US Pharm. 2007:32(7):30-36.
Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality in the United States. In fact, 11.4 million Americans ages 18 and older were reported to suffer from COPD in 2004; however, an estimated 24 million Americans have evidence of lung dysfunction, indicating an underdiagnosis of the condition. Additionally, an estimated 638,000 hospital discharges attributed to COPD were reported in 2004. Currently ranking as the fourth leading cause of death behind cardiovascular disease, cancer, and stroke, COPD is expected to be the third leading cause of death in 2020. COPD is also an expensive disease state to manage, costing the U.S. a total of $37.2 billion in 2004 to treat COPD, with $20.9 billion accounting for direct costs.1
Pathology and Clinical Presentation
COPD is a condition involving largely irreversible obstruction of the airways.2 Although other risk factors such as occupational exposures (e.g., chemicals, dust, asbestos), genetics, and childhood illnesses have been identified, tobacco smoking is responsible for 80% to 90% of deaths from COPD.1 Particles from cigarette smoke activate neutrophils and macrophages in the lungs, which results in a cascade of events involving the release of proteases that eventually break down the connective tissue in the lungs. The release of chemical mediators such as interleukin-8, leukotriene-B4, and tumor necrosis factor by the inflammatory cells is also linked to structural damage. Increased oxidative stress arising from an elevation in oxidants due to cigarette smoke has been implicated. Excessive mucus production and cough are attributed to an increase in goblet cells and mucus-producing glands as part of the inflammatory response by the bronchi.2,3
Specifically, COPD is a term that encompasses both emphysema and chronic bronchitis. Emphysema is characterized by alveolar wall destruction involving compression of the airways during inspiration due to loss of elastic recoil. Gases become trapped, and ventilation and perfusion are impaired. Patients with emphysema are commonly referred to as pink puffers, as they are generally thin and present with dyspnea, tachypnea, pursed-lip breathing, and a flushed appearance. Airway inflammation and narrowing and excessive mucus secretion are characteristic of chronic bronchitis. Patients with chronic bronchitis typically report chronic or recurrent mucus hypersecretion and a cough that occurs on most days during three months of the year for at least two consecutive years. Additionally, the function of cilia in the lungs is impaired and can trap bacteria and viruses under the thick mucus secretions, leading to an increased susceptibility to respiratory infections. Patients with predominant chronic bronchitis also tend to be overweight. They may present with a "barrel chest," cyanosis occuring from an increase in the partial pressure of carbon dioxide relative to a decrease in the partial pressure of oxygen, and peripheral edema due to right ventricular failure in the setting of chronic hypoxia and pulmonary hypertension. Thus, patients with chronic bronchitis are often referred to as blue bloaters. Although distinctions are made with regard to clinical presentations of the COPD subtypes, patients commonly present with signs and symptoms of both emphysema and chronic bronchitis.2-5
Staging and Treatment Recommendations for COPD
A staging system for COPD has been developed as part of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines to help establish disease severity and appropriate treatment recommendations (Table 1). Staging a patient with suspected COPD involves the use of spirometry, including the forced expiratory volume in one second (FEV1) and the forced vital capacity (FVC). The presence of an FEV1/FVC ratio of less than 0.70 indicates airflow obstruction, while postbronchodilator FEV1 values further assist in establishing the severity of COPD. Based on this staging system, all patients classified with any degree of COPD severity are recommended to reduce exposure to modifiable risk factors.6
Since most deaths associated with COPD are attributed to tobacco smoking, patients are highly encouraged to stop smoking. The Lung Health Study has demonstrated that smoking cessation is the only intervention to reduce the decline in FEV1 and slow COPD progression.7 Patients should be asked about their interest in smoking cessation and assured that help is readily available when they are committed to stop smoking.
The GOLD guidelines also recommend the annual influenza vaccine to lower the risk for acute exacerbations of COPD. The pneumococcal vaccination is advised in patients with COPD who are 65 and older and for those who are younger than 65 and have an FEV1 of less than 40% predicted in order to lower the incidence of community-acquired pneumonia. As both Haemophilus influenzae and Staphylococcus pneumoniae have been implicated as predominant bacteria involved in COPD exacerbations, vaccinations against these microorganisms can help reduce the risk of infection.
