Ch05

CHAPTER 5
PHARMACOLOGIC
MANAGEMENT OF
STABLE COPD
Nicholas Anthonisen and Martin Boulé

OBJECTIVES

The general objective of this chapter is to help the allied health care professionals and physicians become
more familiar with the drug therapy commonly employed in patients with stable, symptomatic chronic
obstructive pulmonary disease (COPD). Pharmacologic management is often based on an individualized
assessment of the disease and patient response to various medications.
After reading this chapter, the physician and allied health care professional will be able to
• identify the different classes of drugs used in COPD: bronchodilators, corticosteroids, and antibiotics;
• appropriately use these drugs according to their benefits and potential adverse effects;
• recognize that, at this time, there are few other pharmacologic considerations;
• recognize that there are many guidelines with differing recommendations; however, most recommenda-
tions for pharmacologic management are empiric because of a lack of scientific information;
• recognize that patients can be noncompliant with drug therapy; and
• refer to specific professionals from the health care team when needed.

P harmacologic therapy is an important part of
managing COPD. However, it must be noted at
the outset that no drug therapy has been shown to
the health status of patients with COPD is usually
reflected by improvements in these areas. Although
the management strategy is based on the patient’s
change the course of the disease or to alter its long- symptoms and response to various therapies, it may
term outlook and/or prognosis. Therefore, the ratio- also depend on adverse drug effects, patient skills in
nale for the use of these drugs is that they relieve using a specific inhalation device, and availability of
symptoms and improve quality of life.1 medications.
Since most patients with COPD seen in clinical In this chapter, we will review the accepted forms
practice have less than optimal quality of life, this is of drug therapy for COPD and discuss their use.
an important objective that is best assessed by care- Recommendations from national and international
fully interviewing the patient. Such interviews must guidelines will be reviewed. Finally, issues related to
be structured to some extent to ascertain the sever- drug compliance will be discussed. Since exacerba-
ity of symptoms such as dyspnea, cough, sputum, tions are covered elsewhere in this textbook and hos-
and wheeze and the degree of exercise tolerance. pital management is beyond the textbook’s scope,
Questions should be aimed at determining the pos- the main focus of the discussion will be on the treat-
sibility of recent changes because improvement in ment of stable outpatients with COPD.
65

