Mono- and Combination Therapy of Long-acting Bronchodilators and Inhaled Corticosteroids in Advanced COPD

Jill A. Ohar; James F. Donohue

Disclosures

Semin Respir Crit Care Med. 2010;31(3):321-333. 

In This Article

Beta-2 Adrenergic Agonists

Pharmacology

These sympathomimetic agents stimulate β-2 receptors in airway cells to produce a variety of effects.[6] Chief among these are smooth muscle relaxation and bronchodilation caused by activation of adenyl cyclase to produce cyclic 3'5' adenosine monophosphate (AMP). β2-adrenergic receptor (β2AR) agonists act through binding to the β2-adrenergic receptor, which is a member of the seven transmembrane domains, G protein-coupled family of receptors. Adenyl cyclase is activated via the signal transducing Gs protein, which results in a rise in cellular cyclic AMP (cAMP) levels and activation of protein kinase A (PKA) when ligand binds to the β2AR. The precise PKA phosphorylation targets mediating bronchial smooth muscle relaxation are not fully understood but are likely to include myosin light chain kinase and Ca2+-dependent K+ (Kca) channels.[7] Although β2ARs are present in high density in airway smooth muscle cells, they are also present in submucosal glands, vascular endothelium, ciliated epithelium, mast cells, circulating inflammatory cells such as eosinophils and lymphocytes, Clara cells, type II pneumocytes, and cholinergic ganglia. β2AR agonists are delivered through the inhaled or oral route; although use of the latter is limited because of the increased risk of adverse effects.

There are several important pharmacological differences among the existing agents.[7,8] Beta-2 agonists are differentiated as short-acting β-agonists (SABAs) with 3- to 6-hour duration of action and long-acting β-agonists (LABAs) with duration of action of or exceeding 12 hours. Figure 1 depicts the evolution of the most commonly used SABA, albuterol, from the less selective agents epinephrine, norepinephrine, and isoproterenol. Figure 1 also depicts the structure of the two currently available LABAs, salmeterol and formoterol. The onset of action is short (1 to 5 minutes) with albuterol and formoterol, whereas it is more prolonged with salmeterol (30 to 45 minutes). The difference in onset of action is related to the lipophilicity of each of these agents and their ability to activate the β2AR in the aqueous phase (albuterol and formoterol). Albuterol has a short duration of action lasting less than 6 hours, whereas the duration of action of salmeterol and formoterol is ~12 hours. These agents also differ significantly in their ability to activate the β2AR (intrinsic efficacy), which is dependent on their affinity and potency.[7] Although formoterol has a high intrinsic efficacy (strong agonist), albuterol and salmeterol have a very low intrinsic efficacy (weak agonists). The clinical relevance of this difference needs to be further explored in future trials.

Figure 1.

Structures of b-adrenergic agonists.

Clinical Benefits

Because of their rapid onset of action, short-acting β2-adrenoceptor agonists are very effective for rescue from symptoms of COPD. In addition to their bronchodilatory properties, these agents are effective in increasing mucociliary clearance. A systematic review showed that regular use of short-acting β2AR agonists in COPD was associated with improvement in lung function and dyspnea.[9] The two currently available LABAs—salmeterol and formoterol—have been shown in some studies to significantly improve lung function, health status, and symptom reduction, compared with both placebo[10–13] and ipratropium.[14,15] However, a recent Cochrane meta-analysis concluded that, although salmeterol is more effective in improving lung function variables than ipratropium, there was no significant difference in these agents' effect on quality of life, exacerbation frequency, or symptoms.[16] Because of formoterol's fast onset of action, it has a potential role as monotherapy or in combination with another bronchodilator in the management of acute COPD exacerbations[17–19] and for use as both a rescue and maintenance medication.[20] A recent study demonstrated a superior effect of formoterol compared with tiotropium bromide in improving FEV1 in the first 2 hours after administration; however, the area under the curve (AUC) FEV1 over 12 hours was similar between these two agents.[21] Several systematic reviews of LABAs reveal that these agents can reduce the rate of COPD exacerbations.[22,23] This has been confirmed by a recent Cochrane systematic review and meta-analysis of 27 trials.[24] This study went on to show that LABAs had significant benefits on airflow limitation measures, quality of life, and use of rescue medication.[24] In a study of 634 patients with COPD, the administration of salmeterol for 12 months improved health outcomes, including exacerbations, especially in patients who complied with therapy.[23]

