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The Proceedings of the American Thoracic Society 4:526-534 (2007)
© 2007 The American Thoracic Society
doi: 10.1513/pats.200701-016FM
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Pharmacologic Interventions in Chronic Obstructive Pulmonary Disease

Bronchodilators

Nicola A. Hanania1 and James F. Donohue2

1 Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, Texas; and 2 Section of Pulmonary and Critical Care Medicine, University of North Carolina, Chapel Hill, North Carolina

Correspondence and requests for reprints should be addressed to Nicola A. Hanania, M.D., Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, 1504 Taub Loop, Houston, Texas 77030. E-mail: hanania{at}bcm.edu

ABSTRACT

Chronic obstructive pulmonary disease (COPD) is a treatable disease characterized by progressive airflow limitation. Prevention of disease progression, improvement of symptoms, exercise tolerance, health status, and decrease in exacerbations and in mortality are the main goals of the management of COPD. Bronchodilators play a pivotal role in the treatment of symptomatic patients with COPD. Inhaled short-acting bronchodilators are currently recommended for rescue of symptoms in patients with mild disease, whereas inhaled long-acting bronchodilators are recommended as first-line agents for maintenance therapy in patients with moderate and severe disease and those with daily symptoms. Long-acting bronchodilators improve symptoms, exercise tolerance, and health status, and reduce exacerbations in patients COPD. However, their effects on long-term decline in lung function and mortality are currently under investigation. When symptoms are not sufficiently controlled by the use of one bronchodilator, combining bronchodilators of different classes may be a more effective approach. In fact, recent evidence supports the regular use of a combination of a long-acting ß2-adrenoceptor agonist and a long-acting anticholinergic agent in patients with severe COPD. Combining a long-acting ß2-adrenoceptor agonist with an inhaled corticosteroid has also been shown to be more effective than the use of either agent alone. The use of theophylline has declined in recent years because of its narrow therapeutic index, and should be reserved as a third-line option in patients with very severe disease. Several novel bronchodilators are now in different stages of development for use alone or in combination with other agents.

Key Words: anticholinergics • ß2-adrenoceptor agonists • bronchodilators • chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a multicomponent disease characterized by progressive airflow limitation and an inflammatory response of the lung, principally caused by cigarette smoking. Progressive airflow limitation in COPD has significant consequences, which lead to deterioration of health status (Figure 1). As airflow obstruction is the mechanical hallmark of COPD, it would be expected that, as the level of airflow limitation increases, so too would the severity of symptoms. By far the most distressing symptoms for patients with COPD are dyspnea and the progressive inability to engage in activities of daily living. Furthermore, the risk of acute exacerbation of COPD increases with the severity of airflow limitation, causing further increase in morbidity from this disease. The main goals of management of COPD are focused on relieving symptoms, improving health status, preserving lung function decline, improving exercise performance, preventing exacerbations, and decreasing mortality. The National Heart, Lung, and Blood Institute, the World Health Organization, the American Thoracic Society (ATS), the British Thoracic Society, and the European Respiratory Society have published guidelines for the management of COPD (1–4). These guidelines emphasize the comprehensive and stepwise approach to the management of COPD and stipulate that all patients who are symptomatic merit a trial of pharmacologic intervention (Table 1). Current medications used for COPD can reduce or abolish symptoms and number and severity of exacerbations, and can improve exercise capacity and health status.


Figure 1
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  		Figure 1. Consequences of airflow limitation in chronic obstructive pulmonary disease (COPD). Dynamic hyperinflation is an important physiologic consequence of airflow limitation in COPD. It leads to progressive dyspnea, decline in exercise tolerance, inactivity, and deconditioning. In addition, exacerbations in patients with COPD contribute to further deterioration of their functional and health status.

