Effects of long-acting and short-acting beta-agonists on methacholine dose-response curves in asthmatics

Abstract

Regular use of short-acting β-agonists may decrease control of asthma and increase airway responsiveness to bronchoconstrictor stimuli. The aim of this study was to determine the effects of regular treatment with the long-acting β-agonist, salmeterol, on the methacholine dose-response curve (DRC) in mild-tomoderate asthmatics.Changes in methacholine airway responsiveness were measured in 14 stable adult asthmatics, randomized in a double-blind, three-way cross-over design to receive salmeterol 50 µg, salbutamol 200 µg or placebo, each twice daily for 4 days. Two baseline methacholine DRC, were performed, one without premedication and one following a single dose of 200 µg salbutamol. Following 4 days of regular treatment, methacholine DRC to plateau were carried out commencing 15 min after the final dose of trial medication.There were no significant differences in mean baseline forced expiratory volume in one second (FEV1) between treatments. Four days treatment with salmeterol and salbutamol shifted the DRC to the right, but salmeterol provided less protection than salbutamol. The point of inflection of the curve from baseline moved 1.9 and 3.2 doubling doses, respectively, compared to placebo (p≤0.001), and the provocative concentration of methacholine required to produce a 20% fall in FEV1 (PC20) increased 1.6 and 3.1 doubling doses, respectively (p≤0.001). The slope of the DRC was increased slightly by both β-agonists compared to placebo (log slope 3.11, 3.06 and 2.77 for salmeterol, salbutamol and placebo, respectively). This effect of regular salmeterol on slope was more marked in subjects with lower baseline FEV1. Maximal response plateaus did not differ between the three treatments.These results suggest that regular use either of short-or long-acting β-agonists could increase the risk of a more precipitous asthma episode associated with "breakthrough" bronchoconstrictor responses, particularly in those with more severe initial airflow obstruction, if subjects are exposed to a sufficiently potent stimulus.

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

“…Asthma deaths, adverse events and effect of glucocorticoids Long-term use of b 2 -adrenoceptor agonists is common in the management of asthma and airways hyperresponsiveness (AHR), which is defined as an increase in the sensitivity of the ASM to constrictor stimuli [129][130][131][132]. 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].…”

Effect of chronic theophylline treatment on the methacholine dose-response curve in allergic asthmatic subjects

“…*: significant increase in PC20 in the theophylline group (p=0.008, two-sided); no significant differences between groups. Furthermore, unlike short-and long-acting β 2 -adrenoceptor agonists [15,16], theophylline does not cause a worsening of the slope of the dose-response curve to methacholine in mild asthmatics.…”

“…Thus, salbutamol [15,16] and salmeterol [16] provide protection against bronchospastic agents, as assessed by rightward shifts in the dose-response curve to spasmogens. However, prolonged use of salbutamol or terbutaline reduces the protection afforded against bronchoconstriction induced by methacholine [21][22][23], exercise [24] or antigen challenge [21,23] and has been shown to increase the magnitude of the late asthmatic response induced by allergen [25].…”

“…Similarly, regular treatment with salmeterol also leads to a loss in protection against bronchospasm induced by methacholine [26,27] and exercise [28]. Furthermore, β 2 -adrenoceptor agonists have been demonstrated to steepen the dose-response curve to methacholine [15,16]. The slope of the dose-response curve is thought to reflect the degree of airway narrowing and may represent an index of thickened airway wall secondary to inflammation [14].…”

“…Whilst many studies have been undertaken to evaluate the effect of drugs on airway sensitivity to spasmogens, only a few studies have been undertaken to evaluate the effect of antiasthma drugs on airway reactivity. Thus, chronic treatment with either short-or long-acting β 2 -adrenoceptor agonists [15,16] has been demonstrated to increase airway reactivity, whereas the anti-inflammatory glucocorticosteroid budesonide [17,18] decreased airway reactivity to spasmogens. Thus, whilst theophylline has been investigated for its effect on airway sensitivity (PC20) to spasmogens [2-4, 19, 20], no study to date has evaluated the effect of this drug on the full dose-response curve to inhaled methacholine.…”