Opinion
Long-acting β2-adrenoceptor agonists: a smart choice for asthma?

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An endogenous defect in β2-adrenoceptors that results in impaired relaxation of airway smooth muscle was originally proposed as a putative underlying cause of the asthmatic condition. Short-acting β2-adrenoceptor agonists such as salbutamol are still recommended for relieving acute episodes of bronchial smooth muscle spasm. Twice-daily long-acting β2-adrenoceptor agonists (LABAs) such as salmeterol are advocated for use as add-on bronchodilator therapies to inhaled corticosteroids such as beclomethasone, which are used as first-line anti-inflammatory therapy. There is recent evidence of increased asthma exacerbations and associated deaths in subjects taking salmeterol compared with those taking placebo. My opinion is that, in certain situations, the use of LABAs could have adverse effects on asthma control because of the particular pharmacological properties of this class of drug. In this article, I examine the possible pharmacological mechanisms and use of LABAs in certain situations, which are relevant to the benefits and risks of these drugs in 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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