66 Comprehensive Management of Chronic Obstructive Pulmonary Disease

BRONCHODILATOR THERAPY and greater bronchodilation8 simply because there
are higher fractions of the total dosage in the lungs
Bronchodilators are the most important agents in and airways. For this reason, β2 agonists are very
the pharmacologic treatment of COPD.2 Bron- commonly administered by inhalation and should
chodilator agents dilate the intrapulmonary airways, rarely be prescribed by other methods. The usual
thereby decreasing airway resistance and improving short-acting β2 agonists specified above have a rela-
flow rates in and out of the lungs.3 Essentially, they tively short onset of action with noticeable effects in
act as relaxants of the airway smooth muscle,4 which 15 minutes that can last 2 to 6 hours (Table 5–1).9
is arranged so that its constriction, or even a normal Recently, long-acting β2 agonists such as salmeterol
amount of muscle tone, tends to decrease the caliber xinafoate and formoterol fumarate have become
of the airway and increase the resistance of airflow available. These agents induce bronchodilation that
through it. It should not be assumed that patients lasts 8 to 12 hours (Table 5–2).10
with COPD have a poor response to bronchodila- Beta2 agonists have minor side effects such as fine
tors, even in those appearing to have essentially fixed tremor, which is usually apparent only after large
airflow obstruction; several studies have demon- doses. With a conventional dose, the risk of side
strated improvement in airflow following the use of effects is uncommon in patients with COPD (see
regularly dosed bronchodilators in most patients Table 5–1). Larger than conventional doses of β2
with COPD, albeit to a lesser degree than in patients agonists may produce additional bronchodilation,
with asthma.5,6 but further functional or symptomatic benefit from
There are essentially three types of bronchodila- such increased doses is limited to a small group of
tor drugs: β2 agonists like salbutamol, anticholiner- patients with COPD with a lack of reproducibility
gic agents like ipratropium bromide, and methyl- for any given patient.11 Larger than conventional
xanthines like theophylline. There is excellent doses also increase the risk of side effects.
evidence that ipratropium does not change the
underlying course of COPD7 and little reason to Anticholinergic Agents
believe that the other types of drugs differ from ipra- Anticholinergic drugs block receptors for acetyl-
tropium in this respect. However, all of these drugs choline, a widely distributed substance that trans-
are widely used because they tend to increase expi- mits impulses from one nerve to another and from
ratory flow rates such as the forced expiratory vol- nerve to muscle, including airway smooth muscle.4
ume in 1 second (FEV1), tend to relieve dyspnea, As might be expected, anticholinergic agents that
and, finally, increase exercise tolerance.1 By optimiz- gain access to the circulation, like atropine sulfate,
ing bronchodilator treatment, it may be possible to have a wide variety of effects, some of which are
sufficiently reduce symptoms to permit patients to unpleasant. One effect is the blocking of impulse
gradually increase their levels of activity as a form of transmission from the vagus nerve to the airway
self-directed pulmonary rehabilitation. smooth muscle; this produces bronchodilation since
vagal impulses tend to increase the tone or tension in
β2 Agonists airway smooth muscle. Ipratropium is an agent that
Beta agonists directly stimulate receptors on airway is poorly absorbed from the lungs and gastrointesti-
smooth muscle, thus causing it to relax. There are nal tract but does gain access to smooth muscle when
several types of beta receptors in the body, including inhaled. Therefore, it produces bronchodilation by
the heart and blood vessels and the airways. Airway blocking vagal transmission to airway smooth mus-
smooth muscle contains type 2 beta receptors, and cle. The onset of ipratropium action is slower than
prescribed agents that are specific to these types of that of the short-acting β2 agonists; furthermore, its
receptors have fewer side effects than others. The duration is longer, lasting more than 4 hours (Table
prototypical short-acting β2-receptor agonist, or 5–3).12 Inhaled ipratropium has been shown to have
stimulant, is salbutamol; other similar drugs include virtually no systemic side effects, with the only well-
fenoterol hydrobromide and terbutaline sulfate. established risk of the drug occurring when it is mis-
These agents cause bronchodilation when adminis- takenly squirted into the eyes (see Table 5–3).
tered systemically, orally, or intravenously and when A longer-acting version of ipratropium, tiotropium,
inhaled. Inhaled agents produce fewer side effects is currently undergoing clinical testing. Tiotropium

Pharmacologic Management of Stable COPD 67

TABLE 5–1 Pharmacology of Short-Acting β2 Agonists
Adrenergic Administration Route Adverse Effects
Agents and Dosage* Pharmacodynamics Monitoring, and Interactions
Fenoterol hydrobromide Most frequent side effects
(Berotec®) MDI Tremor
100 µg/inh Onset: 5–10 min Headache
Sig: (dose)1–2 inh tid–qid Nervousness
prn/regularly Peak: 30–60 min Hypotension
Max: 8–12 inh/d Flushing
Duration: 3–6 h Hypokalemia
Nebulization Tachycardia/palpitations
Nebules: 0.5 mg/2 mL Dizziness
1.25 mg/2 mL
Solution: 1 mg/mL
Sig: 0.5–1.25 mg qid
prn/regularly
Pirbuterol acetate MDI Onset: 5–10 min Monitoring
(Maxair®) 250 µg/inh Blood pressure
Sig: 1–2 inh tid–qid Peak: 30–60 min Heart rate
prn/regularly Ion values
Max: 8–12 inh/d Duration: 3–5 h Physical signs
Salbutamol (Ventolin®) MDI Onset: 5–15 min
100 µg/inh
Sig: 1–2 inh tid–qid Peak: 30–90 min
prn/regularly Interactions
Max: 8–12 inh/d Duration: 3–6 h β-blockers
Diskus MDI Choose cardioselective
200 µg/inh • Atenolol (Tenormin®)
Sig: 1 inh tid–qid
prn/regularly • Acebutolol (Sectral®)
Max: 6 inh/d
Nebulization Rotahaler • Metoprolol tartrate
Nebules 200 and 400 µg/capsule (Lopressor®)
1.25 mg/2.5 mL Sig: 1–2 capsules tid–qid • Bisoprolol (Monocor®)
2.5 mg/2.5 mL prn/regularly
5 mg/2.5 mL Max: 1,600 µg/d
Solution: 5 mg/mL
Sig: 2.5–5 mg tid–qid Oral solution 0.4 mg/mL Attention: potential
prn/regularly Sig: 2–4 mg (5–10 mL) cardiac toxicity
tid–qid Monoamine
Diskhaler MDI prn/ regularly oxidase inhibitors
200 and 400 µg/blister Max: 16 mg/d Tricyclic antidepressants
Sig:1–2 blisters tid–qid Diuretics
prn/regularly Digoxin
Max: 1,600 µg/d Systemic corticosteroids
Salbutamol (Airomir®) MDI (Hydroﬂuroalkane-134a) Onset: 5–15 min Methylxanthines
100 µg/inh
prn/regularly
Max: 8–12 inh/d Duration: 3–6 h
Terbutaline sulfate Turbuhaler Onset: 5–15 min
(Bricanyl®) 500 µg/inh
prn/regularly
Max: 8–12 inh/d Duration: 3–6 h
*Dosage in clinical practice can be higher than those recommended in this table.
MDI = metered dose inhaler.


