Tolerance to the nonbronchodilator effects of inhaled beta 2-agonists in asthma

N Engl J Med. 1992 Oct 22;327(17):1204-8. doi: 10.1056/NEJM199210223271704.


Background: Tolerance to the direct bronchodilator effects of beta 2-agonists does not appear to occur in asthma. However, it is not known whether this is true for the nonbronchodilator effects of these agents, which protect the airways against bronchoconstrictive stimuli.

Methods: We investigated whether tolerance develops to the protective effect of inhaled terbutaline on airway responsiveness to the bronchoconstrictors methacholine (which acts directly on airway smooth muscle) and AMP (which acts indirectly by stimulating the release of mediators from mast cells) during sustained treatment with terbutaline. In a randomized, double-blind, crossover study, 12 patients with mild asthma each inhaled a single dose of terbutaline (500 micrograms) or placebo before a challenge with a series of doubling doses of inhaled methacholine or AMP, before and after treatment for seven days with 500 micrograms of terbutaline four times daily or placebo.

Results: Before the seven days of treatment with terbutaline, a single dose of terbutaline reduced airway responsiveness to methacholine by 2.7 doubling doses (95 percent confidence interval, 1.9 to 3.5), but it had an even greater protective effect against AMP, reducing airway responsiveness by 3.8 doubling doses (95 percent confidence interval, 2.7 to 4.9; P less than 0.001). After seven days of treatment with terbutaline, the protective effect of terbutaline against methacholine decreased to 2.2 doubling doses (95 percent confidence interval, 1.3 to 3.0; P = 0.04), and that against AMP decreased even more, to 1.7 doubling doses (95 percent confidence interval, 1.1 to 2.4; P less than 0.001). By contrast, the bronchodilator response to terbutaline was unchanged during seven days of treatment with this agent.

Conclusions: We observed tolerance to the nonbronchodilator actions of the inhaled beta 2-agonist terbutaline in patients with mild asthma, an effect that may be more pronounced in mast cells than in bronchial smooth muscle. This property of beta-agonists may constitute a drawback to their regular use in patients with asthma.

Publication types

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

MeSH terms

  • Adenosine Monophosphate / pharmacology
  • Administration, Inhalation
  • Adrenergic beta-Agonists / administration & dosage
  • Adrenergic beta-Agonists / pharmacology*
  • Adult
  • Asthma / physiopathology*
  • Bronchi / drug effects*
  • Double-Blind Method
  • Drug Tolerance
  • Female
  • Humans
  • Male
  • Methacholine Chloride / pharmacology
  • Middle Aged
  • Terbutaline / administration & dosage
  • Terbutaline / pharmacology*


  • Adrenergic beta-Agonists
  • Methacholine Chloride
  • Adenosine Monophosphate
  • Terbutaline