 

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  		TABLE 1. STEPWISE APPROACH TO THE PHARMACOLOGIC MANAGEMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND THE POSITION OF BRONCHODILATORS

 
Bronchodilators are the mainstay of pharmacologic therapy for COPD, and are recommended by current national and international guidelines as first-line therapy in symptomatic patients and those who demonstrate airflow limitation. Bronchodilators are given on an as-needed basis or on a regular basis to prevent or reduce symptoms. Short-acting agents are usually used for immediate relief of symptoms, whereas long-acting inhaled agents are generally preferred and are more convenient. Combinations of bronchodilators may improve efficacy and reduce risk of adverse effects rather than increasing the dose of a single agent. This review provides the rationale for use and safety of bronchodilators in COPD.

RATIONALE FOR THE USE OF BRONCHODILATORS IN COPD

Bronchodilators work through their direct relaxation effect on airway smooth muscle cells (Table 2). However, several issues need to be considered when assessing the response to bronchodilator therapy. First, the lack of acute response to one class of bronchodilator does not necessarily imply nonresponsiveness to another. Donohue and colleagues (5) reported that 73% of 813 patients with COPD increased their FEV1 by at least 12%, or 200 ml, after long-term salmeterol treatment. However, 11% of patients showed a similar increase in FEV1 after acute administration of ipratropium, 27% after albuterol, and 35% with both drugs combined. One further consideration is that a patient's FEV1 response to acute bronchodilator therapy does not predict long-term response to bronchodilator therapy and may vary from day to day. Calverley and colleagues (6) performed acute bronchodilator testing using albuterol, ipratropium bromide, or a combination of the 2 on 660 patients with COPD who had been classified according to both European Respiratory Society and ATS spirometric criteria. Over the 2-month study period, 55% of patients classified as irreversible under ATS criteria changed to reversible status on at least one of the visits. In summary, the acute response to short-acting bronchodilators is of limited value in predicting future response to long-acting agents. In addition, studies that stratified patients as "responders" versus "nonresponders" consistently demonstrate a similar trend in the response to the therapeutic agent being investigated in both groups. In addition, to direct bronchodilator properties through their effects on airway smooth muscles, bronchodilators, such as ß2-adrenoceptor agonists and theophylline, may have several nonbronchodilator activities that may contribute to their beneficial effects in COPD (7–13).


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  		TABLE 2. RATIONALE FOR THE USE OF BRONCHODILATORS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

 
The clinical efficacy of bronchodilators has traditionally been assessed by the degree of improvement in FEV1. This, however, is seemingly at odds with the poor correlations recognized between change of FEV1 and both dyspnea and exercise performance. The change in lung volumes, such as inspiratory capacity correlates better than the change in FEV1 with change in symptoms, such as dyspnea and exercise tolerance (14). This suggests that assessment of bronchodilator treatment using indices of hyperinflation or air trapping may provide a better indicator of efficacy (15). Although changes in lung volumes are independent of changes in FEV1, several studies have demonstrated that the more sustained airway patency offered by long-acting bronchodilators reduces air trapping (16, 17). Several other outcome measures are now used to assess response to bronchodilator therapy. The effects of commonly used bronchodilators on clinical outcomes in COPD are listed in Table 3.


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  		TABLE 3. SUMMARY OF THE EFFECTS OF COMMONLY-USED BRONCHODILATORS ON CLINICAL OUTCOMES IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

 
COPD exacerbation is another important but occasionally overlooked parameter (18). COPD exacerbations are very common, affecting about 20% of patients with moderate to severe COPD (1.3 events/yr in patients with 40–45% predicted FEV1), and contribute to the deterioration in health status. The use of long-acting ß2-adrenoceptor agonists (LABAs) and long-acting anticholinergic agents reduces the frequency of exacerbation and severity of individual exacerbations (19–21).

