ABSTRACT: Bronchodilators are central to COPD symptom management; current options include the anticholinergic ipratropium, short- and long-acting ß2-agonists, and theophylline. Tiotropium, which is not yet available in the United States, may become a useful addition to the armamentarium. Novel phosphodiesterase 4 inhibitors with both anti-inflammatory and bronchodilatory effects, including roflumilast, piclamilast, and cilomilast, are being investigated. Combination therapy with bronchodilators that have different mechanisms and durations of action may prove key in achieving the greatest symptom control with the fewest side effects. For example, prescribing a first-generation ß2-adrenergic agonist, such as albuterol, together with an antimuscarinic agent is reasonable from the standpoints of both efficacy and safety.
Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of chronic morbidity and mortality in the United States.1 Its prevalence and impact are increasing, and the World Bank/World Health Organization has projected that it will rank fifth in 2020 as a global burden of disease.2,3 The economic and public health impact of COPD is staggering, because this chronic condition requires long-term care, frequent office visits, and use of emergency department and hospital services. Thus, there is a pressing need to discover new therapies that control symptoms and prevent disease progression.
An increased understanding of the pathophysiologic mechanisms of COPD has helped researchers identify potential targets for new treatments. These include many chemoattractants and cytokines that drive the inflammatory responses in COPD; the signal transduction pathways activated during these processes; the mediators released, including proteases and oxidants; and the cellular responses that lead to abnormalities in tissue functions, such as mucociliary clearance and repair.
Increased interest in COPD is also reflected in the number of important pulmonary guidelines that have been published since 1974 at both local and international levels.4 Pharmacologic and nonpharmacologic measures are aimed at improving the quality of care for patients who have COPD, with smoking cessation mandatory for all patients to slow the progression of lung function loss.
Our focus here is on the pharmacologic options for COPD. We identify the currently available agents and outline appropriate treatment strategies. We also highlight new areas of research that may help guide management in the future.
CLASSIFICATION OF COPD
In the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, COPD is defined as a "disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases."5 The guidelines also provide a simple classification of disease severity into 4 stages (Table 1); this staging system can help guide treatment (Table 2).
The major physiologic abnormality in COPD is expiratory airflow limitation, which is measured best by spirometry. Airflow has, therefore, become the international measure by which most drugs are considered for the management of COPD. Although several recent trials have highlighted other useful end points, such as quality of life, exacerbation frequency, exercise performance, and survival, therapies have been based on objective improvements in expiratory airflow. Current pharmacologic therapy is used mainly to control symptoms; it may also reduce the frequency and severity of exacerbations, improve health status, and improve exercise tolerance.
An effective COPD management plan includes 4 components: assessing and monitoring disease, reducing risk factors, managing stable COPD, and managing exacerbations.5 Once COPD has been diagnosed, the treatment goals are:
Bronchodilators. The hallmark of COPD is airflow obstruction, which leads to incomplete expiration. During exertion, patients with emphysema may experience a significant amount of air trapping, which leads to hyperinflation (dynamic hyperinflation) with auto-peak end-expiratory pressure phenomenon. Hyperinflation attributable to incomplete lung emptying-especially with exercise-leads to a further increase in intra-alveolar pressure and decreased inspiratory capacity; it affects the operation of the inspiratory muscles and results in dyspnea.
Bronchodilators are central to COPD symptom management.7-10 These agents improve airflow by decreasing airway smooth muscle tone; as a result, improved emptying of the lungs at rest and during exercise leads to a reduction in dynamic hyperinflation.11 Generally, bronchodilators are given on an as-needed or a regular basis to relieve persistent or worsening symptoms or on a regular basis to prevent or reduce symptoms.
The major side effects are dose-dependent. Both oral and inhaled formulations are available, but the latter is preferable, because adverse effects are less likely to occur and resolve more quickly after treatment has stopped. Tailor bronchodilator therapy to the specific patient (Table 3).
Anticholinergics. Contributing factors that lead to bronchial obstruction in COPD include mucus hypersecretion and an increased bronchial muscle tone, which is mediated by cholinergic mechanisms. The anticholinergic bronchodilators decrease vagal cholinergic tone, which is the main reversible component of COPD; hence, they are usually the first-line drugs in the management of COPD.
Anticholinergic drugs block muscarinic receptors on airway smooth muscle and, possibly, on submucosal gland cells. Autoradiographic mapping and functional studies have shown M1 (Hm1), M2 (Hm2), and M3 (Hm3) receptors in human airways, and these receptors appear to have different physiologic functions.12
M1 receptors in parasympathetic ganglia facilitate cholinergic neurotransmission and, thus, enhance cholinergic bronchoconstriction, whereas M3 receptors on airway smooth muscle cells and glands mediate bronchoconstriction and mucus secretion. M2 receptors on cholinergic nerve endings inhibit the release of acetylcholine and act as feedback inhibitory receptors (autoreceptors). In human airways, blockade of M2 receptors results in increased acetylcholine release (Figure 1).
