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Risk versus Benefit Considerations for the 2-Agonists
Short-acting ␤2-agonists are the mainstay of therapy for acute bronchospasm
associated with asthma and chronic obstructive pulmonary disease, whereas
long-acting ␤2-agonists are used in maintaining disease control in these
respiratory disorders. This review describes and compares the pharmacology
of the ␤2-agonists and explains how these differences translate into differences
in efficacy and ␤2-adrenergic–mediated adverse effects. Questions commonly
asked by clinicians regarding the efficacy and safety of short- and long-acting
␤2-agonists include issues about cardiovascular effects, tolerance to their
bronchodilator and bronchoprotective effects, blunting of albuterol response
by long-acting ␤2-agonists, potential masking of worsening asthma control,
and the role of long-acting ␤2-agonists as adjunctive therapy with inhaled
corticosteroids in maintaining asthma control. Pharmacogenetics may play a
role in determining which patients may be at risk for a reduced response to a
␤2-agonist. The continued use of racemic albuterol, which contains a mixture
of R-albuterol and S-albuterol, has been questioned because of data from
preclinical and clinical studies suggesting that S-albuterol causes
proinflammatory effects and may increase bronchial hyperreactivity. The
preclinical and clinical effects of these two stereoisomers are reviewed. Data
describing the efficacy and safety of levalbuterol (R-albuterol) and racemic
albuterol are presented.
Key Words: asthma, chronic obstructive pulmonary disease, COPD,
bronchial spasm, albuterol, ␤2-adrenergic receptor agonists, stereoisomerism,
inhaled corticosteroids.
(Pharmacotherapy 2006;26(9 Pt 2):164S–174S)
The ␤2-agonist controversy, which has been of the undesirable effects observed with this class debated at clinical congresses for more than 20 of agents. The purpose of this article is to review years, was sparked by reports of increased deaths the clinical pharmacology of the ␤2-agonists, in the 1960s in patients with asthma after discuss the therapeutic outcomes that assess administration of high-dose inhaled isoproterenol efficacy and safety of this class of agents in the and by an increase in asthma mortality associated treatment of asthma and chronic obstructive with the use of inhaled fenoterol in the 1980s.1, 2 pulmonary disease (COPD), review selected Since then, many investigators have conducted clinical trials that provide insight into the risks studies to further evaluate the efficacy and safety and benefits of ␤2-agonists, and outline the of ␤2-agonist bronchodilators. Also, advances in current controversies and remaining clinical the field of pharmacogenetics have provided questions associated with short- and long-acting insights into the potential genetic basis of some From the Departments of Pediatrics and Pharmacy, Pharmacology of 2-Agonists
University of New Mexico, Albuquerque, New Mexico.
Address reprint requests to H. William Kelly, Pharm.D., All ␤2-agonists have a similar mechanism of BCPS, Department of Pediatrics, ACC Building 3rd Floor, action with regard to their effect on the ␤2- University of New Mexico Health Sciences Center, 2211 adrenergic receptor.3 These agents stimulate the Lomas Boulevard NE, Albuquerque, NM 87131-5311; e-mail:[email protected]
␤2-adrenergic receptor, activating adenyl cyclase Supplement PHARMACOTHERAPY Volume 26, Number 9, 2006 worsening asthma control. Tolerance to the outcomes that measure asthma control, and bronchodilating effects of short- and long-acting identify whether safety issues are class, dose, or ␤2-agonists after long-term use does not appear to be clinically significant, and small changes inbronchial hyperresponsiveness observed in some Acknowledgments
small studies after routine use of short-acting ␤2- agonists are difficult to interpret. Although some contributions of Kim Poinsett-Holmes, Pharm.D., studies show a blunting of the albuterol response Poinsett Publications, Inc., for editorial assistance in after long-term use with long-acting ␤2-agonists, the preponderance of data suggests that routineuse of a long-acting ␤2-agonist does not mask References
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