Inhaled Salmeterol and Salbutamol in Asthmatic Patients: An Evaluation of Asthma Symptoms and the Possible Development of Tachyphylaxis

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159

The extended duration of bronchodilation due to formoterol and salmeterol greatly exceeds that of short acting beta 2-adrenoceptor agonists, such as salbutamol or terbutaline. This extended duration and their capacity to "reassert" airway smooth muscle relaxation in vitro despite repeated washing has prompted considerable debate on the underlying mechanism(s). The comparative pharmacology, and molecular modelling of these drugs and of the beta 2-adrenoceptor and its ligand binding core have cast doubt on the exosite/exoceptor model previously proposed to explain the behaviour of salmeterol. We present evidence supporting a unifying hypothesis that the duration of action both of formoterol and salmeterol is determined principally by their physicochemical interactions with membrane lipid bilayers (plasmalemma diffusion microkinetic model), rather than putative distinct exosite/exoceptor binding sites in or near the beta 2-adrenoceptor. This model provides a clearer understanding of the pharmacological profile of these drugs (rate of onset, duration, "reassertion", interaction with hydrophilic and hydrophobic beta 2-adrenoceptor antagonists), and explains why in human airway smooth muscle in vitro a true relaxation-concentration response may not exist for salmeterol.

mentioning

confidence: 99%

Why are long-acting beta-adrenoceptor agonists long-acting?

Anderson¹,

Lindén²,

Rabe³

1994

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159

“…Treatment ranging from 2 weeks to 12 months with salmeterol 50 µg b.d. has also demonstrated that responsiveness to inhaled salbutamol was not decreased during or after treatment, suggesting no change in β 2 -receptor sensitivity [8,9] Other published data have, conversely, reported that 4 weeks of treatment with the long-acting β 2 -agonist formoterol, results in tolerance to its acute bronchodilator effects [10] and a recently published study has claimed that continuous exposure to salmeterol 50 µg b.d. results in reduced bronchodilator response to repeated doses of inhaled salbutamol [11].…”

mentioning

confidence: 99%

“…Inhaled β 2 -agonists have become the treatment of choice in acute asthma because of their excellent bronchodilating effects [1,2]. In recent years however, the regular use of short-acting inhaled β 2 -agonists for the treatment of asthma has been controversial, with reports of worsening of asthma control, a desensitization of β 2 -receptors and rebound increases in bronchial hyperresponsiveness [3,4].…”

mentioning

confidence: 99%

“…The introduction of long-acting β 2 -agonists such as salmeterol, which has a bronchodilator action in excess of 12 h [2,5], has increased the controversy. It has been suggested that prolonged receptor occupancy by these long-acting agonists might increase the likelihood of β 2 -receptor down regulation and subsensitivity compared to their short-acting counterparts [3].…”

mentioning

confidence: 99%

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Bronchodilator response to salbutamol after chronic dosing with salmeterol or placebo

Langley¹,

Masterson²,

Batty³

et al. 1998

It has been hypothesized that regular inhaled beta2-agonist therapy causes desensitization of beta2-receptors. The aim of this study was to define whether beta2-receptor desensitization occurs after treatment with the long-acting beta2-agonist salmeterol, assessed by measuring the bronchodilator response to cumulative repeated doses of inhaled salbutamol before and after treatment. Forty nine stable adult patients with asthma were randomized to receive either salmeterol 50 microg b.d. or placebo b.d. from an Accuhaler for 4 weeks after an initial 2 week run-in period without beta2-agonists. All patients were receiving inhaled corticosteroids. Bronchodilator responsiveness to cumulative repeated doses of inhaled salbutamol were measured before and 12 and 36 h after the last dose of study treatment. The primary efficacy endpoint was the peak forced expiratory volume in one second (FEV1) response before and after treatment. There were no significant differences between the two treatment groups in the absolute peak FEV1 or maximal peak expiratory flow (PEF) results 12 or 36 h after the last dose of study treatment. Significantly higher clinic lung function and diary card parameters were noted in the salmeterol group when compared to the placebo-treated patients, demonstrating the beneficial effects of regular salmeterol. Regular salmeterol usage did not lead to reduced efficacy of usual or higher than usual doses of salbutamol.

“…Chronic use does not appear to lead to tachyphylaxis to its bronchodilator effects [13]. However, CHEUNG et al [14] found that regular treatment with salmeterol in mild asthmatics led to significant tolerance to its bronchoprotective effects against methacholine challenge [14].…”

mentioning

confidence: 99%

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

Wong¹,

O'Shaughnessy²,

Walker³

et al. 1997

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.