The effects of long-acting bronchodilators on health status have been well documented in several clinical trials (19, 21–24). Several instruments have been designed to provide a standardized method by which health status or level of health impairment could be measured and compared in individual patients as well as in groups of patients. The most commonly used instruments include generic and disease-specific health measures. Generic instruments, such as the Sickness Impact Profile, the Short-Form 36-item questionnaire, and the Nottingham Health Profile, although important, are relatively insensitive to small changes in response to a therapeutic intervention. Disease-specific instruments may be superior to generic instruments, and were developed to consider the major or key components that influence COPD. The Chronic Respiratory Questionnaire includes components for evaluation of dyspnea, fatigue, emotional function, and mastery; the St. George's Respiratory Questionnaire includes the domains of symptoms, activity, and impacts; and the Seattle Obstructive Lung Disease Questionnaire incorporates the dimensions of physical function, emotional function, coping skills, and treatment satisfaction. The most widely used application of assessment of health status is the detection of change (improvement or worsening) in response to therapy (an evaluative instrument). Minimum, clinically significant changes have been established for these disease-specific measures in order to indicate the relative value of any measured change in health status and to guide the interpretation as to whether the change is "clinically meaningful": a change of 4 points in the overall score on St. George's Respiratory Questionnaire and a change of 10 points for the Chronic Respiratory Questionnaire (25).

Dyspnea is a common and troublesome manifestation of COPD, and its relief is an important goal of bronchodilator therapy. Instruments available to assess dyspnea can either discriminate the level of dyspnea (discriminative) or evaluate dyspnea over time (evaluative). Evaluative measures have greater clinical utility and can be applied for outcome purposes. In general, the use of multidimensional instruments is preferred, as they are more responsive to the change in patient-perceived dyspnea. An instrument that is widely used is the Baseline Dyspnea Index and the Transition Dyspnea Index (TDI) that assess breathlessness in domains related to functional impairment, magnitude of task, and magnitude of effort. The Baseline Dyspnea Index uses a scale of 0–12, and the TDI uses a scale of –9 to +9 (26–29). The TDI, when measured repeatedly, can provide evidence of changes in dyspnea. A 1-unit change in the TDI score has been shown to be clinically important. This instrument has been shown to be responsive to a variety of therapeutic modalities, such as long-acting bronchodilator use. More recently, self-administered versions of this instrument have been described, which may eliminate interviewer bias and decrease the time needed for their administration.

Exercise limitation is a significant problem for patients with COPD, and it can be assessed using different techniques. The simplest method to assess exercise tolerance is the 6-minute walk distance, commonly used to assess the functional status of patients with COPD (30). It is a reliable, objective, inexpensive, and easy-to-apply tool, regardless of the patient's age or educational level. Other methods to assess exercise tolerance include incremental and steady-state cardiopulmonary exercise testing (CPET). The CPET is the gold standard for measuring exercise tolerance and gas exchange during exercise. VO2max is a predictor of mortality in patients with COPD. In addition, CPET is helpful in evaluating mechanisms of improvement in dyspnea secondary to pharmacologic agents, such as long-acting bronchodilators (31–33).

The long-term effects of currently used bronchodilators are not well known, and long-term studies will contribute to our understanding of their effects on the natural history of the disease (34). The long-term effects of the long-acting ß-agonist, salmeterol, and salmeterol/fluticasone combination on all-cause mortality and other outcomes over 3 years have been investigated in a recently published trial (Towards a Revolution in COPD Health trial [TORCH]) (35, 36). Another trial, now underway, will examine the effect of tiotropium on the decline in postbronchodilator FEV1 over 4 years (the Understanding of Potential Long-term Impact on Function with Tiotropium trial [UPLIFT]) (37).

PHARMACOLOGY OF BRONCHODILATORS IN COPD

Three classes of bronchodilators—ß2-adrenoceptoragonists, anticholinergics, and methylxanthines—are currently available and can be used individually or in combination (Table 4). Several novel bronchodilators are under development (38) (Table 5). The use of short-acting bronchodilators is currently advocated for rescue of symptoms, whereas inhaled long-acting bronchodilators are recommended as the treatment of choice for maintenance therapy.