TABLE 5–2 Pharmacology of Long-Acting β2 Agonists
Adrenergic Administration Route Adverse Effects,
Agents and Dosage* Pharmacodynamics Monitoring, and Interactions
Salmeterol xinafoate MDI
(Serevent®) 25 µg/inh Onset: 10–20 min See short-acting β2
Sig: 1–2 inh id–bid agonists
regularly Duration: 12 h
Max: 100 µg/d
Diskhaler
50 µg/blister
Sig: 1 blister id–bid
regularly
Diskus
50 µg/inh
Sig: 1 inh id–bid
regularly
Formoterol fumarate Aerolizer Onset: 3 min
(Foradil®) 12 µg/capsule Duration: 12 h
Sig: 1 inh id–bid
regularly
Max: 2 inh bid regularly
(48 µg/d)
Oxeze® Turbuhaler
612 µg/inh
Sig: 1 inh id–bid regularly
Max: 48 µg/d
MDI = metered-dose inhaler.

will be suitable for once-daily dosing.13 It is undeter- convulsions and other serious central nervous system
mined whether its kinetic selectivity for M1 and M3 abnormalities. The most common side effects are gas-
receptors over M2 receptors will be clinically useful. trointestinal and include nausea, vomiting, poor
appetite, and even diarrhea (see Table 5–4). The side
Methylxanthines effects are dose related, as is the degree of bronchodi-
Methylxanthines such as theophylline are chemically lation achieved with these agents. A problem with the
related to caffeine and cause a variety of effects that are use of this drug is difficulty in predicting its clearance
of interest in patients with COPD. Alhough its mech- and therefore in establishing the dose that does not
anism of action is uncertain, theophylline is a well- cause adverse effects. Theophylline clearance may be
documented bronchodilator. It is also a central ner- modified by factors such as age, cigarette smoking,
vous system stimulant that causes hyperventilation cardiac failure, liver disease, respiratory failure with
and has been reported to strengthen the diaphragm.14 cor pulmonale, and drug interactions. Theophylline
The clinical significance of these latter effects has not levels can be measured in the blood; significant bron-
been well demonstrated,15 and thus far, theophylline chodilation is obtained at levels approximating
is employed in COPD largely as a bronchodilator, 10 µg/mL, whereas greater bronchodilation, but fre-
although it might also elicit improvements in breath- quent side effects, is present at levels approximating
lessness.16,17 Theophyllines are administered orally and 15 µg/mL or more. Generally speaking, levels of about
are available in long-acting preparations given twice 10 µg/mL are obtained when standard doses of theo-
daily (Table 5–4). As might be expected, theophyllines phyllines are given, that is, 300 mg twice a day of
have significant potential for side effects including long-acting generic theophylline.16


