Key Point:

Regular β-agonist use may increase the risk of tachyphylaxis and cardiovascular events in asthma and COPD patients.

rsity School of Medicine and Director of the Medicine Consultation Service at the Santa Clara Valley Medical Center in California.

DRUG TOLERANCE

In the first meta-analysis, Salpeter et al examined the effects of β-agonist use on leukocyte β-receptor function and the concentration of bronchoconstrictive agents causing a 20% reduction in FEV₁ (PC₂₀) in 22 trials involving 323 asthma patients. None of the trials allowed as-needed β-agonist use in the placebo groups. The mean duration of drug or placebo use in the studies ranged from one to six weeks. The net FEV₁ treatment effect and mean FEV₁ after treatment did not change between placebo and treatment groups. However, when the acute response to subsequent β-agonist therapy was measured, β-agonist use was associated with a reduction of 17.8% in peak FEV₁ response and a decrease of 34.8% in the FEV₁ dose response to subsequent β-agonist administration compared with placebo administration.

PC₂₀ values to combined bronchoconstrictive stimuli (methacholine, allergen) decreased significantly in the β-agonist users as well, by 26%. Additionally, leukocyte β-receptor density decreased by 18.4%, and in vitro response to isoproterenol decreased by 32.7%. These reductions indicate an attenuation of the bronchodilator response to subsequent β-agonist administration (drug tolerance or tachyphylaxis). The drug tolerance was evident in both long- and short-acting classes of the drug.

Dr. Salpeter speculated that “desensitization and down-regulation of the β-agonist receptors in the lung” may be one of the mechanisms behind the drug tolerance. Additionally, cross talk with the cholinergic system may be involved in the worsening lung function observed with β-agonist use. Pulmonary smooth-muscle activity is mediated by the adrenergic system, which causes relaxation, and the cholinergic system, which causes contraction. Studies in animal models indicate that with β-agonist use, the β₂-adrenergic receptors are stimulated, causing increased sensitivity to cholinergic receptors and thus an increased response to bronchoconstrictive stimuli. Given the evidence in their meta-analysis, the authors caution against regular use of β-agonists and call for longer trials comparing these agents with other therapies such as inhaled corticosteroids, which can reduce the inflammation associated with asthma.

CARDIOVASCULAR EFFECTS

Dr. Salpeter’s second meta-analysis evaluated the effects of β-agonist use on heart rate, potassium concentration, and cardiovascular events in 13 single-dose and 20 longer duration trials involving 6,855 asthma and COPD patients. The study found that a single dose of a β-agonist caused heart rate to increase by 9.12 beats/min and potassium concentration to drop by 0.36 mmol/L. In the longer duration trials, β-agonist use was associated with a significantly increased risk of adverse cardiovascular events (relative risk, 2.54; 95% CI, 1.59 to 4.05) compared with placebo.

“β-agonists exert opposite physiological effects than β-blockers do,” Dr. Salpeter explained. In this study, β-agonists increased heart rate rather than lowered it as β-blockers would have done, which could have led to cardiovascular problems. β-agonist use also lowered potassium levels, which have been associated with an increased risk for ventricular tachycardia and fibrillation.

Given that many COPD and asthma patients taking β-agonists also have underlying heart disease, how should clinicians proceed? Dr. Salpeter suggests treating these patients with cardioselective β-blockers, inhaled corticosteroids, and anticholinergic medications. She cautions against regular β-agonist use because “downregulation and tachyphylaxis develop in all patients.”

CHANGING STANDARDS OF CARE

Dr. Salpeter and colleagues believe that it will be difficult to transform attitudes towards β-agonists because they are so widely used. She and her team pointed out that widespread β-agonist use began 50 years ago, before there was good evidence of their safety or efficacy. The problem was further compounded by the fact that many of the studies that have shown a benefit for the agents were funded by pharmaceutical companies. “Once a therapeutic practice is considered to be the standard of care, it often takes numerous studies and many years … to transition from myth to evidence-based practice,” the researchers concluded.

—Tamara Gibb

References
1. Salpeter SR, Ormiston TM, Salpeter EE. Meta-analysis: respiratory tolerance to regular β₂-agonist use in patients with asthma. Ann Intern Med. 2004;140:802-813.
2. Salpeter SR, Ormiston TM, Salpeter EE. Cardiovascular effects of β-agonists in patients with asthma and COPD. Chest. 2004;125:2309-2321.

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