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  		TABLE 4. COMMONLY USED BRONCHODILATORS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

 

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  		TABLE 5. BRONCHODILATORS IN CLINICAL DEVELOPMENT

 
I. ß2-Adrenoceptor Agonists
Pharmacology.
ß2-adrenoceptor agonists act by binding to the ß2-adrenergic receptor (ß2AR), which is a member of the seven transmembrane domains, G protein–coupled family of receptors. Although ß2ARs 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. Upon agonist binding to receptor, adenylyl cyclase is activated via the signal-transducing Gs protein, which results in a rise in cellular cAMP levels and activation of protein kinase A. The precise protein kinase A phosphorylation targets mediating bronchial smooth muscle relaxation are not fully understood, but likely include myosin light-chain kinase and Ca2+-dependent K+ (Kca) channels (39). ß2-adrenoceptor agonists are delivered through the inhaled or oral route, although the latter is limited because of the increased risk of adverse effects. There are several important pharmacologic differences among the existing agents (39, 40). First is the onset of action, which is similar with albuterol and formoterol (1–3 min), whereas it is more prolonged in the case of salmeterol. This difference in onset of action is related to the lipophilicity of each of these agents and their ability to activate the ß2-adrenergic receptor in the aqueous phase (albuerol and formoterol). Albuterol has a short duration of action, lasting less than 6 hours, whereas the duration of action of salmeterol and formoterol is approximately 12 hours. Second, these agents also differ significantly in their ability to active the ß2-receptor (intrinsic efficacy), which is dependent on their affinity and potency (39). 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.

Clinical benefits.
Short-acting ß2-adrenoceptor agonists have a rapid onset of action, and are very effective for rescue of symptoms in COPD. Albuterol is the most commonly used agent. In addition to their bronchodilatory properties, these agents are effective in increasing mucociliary clearance. A systematic review showed that regular use of short-acting ß2-adrenoceptor agonists in COPD was associated with improvement in lung function and dyspnea (41).

The two currently available LABAs—salmeterol and formoterol—have been shown to significantly improve lung function, health status, and symptom reduction compared with both placebo (16, 42–44) and ipratropium (21, 45). In addition, because of formoterol's fast onset of action, it has a potential role as stand-alone medication or in combination with another bronchodilator in the management of acute COPD exacerbation (46, 47) and for use as a rescue and maintenance medication (48). 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 FEV1 over 12 hours was similar between these two agents (49).

Several systematic reviews of LABAs reveal that these agents can reduce the rate of COPD exacerbations (19, 50). 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 (51).

Role of stereoisomers.
The majority of currently used ß2-adrenoceptor agonists are racemic compounds that contain a 50–50 mixture of the R- and S-enantiomers of the agonist. Recently, the R-enantiomer of albuterol (levalbuterol) (52, 53) and the R,R-enantiomer of formoterol (arformoterol) were approved for clinical use in the management of COPD (54). Much of the pharmacologic 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, induces deleterious effects. Data from an in vitro study indicate 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 (55). However, the effectiveness and cost-effectiveness of isomeric versus racemc ß2-adrenoceptor agonists in the management of airway diseases, such as COPD, need to be further explored and remain controversial (56, 57). 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 was comparable to salmeterol (58).

Nonbronchodilator effects of ß2-adrenoceptor agonists.
Although the major action of ß2-adrenoceptor agonists on airways is relaxation of airway smooth muscles, they also exert several effects mediated through the activation of ß2-ARs expressed on resident airway cells, such as epithelial cells and mast cells and circulating inflammatory cells (e.g., eosinophils and neutrophils) (8, 9). 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 (59), cytoprotection of the respiratory mucosa, and attenuation of neutrophil recruitment and activation (9). However, many of these effects have been described in in vitro studies, and in vivo studies are still needed to fully explore these effects. More recently, the physiologic and clinical benefits of LABAs have been shown to be enhanced when administered in conjunction with inhaled corticosteroids (ICS) (60–63), which translate to clinical benefits. ICS and LABA combination products have been shown to improve lung function, symptoms, health status, and to reduce exacerbations in patients with moderate to severe COPD (64–67).