The addition of a short-acting bronchodilator, such as albuterol or ipratropium, is recommended during all stages of COPD on an as-needed basis for the quick relief of symptoms. These agents work in a matter of minutes to provide bronchodilation. As patients progress to stage II or moderate COPD, the addition of a long-acting bronchodilator such as a beta-2 agonist (e.g., salmeterol, formoterol), an anticholinergic (e.g., tiotropium, scheduled ipratropium), or a methylxanthine (e.g., aminophylline, theophylline) is advised. Initiation of inhaled corticosteroids continues to be debated in COPD owing to minimal effects on the deterioration of lung function; however, GOLD guidelines suggest potential addition during stage III or severe COPD if patients experience repeated exacerbations. Oxygen therapy is reserved typically for the later stages of COPD when hypoxemia is present.6,7
Use of Anticholinergics in COPD
Anticholinergics are used in the management of COPD for their bronchodilatory effects. These agents are antagonists of muscarinic receptors (i.e., M1, M2 , and M3 subtypes). Blockade of these receptors in the smooth muscle of the airways inhibits the activity of acetylcholine, which reduces cyclic guanosine monophosphate levels to yield bronchodilation.8,9 Data regarding improvement of lung function with anticholinergic therapy have ranged from no effect on lung function to modest improvements that are equal or superior in efficacy to beta-2 agonists.7,10,11 A recent meta-analysis of 22 trials involving 15,276 patients was conducted involving clinical trials that studied anticholinergics or beta-2 agonists compared with each other or to placebo administered for at least three months.12 Pooled results indicated that anticholinergic use resulted in a reduction in severe COPD exacerbations by 33% and in respiratory mortality by 73% (absolute risk reduction, 0.36%; number needed to treat, 278) when compared to placebo. However, compared to placebo, beta-2 agonists were associated with an increase in the risk of death (relative risk [RR] 2.47, confidence interval [CI] 1.12-5.45). When compared to anticholinergics, the use of beta-2 agonists was associated with higher rates of COPD exacerbations requiring hospitalizations (RR 1.95, CI 1.06-3.59). Clinical outcomes were not improved with combination therapy of an anticholinergic and a beta-2 agonist.12 Additionally, anticholinergics notably improve exercise tolerance in patients with COPD.13,14 Two commonly used anticholinergics in patients with COPD include ipratropium bromide (Atrovent) and tiotropium bromide (Spiriva). The addition of tiotropium to the market in 2004 has led to further studies assessing its role in the management of COPD.8,9
Ipratropium and Tiotropium: Ipratropium is considered a short-acting anticholinergic because its effects last for four to six hours, although it may be prescribed on a scheduled basis to provide sustained effects. However, tiotropium can be given once daily because it has a duration of action extending beyond 24 hours. This is related to the fact that tiotropium dissociates much more slowly from the M1 and M3 receptors, compared to ipratropium. Ipratropium's onset of action is slower (about 20 minutes) than that of albuterol (about five minutes), but ipratropium is commonly used to provide quick relief and is available in both a metered-dose inhaler (MDI), alone and in combination with albuterol, and as a solution for inhalation. Tiotropium is not recommended to be used acutely, as its onset of action is approximately 30 minutes following inhalation. It is available for use in a HandiHaler device. Appropriate use of this device involves several key steps ( Table 2) and requires significant manual dexterity. Thus, this device may be challenging for some patients such as those with arthritis.2,3,8,9
Dahl and colleagues conducted a single-blind study to assess patient performance of appropriate HandiHaler and MDI techniques four weeks after providing instructions for use. Patients were given ipratropium two puffs four times daily via MDI and one placebo capsule daily in the HandiHaler device. In the total population, patients using the HandiHaler device had fewer errors in their technique compared to those using a MDI (P <.01). Similar findings were demonstrated when evaluating the subgroup of patients classified as "MDI beginners," indicating they had never used a MDI before. However, findings among patients classified as "MDI experienced," indicating they had used a MDI before, were similar but not statistically significant (P = .096).15
