Since the introduction of ₂-selective adrenergic drugs in the 1960s and the development of the metered-dose inhaler (MDI) delivery system, these agents have rapidly become the most commonly prescribed medications for asthma. In 1993, for example, -adrenergic drugs represented 71% of the total prescriptions written by pediatricians for asthma.¹

At the same time that the drugs were becoming widely accepted by physicians and patients, reports have appeared suggesting that the drugs have subtle but important toxicity. The first suggestions came from epidemiologic studies in England showing that the timing of a nationwide surge in deaths attributable to asthma coincided with the introduction of a new MDI that delivered a large dose of isoproterenol.² A similar correlation was found 20 years later in New Zealand when an MDI was introduced that dispensed high doses of a potent new agent, fenoterol.³ More recently, Canadian case-control studies showed that hospitalizations and deaths were more frequent in persons who used two or more canisters per month, ie, who took more than 10 to 15 puffs of the drugs per day.⁴ Because these were case-control studies, it was not possible to look beyond the relationship and to determine whether the excess use of the drug somehow contributed to the deaths or whether sicker patients both used more inhalers and died more commonly.

A second suggestion of subtle toxic effects came from experiments such as those that Simons . . . [Full Text of this Article]