Novel ß2-adrenoceptor agonists.
A variety of ß-agonists with longer half lives are currently under development with the hopes of achieving once-daily dosing (38) (Table 5). These include carmoterol, indacaterol, GlaxoSmithKline (GSK)-159797, GSK-597901, GSK-159802, GSK-642444, and GSK-678007. These compounds are mainly (R,R)-enantiomers, have high intrinsic efficacy, and have 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—a fact that may limit their clinical use (39). This needs to be taken into consideration in the evaluation of new agents under development. However, it is likely that once-daily dosing of an LABA will lead to enhancement of compliance with therapy, and may have advantages leading to improved overall clinical outcomes in patients with COPD.

II. Anticholinergics
Pharmacology.
Parasympathetic activity in the large- and medium-size airways is mediated through the mascurinic receptors (M1 and M3), and results in airways smooth muscle contraction, mucus secretion, and, possibly, increased ciliary activity. Interestingly, M2 receptors are located on the postganglionic parasympathetic nerves, and inhibit acetylcholine release from the nerve terminals. Increased cholinergic tone is important in the pathogenesis of COPD, contributing both to increased bronchial smooth muscle tone and to mucus hypersecretion (68, 69). Thus, anticholinergics reduce airway tone and improve expiratory flow limitation, hyperinflation, and exercise capacity in patients with COPD. Two anticholinergic bronchodilators are currently available in the United States for clinical use. The short-acting anticholinergic agent, ipratropium bromide, acts on all three muscarinic receptors. Its short duration of action requires dosing every 6 hours. Tiotropium is a relatively new anticholinergic agent, which also binds to all three receptor subtypes; however, it dissociates rapidly from M2 receptors. In contrast, its dissociation half-life from M3 receptors is close to 35 hours, which results in a prolonged bronchodilatory effect. Its peak bronchodilatory effect occurs in 1–3 hours, and continues for up to 32 hours, with a dip between 16 and 24 hours related to circadian change. However, its bronchoprotective effect against a bronchospastic agent continues up to 48 hours (70).

Clinical benefits.
The short-acting ipratropium has long been used as monotherapy or in combination with albuterol in the maintenance therapy of COPD (15, 71, 72). However, several studies have now shown that the use of long-acting bronchodilators is superior in improving health outcomes. The use of tiotropium in patients with COPD results in improved health status, dyspnea, and exercise capacity, as well as reduced hyperinflation and COPD exacerbation rate in patients with moderate to severe COPD relative to placebo (23, 32, 73) and ipratropium (24). Data from large long-term trials showed that trough FEV1 increased by 100 to 150 ml, and the peak FEV1 increased by 150 to 200 ml above trough level after inhalation of 18 µg of tiotropium. No loss of efficacy was seen over the course of 1 year of regular treatment with tiotropium. Furthermore, in a multicenter Veterans Administration trial involving 1,829 patients with severe COPD, the addition of tiotropium to other COPD therapies significantly reduced acute COPD exacerbations and reduced COPD hospitalizations when compared with placebo (20). Data from three more recent studies, specifically designed to explore the potential differences between tiotropium and salmeterol, seem to indicate a greater efficacy of tiotropium (74–76). An ongoing, large, clinical trial will evaluate the effect of tiotropium on the decline of lung function over a 4-year period (37).

Nonbronchodilator effects of anticholinergics.
Some nonbronchodilator effects for the existing anticholinergics have been reported (77). Furthermore, results from a recent study performed on sputum cells obtained from patients with COPD demonstrate that muscarinic receptors may be involved in airway inflammation in subjects with COPD through acetylcholine-induced, ERK1/2-dependent leukotriene B4 release (78). These results suggest that anticholinergic therapy may contribute to reduced neutrophilic inflammation in COPD; however, these findings need to be further evaluated in humans.

