Antagonism of long-acting beta2-adrenoceptor agonism

Abstract

The established place of regular long-acting beta2-adrenoceptor agonists at step 3 in asthma management guidelines has evolved as a consequence of evidence showing additive effects of salmeterol and formoterol on exacerbation rates, resulting in a putative inhaled corticosteroid sparing effect. There is however, evidence to show that although long-acting beta2-adrenoceptor agonists facilitate using a lower dose of inhaled corticosteroid, this may occur at the expense of suboptimal anti-inflammatory control. This is likely to be the case especially with fixed dose combination inhalers where it is not possible to properly titrate anti-inflammatory therapy with inhaled corticosteroids without also inadvertently overtreating with unnecessarily high doses of long-acting beta2-adrenoceptor agonists. Most patients with mild to moderate persistent asthma can be adequately controlled on monotherapy with inhaled corticosteroid in low or medium dosage, which is considerably cheaper than concomitant use of a long-acting beta2-adrenoceptor agonist. Subsensitivity to long-acting beta2-adrenoceptor agonists is a predictable pharmacological phenomenon which occurs despite concomitant inhaled corticosteroid therapy and occurs more readily for bronchoprotective than bronchodilator effects. Subsensitivity of salbutamol protection against bronchoconstrictor stimuli occurs in patients receiving concomitant long-acting beta2-adrenoceptor agonists, which may be due to beta2-adrenoceptor down-regulation or prolonged receptor occupancy. Prospective large scale long-term studies are required to further define the clinical relevance of beta2-adrenoceptor polymorphisms, to look at clinical control outcomes as well as propensity for subsensitivity. It would therefore make more sense to first of all optimize the dose of anti-inflammatory therapy with inhaled corticosteroid and to then consider adding a long-acting beta2-adrenoceptor agonist for patients who are poorly controlled.

Figure 1

Effects of low or medium dose inhaled budesonide given alone or in combination with formoterol, for effects on (a) bronchial hyperresponsiveness to adenosine monophosphate challenge and (b) suppression of exhaled nitric oxide. Asterisk denotes a significant (P < 0.05) difference from placebo. Formoterol (FM) did not potentiate the response to budesonide (BUD) at either dose. Modified after [23].

Figure 2

Protection against methacholine after the first (day 1) and fifteenth dose (day 8), and eighteenth dose (day 10 with salbutamol) of continuous treatment with placebo (○) and formoterol (□) or salmeterol (▵). * denotes P < 0.05 between active treatments and placebo. † denotes P < 0.05 among day 1, 8 or 10 of the same treatment. Taken from reference [58] with permission.

Figure 3

Bronchodilator dose–response curve (DRC) to formoterol and time profile after last dose for change in FEV₁, after regular treatment with placebo (PL) and formoterol (FM), with or without acute administration of systemic corticosteroid (S). * denotes a significant (P < 0.05) difference vs formoterol alone for area under curve. Taken from reference [69] with permission.

Figure 4

Effects of regular formoterol (FM) after the first or last dose of treatment. Effects are shown for (a) the provocative concentration of adenosine monophosphate required to produce a 20% fall in FEV₁ (PC₂₀ AMP) or (b) peripheral blood lymphocyte β₂-adrenoceptor binding density (B_max). * denotes a significant difference between the first and last dose of formoterol, whilst cross denotes significant difference between the last dose of formoterol plus placebo vs the last dose of formoterol with budesonide. Taken from reference [73] with permission.

Figure 5

Individual scatterplot with mean values for the degree of bronchodilator desensitization after regular formoterol, according to β₂-adrenoceptor genotype as position 16. Data are shown for FEV₁ response. Taken from reference [87] with permission.