Inhaled beta(2)-adrenoceptor agonists (beta(2)-agonists) are the most commonly used
asthma medications in many Western countries. Minor adverse effects such as palpitations,
tremor,
headache and metabolic effects are predictable and dose related. Time series studies suggested an association between the relatively nonselective beta-agonist
fenoterol and
asthma deaths. Three case-control studies confirmed that among patients prescribed
fenoterol, the risk of death was significantly elevated even after controlling for the severity of
asthma. The Saskatchewan study not only found an increased risk of death among patients dispensed
fenoterol, but also suggested this might be a class effect of beta(2)-agonists. However, in subsequent studies, the long-acting beta(2)-agonist
salmeterol was not associated with increased
asthma mortality. In a case-control study blood
albuterol (
salbutamol) concentrations were found to be 2.5 times higher among patients who died of
asthma compared with controls. It is speculated that such toxic concentrations could cause
tachyarrhythmias under conditions of
hypoxia and
hypokalemia. The risk of
asthma exacerbations and near-fatal attacks may also be increased among patients dispensed
fenoterol, but this association may be largely due to confounding by severity. Although
salmeterol does not appear to increase the risk of near-fatal attacks, there is a consistent association with the use of nebulized beta(2)-agonists. Nebulized and oral beta(2)-agonists are also associated with an increased risk of cardiovascular death,
ischemic heart disease and
cardiac failure. Caution should be exercised when first prescribing a beta-agonist for patients with
cardiovascular disease. A potential mechanism for adverse effects with regular use of beta(2)-agonists is tachyphylaxis. Tachyphylaxis to the
bronchodilator effects of long-acting beta(2)-agonists can occur, but has been consistently demonstrated only for
formoterol (
eformoterol) a full agonist, rather than
salmeterol, a partial agonist. Tachyphylaxis to protection against induced
bronchospasm occurs with both full and partial beta(2)-agonists, and probably within a matter of days at most. Underlying airway responsiveness to directly acting bronchoconstricting agents is not increased when the
bronchodilator effect of the regular beta(2)-agonist has been allowed to wear off, although there may be an increase in responsiveness to indirectly acting agents. While there has been speculation that underlying airway
inflammation in
asthma may be made worse by regular use of short-acting beta(2)-agonists, in contradistinction, a number of studies have shown that long-acting beta(2)-agonists have positive anti-inflammatory effects. An Australian Cochrane Airways Group systematic review of the randomized, controlled trials of short-acting beta-agonists found only minimal and clinically unimportant differences between regular use and use as needed. Regular short-acting treatment was better than placebo. However, a subsequent systematic review has found that regular use of long-acting beta-agonists had significant advantages over regular use of short-acting beta-agonists. More studies and data are needed on the regular use of beta(2)-agonists in patients not taking inhaled
corticosteroids, and in potentially vulnerable groups, such as the elderly and those with particular genotypes for the beta-receptor, who might be more prone to adverse effects.