Beta-2 Adrenergic Agonist Therapy in Asthma Revisited

At a symposium held in conjunction with the American College of Allergy, Asthma, & Immunology Annual Meeting in San Antonio, Texas, three leaders in respiratory medicine discussed recent developments in our understanding of beta agonist stereoisomers and their respective roles in treatment efficacy and safety.

This program was supported by an unrestricted educational grant from Sepracor Inc.

Stereoisomer Therapy in the Treatment of Asthma

The most common bronchodilator available is the ß₂-agonist, albuterol. It is a racemic compound of (R)- and (S)-isomers. “Half (R), half (S), and that includes the generic albuterol that you’re familiar with,” said Larry Borish, MD, professor of Allergy and Immunology at the University of Virginia, adding, “levalbuterol has now been made commercially available and marketed as Xopenex. It represents the active (R)-isomer of this compound and binds to the ß₂-adrenergic receptor.” In contrast, the (S)-albuterol is not a ß₂-agonist and for a long time it was thought to be an inert compound. Recent studies, however, indicate that it does have a distinct pharmacology that may be harmful.

A clear example of the distinct pharmacology and pharmacokinetics of the (R)- and (S)-isomers of albuterol can be seen when the two are given to an individual. “When you give a person by nebulization an inhaled dose of (R)-albuterol it produces the data that you’re all familiar with: it peaks very rapidly but pretty much clears within the next several hours,” said Dr. Borish, adding, “since the mechanisms for clearing (S)-albuterol are much less efficient, you see much higher peak levels and a much longer half-life” (Figure 1). Normally, the latter is not a problem but in situations when the racemic albuterol is given at regular intervals (every 4-6 hours) or in emergency/ICU environments when patients are given continuous nebulizations, the accumulation of (S)-albuterol can create adverse events (Figure 2).

Preclinical Data with(R)-albuterol and (S)-albuterol Inflammation
ß₂-receptors are present on T-lymphocytes and, although receptor density is low, they are in a high affinity state (Eur J Clin Invest 1988;18:213-217). In studies by Dr. Borish, when tetanus-specific T-cell lines were incubated with (R)-albuterol, a 40%-50% inhibition of T-cell proliferation was observed. In contrast, the addition of (S)-albuterol produced no significant change in proliferation at normal physiologically-relevant concentrations but an increase in proliferation did occur at higher concentrations (J Allergy Clin Immunol 2002;109:449-454). Whether or not this is clinically significant remains to be determined, but the accumulation of (S)-albuterol following repeated administration of racemic albuterol may explain why the anti-inflammatory actions of albuterol are not observed.

Cytokine Production
The tetanus cell lines were also used to study cytokine production following incubation with the (R)- and (S)-isomer. With the (R)-isomer, there was a trend to inhibit IL-13 and IL-5, and a statistically significant inhibition of interferon-gamma. In contrast, high concentrations of the (S)-isomer increased IL-2, IL-5 and interferon-gamma (J Allergy Clin Immunol 2002;109:449-454). A study by Chad Oh performed on mast cells ( J Allergy Clin Immunol 2000;105:S22) found incubation with the (R)-isomer had no significant effect on IL-4 production but the (S)-isomer increased IL-4 production.
In addition, histamine production within mast cells is increased by the (S)-isomer (possibly by increasing histidine decarboxylase) but is unaffected by the (R)-isomer ( J Allergy Clin Immunol 2000;105:S22).

Finally, the (S)-isomer may also stimulate superoxide production in eosinophils while (R)-albuterol and racemic albuterol have no affect (J Allergy Clin Immunol 1998;102:149-151).

Mucociliary Transport
In vitro studies using cow trachea explants have shown incubation with the (R)-isomer to increase mucous movement while (S)-albuterol has little or no effect (Chest 2002;122:188S). Further-more, Dr. Borish stated, “with (R)-albuterol, all of the ciliary beating was uni-directional,” adding, “when you start adding (S)- to the (R)-albuterol, you see this sort of non-specific swirling phenomenon on the cells.”

Bronchial hyperactivity
Studies have shown the (R)-isomer completely blocks the bronchoconstrictive effects of histamine or methacholine in vitro. When the (S)-isomer is added to histamine, however, “there’s a shifting of the curve so that there’s now enhanced bronchoconstriction, so you’re seeing both enhanced response to histamine and an enhanced maximal effect,” said Dr. Borish (Pulm Pharmacol Ther 1998; 11:1-6).

