Course Authors
E. Neil Schachter, M.D.
Dr. Schachter reports no commercial conflict of interest.
This activity is made possible by an unrestricted educational grant from the Novartis Foundation for Gerontology.
Estimated course time: 1 hour(s).
Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Upon completion of this Cyberounds®, you should be able to:
Delineate pathophysiologic elements of COPD that determine approaches to therapy
List potential advantages/indications for the use of stereisomer specific beta agonists in COPD
Describe the role of corticosteroids in COPD.
Chronic Obstructive Pulmonary Disease (COPD) is the descriptive title of a progressive respiratory disorder affecting the adult population. Almost invariably associated with cigarette smoking, it is probably the final common pathway of several genetically determined disorders that are expressed in the presence of environmental injuries. Clinically and pathologically, the disease is characterized by chronic bronchitis with airway obstruction and emphysema. These two elements are frequently superimposed in patients with COPD but can exist alone in relatively independent form.
Clinical and pathologic features of chronic bronchitis make this disease difficult to distinguish from asthma in the adult population and, in the smoking adult over the age of 40, the distinction may be academic. The management of this debilitating, often fatal disease is complicated by frequent confusion in establishing the diagnosis and gaps in our understanding of the pathogenesis of COPD.
The Irreversible Lung Disease
COPD is the fourth leading cause of death in the United States.(1) Over fourteen million Americans are estimated to suffer from chronic bronchitis and emphysema.(2) Together, they account for over 17 million office visits and nearly two million hospitalizations yearly.(3),(4)
Approximately 50% of smokers develop chronic bronchitis but only 15% of smokers develop symptomatic airway obstruction. A number of hypotheses seek to explain the susceptibility of certain smokers for the development of COPD. These include the possible central role of respirable irritants in provoking mucous hypersecretion and subsequent airway obstruction (e.g., active and passive smoking, air pollution, occupational exposures), the contributing role of underlying airway sensitivity (hyper-responsiveness) and atopy, and the contribution of genetic factors such as alpha one antitrypsin deficiency and related anti-protease disorders. To date, none of these pathogenic mechanisms successfully characterize and explain the cause of increased susceptibility to lung damage in a majority of those affected. Nevertheless, many of our therapeutic and pharmacologic strategies are based on these concepts.
Pathologically, features which are felt to contribute to airway obstruction in COPD are associated with the smaller airways. Inflammatory responses with fibrosis, goblet cell metaplasia and smooth muscle hypertrophy in the terminal bronchioles and loss of alveolar attachments to bronchioles due to destructive emphysema contribute to airway obstruction. Pathological changes are not felt to be the only features contributing to the airway obstruction since bronchoconstriction is also significant.(5)
COPD patients have often received the label of irreversible airway obstruction. This characterization has led to reduced enthusiasm for treatment, particularly with agents known to reverse airway obstruction. A response to bronchodilator of >12% in FEV1 is frequently used to characterize "asthma" and, thereby, exclude COPD. Up to one third of otherwise typical COPD patients experience more than 15% reversibility following treatment with bronchodilator aerosol.
While objective measurements of FEV1, in particular, remain the mainstay of COPD severity evaluation, it has recently been appreciated that the subjective symptoms which clinicians have long used to assess their patients can be quantified with specifically designed questionnaires, thereby providing a sensitive measures of health status.(6) It has been noted that in patients with very mild airway obstruction, as indicated by spirometry, health status scores may be poor. Such discordant observations imply that FEV1 and related parameters may not always accurately reflect patient status, especially their response to therapy.
Treatment of COPD
Pharmacological therapy for COPD includes a number of agents, enthusiasm for which has waxed and waned as our understanding of this disease has evolved. Table 1 lists agents that have been used in COPD for
- alleviation of symptoms, for
- treatment of acute exacerbations and
- for the management of its long term consequences.
Table 1. Pharmacotherapeutic Agents for COPD.
| Agent | Acute Exacerbation of COPD | Chronic Stable Symptomatic | Prophylaxis for Chronic Deterioration |
| Smoking Cessation | + | + | + |
| Beta Agonists | + | + | - |
| Anticholinergic | + | + | - |
| Theophylline | + | + | - |
| Corticosteroids | + | + | ? |
| Anti-inflammatory | ? | ? | ? |
| Immunization* | - | + | ? |
| Antibiotics** | + | ? | ? |
| Oxygen*** | + | + | + |
* Influenza, pneumonia.