Ipratropium and tiotropium are both quarternary compounds and are minimally absorbed into systemic circulation upon inhalation, thereby reducing the incidence of adverse drug reactions. The most commonly reported side effects associated with these two agents include dry mouth, nausea, and metallic taste. Other potential side effects are tachycardia, blurred vision, urinary retention, and constipation. Although minimal absorption is predicted, cautious use is warranted in patients with benign prostatic hyperplasia and glaucoma, as anticholinergics may worsen these conditions.2,3,8,9,16
The effects of ipratropium and
tiotropium on lung function have been compared and reported in the medical
literature. Vincken and colleagues designed two identical, randomized,
double-dummy studies to assess the effects of ipratropium and tiotropium on
lung function and other clinical outcomes after one year of use.17
The results were included into one report. Five hundred thirty-five patients
with COPD were randomized to receive tiotropium 18 mcg once daily or
ipratropium 40 mcg four times a day. At the end of one year of treatment, the
FEV1 improved by 120 mL from baseline in the tiotropium group but
declined by 30 mL from baseline in the ipratropium group (P<.001). In
the tiotropium group, 31% experienced clinical improvement in the Transition
Dyspnea Index score compared to 18% in the ipratropium group (P =
.004). Hospitalizations and exacerbations were lower in patients receiving
tiotropium than in those receiving ipratropium (7.3% vs. 11.7%, P =
.014 and 35% vs. 46%, P= .11, respectively). The authors concluded that
tiotropium is beneficial in maintaining improvements in lung function and
dyspnea. The reduced effects noted with ipratropium may be explained by
frequent dosing that can lead to patient nonadherence.17
Typically, more medications are added to the patient regimen as COPD progresses in order to reduce the risk for hospitalizations due to exacerbations and to prevent death. Patients with severe COPD frequently receive a combination of a short-acting bronchodilator with a long-acting bronchodilator and perhaps an inhaled corticosteroid depending on the frequency of exacerbations. Recently, the results of a randomized, double-blind, placebo-controlled study of combination therapy in COPD by Aaron and colleagues was reported.18 Patients with moderate to severe COPD were randomized to receive tiotropium and placebo, tiotropium and salmeterol, or tiotropium, fluticasone, and salmeterol for one year. Interestingly, the primary end point--the proportion of patients who experienced exacerbations requiring the use of antibiotics or hospitalizations--did not significantly differ among the groups (62.8% for tiotropium and placebo, 64.8% for tiotropium and salmeterol, and 60% for tiotropium, fluticasone, and salmeterol). However, patients receiving a combination of the three drugs had a lower rate of severe COPD exacerbations requiring hospitalizations (CI 0.33-0.86, P = 0.01) and improved lung function (0.086 L vs. 0.027 L, P = .049) when compared to the tiotropium and placebo group. Similar findings were not demonstrated when comparing tiotropium and salmeterol to tiotropium and placebo. However, cautious interpretation of the effects on lung function and severe COPD exacerbations is warranted, as these clinical outcomes were secondary end points. Additionally, the authors raise the issue of whether the lack of finding a significant primary outcome is attributed to the fact that a true clinical difference does not exist or if it was a lack of statistical power in the study.18 Although this trial did not find any differences with regard to treatment strategies affecting the primary outcome, the decision to add medications to patients with worsening COPD should continue to be based on sound clinical judgment, evidence-based recommendations, and patient-specific parameters.
Current treatment modalities have minimal to modest impacts on the decline in pulmonary function associated with COPD. However, they can improve patient quality of life. GOLD guidelines recommend the addition of a long-acting bronchodilator for patients with moderate COPD; however, the selection of bronchodilator is not specified. Results from the recent meta-analysis indicate that anticholinergics may be more beneficial to reduce COPD exacerbations and mortality, compared to beta-2 agonists. Until further head-to-head clinical studies can definitively determine the superiority of a particular anticholinergic agent, the decision of which anticholinergic to use should be based on patient-specific parameters.