TABLE 5–3 Pharmacology of Anticholinergic Agents
Administration Route Adverse Effects
Anticholinergics and Dosage* Pharmacodynamics Monitoring
Ipratropium (Atrovent®) MDI Most frequent side effects
20 µg/inh Onset: 5–15 min Dry mouth
Sig: 2–4 inh tid–qid Bad taste
regularly Peak: 60–120 min Headache
Max: 8–12 inh/d Irritation of upper
Duration: 4–8 h respiratory airways
Nebulization
Nebules: 0.25 mg/2 mL Monitoring
0.50 mg/2 mL Hydration
Solution: 0.25 mg/mL Oral hygiene
Sig: 250–500 µg qid
regularly
Ipratropium/salbutamol MDI Onset: 5–15 min Side effects
(Combivent®) 20 µg/inh ipratropium Good tolerance
100 µg/inh salbutamol Peak: 60–120 min Side effects of both
Sig: 2 inh qid drugs
prn/regularly Duration: 6–8 h Contraindications
Max: 12 inh/d Hypersensitivity
to soya, lecithin or
Nebulization similar food products
0.5 mg/UDV ipratropium (soybean, peanut)
2.5 mg/UDV salbutamol
Sig: 1 nebul. tid–qid
prn/regularly
Ipratropium/fenoterol Nebulization Onset: 5–15 min
(Duovent® UDV) 0.125 mg/mL ipratropium
0.3125 mg/mL fenoterol Peak: 60–120 min
Sig: 4 mL qid
prn/regularly Duration: 6–8 h
MDI = metered-dose inhaler; UDV = unique dose vial.

Choosing Bronchodilator Therapy absolute guide to therapy; the response to bron-
Given this armamentarium, how should bronchodilators on a particular occasion may not accu-
chodilator therapy be used in patients with COPD? rately reflect responses at other times.5 It is better to
Inhaled bronchodilators should have preference over offer a trial of inhaled bronchodilators to all patients
oral bronchodilators. They should be given to all with COPD and discontinue them in the rare indi-
patients with COPD who obtain symptomatic ben- vidual who does not derive any symptomatic bene-
efit from this treatment, which, in our experience, fit. It is important to listen to patients because they
applies to virtually all of them. In general, a metered- can describe how they feel better than any given test,
dose inhaler or powder is used; nebulized therapy that is, if there is any reduction in symptoms allow-
for stable patients is usually not necessary unless it ing for an increase in the daily level of activities.
has been shown to be more effective than conven-
tional devices. The response to inhaled bronchodila- Inhaled Bronchodilators: β2 Agonists
tors can be assessed by measuring lung function, usu- versus Anticholinergic Agents
ally FEV1, before and after drug administration. This Considerable energy has been expended by investi-
may be a useful test but should not be used as an gators to determine which inhaled bronchodilator


TABLE 5–4 Pharmacology of Methylxanthines
Methylxanthines and Dosage Monitoring Pharmacology Interactions
Theophylline Adult dose Mechanisim of action Most frequent side effects
Theo-Dur® Caution re: purity of Nonspecific PDE* inhibitor Nausea/vomiting
Quibron-T/SR® the molecule Anti-inflammatory and Headache
Uniphyl® immunoregulatory Anxiety
Theolair-SRTM Theophylline = 100% properties Irritability
Slo-Bid® Aminophylline = 80% Insomnia
Theochron SR® Oxtriphylline = 65% Tremor
Diarrhea
Aminophylline Oral route Metabolism Gastroesophageal
Phyllocontin® Theophylline 200 mg/d or Cytochrome P-4501A2 reflux
Phyllocontin-350® 6–8 mg/kg/d Diuresis
up to 900 mg/d or Metabolic clearance Tachycardia
13 mg/kg/d or influenced by Arrhythmia
equivalent conversion Age
Cigarette smoking Interactions
Oxtriphylline Monitoring Diet (a few examples)
Choledyl® Therapeutic deviation Drugs
Choledyl SA® 10–20 µg/mL Cardiac disease ⇑Serum concentrations
Aim: 10–15 µg/mL (congestive heart Allopurinol
Dosing: every 6–12 mo failure) Cimetidine
when stable Liver disease Ciprofloxacin
Samples (cirrhosis ) Clarithromycin
Long-acting preparation Viral infection Erythromycin
measure peak concentration Influenza vaccine Propranolol
12 h preparation: 4–8 h after Ticlopidine
the dose Absorption influenced by
24 h preparation: 12 h after Food ⇓Serum concentrations
the dose Time of day Rifampin
Short-acting preparation (slower at night) Phenobarbital
measure through Drugs (antacids) Phenytoin
concentration Tobacco
6 hours preparation: before Activated charcoal
next dose
If toxicity suspected, any time
*PDE = phosphodiesterase.

