Scientific rationale for inhaled combination therapy with long-acting β₂-agonists and corticosteroids

Abstract

Scientific rationale for inhaled combination therapy with long-acting b 2 -agonists and corticosteroids. P.J. Barnes. #ERS Journals Ltd 2002. ABSTRACT: The addition of an inhaled long-acting b 2 -agonist (LABA) to an inhaled corticosteroid (ICS) gives optimal control of asthma in most patients and two fixed combination inhalers (salmeterol/fluticasone and formoterol/budesonide) are increasingly used as a convenient controller in patients with persistent asthma. There is a strong scientific rationale for the combination of these two drug classes.ICS suppress the chronic inflammation of asthma and reduce airway hyperresponsiveness and this is achieved at low doses in most patients. LABA act on different aspects of the pathophysiology of asthma. In addition to their bronchodilator action, LABA also inhibit mast cell mediator release, plasma exudation and may reduce sensory nerve activation. Thus these two classes of drug address complementary aspects of the pathophysiology of asthma that neither drug class is able to achieve alone.There are several positive interactions between LABA and ICS. Corticosteroids increase the expression of b 2 -receptors by increasing gene transcription. Experimentally this protects against the loss of b 2 -receptors in response to long-term exposure to b 2 -agonists. While this is unlikely to be important in bronchodilator responses to b 2 -agonists, in view of the large b-receptor reserve, it is probably important in preventing loss of b-agonist effects on the nonbronchodilator actions of LABA discussed earlier. b 2 -Agonists may potentiate the molecular mechanism of corticosteroid actions, with increased nuclear localization of glucocorticoid receptors and additive or sometimes synergistic suppression of inflammatory mediator release. Thus LABA and ICS may optimize each others beneficial actions in the airways, but the low systemic effects of these drugs do not result in any increase in adverse effects.Long-acting b 2 -agonists corticosteroid inhaler therapy is therefore a logical advance and results in effective control of asthma in the majority of patients without significant adverse effects. This simplified approach to long-term asthma therapy has a strong scientific rationale.

Anti-inflammatory functions of glucocorticoid-induced genes

“…β adrenergic agonists cooperate with GCs to exert anti-inflammatory effects in asthma (Barnes, 2002;Hancox, 2006). GCs can upregulate expression of β1 and β2 adrenergic receptors (Collins et al, 1988;Mak et al, 1995;Tseng et al, 2001), potentially providing a rather indirect anti-inflammatory mechanism by sensitizing target cells to additional anti-inflammatory stimuli.…”

How Do Corticosteroids Work in Asthma?

“…Indeed, fixed combination inhalers of long-acting ␤ 2 -agonists and corticosteroids are now available and seem to be the most effective way to control asthma because these two classes of drug have complementary and synergistic effects (41). Corticosteroids increase the expression of ␤ 2 -adrenergic receptors in the lung and prevent their downregulation and uncoupling in response to ␤ 2 -agonists (42)(43)(44).…”

Budesonide/formoterol for maintenance and reliever therapy in the management of moderate to severe asthma

“…All these features may contribute to the effectiveness of budesonide/formoterol maintenance and reliever therapy. Budesonide and formoterol are reported to have a synergistic relationship whereby their combined effects are complementary and additive (23,59,60), most likely contributing to the efficacy of this treatment approach (Fig. 5A,B).…”

“…Following binding to glucocorticoid receptors (GR) in the cell cytoplasm, translocation to the cell nucleus leads to activation of glucocorticoid response elements, recognition sites on the promoter regions of some genes which are activated by interaction with a GR (23,59,60) (Fig. 5A).…”