An inhaled glucocorticoid does not prevent tolerance to the bronchoprotective effect of a long-acting inhaled beta 2-agonist

Am J Respir Crit Care Med. 1996 Dec;154(6 Pt 1):1603-7. doi: 10.1164/ajrccm.154.6.8970342.


There is increasing evidence for the development of tolerance to the protective effects of inhaled beta 2-agonists against bronchoconstrictor stimuli. Animal studies have suggested that glucocorticoids protect against the down-regulation of beta 2-receptors after chronic exposure to beta 2-agonists. In a double-blind placebo-controlled crossover study in 12 patients with mild asthma, we investigated the effect of inhaled budesonide or identical placebo on the protection conferred by albuterol (200 micrograms) against methacholine-induced bronchoconstriction before and after treatment with the long-acting beta 2-agonist salmeterol. Patients were randomized to be treated for 3 wk with inhaled budesonide (800 micrograms twice a day) or placebo; salmeterol (50 micrograms twice a day) was added during the third week. Airway responsiveness to methacholine was measured 15 min after albuterol, both before and exactly 12 h [corrected] after the last salmeterol dose. Mean FEV1 increased significantly after 2 wk of budesonide (p < 0.05) and increased further after salmeterol (p < 0.05) compared with placebo. After 2 wk, the bronchoprotective effect of albuterol against methacholine was significantly greater with budesonide than with placebo (3.4 versus 2.4 doubling dilutions; p < 0.05), consistent with an improvement in airway hyperresponsiveness with budesonide therapy. However, regular salmeterol treatment for 1 wk significantly diminished the protection conferred by albuterol against methacholine challenge, both with budesonide and with placebo (-1.1 +/- 0.42 and -1.41 +/- 0.30 doubling dilutions, respectively). There was no significant difference in the loss of bronchoprotection seen with salmeterol between budesonide and placebo treatment periods. Our study suggests that even a high dose of an inhaled glucocorticoid fails to prevent the loss of bronchoprotection produced by regular beta 2-agonist therapy.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Administration, Topical
  • Adrenergic beta-Agonists / administration & dosage*
  • Adult
  • Albuterol / administration & dosage
  • Albuterol / analogs & derivatives
  • Anti-Inflammatory Agents / administration & dosage*
  • Asthma / drug therapy*
  • Bronchoconstriction / drug effects*
  • Bronchodilator Agents / administration & dosage*
  • Budesonide
  • Cross-Over Studies
  • Double-Blind Method
  • Drug Tolerance
  • Female
  • Forced Expiratory Volume / drug effects
  • Glucocorticoids
  • Humans
  • Male
  • Methacholine Chloride / pharmacology
  • Pregnenediones / administration & dosage
  • Salmeterol Xinafoate


  • Adrenergic beta-Agonists
  • Anti-Inflammatory Agents
  • Bronchodilator Agents
  • Glucocorticoids
  • Pregnenediones
  • Methacholine Chloride
  • Budesonide
  • Salmeterol Xinafoate
  • Albuterol