should be “first-line therapy.” However, the results 2. Patients with asthma respond better to β2 ago-
have not been entirely clear, and there is a general nists than to anticholinergic agents, implying that
consensus on several issues: bronchoconstriction in asthma is not entirely
1. Although they are probably not much larger,18 attributable to vagal influences.19
the responses to ipratropium in patients with 3. The onset of the effect of short-acting β2 agonists
COPD are at least as important, if not more so, is more rapid than ipratropium so that the former
than those to short-acting β2 agonists. This are considered better “rescue” drugs.
implies that bronchodilator response in COPD 4. Concerning the utility of long-term treatment of
is essentially owing to the blocking of vagal COPD with β2 agonists and anticholinergic
impulses, which, although an interesting obser- agents, Colice demonstrated that the acute
vation, remains of unknown clinical significance. bronchodilator response to salbutamol on FEV1


decreased over time but not to ipratropium after agents might also be indicated in patients who expe-
an 85-day treatment.20 As well, there are studies rience nocturnal symptoms that disturb their sleep,
showing that the acute bronchodilator response but this is less common in COPD than in asthma.
to salbutamol does not decrease over time. Long-acting anticholinergic agents will soon be
Anthonisen and Wright demonstrated that the available, as well. Tiotropium causes an early im-
bronchodilator response to salbutamol did not provement in FEV1, which is well maintained23 and
decrease over a 3-year period.5 Therefore, a significantly superior to ipratropium at 6 hours.24
patient should take his or her bronchodilator as Less salbutamol was used by patients receiving
regularly as needed; since COPD is a chronic tiotropium, suggesting that the control of COPD
progressive disease, it usually means that the was improved. Adverse effects do not appear to be
patient will need to use the bronchodilator for a problem with doses that are clinically useful. To
the rest of his/her life. date, there are no published data on direct com-
5. Finally, in many patients with COPD, conven- parison with long-acting β2 agonists, measurements
tional doses of either ipratropium or short-acting of exercise tolerance, symptoms and health status,
β2 agonists do not achieve the maximal bron- and effects on acute exacerbations. Tiotropium is
chodilation obtainable. Many patients with an inhaled long-acting anticholinergic drug with a
COPD are treated with both ipratropium and simple treatment regimen of being taken once daily.
short-acting β2 agonists,18 with the former being It may prove to be a more convenient and consis-
used on a regular, four-times-a-day basis and the tent bronchodilator than the currently recom-
latter sometimes regularly or simply as a rescue mended four times daily needed for ipratropium.
medication.12 Of the two agents, combinations
are also available that can be used both in regular Methylxanthines: An Add-On Therapy
maintenance and as rescue medication, but there Theophyllines are not routinely recommended in
is no evidence that these combinations are more patients with COPD. However, they may provide
effective than larger doses of either of their indi- distinct benefit to some individuals whose symptoms
vidual components. Larger doses of both iprat- are not controlled by inhaled bronchodilators.16
ropium and short-acting β2 agonists are generally Theophyllines can cause further bronchodilation in
well tolerated, with the latter commonly limited patients with COPD who are on maximum inhaled
by its adverse effects. It is probably safe to say that therapy,25 because as systemically administered drugs,
either type of drug is effective and to allow they likely have access to more peripheral airways
patients to increase the dose above conventional than inhaled agents. It has also been shown in clini-
levels if they perceive added benefits; moreover, in cal trials using validated instruments of quality of
patients with COPD there is little to choose from life, that theophylline does indeed improve dyspnea
between ipratropium, short-acting β2 agonists, and health status.26–28 A recent randomized trial
and/or combinations of the two. showed that 21% of 34 patients with COPD had
improvements in dyspnea as measured by the
Long-Acting Inhaled Bronchodilators Chronic Respiratory Questionnaire during theo-
Long-acting β2 agonists are now available. They are phylline treatment.17 Thus, there is a rationale for a
effective in COPD,21,22 although not consistently trial of theophylline in patients with COPD who
more effective than the shorter-acting variety. Stud- remain symptomatic and limited in their activities
ies have shown that long-acting β2 agonists improve despite having inhaled bronchodilators. It is seldom
FEV1, attenuate daytime and nighttime symptoms, necessary or advisable to use theophylline doses
decrease the use of rescue salbutamol,10 and improve larger than the standard of 300 mg twice a day or to
health-related quality of life.22 Since the long-act- try to increase serum theophylline levels beyond
ing agents are expensive, their cost-effective use about 15 µg/mL. It is advisable to check serum theo-
requires that the patient’s symptoms or activities of phylline levels in patients who are taking the drug,
daily living improve and that they are comfortable especially when patients are still symptomatic or
using smaller amounts of the short-acting drugs, other drugs are given that might influence the rate of
which may not always be the case. Long-acting theophylline metabolism.


