RX for COPD

Chronic obstructive pulmonary disease (COPD) is defined by the American Thoracic Society and European Respiratory Society as a lung disease characterized by airflow limitation that is usually progressive and is associated with an abnormal inflammatory response by the lungs to noxious inhalants.¹ Chronic obstructive disease is a heterogeneous disorder that includes emphysema, chronic bronchitis, obliterative bronchiolitis, and asthmatic bronchitis. Cigarette smoke is most often the causative agent. The diagnosis and severity of COPD are based on history and confirmed by spirometry. A FEV₁/FVC ratio of less than 70% confirms airflow limitation. The natural history of COPD varies among individuals. Patients often complain of dyspnea and cough. Severe lung hyperinflation during activity due to gas trapping may cause severe dyspnea and lead to severe pulmonary limitations. Changes in spirometry, however, are not as clinically meaningful to patients as the degree of dyspnea they report. Severity of FEV₁ does not correlate well with survival when compared to the composite BODE index.² As of 2001, COPD was the fifth leading cause of death in high-income countries,³ and it is a huge burden on many health care systems around the world.

COPD Management

The goals of COPD management are avoidance of tobacco and other noxious inhaled particles and gases, nonpharmacologic interventions such as pulmonary rehabilitation, proper vaccinations to prevent infections, and pharmacotherapy to treat daily symptoms and exacerbations. Avoidance of cigarette smoke is paramount in patients with COPD. Smoking cessation leads to disease modification by slowing the rate of decline in FEV₁.⁴ The debilitating symptoms of COPD include dyspnea and exercise intolerance. Frequent exacerbations have a profound impact on quality of life for patients with COPD and can result in hospitalizations. Pharmacotherapy is aimed at reducing the symptoms and frequency of exacerbation as well as increasing exercise tolerance. Short- and long-acting bronchodilators, inhaled corticosteroids, oxygen, and antibiotics are used to improve symptoms and improve overall health status. Surgical intervention is less frequently used. Guidelines for the management of COPD are updated and published by the American Thoracic Society, the European Respiratory Society, and The Global Initiative for Chronic Obstructive Lung Disease (GOLD).

Pharmacology

Bronchodilator medications are essential to the symptomatic management of COPD and are the primary pharmacologic intervention. β₂-adrenergic receptor agonists, anticholinergics, and methylxanthines are the three classes of bronchodilators available for COPD. In the early stages of COPD, short-acting β₂-agonist (SABA) like albuterol or anticholinergic (SAAC) bronchodilators such as ipratropium bromide are given on an as-needed basis for prompt symptomatic control. As disease severity worsens, long-acting b-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are given as the treatment of choice for maintenance therapy. Salmeterol and formoterol are the two LABAs used for COPD. Tiotropium bromide is a LAMA and is a fairly recent addition to COPD medications. Theophylline is the only approved methylxanthine for patients with COPD and is a weak bronchodilator. Bronchodilators induce relaxation on airway smooth muscle cells. Thus, improvements in FEV₁ are observed on pulmonary function tests with their use, and, as the degree of air trapping lessens, patients have less lung hyperinflation with exertion.

When single-agent therapy does not control symptoms, combination treatment should be initiated. Combination therapies with LABAs and LAMAs have been shown to provide better control than single-agent treatment. Anti-inflammatory medications such as inhaled corticosteroids, when combined with a LABA, improve FEV₁, reduce exacerbations, and reduce hyperinflation. Common strategies for COPD management are outlined in Table 1. These interventions and the rationale for their use will be discussed.