Novel anticholinergics.
Several new long-acting anticholinergic agents are under development, and these include Almirall (LAS)-34273, LAS-35201, GSK656398, GSK233705, and Novartis (NVA)-237 (glycopyrrolate) (Table 5). Although clinical details are still not available, potential advantages of such agents over tiotropium may include a quicker onset of action and a better safety profile.

III. Methylxanthines
Pharmacology.
Theophylline is a nonselective phosphodiesterase inhibitor that acts both as a weak bronchodilator and a respiratory stimulant. It has been shown to improve diaphragmatic contractility, and has some antiinflammatory properties (10). Because of its potential ability to activate the histone deacetylase system, theophylline may have the ability to enhance the effects of inhaled corticosteroids in patients with COPD. However, because of its potential adverse effects and narrow therapeutic index, it should only be used when symptoms persist despite optimal bronchodilator therapy. Several studies have demonstrated the beneficial effects for theophylline when added to other treatments in patients with COPD (79, 80).

Novel phosphodiesterase inhibitors.
Phosphodiesterase (PDE)-4 metabolizes cAMP in airway smooth muscle cells and in many inflammatory cells that play a major role in the inflammatory cascade of COPD. A number of PDE-4 inhibitors are currently in various stages of development. Selective inhibition of this enzyme has been shown to cause smooth muscle relaxation, antiinflammatory effects. Although the bronchodilator effects of these agents are very modest, their combined antiinflammatory and bronchodilator effects make them very appealing. Although these agents have a generally better safety profile compared with theophylline, their use may be associated with gastrointestinal adverse effects, which may limit their use in some patients. Preliminary studies have been published on the clinical efficacy and safety of roflumilast (81) and cilomilast (82, 83) in COPD, although none of these compounds is currently approved for clinical use.

IV. Combination Therapies
Bronchodilator combination therapy.
Current guidelines highlight the fact that, for patients whose conditions are not controlled with bronchodilator monotherapy, the use of a combination of more than one class of bronchodilators may be more effective than the use of single agents with respect to improvements in lung function, symptoms, and reducing the risk of adverse events (84–86). In particular, the use of an inhaled anticholinergic with a ß2-adrenoceptor agonist seems to be a convenient way of delivering treatment and obtaining better results. Large studies have demonstrated that the combination of the short-acting ß2-adrenoceptor agonist, albuterol, with the short-acting anticholinergic, ipratropium, is superior to either single agent alone (87).

Some trials have highlighted that the addition of LABAs to ipratropium is more effective than either agent used alone (88, 89). In a 12-week trial, ZuWallack and colleagues showed that salmeterol plus theophylline caused significantly greater improvements in pulmonary function and symptoms compared with either single agent (90).

Considering that formoterol provides a greater degree of early bronchodilation (in the first 2 h) than tiotropium and comparable bronchodilation over 12 hours (49), the bronchodilator effect of single doses of 12 µg formoterol and 18 µg tiotropium, and 12 µg formoterol plus 18 µg tiotropium given together, was examined in stable COPD (91). Formoterol and tiotropium appeared complementary. More recently, van Noord and colleagues (92) explored these effects elicited by 6 weeks of treatment with 18 µg tiotropium once daily in the morning, 12 µg formoterol twice daily, and 18 µg tiotropium plus 12 µg formoterol once daily in the morning in patients suffering from moderate-to-severe COPD. Patients receiving combination treatment had a greater improvement in FEV1 and FVC compared with those receiving the individual agents over 24 hours. Tiotropium was superior to formoterol for FEV1 response over 0–12 h (owing to significant differences from 8 to 12 h), but the two treatments were not significantly different for FEV1 over 12–24 hours or 0–24 hours. Similar observations were documented from a more recently published, 2-week study with tiotropium alone or tiotropium plus formoterol once or twice daily after a 2-week pretreatment period with tiotropium. In this study, the use of an additional evening dose of formoterol had clear added benefit compared with once a day formoterol (93).