CORTICOSTEROID THERAPY confined to patients who demonstrated little
response to oral corticosteroids and/or an inhaled
Oral Corticosteroids bronchodilator, which, in other words, refers to peo-
The question of whether anti-inflammatory cortico- ple who were unlikely to be “steroid responders.” At
steroids have a useful role in COPD has a long and the present time, it seems clear that in such patients
controversial history. They are of undoubted benefit with COPD, substantial doses of inhaled cortico-
in the airway obstruction of asthma, thus making it steroids do not have a worthwhile effect on the rate
tempting to think that they might have a comparable of change of lung function, which is often thought
effect in the similar airway obstruction of COPD. to represent the course of the disease.34
Until very recently, most studies of corticosteroids in On the other hand, there are at least two trials
COPD have involved short-term trials of high-dose that indicate that in severely ill patients with
oral therapy. Most of these studies have shown that a COPD, high-dose inhaled corticosteroids reduce
significant minority of patients with COPD, about the number and severity of exacerbations such as
15%, show a distinct decrease in obstruction with episodes of increased dyspnea, cough, sputum, and
improvement of FEV1 on such therapy.29 It is not wheeze.33 Exacerbations can have major negative
known how reproducible these responses are or effects on the quality of life and health care costs in
whether oral corticosteroids are effective in longer-term such patients, so that decreasing the number and/or
therapy. Nevertheless, the results of these short-term severity of such episodes is a worthy goal of ther-
trials are such that most COPD guidelines recommend apy. However, it remains uncertain if using high-
that patients who do poorly on bronchodilator therapy dose inhaled corticosteroids for long periods of time
be given a therapeutic trial of high-dose oral cortico- is associated with favorable benefit-to-risk ratios. At
steroids, such as prednisone 40 mg per day for 2 weeks. present, one could consider the use of relatively
If the trial produces an improvement in the FEV1 that high-dose inhaled corticosteroids (500 µg fluticas-
is greater than 20%, the patient is considered a “steroid one propionate, 800 µg budesonide, or 1,000 µg
responder.” In such individuals, long-term cortico- beclomethasone dipropionate per day) in patients
steroid therapy is considered using either low-dose oral with severe COPD who have frequent exacerbations
prednisone (10 mg/day) or higher-dose inhaled corti- (Table 5–5). However, it is difficult to determine in
costeroids (see below). However, there is mounting evi- a given patient if inhaled corticosteroids actually
dence that this approach poorly predicts long-term have an impact on acute exacerbations since the
benefits. There is also evidence that there are undesir- exacerbations are very hard to predict. In addition,
able side effects with either long-term choice.30 In spite since the original studies were done with high
of this, most experts still regard the identification of doses of inhaled corticosteroids, beclomethasone
“steroid responders” and their subsequent treatment equivalent to 2,000 µg per day,33,36 further confir-
with corticosteroids to be justifiable. mation of this approach is needed using lower doses
As a general rule, chronic treatment with systemic of inhaled corticosteroids. Such high doses may
corticosteroids should be avoided, considering their cause significant adverse effects, such as osteoporo-
modest beneficial effects, if any, and their well- sis in some patients. Moreover, inhaled cortico-
established long-term adverse effects. It has recently steroids in COPD need to be re-examined while
been shown that daily oral corticosteroids can be suc- taking into account relevant complications of acute
cessfully discontinued in many “steroid-dependent” exacerbations such as hospitalizations and mortality.
patients without apparent harm, thereby reducing
cumulative corticosteroid exposure.31
ANTIBIOTICS
Inhaled Corticosteroids
In asthma, inhaled corticosteroids have become the Antibiotic therapy of patients with COPD should
cornerstones of therapy because they are of unques- be reserved for the therapy of exacerbations; there
tionable benefit and are believed to cause no serious is no evidence that regular antibiotic therapy is of
side effects. This experience has led to a number of any benefit. This will be covered in more detail else-
large inhaled corticosteroid trials in patients with where in this textbook (Chapter 8, “Managing
COPD.32–37 For the most part, these trials have been Acute Exacerbation”).