Because ipratropium is a comparatively nonselective muscarinic antagonist, it blocks M2 receptors as well as M1 and M3 receptors, and increased acetylcholine release may overcome the blockade of muscarinic receptors in the muscle. This has prompted a search for selective muscarinic receptor antagonists that block either just M3 or both M1 and M3 receptors.
Tiotropium is a novel, potent, long-lasting muscarinic antagonist. Like ipratropium, tiotropium has a positively charged quaternary ammonium structure that is responsible for its limited systemic absorption. Studies with cloned human muscarinic receptors have shown that tiotropium binds equally well to M1, M2, and M3 receptors. However, when compared with other muscarinic antagonists, it dissociates very slowly from M1 and M3 receptors and more rapidly from M2 receptors.13,14 Takahashi and colleagues15 confirmed the long duration of action of tiotropium in binding studies with cholinergic neural responses in both guinea pig and human airways in vitro.
Maesen and colleagues16 demonstrated the dose-dependent bronchodilatory efficacy and duration of action of tiotropium in patients with COPD.
In a well-controlled study, Littner and associates17 administered tiotropium inhalation powder once daily to stable patients with COPD (mean forced expiratory volume in 1 second [FEV1], 1.08 L [42% of predicted]) and evaluated dose-response characteristics. Tiotropium was shown to be safe and effective in once-daily doses ranging from 4.5 to 36 µg, and patients had improved spirometric results compared with patients given placebo.
In patients with COPD, tiotropium provides a dose-related bronchodilatation that persists for more than 24 hours (Figure 2).16 Long-term studies on the safety and efficacy of 18 µg of tiotropium once daily are being conducted. This drug, which has been filed with the FDA for approval, is likely to be a useful addition to COPD therapy.
β2-Agonists. If the outcome of anticholinergic therapy is not optimal, add an inhaled short-acting β2-agonist. These bronchodilators improve lung function, reduce symptoms, and protect against exercise-induced dyspnea in patients who have COPD.18,19 The principal action of β2-agonists is to relax airway smooth muscle via activation of adenylate cyclase in the muscle, which, in turn, increases the concentration of intracellular cyclic adenosine monophosphate (AMP).20
Albuterol, a short-acting β2-agonist, has proved a major advance in therapy in the 30 years it has been used to treat and prevent the symptoms of COPD. This drug usually is administered via metered-dose inhaler (MDI), dry-powder inhaler, or nebulizer, but also is available in an oral formulation. Albuterol remains the standard bronchodilator for the treatment of COPD-related acute bronchospasm and acute exacerbations of chronic bronchitis.
The main disadvantage of a first-generation β2-adrenergic agonist, such as albuterol, is short duration of action (2 to 4 hours), which requires the drug to be administered several times a day. Other short-acting β2-agonists (metaproterenol, pirbuterol, terbutaline) are listed in Table 3.
The need for long-acting bronchodilators in patients who have asthma and COPD was met with salmeterol21 and formoterol.22 Salmeterol has prolonged, specific binding to a secondary exocite on the β2-adrenergic receptor, resulting in repeated stimulation of the active site, which leads to longer efficacy.
In an attempt to increase the affinity of agonists for the β2-adrenergic receptor, formoterol was developed. The exact mechanism by which formoterol exerts prolonged effects on lung function is unknown but may involve interaction with the membrane lipid bilayer.23
Both salmeterol and formoterol induce bronchodilatation. Celik and associates24 demonstrated that after 10 minutes, formoterol induced clinically and statistically significant improvement in FEV1 compared with placebo, whereas salmeterol required 20 minutes to induce significant improvement. Both of these long-acting β2-agonists have a 12-hour duration of action and are appropriate for twice-daily use.
The long-acting β2-agonists have other effects that may be beneficial. Salmeterol inhibits airway smooth muscle proliferation and inflamma- tory mediator release. It also exerts non-smooth muscle effects, such as stimulation of mucociliary transport, cytoprotection of respiratory mucosa, and attenuation of neutrophil recruitment and activation.25 Formoterol has not been evaluated for such effects. Treatment with long-acting β2-agonists may reduce the number and severity of exacerbations; thus, it may reduce the overall cost of health care for patients with COPD. In addition, long-acting β2-agonists, which can be used twice daily (in contrast to short-acting β2-agonists that must be used 4 times per day), may improve patient compliance.
Methylxanthines. The effects and role of xanthine derivatives in the treatment of COPD remain controversial. However, if the outcome of therapy is not optimal, adding 100 to 900 mg of theophylline per day to the regimen of ipratropium with or without a β2-agonist can be considered.