Bronchodilators

β₂-adrenergic agonists
Beta₂-adrenergic receptor agonists are commonly used bronchodilators for COPD. They act by binding to the β₂-adrenergic receptor (β₂AR). Binding to the β₂AR leads to increased production of cellular cyclic AMP and subsequent activation of protein kinase A (PKA), which phosphorylates and inactivates myosin light chain kinase. The exact PKA phosphorylation targets are not known, but cellular pathways ultimately lead to relaxation of airway smooth muscles.⁵ Beta₂ARs are located in high density on airway smooth muscle cells, but they are also found in cholinergic ganglia, submucosal glands, vascular endothelium, ciliated epithelium, circulating inflammatory cells, Clara cells, mast cells, and type-II pneumocytes. Beta agonists likely have effects at each of these sites and, therefore, have multiple mechanisms by which they cause bronchodilation and airway protection. Patients with COPD may benefit from the nonbronchodilator effects of β₂-agonists. Beta₂-adrenergic receptor agonists have numerous effects on airway epithelial cells, including increased ciliary beating, hydration of the airway, and increased mucociliary clearance (MCC).⁶ Airway cytoprotective effects of beta agonists are current topics of research. Studies have shown that MCC is reduced in smokers as well as in patients with chronic bronchitis. Beta agonists may improve symptoms and lessen exacerbation by increasing ciliary beat frequency and improving mucus clearance. Most studies of bronchodilators and MCC are one-dose studies, however, and more investigation is needed to determine the clinical significance of beta agonist effects on MCC and airway protection.

Short-acting β₂-agonists
Short-acting β₂-adrenergic receptor agonists have a rapid onset of action and are the primary drug for rescue of worsening symptoms in COPD. The commonly used SABAs are albuterol, pirbuterol, and terbutaline. They are all available by pressurized metered dose inhaler. Albuterol is also available in a nebulized solution. Albuterol and terbutaline are available in parenteral formulation but are not used in older patients because of the side effects. SABAs act within a few minutes and have lasting effects for about 4 to 6 hours. The quick onset of action makes them ideal for rescue of symptoms. Some COPD patients may have little change in spirometry results when using bronchodilators; but, if SABAs are used on a regular basis, patients may have a modest increase in lung function and less dyspnea. If SABAs are given, for instance, shortly prior to 6-minute walk testing, patients have an increase in exercise tolerance.⁷ Short-acting b-agonists are frequently combined with anticholinergics. This is a useful combination and works on both the central and peripheral airways. In COPD patients, the combination of albuterol and ipratropium had a superior bronchodilator response than either agent alone.⁸ Unfortunately, there are an insufficient number of clinical studies to accurately estimate the impact of regular versus intermittent use of SABAs on outcomes in COPD.

Long-acting beta agonists
Salmeterol and formoterol are LABAs and are intended to provide sustained improvements in lung function. In contrast to short-acting agents, salmeterol and formoterol are given every 12 hours and may be more convenient in stable COPD patients. They can be delivered via dry powder inhalation or pMDI. Both formoterol and salmeterol provide improvements in pulmonary function. As airflow improves, patients may have less lung hyperinflation. Reductions in hyperinflation may result in less dyspnea. Studies confirm that in symptomatic patients with COPD, salmeterol has been shown to improve lung function and reduce dyspnea.⁹ Formoterol, unlike salmeterol, has a dose response, is rapid in onset, and is a potent complete β-agonist.

The quick onset and dose response of formoterol are appealing because it can serve as a rescue and maintenance therapy.¹⁰ LABAs can be used in combination therapy with anticholinergic agents as well as with inhaled corticosteroids. Mahler et al¹¹ compared the efficacy of salmeterol to ipratropium bromide. Patients had much more improvement in lung function when given salmeterol. Another study,¹² however, shows that salmeterol used along with ipratropium bromide provides greater improvements in airway obstruction versus ipratropium alone. In patients with mild-to-moderate COPD, salmeterol use resulted in a greater increase in FEV₁ and better quality of life when compared to theophylline.¹³ Both formoterol and ipratropium bromide have been shown to improve lung function, although lung function improvement with formoterol when compared to ipratropium bromide was associated with a reduction in daily symptoms and less use of rescue bronchodilators.¹⁴ When compared to tiotropium, formoterol showed a superior effect on FEV₁ in the first 2 hours after administration. Combination therapy with formoterol and tiotropium exhibited greater improvements in FEV₁ and FVC measurements when compared to monotherapy with those individual agents.¹⁵ Inhaled corticosteroids (ICS) can be combined with LABAs to improve lung function. Improvements in airflow likely reduce the degree of lung hyperinflation and may lead to less dyspnea. There is some controversy as to the potency of their anti-inflammatory effects when used in COPD patients, although GOLD guidelines recommend inhaled corticosteroids as add-on therapy in patients with stage III or IV disease. Inhaled corticosteroids do improve lung function, but their effect on frequency of COPD exacerbation has been the topic of more recent investigations. Kardos and colleagues¹⁶ have shown that when treated with ICS in combination with LABAs, COPD patients have fewer exacerbations. Studies are ongoing in regard to the effect of ICS on health status and mortality in patients with COPD.