In vivo studies with anesthetized ventilated guinea pigs found that (S)-albuterol induced airway hyper responsiveness to spasmogens (Pulm Pharmacol 1994;7:367-376) and airway responsiveness to histamine (AJRCCM 2000; 161:A191). In asthmatic humans, the (S)-isomer increases methacholine hyperreactivity and diminishes the bronchoprotective effects of the (R)-isomer (Lancet 1995; 346:1101).

Concluding Remarks
“I’ve shown you a series of in vitro data suggesting that (S)-isomers are associated with pro-inflammatory influences
on T-lymphocytes, mast cells, and eosinophils,” stated Dr. Borish, adding “there are suggestions that the (S)-isomers may contribute to increased bronchial hyperreactivity and airway inflammation.” The frequent use of racemic agents, especially in the emergency room or the ICU make it imperative that we better understand the possible adverse effects of prolonged accumulation of the (S)-isomer in patients.

Beta-2 Adrenergic Agents in Children with Asthma

David Skoner, MD, Associate Professor of Pediatrics at the Children’s Hospital of Pittsburgh, PA expanded on Dr. Borish’s presentation with a discussion of the clinical safety and efficacy of ß₂-agonists in treating pediatric asthma. Dr. Skoner focused on two recent trials comparing R-isomer (levalbuterol) with the racemic albuterol in children and concluded his presentation with examples of long acting ß₂-agonists and delivery options appropriate for children.

The first study discussed by Dr. Skoner (J Allergy Clin Immunol 2001; 108:938-945) compared levalbuterol (0.31 or 0.63 mg), racemic albuterol (1.25 or 2.5 mg), and placebo in asthmatic children aged 4 to 11 years (n = 319; FEV₁ was 40%-85% of predicted normal) given 3 daily nebulized treatments for 3 weeks. The primary endpoint was FEV₁ (peak percent change). The two levalbuterol doses and the higher dose of the racemic albuterol were found to be effective throughout the 3-week trial. The order of efficacy after 3 weeks was levalbuterol (0.31 mg) > racemic (2.5 mg) > levalbuterol (0.63mg) = racemic albuterol (1.25 mg) > placebo.

In regard to adverse events, the low dose of levalbuterol had no significant effect on heart rate while the higher dose (0.63 mg) and both racemic albuterol doses increased heart rate. Similar changes were observed with serum
glucose levels. Dr. Skoner concluded his review of this study by stating, “levalbuterol, 0.31 and 0.63 mg, were clinically comparable to racemic 2.5 mg and levalbuterol at 0.31 mg was equal to placebo in beta-mediated side effects,” adding, “racemic 1.25 mg produced less bronchodilation and did not diminish the side effects to an extent equal to levalbuterol (0.31 mg).”

In a study presented at the ACAAI Annual Meeting, a comparison of levalbuterol (0.31 or 0.63 mg; t.i.d.), with the racemic albuterol (1.25 or 2.5 mg; t.i.d.) was performed in a randomized, double-blinded, parallel group, placebo-controlled trial in younger children (2-5 years; n = 220) given treatment for 3 weeks (Skoner et al., Annals of Allergy/ Asthma/Immunology 2003, abstract in press). Due to the young age, the primary endpoint in this study was the change in the total pediatric asthma questionnaire score and the greatest improvements were observed in patients given levalbuterol. Unfortunately, the results were not statistically significant likely due to the mild baseline values in this study and small n. However, a statistically significant acute bronchodilatory response, based on change in peak expiratory flow, was observed for both levalbuterol doses.  Moreover, quality of life changes were greatest with levalbuterol.

Long Acting ß2-Agonists in Children
Dr. Skoner began his discussion of long acting ß₂-agonists reminding the audience of the FDA-approved age indications. For the metered dose inhaler, salmeterol, and for the combination product, fluticasone and salmeterol dry powder, children should be at least 12 years of age. For formoterol the minimum age is 5 years and for salmeterol as a dry powder the minimum age is 4 years.

To illustrate the efficacy and safety of long acting ß₂-agonists in children, Dr. Skoner chose a recent clinical trial that examined the efficacy and safety of inhaled formoterol dry powder delivered via the aerolizer twice a day in children with persistent asthma (Ann Allergy Asthma Immunol 2002;89:180-190). In this study, asthmatic children (n = 518; mean age 9 yrs; FEV₁ ~70%) were given formoterol (12 or 24 µg) or placebo. Area under the curve analysis (FEV₁) showed both doses of formoterol to be significantly better than placebo over a 12-month period. Dr. Skoner said, “formoterol also improved clinical outcomes, improved a.m. and p.m. peak flow rates, symptom scores, and nocturnal beta agonist use was improved,” adding however, “the incidence of asthma hospitalizations was higher in the formoterol groups than in the placebo-treated group.” While this first appears to be problematic, Dr. Skoner noted that the placebo group had an unexpectedly low hospitalization rate (0%) and the possibility of a ‘masking’ effect occurring in this study warrants further investigation. In light of these data, it is highly recommended that close disease monitoring occur for early signs of acute exacerbations.

