PubMed  CAS  Google Scholar 

  34. British Thoracic Society, Scottish Intercollegiate Guidelines Network (2003), British guideline on the management of asthma. Thorax 58, 1–83.

    Article  Google Scholar 

  35. Dollery, C. ed (1999), Therapeutic Drugs. Churchill Livingstone, pp. F155–F158.

  36. Yates, D. H., Kharatinov, S. A., and Barnes, P. J. (1996), An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a longacting inhaled β2-agonist. Am. J. Respir. Crit. Care Med. 154, 1603–1607.

    PubMed  CAS  Google Scholar 

  37. Masoli, M., Holt, S., Weatherall, M., and Beasley, R. (2004), Dose-response relationship of inhaled budesonide in adult asthma: a meta-analysis. Eur. Respir. J. 24, 552–558.

    Article  CAS  Google Scholar 

  38. Lipworth, B. J. and Aziz, I. (2000), Bronchodilator response to albuterol after regular formoterol and effects of acute corticosteroid administration. Chest 117, 156–162.

    Article  PubMed  CAS  Google Scholar 

  39. American Thoracic Society. (2000) Guidelines for methacholine and exercise challenge testing—1999. Am. J. Respir. Crit. Care Med. 161, 309–329.

    Google Scholar 

  40. Hancox, R. J., Subbarao, P., Kamada, D., Watson, R., Hargreave, F. E., and Inman, M. D. (2002), Beta2 agonist tolerance and exercise-induced bronchospasm. Am. J. Respir. Crit. Care Med. 165, 1068–1070.

    PubMed  Google Scholar 

  41. Haney, S. and Hancox, R. J. (2005), The bronchodilator response to ipratropium is not affected by regular β-agonist use [abstract]. Eur. Respir. J. 26, 123S.

    Google Scholar 

  42. Makker, H. K. and Holgate, S. T. (1993), Relation of the hypertonic saline responsiveness of the air-ways to exercise induced asthma symptom severity and to histamine or methacholine reactivity. Thorax 48, 142–147.

    PubMed  CAS  Google Scholar 

  43. Sterk, P. J., Fabbri, L. M., Quanjer, P. H., et al. (1993), Airway responsiveness. Standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Eur. Respir. J. 6, 53–83.

    Google Scholar 

  44. Brannan, J., Freed-Martens, R., and Anderson, S. D. (2005), Effect of treatment on recovery to mannitol challenge: a phase 3 study [abstract]. Eur. Respir J. 26, 371S.

    Google Scholar 

  45. Rodrigo, C. and Rodrigo, G. (1998), Therapeutic response patterns to high and cumulative doses of salbutamol in acute severe asthma. Chest 113, 593–598.

    PubMed  CAS  Google Scholar 

  46. Korosec, M., Novak, R. D., Myers, E., Skowronski, M., and McFadden, E. R. (1999), Salmeterol does not compromise the bronchodilator response to albuterol during acute episodes of asthma. Am. J. Med. 107, 209–213.

    Article  PubMed  CAS  Google Scholar 

  47. Windom, H. H., Burgess, C. D., Crane, J., Pearce, N., Kwong, T., and Beasley, R. (1990), The self-administration of inhaled beta agonist drugs during severe asthma. N. Zealand Med. J. 103, 205–207.

    CAS  Google Scholar 

  48. Haney, S. and Hancox, R. J. (2005), Tolerance to bronchodilation is not overcome by high dose salbutamol [abstract]. Eur. Respir. J. 26, 122S, 123S.

    Google Scholar 

  49. Sears, M. R. and Lotvall, J. (2005), Past, present and future—B2-adrenoceptor agonists in asthma management. Respir. Med. 99, 152–170.

    Article  PubMed  Google Scholar 

  50. Zuo, Z. (2005), The role of opioid receptor internalization and beta-arrestins in the development of opioid tolerance. Anesth. Analg. 101, 728–734.

    Article  PubMed  CAS  Google Scholar 

  51. Kosmicki, M., Sadowski, Z., Szwed, H., and Kowalik, I. (2000), What intervals in oral therapy of isosirbide dinitrate in various doses are sufficient to prevent dinitrate tolerance? Med. Sci. Mon. 6, 763–768.