Safety of Beta Adrenergic Agents

SABAs and LABAs are relatively safe in patients with COPD. SABAs have pharmacological predictable dose-related and potency-related adverse effects. The side effects of SABAs include tremor, tachycardia, hypokalemia, and elevated plasma glucose. Tolerance to all of these adverse effects develops with continued exposure. Patients with comorbid heart disease are prone to arrhythmias, and those with long QTc-intervals on ECG are at risk for cardiac events, but the use of high-dose nebulized albuterol in the elderly COPD population does not seem to be harmful. The cause of variability of response and degree of side effects in patients is not completely clear. Genetic variations in the β₂AR might account for the increased side-effect susceptibility to SABAs observed in some populations. This is a focus of ongoing research. The use of LABAs in COPD has a good safety record, and tolerance to these agents is not usually seen in patients with COPD. The Salmeterol Multicenter Research Trial (SMART) study of asthmatic patients was terminated early due to a slight increase in deaths among African Americans on salmeterol. Because of the SMART study, the FDA has a black-box label on all LABAs. In the TOwards a Revolution in COPD Health (TORCH) study, however, salmeterol arms showed a trend toward a survival advantage over placebo and ICS arms.¹⁷

Anticholinergics

Table 1
STEPWISE APPROACH TO THE PHARMACOLOGIC MANAGEMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND THE POSITION OF BRONCHODILATORS
Severity	Spirometric Findings	Pharmacologic Intervention
Stage I: mild	FEV1/FVC<70%; FEV1≤80%	Add a short-acting bronchodilator to be used when needed; anticholinergic or ß2-adrenoceptor agonist
Stage II: moderate	FEV1/FVC<70%; 50%≥FEV1<80%	Add one or more long-acting bronchodilators on a scheduled basis. Consider pulmonary rehabilitation.
Stage III: severe	FEV1/FVC<70%; 30%≥FEV1<50%	Add inhaled steroids if repeated exacerbations.
Stage IV: very severe	FEV1/FVC<70%; FEV1<30%	Evaluate for adding oxygen. Consider surgical options.
Hanania NA, Donohue JE. Pharmacologic interventions in chronic obstructive pulmonary disease: bronchodilators. Proc Am Thorac Soc. 2007;4:526-35. Official Journal of the American Thoracic Society. © American Thoracic Society

Anticholinergic bronchodilators are also used in the treatment of COPD. They are analogs of atropine and act at the muscarinic receptors on airway smooth muscle cells. Cholinergic fibers arise from the dorsal motor nucleus of the vagus nerve. Impulses from the vagus nerve extend down to parasympathetic ganglia. When the post-ganglionic fibers innervating the airway smooth muscle cells, submucosal glands, and the lung are activated, acetylcholine is released and causes bronchoconstriction. It is through the muscarinic receptors that vagal stimulation is mediated in the lung. Receptors M1, M2, and M3 are the subtypes on airway smooth muscle cells. Increased cholinergic tone contributes to increased bronchial smooth muscle tone and mucus hypersecretion. Anticholinergics improve expiratory flow limitations, hyperinflation, and exercise capacity by alleviating bronchoconstriction. Similar to β-adrenergic agents, anticholinergic agents may have a role in airway protection. Muscarinic antagonism may result in reduced airway inflammation in patients with COPD.¹⁸ Anticholinergics are relatively safe medications when used in the proper doses. Class effects include dry mouth, increased risk of glaucoma, and urinary retention, and can be observed even with recommended doses. These drugs should be used cautiously in patients with bladder neck issues or severe glaucoma.