Delivery Systems for Asthmatic Children
In a recent study published in The Journal of Asthma (J Asthma 2002;39: 337-339) a comparison of mouthpiece and face mask delivery systems for nebulized albuterol was performed in children with moderate asthma (n = 18, mean age 10 yrs ; range 8-15 yrs; FEV₁ approximately 50% predicted). In the patients using the mouthpiece, there was a 52%-56% increase in FEV₁ after 15 and 30 minutes while the patients using the face mask had only a 27%-31% increase. Dr. Skoner pointed out that these results are in contrast to a study with nebulized budesonide showing both systems to be equally efficacious (Am J Respir Crit Care Med 2000;162:593-598). One possible explanation is that the latter study used younger children and Dr. Skoner stated for children under 4 years of age a face mask is advised and after 4 years, a mouthpiece.

Concluding Remarks
Dr. Skoner is optimistic with the recent developments in the fields of ß₂-agonists for preschool asthma and is hopeful that the plethora of drugs and formulations available “gives us a number of choices to fulfill the NHLBI guidelines which recommend use of both short acting beta agonists and long acting beta adrenergic agonists,” said Dr. Skoner.

Beta-2 Adrenergic Agents in Acute Asthma

Dr. Richard Nowak, vice-chairman of Emergency Medicine at Henry Ford Health System in Detroit, MI and professor of Emergency Medicine at Case Western University in Cleveland,OH, began his presentation by acknowledging that as an emergency physician, “the patients that I see with acute asthma tend to be the ones that have failed your therapy or at least outpatient therapy.” As a result, many patients will have already taken heavy doses of albuterol prior to visiting the Emergency Department. “Some have been up all night using their inhalation, whether it’s MDI repetitively or whether it’s by nebulization and then come in to see me and what do I do? I give them a lot more,” stated Dr. Nowak, adding, “because I’m not really sure what else to do when somebody is actively wheezing in front of you and it’s the bronchodilator of choice.” To address the realities of the Emergency Department with concerns for (S)- isomer accumulation, Dr. Nowak became involved in a trial examining the safety and efficacy of (R)- versus (R,S)- albuterol.

High Dose Levalbuterol in the Acute Setting
Dr. Nowak and colleagues conducted a study to determine the most effective dose of levalbuterol that can be safely administered and presented the results at the ATS meeting last year. In the study, 92 patients with moderate to severe asthma were given accumulating doses of levalbuterol (0.63,1.25, 2.5, 3.75, and 5 mg) and compared to 2.5 and 5 mg of the racemic albuterol.

The primary endpoint was mean percent change in FEV1 and it was found that the lowest dose of levalbuterol
was as effective as either dose of the racemic albuterol and 1.25 mg of levalbuterol was significantly better than the racemic doses. With the higher doses of levalbuterol, no further improvement was observed and Dr. Nowak said, “it’s most likely the 1.25 mg dose, at least in these sorts of studies is probably the right dose to use.”

Examination of the blood levels of (S)- and (R)-isomers found that the patients given the racemic albuterol continued to show increased levels in the (S)-isomer while the levalbuterol group did not.

The side effects profile in these patients was typical of (R)-isomer, with dose dependent decreases in potassium and increases in heart rate (with the exception of low dose levalbuterol having a slight decrease in heart rate), and typical (R)-isomer effects on blood glucose.

Finally, this study found that as little as 7% of the patients given the (R)-isomer required more therapy while almost half of the patients given the racemic albuterol required further care. “I would argue that this is clinical evidence that suggests that when you give the racemic compound, the (S)-isomer is fighting with the (R)-isomer in terms of producing significant bronchodilatation,” concluded Dr. Nowak.

In a similar trial that has just been completed, ED patients were sent home with an experimental MDI delivering levalbuterol after receiving levalbuterol in the ED. The patients were followed for 10 days and retested. While final analysis has not been completed, Dr. Nowak is optimistic that “we’re going to see better symptom scores, less nighttime awakening, less use of rescue therapy, and better pulmonary function testing and less relapse rate,” stated Dr. Nowak.

All contents Copyright © 1999 - 2003 Medical Association Communications