Safety

SABAs are highly effective rescue agents that can be given by oral, parenteral, or inhalation routes of administration. However, the inhalational route is generally preferred because it has the highest therapeutic ratio (beneficial effects/side effects). Beta-adrenergic bronchodilators, even when inhaled, can have systemic as well as local effects. Older patients may experience more adverse effects due to pharmacodynamic as well as pharmacokinetic changes with drug-drug and drug-disease interactions.

It has been reported that the continued use of β2-AR agonists may be associated with an increase in cardiovascular risk compared with placebo.[25] Beta adrenergic agonists have inotropic and chronotropic effects that can increase arrhythmias and aggravate cardiomyopathy in some patients with cardiovascular disease.[26] A recent study found that the frequency of atrial tachycardia is high in COPD patients at baseline (41.8%); however, atrial flutter/fibrillation and sustained and nonsustained ventricular tachycardia frequency is low.[27] Treatment of these patients with LABA (arforomoterol or salmeterol) resulted in no significant change in the frequency of arrhythmias compared with placebo. Tremor can be bothersome to some while some older patients can have anxiety with regular use. The effects of long -term use on tolerance, deteriorating disease control, and deaths are controversial. One out of a series of meta-analyses,[28] which included randomized, controlled trials of at least 3 months' duration that evaluated anticholinergic or β2-agonist use compared with placebo or each other in patients with COPD, documented that although inhaled anticholinergics significantly reduced severe exacerbations and respiratory deaths in patients with COPD, β2-AR agonists were associated with an increased risk for respiratory deaths. However, as highlighted by the authors themselves, meta-analyses have several problems that limit their validity. Clearly, the use of LABAs as monotherapy in asthma can be considered unsafe;[29] however, the use of these medications in COPD has generally been described as safe. Data from the TORCH study suggest that chronic use of salmeterol as monotherapy in patients with COPD for 3 years produced no increase in mortality.[30] This is in conflict with a reported corresponding increase in asthma, which shows an increase in deaths in the salmeterol monotherapy group.[29] Further, a meta-analysis (N = 2853) of data from seven clinical trials examining the effects of salmeterol in patients with COPD, showed no clinically significant difference in the incidence of cardiovascular events between salmeterol and placebo.[31] This was confirmed by a more recent meta-analysis of 27 COPD studies listed in the Cochrane Controlled Trials Register.[24] This meta-analysis showed no difference in respiratory deaths between LABA and placebo groups. Additionally the use of LABAs with ICS reduced the risk of respiratory death compared with LABAs alone.[24] The safety of nebulized formoterol has also been studied and found to be similar to that of the dry powdered formulation.[31] Nevertheless, β-agonists should be used with caution in patients with underlying cardiac disorders including ischemic heart disease.[25,32] It has also been suggested that tolerance to the bronchodilator effects of LABAs may occur with their prolonged use in COPD.[33,34] However, a recent study examining the bronchodilator effect of long-term use of salmeterol demonstrated a sustained bronchodilator effect for salmeterol administered for 6 months.[13] A recent review of 27 studies revealed that LABAs reduce severe exacerbations compared with placebo but have similar risk for respiratory death as placebo, but the combination of ICS/LABA reduced the risk of respiratory death compared with LABA monotherapy.[24]

