SAN JOSE, CALIF—For years, ß-blockers have been considered contraindicated for patients with asthma and chronic obstructive pulmonary disease (COPD), yet this recommendation is based largely on anecdotal evidence with nonselective ß-antagonists. A recent meta-analysis indicates that cardioselective ß1-blockers are safe in patients with reactive airway disease.[1] Furthermore, research suggests these agents may actually benefit patients by enhancing sensitivity to ß2-agonists.

“Cardioselective ß-blockers have not been shown to have an adverse respiratory effect on patients with asthma or reactive airway disease,” emphasized primary author Shelley R. Salpeter, MD, a Clinical Professor of Medicine at Stanford Medical School in Palo Alto, California. “For those patients with reactive airway disease and concomitant cardiovascular disease, the evidence shows that they should receive ß1-blockers: The benefits exceed the risks.”

Dr. Salpeter and colleagues surveyed 19 randomized, blinded, placebo-controlled trials examining the effects of cardioselective ß-blockers on symptoms, FEV1, and use of inhaled ß2-agonists in patients with reactive airway disease. They found that although a single dose of a ß1-blocker lowered FEV1 by an average of 7.5%, it enhanced FEV1 responses to ß2-agonists by 4.6%. Furthermore, during trials of continuing ß1-blocker use (lasting from three days to four weeks), no significant changes in FEV1, symptoms, or inhaled drug use were observed. However, an average 8.7% enhancement in sensitivity to ß2-agonists persisted.

Guidelines contraindicating ß1-blocker use in asthma and COPD patients are therefore largely unjustified. “They’re based mainly on case reports of respiratory symptoms in patients receiving large amounts of noncardioselective ß-blockers, such as propranolol,” said Dr. Salpeter, who is also Director of Medicine Consultation Services at Santa Clara Valley Medical Center in San Jose. Such recommendations have been made for years without being questioned, she said—despite the fact that ß-blockers have evolved greatly since many of the case reports were published. “Atenolol or metoprolol, which are cardioselective, are over 25 times more selective for the ß1 than the ß2 receptor,” she noted; thus, at therapeutic doses, such drugs interact little with the ß2 receptor, the main target of inhaled ß-agonists.

This failure to distinguish between cardioselective (ß1) and noncardioselective ß-blockers may harm many patients with asthma or COPD who have cardiovascular comorbidities and are denied ß-blocker treatment, Dr. Salpeter suggested. “Patients with hypertension, congestive heart failure, or coronary artery disease would benefit from a ß1-blocker.” In fact, many patients with COPD do have cardiovascular problems, she noted, yet standard guidelines state that ß-blockers are contraindicated for such patients.

Practice guidelines clearly will need to be updated, with cooperation among specialists from disparate fields. “Lung associations and cardiac associations will both need to revise their guidelines according to the evidence, so it’s going to be a slow process,” Dr. Salpeter remarked.

ß-BLOCKERS ENHANCE ß-AGONIST SENSITIVITY

In studies testing the effects of a single dose of ß1-blocker, “there was a small increase in the sensitivity to ß-agonist, which cancelled out the small decrement [in FEV1],” said Dr. Salpeter. “After a few days of ß-blocker use, there is no decrement in FEV1 any more and … about a 9% increase in ß-agonist response.” The response was actually much greater than it would have been in the absence of the ß-blocker. She explained, “After a few days, this ß1-blocker is able to increase sensitivity of both ß1 and ß2 receptors—that’s why there’s an increased ß-agonist response with continued treatment.”

DO ß-AGONISTS WORSEN ASTHMA?

“ß2 receptors have been shown to have increased sensitivity when the ß-blockers are on board. The corollary is that ß-agonists themselves (which are commonly used for asthma) are actually associated with downregulation or desensitization of ß2 receptors,” Dr. Salpeter pointed out. “Therefore, there’s a dependence and tolerance to ß-agonists [that develops] with continued use.”

She added, “There’s now accumulating evidence that ß-agonists, despite their short-term effect at improving symptoms, may actually have a deleterious effect because of the downregulation of ß2 receptors—not only in the lung, but also in, for example, lymphocytes”; the resulting enhancement of inflammatory responses could contribute to asthma worsening.

Thus, Dr. Salpeter suggested, “this downregulation or desensitization of the receptors with ß2-agonist use … could be associated with an increased number of asthma attacks and increased severity of asthma attacks.” She concluded, “We may find out that ß1-blockers are actually better for patients with asthma than [are] ß-agonists.”

Use ß-Blockers for Glaucoma Cautiously

LONDON—Cardioselective ß1-blockers may be safe for patients with reactive airway disease, but topical nonselective ß-blockers for glaucoma may indeed be harmful. A recent study associated topical ß-blocker use with an excess risk for respiratory disease in those previously undiagnosed with reactive airway disease.[1] Primary author James F. Kirwan, FRCOphth, and colleagues examined medical records for 2,645 patients without a prior diagnosis of airways obstruction who first received an ophthalmic topical ß-blocker between 1993 and 1997. They then compared these elderly patients with 9,094 unexposed patients (respective mean ages, 68.6 and 67.5). Relative to patients not given a topical ß-blocker, recipients had an adjusted risk ratio of 2.79 for receiving a new prescription for a ß2-agonist, inhaled corticosteroid, theophylline, or inhaled anticholinergic within six months of ophthalmic ß-blocker use. They were also 2.18-fold more likely to receive a diagnosis for asthma or COPD during this period. The findings confirm reports that topical ß-blockers can affect respiratory function in elderly patients; furthermore, the authors point out, such risks might be even greater in those previously diagnosed with reactive airway disease. Most ß-blockers used topically to treat glaucoma, such as timolol or levobunolol, act on both ß1 and ß2 receptors. Topical ophthalmic preparations of ß1-selective blockers (eg, betaxolol) do exist. But, said Dr. Kirwan, a research fellow at the Institute of Ophthalmology in London, “Current evidence suggests that selective topical ß-antagonists are not ideal as a first-line treatment for glaucoma.” He explained, “There is little doubt that cardioselective topical ß-antagonists are less effective than other topical ß-antagonists in lowering intraocular pressure—approximately 20% to 30% less so.” —Mimi Zucker, PhD

Reference 1. Kirwan JF, Nightingale JA, Bunce C, Wormald R. ß-Blockers for glaucoma and excess risk of airways obstruction: population based cohort study. BMJ. 2002;325:1396-1397.

—Mimi Zucker, PhD

Reference
1. Salpeter SR, Ormiston TM, Salpeter EE. Cardioselective ß-blockers in patients with reactive airway disease: a meta-analysis. Ann Intern Med. 2002;137:715-725.

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