The Beta-agonist Paradox: Is Albuterol Detrimental for Asthma?
ACVIM 2008
Carol Norris Reinero, DVM, DACVIM, PhD
Columbia, MO, USA

Introduction

Feline asthma is a common bronchopulmonary disorders of pet cats, and is associated with substantial morbidity and occasional mortality.1,2 The mainstay of therapy for decades has been glucocorticoids to suppress airway inflammation and bronchodilators to reverse bronchoconstriction. There are two major classes of bronchodilators used in cats: methylxanthines (e.g., theophylline or aminophylline) and beta-2 agonists (e.g., albuterol or terbutaline). In humans, chronic or excessive use of inhaled short acting beta-2 agonists such as albuterol has been associated with an increased risk of death.3,4 The syndrome of asthma is remarkably similar in humans and cats.5 Since albuterol is frequently administered to asthmatic cats using a metered-dose inhalant and spacer, the question arises as to whether adverse effects of beta-2 agonists may also be present in this species. If so, the routine use of this medication for chronic management of cats with asthma should be seriously reconsidered.

Racemic Albuterol

Racemic albuterol (R,S albuterol) is the most commonly prescribed short acting beta-2 agonist in the United States and is composed of a 1:1 mixture of an R-enantiomer (R-albuterol) and an S-enantiomer (S-albuterol). The R-enantiomer has bronchodilatory and anti-inflammatory effects, and the S-enantiomer paradoxically is associated with increased airway hyperreactivity and pro-inflammatory effects. The paradoxical exacerbation of asthma with regular use of inhaled racemic albuterol in humans is thought to be linked to preferential accumulation of S-albuterol in the lung which has a much slower metabolism than R-albuterol.

Inhaled Albuterol in Healthy Cats

To determine if S-albuterol has pro-inflammatory effects in cats without pre-existing airway disease, a prospective study was performed using 6 healthy research cats. Racemic albuterol, R-albuterol, S-albuterol, and placebo (saline) were delivered by aerosol to cats in a blinded, cross-over study design. Cats were randomized to receive 2 weeks of one treatment, followed by a 2 week washout (i.e., no treatment) before crossover to the next treatment. This protocol was repeated until the cats received each of the 4 different treatments. Confirmation of lack of airway inflammation prior to each treatment was performed by collection of bronchoalveolar lavage fluid (BALF) in a blind fashion. Collection of BALF was also performed after each 2 week treatment period. Total nucleated cell counts were obtained using a Coulter Counter and a cytospin was made of the BALF for determination of differential cell counts. Significantly higher group mean total BALF cell numbers and absolute numbers of BALF neutrophils were noted in the healthy cats when treated with R,S-albuterol and with S-albuterol compared with R-albuterol and placebo. In other words, neutrophilic airway inflammation in healthy cats was induced when receiving treatment with albuterol containing the S-enantiomer. This is compelling data to suggest that the form of albuterol commonly prescribed to asthmatic cats can actually cause inflammation in "normal" cats without pre-existing airway disease.

Inhaled Albuterol in Experimentally Asthmatic Cats

Cats are the only animal species which naturally and commonly develop spontaneous asthma that replicates all of the major features of the disease in humans, and have emerged as an excellent preclinical model to study human asthma. The experimental model of feline allergic asthma also mimics naturally developing asthma in pet cats and serves a dual purpose of allowing study of the disease in cats as well as humans. In a similar study design as described above in healthy research cats, racemic albuterol, R-albuterol, S-albuterol, and placebo (saline) were also administered to cats sensitized and challenged with Bermuda grass allergen to induce an asthmatic phenotype. Results showed that significantly higher group mean total BALF cell numbers were found in asthmatic cats when administered racemic albuterol and S-albuterol, compared with R-albuterol and placebo. Similarly, the group mean absolute number of BALF eosinophils was significantly higher in asthmatic cats receiving racemic and S-albuterol compared with R-albuterol and placebo. These data show that the S-enantiomer exacerbates eosinophilic airway inflammation in experimentally asthmatic cats.

Should We Use Beta-2 Agonists in Cats with Asthma?

The results of these studies suggest that chronic (2 weeks) use of racemic albuterol is enough to induce or intensify airway inflammation in both healthy cats and cats with asthma, respectively. Airway inflammation is linked to both exacerbation of airway hyperreactivity and airway remodeling (permanent changes of the lung architecture) in asthmatics. Therefore, it seems reasonable that racemic albuterol should not be administered to asthmatic cats as part of chronic therapy for asthma. This is especially important to consider when reviewing guidelines in the non-refereed veterinary literature that recommend administration of bronchodilators alone to manage mild asthma symptoms in cats. Further studies would need to be performed to determine the effects of concurrent glucocorticoid administration on the induction or exacerbation of airway inflammation by racemic albuterol.

Despite the aforementioned warning, it does not mean that racemic albuterol should be completely avoided in asthmatic cats. On the contrary--albuterol can play a critical role in the management of acute bronchoconstriction (i.e., status asthmaticus). Racemic albuterol still has a place in reversing an episode of acute bronchoconstriction. It can and probably should be sent home with owners to manage an acute crisis leading to respiratory distress until medical attention can be sought.

References

1.  Moise N, et al. J Am Vet Med Assoc 1989;194:1467.

2.  Dye J, et al. J Vet Intern Med 1996;10:385.

3.  Spitzer W, et al. N Engl J Med 1992;326(8):501.

4.  Suissa S, et al. Am J Respir Crit Care Med 1994;149(3)604.

5.  Norris Reinero C, et al. Int Arch Allergy Immunol 2004;135:117.

Speaker Information
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Carol Reinero, DVM, DACVIM, PhD
University of Missouri
Columbia, MO


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