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Beta Blockers and Beta Agonists in Asthma - Unraveling a Paradox

Bond RA, Omoluabi O, Nguyen LP.

RDD Europe 2009. Volume 1, 2009: 15-24.

Abstract:

Asthma is a disease characterized by airway obstruction, airway hyperresponsiveness (AHR) and airway inflammation. The medications used for control and acute relief of asthma vary in their effectiveness and may produce serious side effects. Furthermore, ~30% of asthma patients do not achieve optimal control with any of the currently used medications. Therefore, there is a need for the development of safer and more effective medications. Based on the paradigm shift that occurred with the use of ß-adrenoceptor (ßAR) agonists and antagonists in congestive heart failure (CHF), we tested whether chronic ß-blocker administration may be beneficial in asthma. Using a murine antigen driven model of asthma, we have shown that chronic (28 day) administration of ß-blockers decreased AHR and produced broad anti-inflammatory effects, including dramatic reductions in airway epithelial mucous production. These data suggest the airway epithelium may be a key target affected by chronic ß-blocker therapy. We have also recently shown that mice with targeted gene deletion of the ß2AR are resistant to developing the asthma phenotype, suggesting the ß2AR is required or ‘permissive’ for full development of the asthma phenotype. Therefore, inhibition of ß2AR signaling by both pharmacological and genetic methods attenuated the asthma phenotype, such as AHR and inflammation, in antigen-challenged mice. In addition, in a small clinical trial treating 10 mild asthmatics with the non-selective ß-blocker, nadolol, there was a dose-dependent increase in the PC20 to methacholine that resulted in a change of greater than two doubling doses in patients treated with 40 mg of nadolol. These results appear paradoxical in lieu of the fact that chronic activation of the ß2AR has been viewed as beneficial and has been used as a primary method of pharmacological intervention. However, our findings may result in a paradigm shift similar to that observed in the chronic treatment of CHF. The results also show that the acute or chronic effects of drugs may often be opposite in nature, and that certain drugs currently contraindicated for a disease may actually have a role in the chronic treatment of that very disease, as was the case in CHF.