LABA plus inhaled corticosteroid combination therapy.
The physiologic and clinical benefits of LABAs have been shown to be enhanced when administered in conjunction with ICS (94). Although the exact mechanism of the interaction between these two groups of medications is not very well understood, some in vitro studies suggest that it may be secondary to the receptor cross-talk at the cellular level between the steroid receptor and the ß-adrenergic receptor. A study of 250 µg fluticasone propionate and 50 µg salmeterol showed improvement in lung function in patients with COPD compared with monotherapy (64). Other studies have shown a reduction in exacerbation rate with combination therapy compared with single-drug therapy or placebo (66, 95). In two recent studies comparing ipratropium/albuterol given four times daily with 250 µg fluticasone/50 µg salmeterol given twice daily, a significant difference in improvement in dyspnea scores was seen among the two treatment groups (96, 97). More recently, a large study (n = 6,112) demonstrated a significant effect of therapy with fluticasone proprionate/salmeterol combination over 3 years on several COPD outcomes, such as exacerbations, health status, and a borderline effect on reduction of all-cause mortality (p = 0.052) (36).

Anticholinergic plus inhaled corticosteroid combination therapy.
Emerging evidence from in vitro studies suggests an interaction between corticosteroid and muscarinic receptors, which may provide a rationale for use of anticholinergic/corticosteroid combination therapies (62). However, the clinical effects of such interaction need to be investigated in future clinical trials.

DELIVERING BRONCHODILATORS TO THE LUNG

To achieve maximal benefit, a bronchodilator must be correctly delivered to the airway using a proper technique. Inhaled bronchodilators have traditionally been delivered to the lung using a metered-dose inhaler (MDI). However, a significant number of patients with COPD cannot effectively coordinate their breathing using an MDI. This problem may be remedied by the use of a dry-powder device (DPIs), an MDI with a spacer device, or a nebulizer. The chlorofluorocarbon propellants used in MDIs are currently being phased out, and will eventually be replaced by hydrofluoroalkane propellants. However, the reformulation of some bronchodilators using this propellant may be difficult, and, thus, DPIs are likely to become more popular in the years to come. DPIs are either single-dose, multidose, or reservoir devices that are breath activated. It is important to mention that even the use of DPIs may not be very simple for some patients, and may also be misused (98). Therefore, when prescribed an MDI or DPI, elderly patients with COPD require more training and reinforcement than younger individuals (99).

Nebulizers require little patient cooperation, and can be used at any age for any disease severity or acuity (100). In addition, the use of a nebulizer allows the delivery of larger doses of bronchodilator to the airway, especially during acute episodes of bronchospasm, and the combination of more than one bronchodilator for simultaneous administration. In fact, many patients prefer using a nebulizer over other devices. This was clearly shown in one questionnaire study of patients receiving home nebulizer treatment, which found that the majority of patients using a nebulizer reported increased feeling of personal well being, better symptom control, increased confidence, and a greater perception of independence (101). Small-volume nebulizers are powered by a jet of compressed air to aerosolize the drug, whereas ultrasonic nebulizers use a vibrating crystal. A new generation of low-volume nebulizers, which use a mesh or a multiple-aperture plate, will potentially be more efficient in delivering bronchodilators because they have better deposition characteristics and waste little drug with minimal residual (102).

The results of a systematic review of 59 randomized controlled trials in which the same drug (bronchodilator or inhaled corticosteroid) was delivered using different delivery devices (MDI with or without a spacer, DPI, or a nebulizer) in patients with asthma or COPD were recently published. There were no differences in the efficacy outcomes (lung function or symptoms) in any patient groups between these devices (103). This review concludes that "for the treatment of COPD in the outpatient setting, the MDI, with or without spacer/holding chamber, the nebulizer, and the DPI were all appropriate for the delivery of inhaled ß2-agonists and anticholinergic agents."