** In the presence of documented bacterial infection.
*** In the presence of documented hypoxemia.
Current therapy has evolved in the last decade. Retrospective analysis of clinical studies, comparing various bronchodilator regimens in patients with stable chronic obstructive lung disease from 1987 to 1995, has shown that the proportion of patients using inhaled corticosteroids increased significantly from 13.2% to 41.4%, while theophylline usage dropped from 63.4% to 29% in this same period. Inhaled cholinergic use increased slowly from 48.2 to 53.8%, while oral corticosteroid and beta-adrenergic therapy decreased from 30.1 to 16.4% and from 11.7 to 4.5% respectively. These changes are felt to reflect changing prescribing patterns of practitioners and COPD management practices(7) but not, necessarily, ideal or effective regimens.
Bronchodilators in COPD
Bronchodilator therapy in COPD is currently prescribed primarily for the relief of symptoms. There is no evidence that early regular use of these agents alters the progression of COPD. However, a recent epidemiological study from Copenhagen(8) indicates that COPD patients who underwent standardized reversibility testing, with both bronchodilator and corticosteroid challenge, demonstrated that enhanced reversibility correlated with better survival. The correlation was not felt to imply that these therapies contributed to a better prognosis but that they reflected the maximal attainable lung function for the individual and, hence, those that responded better had more room to improve.
It is well established that both short acting beta-agonists and anticholinergic agents provide modest but significant relief for patients with COPD. Anticholinergics have been favored because they provide more consistent relief with fewer side effects (cardiovascular in particular) in this older population. For anticholinergic therapy, once a patient is found to suffer from daily symptoms, regular use of ipratropium bromide, the only currently available anticholinergic, is recommended on a regular basis, three or four times daily. Similarly, short acting beta-agonists, such as albuterol, pirbuterol or metaproterenol, are prescribed three to four times daily or before exercise.
It is currently established that combined therapy with ipratopium and albuterol offer superior relief than mono-therapy.(9),(10),(11) In two randomized double blind studies evaluating more than 1,000 patients with COPD, FEV1 response rates at baseline and at one, two and three months showed that the combination demonstrated enhanced reversibility of bronchoconstriction over mono-therapy.
Beta-2-agonists
Salmeterol xinafoate, a long acting beta-2-agonist, initially introduced for the treatment of asthma is now FDA-approved for COPD. Recent studies indicate that it is superior to ipratropium alone over a three-month period in patients with COPD, as measured by lung function, respiratory symptomatology and quality of life data.(12),(13),(14) Another long acting beta-2-agonist, formoterol, is available in Europe but not in the United States.(15)
Currently, beta-2-agonists used for asthma and COPD are primarily racemic mixtures of stereoisomers. Naturally occurring adrenergic hormones from which the beta-2-agonists derive are produced by the body in the (R) configuration. The stereochemistry of these molecules has been linked to their ability to actively bind with receptors and produce the physiologic effects they are associated with. Similarly, manufactured beta-2-agonists, such as albuterol, come as (R) and (S) mixtures with the (S) isomer having essentially no normal physiologic activity on smooth muscle preparations studied in vitro.(16) Preparations of stereospecific (R) albuterol are now available as inhalation solutions (levalbuterol HCl) for the treatment of asthma. Preparations of this compound for meter dose inhaler (MDI) are being developed as are long acting stereospecific forms of salmeterol. A number of potential benefits of using these preparations have been postulated and include:
- Enhanced safety associated with fewer side effects.
- Lessened tachyphylaxis
- (S) isomers may have pro-inflammatory properties which make their use counterproductive.(17)
A new agent, tiotropium bromide, not yet approved for clinical use in the U.S., combines anticholinergic safety with long duration of action.(18) Approximately 10-fold more potent than ipratropium bromide in vitro, tiotropium dissociates very slowly from lung muscarinic receptors, compared with ipratropium. Clinical trials show that it protects against cholinergic bronchoconstriction for more than twenty-four hours.(19) Of further benefit is the fact that tiotropium binds selectively longer to M3 receptors (the cholinergic receptors associated with smooth muscle cells and capable of blocking constriction) but less so to M2 receptors found on cholinergic nerve terminals and capable of enhancing cholinergic effects.(20)
Theophylline compounds have lost their popularity because of their frequent GI and CNS side effects. Nevertheless, now given at relatively lower doses than previously prescribed, they offer an important bronchodilatator alternative, since they can be administered once or twice daily in oral form. Such a regimen may improve compliance. Additional potential effects that may benefit the COPD patient include their anti-inflammatory effect and their ability to improve respiratory muscle function.