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American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 972-974, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.2606002

Pro/Con Editorials

Rebuttal by Drs. Ameredes and Calhoun

Bill T. Ameredes, Ph.D and William J. Calhoun, M.D.

University of Texas Medical Branch, Galveston, Texas

RACEMIC ALBUTEROL USE IS ASSOCIATED WITH ASTHMA MORTALITY AND FUNCTION DECREMENTS

The Con position holds that, unlike fenoterol, regular racemic albuterol use is not associated with asthma worsening. However, the odds ratio for asthma-related death with regular racemic albuterol in the Saskatchewan study was 2.4 (1), a risk elevation beyond triviality. Moreover, a recent clinical trial indicated that regular racemic albuterol use is associated with clinically significant declines in lung function in individuals with asthma homozygous for the Arg-16 polymorphism of the beta2-receptor (2) (about one-sixth of individuals with asthma in the United States) (3).

BASIC STUDIES DO SUGGEST CLINICALLY RELEVANT DIFFERENTIAL EFFECTS OF ENANTIOMERS

The Con position did not cite recent studies showing significant (S)-albuterol–dependent increases in airway reactivity in mice (4), and proinflammatory effects in rats (5). Moreover, although there was a significantly greater bronchoprotective effect of (R)-albuterol over the racemate within the early allergic response in the cited guinea-pig study (6), chronic inhalation effects of the drugs were not tested, and remain at issue. As before, these studies do not suggest inert properties for (S)-albuterol.

(S)-albuterol concentrations (1–10 µM) within in vitro studies are physiologically and clinically relevant (7–12), in that therapeutic concentrations of inhaled drugs are known. Calculations indicate that inhaled aerosol drug concentrations from 10 to 1,000 µM are attained in small to large airways (13), which is supported by empiric measures of up to 10 µM of inhaled albuterol in lung airway fluid (14).

Inhaled Corticosteroid and Ipratropium Masking of (S)-Albuterol Effects
A plausible suggestion regarding racemic beta2-agonist and inhaled corticosteroid combinations is potential steroid masking of deleterious effects of (S)-albuterol. A clinical study modeling inhaled corticosteroid withdrawal reported that time to loss of control was approximately 50% more rapid in patients with asthma maintained on racemic albuterol (9 days), as compared with racemic albuterol + ipratropium (17 days) (15). Those data are predictable based on studies in vitro, in which (S)-albuterol significantly reduced antiinflammatory effects of corticosteroids, but also suggest that corticosteroids reduced the proinflammatory effects of (S)-albuterol (8). Consistent with those basic and clinical findings, a prominent, yet minimally addressed facet of the Asthma Clinical Research Network (ACRN) studies is the significantly greater loss of lung function on withdrawal of regular racemic albuterol in the Arg-16 homozygotes with asthma, which remains unexplained, but was only mitigated with ipratropium (2, 16), further suggesting the possibility of an unmasked, cholinergic-associated (S)-albuterol effect.

EXPECTATIONS: (R)-ALBUTEROL VERSUS RACEMIC ALBUTEROL

There is enough (R)-albuterol in racemic (R,S)-albuterol to have a transient bronchodilatory effect, justifying nearly 40 years of use (17), and explaining equivocal physiologic effects in many acute clinical studies comparing racemic and (R)-albuterol. Therefore, moving beyond acute pediatric clinical investigations with masking confounders (18–20), to racemic albuterol metered-dose inhaler (MDI) overuse in patients with moderate to severe asthma, as seen on presentation to the emergency department, is necessary to address the issue of enantiomer versus racemate superiority. One such recent study has shown a nearly 40% difference between racemic and (R)-albuterol in FEV1 and hospitalization rate (21). Recent production of the (R)-albuterol MDI should enhance conduct of head-to-head trials to further establish these effects.

THE ISSUE OF DRUG COST
Higher cost (e.g., $0.32 vs. $1.82/unit dose [22]) is always raised as a factor mitigating a switch from racemic to (R)-albuterol (22–25). However, those costs are more than recovered in increased patient discharge rates and decreased readmissions (26). Furthermore, recent preliminary studies not sponsored by the manufacturer indicated that a whole-hospital switch to (R)-albuterol halved breakthrough rates and produced a 1.0 full-time equivalent (FTE) gain (27, 28). Moreover, the cost of combined racemic (R,S)-albuterol and ipratropium is comparable (e.g., $0.86/unit dose; Ken Hargett, Methodist Hospital, Houston, TX, personal communication), but aggregate findings of basic and clinical studies (2, 4, 7–12, 15, 16, 21) suggest anticholinergic treatment may not be necessary when only (R)-albuterol is administered. Therefore, although the acute studies may be equivocal on cost-effectiveness, more recent and potentially future chronic studies will bear out the superiority of (R)-albuterol, with greater efficacy, long-term cost-savings, and possibly patient preference (29). Finally, cost considerations, while important, should never suspend our judgment about what is the best treatment for our patients.

REFERENCES

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  2. Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ, Deykin A, Fagan JK, Fahy JV, Fish J, et al.; National Heart, Lung, and Blood Institute's Asthma Clinical Research Network. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 2004;364:1505–1512.[CrossRef][Medline]
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Copyright © 2006 American Thoracic Society