11/14/03 The airway beta-agonist paradox - what is the mechanism?SummaryInhaled beta-agonists (IBA) are a major component in the management of chronic asthma. When IBA are used occasionally in a "rescue" role for acute asthma flares, these agents are tolerated well with no overall adverse effects on the long-term course of asthma. However, a number of studies have shown that frequent daily use of IBA by asthmatics frequently leads to decreased bronchodilator responses to IBA, increased bronchial reactivity (assessed by methacholine in inhalational challenge) and even decreases in pulmonary function. These potentially adverse effects have been thought to be due to "desensitization" of the beta 2 adrenergic receptors (BAR) on the airways. McGraw et al have further investigated the mechanisms involved in these adverse effects. They compared the reactivity to a methacholine challenge in mice genetically deficient in the BAR with reactivity in transgenic mice which over express these BAR. Surprisingly, they found an increased broncho constrictive response to methacholine in the mice over-expressing BAR and decreased bronchoconstriction in the BAR-deficient mice. This hyper-reactivity appeared to be due at least in part to sensitization (or not) of a Gq-coupled M3-muscarinic pathway with a phospholipase C-beta 1 playing a key role. Reference J Clin Invest 2003; 112:619-26 Editor's Comments The potentially adverse effects of chronic daily use of IBA continue to be of concern in some quarters, even though most clinical studies have not shown increased asthma exacerbations/hospitalizations in patients so treated. These concerns are of even more relevance with the extensive use of long-acting IBA such as salmeterol and formoterol as chronic co-therapy with inhaled corticosteroids (ICS). This addition of IBA to ICS is a strategy shown to reduce the dose of ICS needed for adequate asthma control. A recent warning has been promulgated by the FDA after what appeared to be an excess of asthma fatalities in patients of one study treated with salmeterol. However, it is not clear whether there is increased risk when salmeterol or formoterol is used along with adequate doses of ICS. The findings in mice described above have to be confirmed in humans although a likely genetically-based heterogeneity in BAR expression has been found in some studies of humans.
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