TABLE 5–5 Pharmacology of Oral and Inhaled Corticosteroids
Corticosteroids and Dosage* Pharmacodynamics Monitoring
Oral route
Prednisone (Deltasone®) 40–60 mg once a day in Onset: a few hours Most frequent side effects
morning and weaning until ⇑ Appetite and weight
minimum effective dose or Maximal response: after Mood swing
discontinuation several days of treatment Dyspepsia
Hyperglycemia
Fluid retention
Acne
Inhibition of hypophy-
seal-pituitary adrenal
(HPA)-axis
Osteoporosis
Infection
Muscle wasting
Inhaled MDI
Beclomethasone 50 µg/inh
(Beclovent®, Vanceril®, Sig: 100–1,000 µg/d Mechanism action Most frequent side effects
QVAR®) bid–qid regularly Hoarseness
Max: 2,000 µg/d Throat irritation
Prophylactic and Oropharyngeal
Diskhaler inhibitory action candidiasis
100 and 200 µg/blister Interferes with the Dysphonia
Rotahaler metabolism and synthesis Increased bruising
100 and 200 µg/capsule of mediators involved in Long term
the inﬂammatory process Inhibition of HPA axis
Osteoporosis
MDI (HFA134-a)/QVAR® Prevents their migration
Sig: 100–400 µg/d and activation
bid regularly
Max: 800 µg/d Decreases vascular
permeability caused by
Budesonide (Pulmicort®) Turbuhaler inﬂammatory mediators
100–200–400 µg/inh
Sig: 200–1,200 µg/d Increases reactivity of
bid–qid regularly β2 receptors located in
Max: 2,400 µg/d bronchial smooth muscle

Nebulization
Nebules Monitoring
0.25 mg/2 mL Oral hygiene
0.5 mg/2 mL Adrenal function
1.0 mg/2 mL Bone loss
Sig: 1–2 mg bid
Fluticasone (Flovent®) MDI HFA 134-a
25–50–125–250 µg/inh
Diskus
50–100–250–500 µg/inh
Sig: 100–500 µg bid
Max: 2,000 µg/d
(continues over...)


TABLE 5–5 Pharmacology of Oral and Inhaled Corticosteroids (continued)
Corticosteroids and Dosage* Pharmacodynamics Monitoring
Triamcinolone (Azmacort®) MDI
200 µg/inh
Sig: 400–600 µg/d
bid–qid regularly
Max: 3,200 µg/d
Fluticasone/salmeterol Diskus
(Advair®) 250 µg/50µg/inh
500 µg/50µg/inh
Sig: 1 inh bid regularly
MDI HFA 134-a
125/250 µg/50µg
Sig: 2 inh bid regularly
MDI = metered-dose inhaler.

OTHER PHARMACOLOGIC tum more liquid, but it does not produce improve-
CONSIDERATIONS ments in lung function or quality of life in patients
with COPD; furthermore, it is expensive and diffi-
The other essentials of COPD management are cov- cult to administer. Because many patients complain
ered elsewhere in this textbook; this section will pri- of difficulty in raising pulmonary secretions, there is
marily focus on the newer but not yet proven meth- still considerable interest in the development of any
ods of treatment. agents that will effectively resolve this problem.