Short-Acting Anticholinergics

Ipratropium bromide and oxitropium (not available in the United States) are the short-acting anticholinergic agents. Ipratropium acts on all three muscarinic receptors and has been used mainly as monotherapy or in combination with albuterol for patients with COPD. Ipratropium bromide is particularly useful during COPD exacerbations and may be given by nebulizer or by MDI with a spacer in higher than maintenance doses. Ipratropium bromide has a dose response in patients with COPD, and because the drug is poorly absorbed, the dose may be increased with little changes in side effects. Ipratropium administration is every 6 hours. The frequency of use may contribute to poor patient compliance. Combination therapy with other bronchodilators is reasonable. As noted above, studies show that salmeterol used along with ipratropium bromide provides greater improvements in airway obstruction versus ipratropium alone.

Long-Acting Anticholinergics

Tiotropium is a long-acting anticholinergic and is becoming a once-a-day preferred treatment for stable COPD. Tiotropium selectively binds the M3 muscarinic receptor. In contrast to ipratropium, tiotropium has a long duration of action and is effective up to 24 hours. O’Donnell and colleagues¹⁹ have shown that daily use of tiotropium improves lung function, reduces dyspnea, and increases exercise tolerance in patients with COPD. In a large Veterans Administration trial,²⁰ the addition of tiotropium to other COPD medications reduced the rate of exacerbations and COPD-related hospitalizations when compare to placebo. The Understanding the Potential Long-term Impacts of Function with Tiotropium (UPLIFT) trial is near completion and will provide data about any survival benefit from tiotropium. Combination therapy is recommended in patients with COPD and, as mentioned above, combination therapy with formoterol and tiotropium resulted in better lung function when compared to monotherapy with either agent. There is little evidence on the benefits of combining anticholinergics with ICS.

Methylxanthines

Theophylline is a nonselective phosphodiesterase (PDE) inhibitor and has been used for the treatment of COPD for more than 70 years. It is a weak bronchodilator, is a respiratory stimulant, has anti-inflammatory properties, and has been shown to improve diaphragmatic contractility. Theophylline’s mechanism of bronchodilation and anti-inflammatory properties are due to its inhibition of PDE. The downstream actions of PDE activation contribute to the inflammatory cascade in COPD. Some new evidence suggests that theophylline may enhance the effects of corticosteroids on airway inflammation in patients with COPD.²¹ This is early data and will likely not change prescribing practice any time soon. In most industrialized nations, theophylline has almost been replaced by other bronchodilators. The frequency of side effects, numerous drug interactions, and low clinical efficacy have demoted it to a third-line agent for the treatment of COPD in the United States.

Theophylline should be used in doses producing a serum level of 8 μg/mL to 12 μg/mL due to the narrow therapeutic window and toxicity concerns. The common side effects include nausea, vomiting, seizures, and arrhythmias. Most side effects can be avoided with judicious monitoring of the drug’s serum level. Despite the toxicities, theophylline is still used worldwide because it is inexpensive, can be given orally, and has some clinical efficacy.

Steroids

Inhaled corticosteroids
Inhaled corticosteroids are recommended for the treatment of asthma and for some patients with COPD. The use of steroids in patients with COPD, however, is controversial. Presumably, they offer protection by reducing the amount of airway inflammation, but the documented effects of ICS on inflammatory cells, inflammatory mediators in lung-lavage fluid, and the pathology of endobronchial biopsies are inconsistent. There is little evidence that ICS slows the decline in lung function or improves mortality in patients with COPD. Studies, however, have shown that the use of ICS reduces the number of exacerbations in patients with severe COPD.²² This is why the GOLD guidelines recommend the use of ICS in COPD patients with frequent exacerbations. Inhaled corticosteroids are not recommended as monotherapy in COPD patients. Data continue to emerge showing the benefit of combining ICS with LABAs. Inhaled corticosteroids have some systemic absorption, and side effects are similar to those of oral steroids. Close monitoring of bone health is essential in COPD patients on therapy. The use of systemic steroids is not recommended in the daily treatment of COPD. Oral steroids worsen comorbid conditions such as osteoporosis and cataracts, and can induce steroid myopathy. Despite these deleterious effects, steroids still are used during COPD exacerbations.

