Tolerance to beta-agonists during acute bronchoconstriction

Abstract

Previous reports suggest that regular use of b-agonists does not lead to tolerance to their bronchodilator effects. However, most studies have been conducted in stable asthma. This study investigates whether bronchodilator tolerance can be demonstrated during acute bronchoconstriction.Thirty-four asthmatic subjects were treated with 6 weeks inhaled terbutaline (1 mg q.i.d.), budesonide (400 mg, b.i.d.), both drugs or placebo in a randomized, doubleblind, cross-over study. After each treatment methacholine was administered to induce a 20% fall in the forced expiratory volume in one second (FEV1). The response to inhaled salbutamol 100, 100, 200 mg at 5 min intervals) was then measured. Doseresponse curves were compared using an analysis of covariance. Pre-methacholine FEV1, the highest pre-methacholine FEV1, the fall in FEV1 induced by methacholine and the logarithm of the provocative dose of methacholine required to induce the 20% fall in FEV1 (PD20) were used as covariates.There was a significantly reduced response to salbutamol after 6 weeks terbutaline treatment: the mean (95% confidence intervals (CI)) area under the dose-response curve was reduced by 36% (24, 47) compared to placebo (p<0.0001). The reduction in bronchodilator response was not affected by concomitant treatment with budesonide.Significant tolerance to the bronchodilator effect of inhaled b-agonists may be demonstrated when tested during acute bronchoconstriction. Continuous treatment with inhaled b-agonists may lead to a reduced response to emergency b-agonist treatment during asthma exacerbations. Eur Respir J 1999; 14: 283±287. b-agonists are highly effective bronchodilators and have an important role in the treatment of asthma exacerbations. However, many of the pharmacological effects of b-agonists diminish during chronic treatment, and there has been some concern that regular use of these drugs could lead to a failure to respond to treatment during severe asthma attacks. Some recent studies have shown a small reduction in bronchodilator response during treatment with long-acting b-agonists [1±3], but in general asthmatics have been found to be surprisingly resistant to the development of bronchodilator tolerance [4,5]. The reason for this is unknown. It may be because there is a high turnover of b 2 -receptors on airway smooth muscle such that receptor down-regulation has little impact on the receptor density [6]. Alternatively, it may be because maximal bronchodilation can be achieved by stimulation of a fraction of the normal receptor number.In contrast, there is increasing evidence that continuous b-agonist treatment leads to a reduction in their bronchoprotective effect for a variety of bronchoconstricting stimuli including methacholine, histamine, adenosine, exercise and allergen [7]. However, the clinical significance of these changes is uncertain in view of the apparently preserved acute bronchodilator response.This dissociation between the tendency to develop tolerance to the bronchodilator and bronchoprotective effects...

Bronchodilator tolerance: the impact of increasing bronchoconstriction

“…In both of these studies, measuring the response to b-agonist in the presence of methacholineinduced bronchoconstriction permitted the demonstration of tolerance which would not otherwise have been detected. These findings raise the possibility that the effects of tolerance to inhaled b-agonists may be further accentuated by bronchoconstriction beyond the 20% fall in FEV1 that was induced in these investigations [12][13][14]. In acute severe asthma, patients will usually have a reduction in their FEV1 that greatly exceeds 20%.…”

“…The sample-size calculation was based on the results of two previous studies [12,14], although in these studies, differences in AUC0-40 FEV1 followed a 20% fall in FEV1 (rather than the 15 and 30% in this study). The primary study end-point was AUC (AUC0-40 FEV1) for change in FEV1 over 40 min following inhaled salbutamol.…”

“…Recently, HANCOX et al [12] have described a method that reliably demonstrates bronchodilator tolerance to b-agonists.…”

Beyond the dogma: novel β2-adrenoceptor signalling in the airways

“…Similarly, the ability of short-and long-acting b 2 -adrenoceptor agonists to protect the airways against bronchoconstrictor stimuli and to promote bronchodilatation may be partially lost with time following long-term use [2,129,131,[133][134][135][136][137][138][139][140]. Indeed, there is a greater tendency for bronchodilator tolerance to develop to longacting b 2 -adrenoceptor agonists compared to their short-acting counterparts, which may relate to some aspect of their prolonged duration of agonism [141,142].…”

Pharmacological strategies for self-management of asthma exacerbations: Table 1—

“…There do not appear to have been any double-blind studies comparing levalbuterol and racemic albuterol in the management of asthma exacerbations in adults, and several recent double-blind studies in acute asthma in children have failed to find a therapeutic advantage for levalbuterol [63][64][65]. The observed development of bronchodilator tolerance with regular administration of SABA [66] is obviously of concern in the context of increasing b 2 -agonist usage during asthma exacerbations, but the initial suggestion that such tachyphylaxis may be due to (S)-albuterol [61] appears not to be supported by evidence [67,68].…”