Trends in Pharmacological Sciences
OpinionLong-acting β2-adrenoceptor agonists: a smart choice for asthma?
Section snippets
Pharmacology of β2-adrenoceptors
An intrinsic defect in β2-adrenoceptors that results in impaired function of airway smooth muscle was originally hypothesized as one of the possible mechanisms underlying the asthmatic condition, resulting in bronchial smooth muscle constriction from an imbalance between sympathetic (bronchorelaxation) and acetylcholine-mediated (bronchoconstriction) airway tone [1]. Inhaled β2-adrenoceptor agonists have been the mainstay of bronchodilator therapy for asthma for >40 years, initially with the
Effects on exacerbations
Current national asthma management guidelines recommend the preventative use of inhaled corticosteroids (ICSs) such as beclomethasone, budesonide, fluticasone, mometasone and ciclesonide as first-line anti-inflammatory therapy, with short-acting β2-adrenoceptor agonists being used on demand for the rapid relief of episodes of breakthrough bronchoconstriction [2]. The frequency of salbutamol reliever use is sometimes considered to be a surrogate marker of disease control when adjusting the dose
The SMART study
The potential safety problems with LABAs were recently highlighted in the Salmeterol Multicenter Asthma Research Trial (SMART) study, which evaluated the use of salmeterol or placebo in 26 355 asthmatic patients for seven months and was prematurely terminated because of findings obtained from African American patients and because of enrolment difficulties [6]. The early termination made it less likely that there would be statistically significant results for all outcomes. The results for the
Tachyphylaxis with LABAs
Given that tachyphylaxis (see Glossary) occurs readily with regular exposure to short-acting β2-adrenoceptor agonists, the advent of LABAs soon led to concerns about the potential for more-profound tachyphylaxis. This is because of prolonged, 24-h receptor occupancy and the associated propensity for agonist-promoted reduction in the number and coupling efficiency of β2-adrenoceptors on airway smooth muscle and inflammatory cells, where such receptors are expressed (Box 2). The first clinical
Genetic variation of β2-adrenoceptors
Several polymorphisms of the β2-adrenoceptor have potential functional consequences for ligand–receptor interactions. Of these polymorphisms, most attention has been focused on allelic variants at position 16 of the β2-adrenoceptor, where a single nucleotide polymorphism results in an amino acid substitution of glycine (Gly) for arginine (Arg) [25]. The allelic frequencies are 36% and 64% for Arg and Gly polymorphisms, respectively, with genotypic frequencies of 14%, 42% and 44% for homozygous
The way forward
There is clearly a potential problem with LABAs whereby worsening asthma control might result in life-threatening exacerbations. The subgroup analysis from the SMART study was inadequate for drawing valid conclusions, but it has been used in some circles to make the point that physicians should not be concerned about using LABAs, as long as they are prescribed for Caucasians and for use in combination inhalers in conjunction with ICSs, which have beneficial anti-inflammatory activity and
Concluding remarks
The dilemma for clinicians will increase because LABAs are likely to become more prevalent in a market driven by an ever-increasing number of proprietary and generic combination inhalers. Moreover, the imminent availability of ultra-long-acting once-daily drugs means that β2-adrenoceptors might be exposed to continuous 24-h occupancy by a high-efficacy, high-affinity agonist that would be expected to induce an even more profound tachyphylaxis. In this regard, opinion leaders need to take a step
Disclosure statement
B.J.L. and the Asthma and Allergy Research Group have received funding support for performing clinical trials, consulting activity, advisory work, giving postgraduate educational talks and departmental meetings from companies that make LABA and ICS, including AstraZeneca, GlaxoSmithKline, Altana, Sanofi-Aventis, Ivax, Schering Plough, Noelab, Cipla, Novartis, Innovata and Verus.
Glossary
- Forced expiratory volume in 1 s (FEV1)
- a measure (in litres) of airway calibre.
- Genotype
- a combination of two polymorphisms (e.g. homozygous Arg–Arg at position 16 of the β2-adrenoceptor.
- Haplotype
- a combination of genotypes at different positions.
- Methacholine challenge
- bronchial challenge with repeated doses of acetylcholine receptor agonist to induce a 20% decrease in FEV1 – a measure of airway hyperresponsiveness.
- Peak flow
- peak expiratory flow rate (l/min) – a measure of airway calibre.
- Polymorphism
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Cited by (29)
Tiotropium in asthma: What is the evidence and how does it fit in?
2016, World Allergy Organization JournalCitation Excerpt :Subsequent studies have shown that LABA/ICS can achieve well-controlled asthma in around 70 % of patients but not all [17]. Over time, LABA therapy loses some of its efficacy, as a result of tachyphylaxis [18]. There is a small reduction in maximal bronchodilator effect, but more importantly a loss of bronchoprotection (i.e., suppression of induced bronchospasm) against inhaled methacholine or histamine [19].
Changing face of β<inf>2</inf>-adrenergic and muscarinic receptor therapies in asthma
2014, Current Opinion in PharmacologyCitation Excerpt :In a position paper, the Canadian Thoracic Society also concluded that LABAs should not be used as monotherapy in any age group [13]. Chronic use of β2-adrenergic agonists results in the down-regulation and uncoupling of β2AR consequently generating a decreased response or tachyphylaxis [14]. This presents as a loss of protection against bronchoconstricting stimuli, as well as a reduced response to fast-acting reliever therapy with salbutamol [15,16].
Chronic treatment with indacaterol and airway response to salbutamol in stable COPD
2013, Respiratory MedicineThe impact of tiotropium on mortality and exacerbations when added to inhaled corticosteroids and long-acting β-agonist therapy in COPD
2012, ChestCitation Excerpt :Alternatively, the addition of tiotropium may partially obviate any β2-adrenoceptor downregulation and tolerance due to LABA as a consequence of prejunctional receptor cross talk.15 The theory of β2-adrenoceptor downregulation following long-term LABA use has been suggested as a potential reason for the concerns seen with LABA monotherapy in asthma.16,17 Although less established in COPD, this phenomenon has been reported.18,19
Effects of intranasal salmeterol and fluticasone given alone and in combination in persistent allergic rhinitis
2012, Annals of Allergy, Asthma and ImmunologyCitation Excerpt :In one study a single dose of intranasal salmeterol produced protection against nasal allergen–induced responses but did not confer any synergistic effects to fluticasone.16 Regular exposure to LABAs in asthmatic patients results in adaptive β2-adrenoceptor downregulation and associated subsensitivity of response, even when given in conjunction with an inhaled corticosteroid, as evidenced by loss of protection against direct or indirect AHR.17 In vitro and ex vivo data have suggested that salmeterol may exhibit ligand-independent activation of glucocorticoid receptors, which might result in potentiation of fluticasone by salmeterol when given in combination.