SAFETY OF BRONCHODILATOR THERAPY IN COPD

Although the safety of LABAs as monotherapy in asthma has recently been questioned (104), the use of these medications in COPD has generally been described as safe. In general, short-acting ß2-agonists are well tolerated, except for occasional episodes of tachycardia and tremor. It has been reported that the continued use of ß2-agonists may be associated with an increase in cardiovascular risk compared with placebo (105). However, a recent metaanalysis (n = 2,853) 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 (106). It has also been suggested that tolerance to the bronchodilator effects of LABAs may occur with their prolonged use in COPD (74, 107). 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 (44). Data from the recently completed TORCH study suggest that 3-year chronic use of salmeterol as monotherapy in patients with COPD produced no increase in mortality (36), as was suggested by the SMART (Salmeterol Multicenter Asthma Research Trial) in patients with asthma (104). Nevertheless, ß-agonists should be used with caution in patients with underlying cardiac disorders, including ischemic heart disease (105, 108).

Although the use of anticholinergics may be associated with class side effects, such as dry mouth, an increased risk of glaucoma, and urinary retention, when used in recommended doses, currently used agents are generally safe, as the quaternary nitrogen atom prevents them from being systemically absorbed. These agents should also be used with caution in patients with bladder neck obstruction due to prostatism, and patients with glaucoma. The long-term safety of tiotropium over 4 years is being investigated in the UPLIFT study, which is currently underway (37). A recent metaanalysis (109), which included randomized controlled trials of at least 3-months duration that evaluated anticholinergic or ß2-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, ß2-adrenoceptor agonists were associated with an increased risk for respiratory deaths. However, as highlighted by the authors themselves, this metaanalysis had several limitations, the fact that limits the validity of its results.

Theophylline is associated with tremors and nausea, and, less frequently, with cardiac arrhythmias and seizures (110). The risk of such adverse events can be reduced by monitoring the drug's plasma levels and reducing the dose accordingly.

CONCLUSIONS

The use of bronchodilators is central in the symptomatic management of COPD, and currently available agents have been shown to have significant effects on the long-term outcome and management of COPD. The use of the inhaled route is currently preferred to minimize systemic effects. Quick-acting and short-acting agents are best used for rescue of symptoms, whereas long-acting agents are best used for maintenance therapy. The choice of agents may be based primarily on individual response, cost, side-effect profile, and availability.

Several new bronchodilators are currently being studied in ongoing clinical trials that may improve the future treatment of COPD. The current opinion is that it will be advantageous to develop inhalers containing combination of several classes of long-acting bronchodilator drugs in an attempt to simplify treatment regimes as much as possible. Other agents include ß2-adrenoceptor agonists, which can be administered once a day or through nebulization, PDE-4 inhibitors, and other combination agents. Specific future research should examine the long-term efficacy and long-term safety of the different combination of bronchodilators with and without inhaled corticosteroids, as well as their effects on the natural history of COPD when used early in the disease progression. Furthermore, future studies should also identify more sensitive methods of assessing response to bronchodilators and, through responder analyses, specific groups based on gender, age, race, or pharmacogenetic makeup.

FOOTNOTES

Conflict of Interest Statement: N.A.H. has received research grant support from Sepracor, GlaxoSmithKline (GSK), Boehringer Ingelheim, Dey Inc., and Altana, and has served on the Speakers Bureau of GSK, Boehringer Ingelheim, and Dey, Inc. He has served on an advisory board and received honoraria from GSK, Altana, Novartis, Sepracor, and Dey, Inc. J.F.D. has been reimbursed by GSK, Boehringer Ingelheim, AstraZeneca, Dey, Inc., Altana, Novartis, Chiesi, Pfizer, Almirall, and Sepracor as an investigator, consultant, and advisor, for less than $10,000 per year.

(Received in original form January 15, 2007; accepted in final form March 5, 2007)

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