β-Agonists have clearly demonstrated benefits for the treatment of both acute and chronic asthma. Therefore, it is perhaps surprising that many of the articles in this issue have focused on concerns about their safety. Much of this concern can be traced back to the “β-agonist controversy” —the association of high-dose isoprenaline and fenoterol inhalers with asthma mortality in the 1960s and 1970s. Although a causal link was never proven, lingering doubts about the safety of β-agonists remain. It is unclear whether a similar adverse effect is responsible for recently reported association of long-acting β-agonists with asthma deaths.
No mechanism for the β-agonist controversy was established, but the evidence presented in this collection of articles points to a number of contributing factors. I suggest that a combination of these effects provides a plausible mechanism for the association of frequent β-agonist use asthma mortality.
Rebound bronchoconstriction and bronchial hyperresponsiveness occur on withdrawal of regular β-agonist treatment. Regular use of fenoterol is associated with a reduction in morning peak flow suggesting that the overnight interval between doses is sufficient to allow rebound bronchoconstriction. This has not been observed with terbutaline or salbutamol, although rebound phenomena do occur when these drugs are withdrawn for slightly longer periods.
Regular use of β-agonists also leads to to lerance to their bronchoprotective and bronchodilator effects. Tolerance becomes more apparent with worsening bronchoconstriction. In severe asthma, this could result in a poor response to emergency treatment.
The combination of rebound deterioration of asthma and a poor response to β-agonist treatment resulting from tolerance could explain the increased mortality associated with fenoterol and isoprenaline. Both effects are probably caused by downregulation of β-receptors which occurs with all β-agonists. Long-acing β-agonists cause a similar degree of tolerance to short-acting β-agonists, but avoid the problem of overnight withdrawal. Long-acting β-agonists have also been shown to improve asthma control when taken in combination with inhaled corticosteroids. The clinical significance of tolerance in this context remains to be determined.
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