Role of Stereoisomers

The majority of currently used β2AR agonists are racemic compounds, which contain a 50:50 mixture of the R and S-enantiomers of the agonist. Recently, the R-enantiomer of albuterol (levalbuterol)[35,36] and the R,R-enantiomer of formoterol (arformoterol) were approved for clinical use in the management of COPD.[37] Much of the pharmacological activity of the agonist usually resides in the effects of the (R)-enantiomer; the (S)-enantiomer is believed to have no bronchodilator effects but in fact may induce deleterious effects. An in vitro study suggests that S,S-formoterol is not biologically inert, such that in racemic mixtures, it inhibited the beneficial effects of R,R,-formoterol on proliferation, antiinflammatory cellular surface marker expression, and cytokine secretion.[38] A recent study by Donohue and coworkers showed that patients hospitalized for COPD or asthma exacerbations could receive less frequent levalbuterol nebulized treatments than those treated with racemic albuterol.[39] However, there was no significant difference between the groups for length of stay and hospital costs. The effectiveness and cost-effectiveness of isomeric versus racemic β2AR agonists in the management of airway diseases such as COPD remain controversial and need to be further explored.[40,41] A recent trial investigating the efficacy and safety of different dose formulations of arformoterol nebulization solution administered over 12 weeks to patients with moderate to severe COPD demonstrated a significant sustained improvement in FEV1 compared with placebo but comparable to salmeterol.[42]

Nonbronchodilator Effects of β2AR Agonists

Although the major action of β2-AR agonists on airways is relaxation of airway smooth muscles, they also exert several effects mediated through the activation of β2-ARs expressed on resident airway cells such as epithelial cells and mast cells and circulating inflammatory cells such as eosinophils and neutrophils.[43,44] These effects include inhibition of airway smooth muscle cell proliferation and inflammatory mediator release, as well as non-smooth muscle effects, such as stimulation of mucociliary transport,[45] cytoprotection of the respiratory mucosa, and attenuation of neutrophil recruitment and activation.[44] Recently both formoterol and salmeterol have been shown to inhibit LPS (lipopolysaccharide)-stimulated release of tumor necrosis factor (TNF), and granulocyte/monocyte colony-stimulating factor (GM-CSF) but not CXCL-8 from monocyte-derived macrophages in culture.[46] Budesonide inhibited the release of all three cytokines and when combined with formoterol inhibited TNF release in an additive manner. However, many of these effects have been described by in vitro studies, and in vivo studies are still needed to fully explore these effects.

Novel β2-Adrenoceptor Agonists

In the future, new 24-hour, ultra-long-acting β-agonists such as indacaterol, GSK 444, combined with novel anticholinergics such as aclidinium bromide, stereoisomeric formulations including arformoterol and levalbuterol, and new combination platforms such as M3 antagonist-β-2 agonist (MABAs) are likely to be introduced for both asthma and COPD. Novel bronchodilators for COPD in late-stage development include the β-agonists indacterol and carmoterol. Indacaterol is a 24-hour LABA. In a dose-ranging study of indacterol in COPD, doses of 200 μg via multidose dry powder inhaler or 400 μg via single-dose inhalation increased trough FEV1, whereas all doses (50 μg, 100 μg, 200 μg, and 400 μg) increased AUC at day 7 and FEV1 from 5 minutes to 24 hours postdose. The 400 μg and 200 μg doses were most effective.[47] The bronchodilator effects of indacterol and formoterol on IC and FEV1 were studied in 30 patients with COPD. Although both increased FEV1 and IC, indacterol increased peak IC 31 versus 23%, FEV1 at hour 8 (1.47 vs 1.35), 24 hours (1.44 vs 1.35), and at 24 hours FEV1 17.7 versus 25%[48]

Furthermore, indacaterol had a greater effect than formoterol on inspiratory capacity, a marker of hyperinflation, from 4 to 24 hours after dosing.[48] A variety of β2-AR agonists with longer half-lives are currently under development with the hopes of achieving once-daily dosing.[5] These include carmoterol, indacaterol, GSK-159797, GSK-597901, GSK-159802, GSK-642444, and GSK-678007. These compounds are mainly (R,R)-enantiomers and have high intrinsic efficacy and quick onset of action. Although a quick onset of action and a prolonged 24-hour effect are desirable in the management of COPD, the use of agonists with high intrinsic efficacy may theoretically be associated with a rapid onset of tolerance, the fact that may limit their clinical use.[7] This needs to be taken in consideration in the evaluation of new agents under development. However, it is likely that once-daily dosing of a LABA will lead to enhancement of compliance with therapy and may have advantages leading to improved overall clinical outcomes in patients with COPD.

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