Tiotropium offers the convenience of once-daily dosing and may increase patient adherence to therapy. However, ipratropium can be effectively scheduled throughout the day and may provide a more cost-effective treatment option for patients, especially for those paying out of pocket. Patients requiring therapy with a long-acting bronchodilator are likely receiving treatment with a short-acting bronchodilator for quick relief based on GOLD guidelines. Thus, patients prescribed tiotropium and a short-acting bronchodilator will receive two devices that each require patient education for appropriate use. This may be time intensive for some health care providers, who can simplify medication regimens by having patients take both medications in MDI formulations. Patients with significant limitations in manual dexterity may find the HandiHaler device challenging and difficult to use; however, Dahl and colleagues found that patients experienced fewer errors with the HandiHaler device than with MDIs.15
Although different anticholinergics are currently available, ensuring that the patient is receiving the most appropriate therapy and optimizing the pharmacotherapy for the patient based on disease severity are most important to reduce COPD exacerbations, improve quality of life, and prevent mortality. As pharmacists are considered among the most trusted health care providers, they are in an ideal position to make appropriate, evidence-based recommendations to primary care providers regarding the management of COPD on behalf of the patient. Patient counseling about the role and importance of medications in COPD treatment, appropriate device usage, and the importance of smoking cessation is essential for pharmacist involvement in the management of patients with COPD.
1. American Lung Association COPD resources page. American Lung Association Web site. Available at: www.lungusa.org/site/pp.asp?c=dvLUK9O0e&b=35020. Accessed April 27, 2007.
2. MacIntyre NR Jr. Chronic obstructive pulmonary disease. Pharmacotherapy. 2004;24:33S-43S.
3. Bourdet SV, Williams DM. Chronic obstructive pulmonary disease. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York, NY: McGraw-Hill; 2005:537-556.
4. Hunter MH, King DE. COPD: management of acute exacerbations and chronic stable disease. Am Fam Physician. 2001;64:603-612.
5. Dewar M, Curry RW Jr. Chronic obstructive pulmonary disease: diagnostic considerations. Am Fam Physician . 2006;73:669-676.
6. Buist AS, Anzueto A, Calverley P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization global initiative for chronic obstructive lung disease (GOLD executive summary). Available at: www.goldcopd.com/Guidelineitem.asp?l1=2&l2=1&intId=996. Accessed May 19, 2007.
7. Anthonisen NR, Connett JE, Kiley
JP, et al. Effects of smoking intervention and the use of an inhaled
anticholinergic bronchodilator on the rate of decline of FEV1. The
Lung Health Study. JAMA. 1994;272:1497-1505.
8. Olin JL. Tiotropium: an inhaled anticholinergic for chronic obstructive pulmonary disease. Am J Health-Syst Pharm. 2005;62:1263-1269.
9. Spiriva [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2006.
10. Friedman M. A multicenter study of nebulized bronchodilator solutions in chronic obstructive pulmonary disease. Am J Med. 1996;100(suppl 1):S30-S39.
11. Colice GL. Nebulized bronchodilators for outpatient management of stable chronic obstructive pulmonary disease. Am J Med. 1996;100(suppl 1):11S-18S.
12. Salpeter SR, Buckley NS, Salpeter EE. Meta-analysis: anticholinergics, but not beta-agonists, reduce severe exacerbations and respiratory mortality in COPD. J Gen Int Med. 2006;21:1011-1119.
13. Blosser SA, Maxwell SL, Reeves-Hoche MK, et al. Is an anticholinergic agent superior to a beta 2-agonist in improving dyspnea and exercise limitation in COPD? Chest. 1995;108:730-735.
14. Casaburi R, Kukafka D, Cooper CB, et al. Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest. 2005;127:809-817.
15. Dahl R, Backer V, Ollgaard B, et al. Assessment of patient performance of the HandiHaler compared with the metered dose inhaler four weeks after instruction. Respir Med. 2003;97:1126-1133.
16. Somand H, Remington TL. Tiotropium: a bronchodilator for chronic obstructive pulmonary disease. Ann Pharmacother. 2005;39:1467-1475.
17. Vincken W, van Noord JA, Greefhorst AP, et al. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur Respir J.2002;19:209-216.
18. Aaron SD, Vandemheen KL,
Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or
fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease.
Ann Intern Med. 2007;146:545-555.
To comment on this article, contact email@example.com.