    CAS  Google Scholar 

  52. Davis, B. E., Reid, J. K., and Cockcroft D. W. (2003), Formoterol thrice weekly does not result in the development of tolerance to bronchoprotection. Can. Respir. J. 10, 23–26.

    PubMed  Google Scholar 

  53. Brodde, O. E., Daul, A., Michel-Reher, M., et al. (1990), Agonist-induced desensitization of β-adrenoceptor function in humans. Circulation 81, 914–921.

    PubMed  CAS  Google Scholar 

  54. van den Berg, W., Leferink, J. G., Fokkens J. K., Kreukniet, J., Maes, R. A. A., and Bruynzeel, P. L. B. (1982), Clinical implications of drug-induced desensitization of the beta receptor after continuous oral terbutaline. J. Allergy Clin. Immunol. 69, 410–417.

    Article  PubMed  Google Scholar 

  55. Bhagat, R., Kalra, S., Swystun, V. A., and Cockcroft D. W. (1995), Rapid onset of tolerance to the bronchoprotective effect of salmeterol. Chest 108, 1235–1239.

    PubMed  CAS  Google Scholar 

  56. van Veen, A., Weller, F. R., Wieranga, E. A., Jansen, H. M., and Jonkers R. E. (2003), A comparison of salmeterol and formoterol in attenuating airway responses to short-acting β2-agonists. Pulmon. Pharmacol. Therapeut. 16, 153–161.

    Article  CAS  Google Scholar 

  57. Smith, A. P., Orehek, J., and Charpin, J. (1977), Bronchodilator drug tests in normal subjects. Br. J. Dis. Chest 71, 234–236.

    Article  PubMed  CAS  Google Scholar 

  58. Houghton, C. M., Woodcock, A. A., and Singh, D. (2004), A comparison of lung function methods for assessing dose-response effects of salbutamol. Br. J. Clin. Pharmacol. 58, 134–141.

    Article  PubMed  CAS  Google Scholar 

  59. Israel, E., Chinchilli, V. M., Ford, J. G., et al. (2004), Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebocontrolled cross-over trial. Lancet 364, 1505–1512.

    Article  PubMed  CAS  Google Scholar 

  60. Adler, A., Uziel, Y., Mei-Zahav, M., and Horowitz, I. (2006), Formoterol induces tolerance to the bronchodilating effect of salbutamol following methacholine-provocation test in asthmatic children. Pulmon. Pharmacol. Therapeut. 19, 281–285.

    Article  CAS  Google Scholar 

  61. Shrewsbury, S., Pyke, S., and Britton, M. (2000), Meta-analysis of increased dose of inhaled steroid or addition of salmeterol in symptomatic asthma (MIASMA). BMJ 320, 1368–1373.

    Article  PubMed  CAS  Google Scholar 

  62. Pauwels, R. A., Lofdahl, C. G., Postma, D. S., et al. (1997), Effect of inhaled formoterol and budesonide on exacerbations of asthma. N. Engl. J. Med. 337, 1405–1411.

    Article  PubMed  CAS  Google Scholar 

  63. Castle, W., Fuller, R., Hall, J., and Palmer, J. (1993), Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator therapy. BMJ 306, 1034–1037.

    Article  PubMed  CAS  Google Scholar 

  64. Mann, M., Chowdhury, B., Sullivan, E., Nicklas, R. A., Anthracite, R., and Meyer, R. J. (2003), Serious asthma exacerbations in asthmatics treated with high-dose formoterol. Chest 124, 70–74.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Respiratory Medicine, Waikato Hospital, Hamilton, New Zealand

    Sarah Haney & Robert J. Hancox

  2. Department of Preventive and Social Medicine, Dunedin School of Medicine, Dunedin, New Zealand

    Robert J. Hancox

Authors
  1. Sarah Haney
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert J. Hancox
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert J. Hancox.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Haney, S., Hancox, R.J. Recovery from bronchoconstriction and bronchodilator tolerance. Clinic Rev Allerg Immunol 31, 181–196 (2006). https://doi.org/10.1385/CRIAI:31:2:181

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/CRIAI:31:2:181

Index Entries

Search

Navigation