Combination Therapy

Patients with COPD suffer from a multicomponent lung disease, and pharmacotherapy for COPD might include more than one medication. The use of bronchodilators is essential to the treatment of COPD, and many trials have focused on which bronchodilator is superior. Since the addition of LABAs and LAMAs to COPD treatment, investigators have compared their clinical efficacy to each other and to theophylline. Emerging data supports that the use of ICS alone or in combination with LABAs may prolong life in patients with moderate to severe COPD.²³ More studies need to be conducted, however. Thus, the efficacy of SABAs, LABAs, anticholinergics, methylxanthines, and ICS remains of significant clinical importance and the subject of ongoing research. Newer β₂AR agonist, LAMAs, and methylxanthines are in development, and preliminary data are promising. Current SABAs such as albuterol are recemic mixtures containing equal parts of R and S isomers. The R isomer has been shown to produce more bronchodilation over a longer period than the S isomer. The R-enantiomer or levalbuterol (LEV) was recently introduced, and a study²⁴ showed that the LEV group had fewer exacerbations and less use of rescue short-acting bronchodilators. The newer β₂AR agonists are mainly (R,R)-enantiomers and have quick onset of action and high affinity. Ultra LABAs are in phase three trials. Ultra LABAs such as arformoterol are stereoisomers of existing LABAs. These agents could promote better patient compliance due to once daily dosing.

A randomized trial²⁵ showed that COPD patients receiving nebulized arformoterol had sustained improvements in lung function. Triple therapy including a LAMA, LABA, and ICS is being used in moderate to severe COPD. These agents may be combined in one canister and available as soon as 2012. Combination therapy including tiotropium and an 8-week pulmonary rehabilitation program has been shown to increase exercise endurance when compared to an 8-week pulmonary rehabilitation program alone.²⁶ New anticholinergics that are under development could have better safety profiles, and have a quicker onset of action. Cilomilast and roflumilast are two new PDE₄ inhibitors, but are not approved for clinical use. The therapeutic benefits of these agents have been studied, but the results are inconsistent. Newer and better drugs (Table 2) are on the way, but the appropriate inhaled medications for patients with COPD may remain a challenge for health care providers.

Table 2	BRONCHODILATORS IN CLINICAL DEVELOPMENT
LABAs	LAACs	LABA/LAAC/strong	Combination PDE-4 Inhibitors*
Carmoterol	NVA237 (glycopyrrolate)	Carmoterol + tiotropium	Cilomilast
Indacaterol	OrM3	Indacaterol + NVA237	Roflumilast
GSK-159797	LAS-34273	GSK-159797 + GSK233705
GSK-597901	LAS-35201	GSK-961081
GSK-159802	GSK-656398
GSK-642444	GSK-233705
GSK-678007
Definitions of abbreviations: GSK = GlaxoSmithKline; LAAC = long-acting anticholinergic; LABA = long-acting β2-adrenoceptor agonist; LAS = Almirall; NVA = Novartis; OrM = Oral muscarinic M3-selective; PDE = phosphodiesterase. *Several agents of this class are under development. Hanania NA, Donohue JE. Pharmacologic interventions in chronic obstructive pulmonary disease: bronchodilators. Proc Am Thorac Soc. 2007;4:526-35. Official Journal of the American Thoracic Society. © American Thoracic Society

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Craig Rosebrock, MD, is a clinical fellow and James Donohue, MD, is professor of medicine, School of Medicine, University of North Carolina, Chapel Hill. For further information, contact [email protected]

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