Because methylxanthines are nonspecific inhibitors of all phosphodiesterase enzyme subsets, they have a wide range of toxic effects. Toxicity in xanthine derivatives is dose-related because the toxic-therapeutic ratio is small. Theophylline is the most widely available methylxanthine, and it is metabolized by cytochrome P-450 mixed-function oxidases. Clearance of theophylline decreases with age, and a number of drugs and physiologic variables affect its metabolism.
The phosphodiesterase inhibitors have been reported to have a wide range of nonbronchodilator actions that may help the COPD patient. Mahler26 showed a reduction in breathlessness in patients who received theophylline. Kirsten and coworkers27 found that cessation of theophylline therapy resulted in significant (P < .05) deterioration in lung function, exercise performance, and 2 indices of overall dyspnea; and a significant increase in symptoms and abnormal auscultatory findings.
Changes in inspiratory muscle function have been reported in patients treated with theophylline,28,29 but whether this reflects changes in dynamic lung volumes or a primary effect on the muscle is not clear. Results suggest that theophylline is effective in some patients with COPD and support its use for patients who remain symptomatic despite the use of inhaled bronchodilators.
Second-generation inhibitors of phosphodiesterase 4 (PDE4) have been evaluated. The earliest medications, such as rolipram, demonstrated marked anti-inflammatory and bronchodilatory effects in vitro and in vivo,30 but use of these compounds was limited by GI side effects. Novel PDE4 inhibitors that maintain the anti-inflammatory and bronchodilatory activity of rolipram with fewer side effects are being sought. Currently, roflumilast, piclamilast, and cilomilast are being investigated.31
Bronchodilator combination therapy. Anticholinergics, β-agonists, and phosphodiesterase inhibitors have different mechanisms of action, and the relative importance of each of these may differ at various airway sites. Thus, β-agonists may increase cyclic AMP and mutually potentiate the action of methylxanthines that inhibit cyclic AMP breakdown. Crosstalk between muscarinic cholinergic receptors and β-agonist receptors may promote synergies between agents that act at these sites.
Clinical trials have supported the combined use of bronchodilators.32 Ipratropium has been given effectively with several short-acting bronchodilators, and an MDI combining ipratropium and albuterol was approved by the FDA for use in 1996. When added to salmeterol, ipratropium therapy results in further bronchodilatation. This potentiation may last up to 10 hours-well beyond the usual duration of action of ipratropium. Theophylline also has been used effectively in combination with ipratropium and with short- and long-acting β-agonists.33
Corticosteroids. In COPD, systemic corticosteroids are recommended for treatment of acute exacerbations only, and several studies have shown benefits in this setting.34 Extended treatment for 8 weeks is not more beneficial than treatment for 2 weeks.
Four large studies evaluated the long-term effects of inhaled corticosteroids on lung function decline.35-38 The principal outcome measure for all the studies was longitudinal decline in FEV1. Investigators showed that inhaled corticosteroids did not slow the decline in lung function that characterizes COPD and that regular treatment with these drugs is appropriate only for symptomatic patients with documented spirometric responses or for those with FEV1 of less than 50% of predicted and persistent exacerbations requiring treatment with antibiotics or oral corticosteroids.5,6
However, in the Inhaled Steroids in Obstructive Lung Disease (ISOLDE) trial, which assessed patients with the most severe disease, a significant reduction in exacerbation frequency was noted.39 This was associated with a reduction in the rate of decline in health status. Reduction of exacerbations with inhaled corticosteroids was confirmed in a prospective study with exacerbations as the primary outcome.40 Current recommendations, therefore, suggest that inhaled corticosteroids can be used to help prevent exacerbations, particularly in patients with severe pulmonary function abnormalities who are at increased risk for exacerbations or severe exacerbations.5,6
Inhaled corticosteroids can result in a modest improvement in airflow in COPD patients, but these improvements are considerably smaller than those seen with bronchodilators. Nevertheless, if dyspnea persists despite maximal treatment with bronchodilators, a trial with inhaled corticosteroids is reasonable (Table 4). This trial may require at least 3 months to discern benefit. Trials with oral corticosteroids are no longer recommended.
We believe that combining drugs with different mechanisms and durations of action will occupy a central role in future management of COPD. The availability of combination therapy should help enhance patient compliance and result in cost savings.
There is an urgent need to develop new drugs that will offer significant improvement in airflow and arrest long-term decline in lung function in patients with COPD. The development of drugs with low bioavailability, long durations of action, predictable side effects, and targeted pharmacologic effects will improve symptomatic management of this disease.
Future COPD treatments will likely be based on mechanisms that are distinct from those of current therapies. A better understanding of the basic pathophysiologic processes underlying the inflammation and tissue remodeling that are characteristic of COPD has created novel therapeutic opportunities.
The agents that are being investigated can block various aspects of the inflammatory response, attenuate the effect of inflammatory mediators, modulate tissue destruction, and stimulate tissue restoration. These drugs may alter the natural course of COPD and, potentially, reverse physiologic compromise.
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