Other Anti-inflammatory Therapy Sedatives and Anxiolytic Drugs
There is a need for the development of new anti- A variety of sedatives, tranquilizers, and even nar-
inflammatory drugs as evidence shows that the cotics have been used to treat patients with COPD
inflammatory process initiated by smoking is not who have severe dyspnea. There is little evidence to
responsive to corticosteroids and may continue suggest that these approaches are helpful; thus, they
even when smoking has ceased. Several new drugs should be attempted only in special circumstances
are under development such as leukotriene B4 and under the supervision of specialists.
inhibitors, 5-lipoxygenase inhibitors, PDE4 inhi-
bitors (phosphodiesterase inhibitors), new antiox- Proteinase Inhibitors
idants, neutrophil elastase, and matrix metallo- A small minority of patients with COPD have a
proteinase inhibitors. However, more studies and genetic deficiency of α1-antitrypsin, which is a sub-
large trials will be needed to establish the effect stance that tends to prevent digestion of lung pro-
of any of these drugs on the rate of decline in teins. It is believed that these patients develop
lung function. emphysema because their lungs are incapable of cop-
ing with protein-cleaving enzymes from inflamma-
Mucolytic Therapy tory cells, recruited to the lungs by smoke inhala-
Mucolytic therapy has a long history in the treat- tion. This mechanism may apply to patients without
ment of COPD. Acetylcysteine (Mucomyst) is α1-antitrypsin deficiency, with emphysema develop-
apparently used in Europe to help patients eliminate ing when the normal defenses against protein diges-
secretions but is used very little in North America tion are overwhelmed.
because it has not been proven beneficial, and we do In patients with α1-antitrypsin deficiency, intra-
not recommend its use.38 Similarly, there is a genet- venous augmentation therapy with naturally derived
ically engineered enzyme that lyses deoxyribonucleic α1-antitrypsin has been demonstrated to have bio-
acid (dornase alfa) and unquestionably makes spu- chemical efficacy in achieving and maintaining ele-


vated serum and lung α1-antitrypsin levels.39 Pub- (3) in some cases, homeopathic remedies might even
lished results from registries have suggested that cause aggravation of symptoms. In addition to these
patients with FEV1 35 to 49% of the predicted nor- adverse effects, safety issues are sometimes neglected,
mal value who received replacement therapy had a such as advice against immunizations or conventional
slower rate of decline of lung function than those who drug therapies. Therefore, in light of the absence of
did not receive replacement.40 However, these patients evidence-based alternative medicine, these therapies
were not randomly assigned to replacement therapy, cannot be recommended at this time.
and the absence of randomized, placebo-controlled
trials precludes definitive conclusions regarding intra-
venous replacement therapy in patients who have the RECOMMENDATIONS
deficiency. In patients without α1-antitrypsin defi- FROM INTERNATIONAL AND
ciency, such therapy is even harder to justify. NATIONAL GUIDELINES
Leukotriene Antagonist Drugs Over the last several years, international and national
There is data to suggest that leukotriene (LT)B4 is a guidelines on the management of COPD have been
potent chemoattractant of neutrophils and that its produced.38,41–44 Even though guideline recommen-
concentrations are increased in the sputum of dations are based on scientific information as much
patients with COPD. However, leukotriene antago- as possible, except for the Global Initiative for
nist drugs that are available for the treatment of Chronic Obstructive Lung Disease (GOLD) guide-
asthma (zafirlukast, montelukast sodium) are not lines,44 none of the guidelines provide evidence-
LTB4 antagonists but involve direct antagonism of based documentation; in many instances, the rec-
the Cys LT1 receptor for LTC4 and LTD4. They will ommendations are essentially empiric because of a
almost certainly be tried in COPD, but, at present, lack of scientific data. There are many similitudes
there are essentially no data indicating whether they and some differences in the recommendations for
are helpful. Several potent leukotriene B4 antagonists pharmacologic management of stable COPD.
may be more promising, but they are now only in All guidelines recommend inhaled bronchodila-
early development, and it is not known if they will tors as central to the symptomatic management of sta-
have clinical significance in COPD. ble COPD, with the GOLD guidelines44 and the
European Respiratory Society (ERS)42,43 offering no
Complementary/Alternative Medicine preference between β2 agonists and anticholinergic
Complementary/alternative medicine has become an agents for intitial therapy. The Canadian Thoracic
increasingly topical theme in respiratory medicine. Society (CTS)41and the American Thoracic Society
Alternative medicine comprises hundreds of different (ATS)38 suggest initial therapy with an anticholinergic
therapies that vary in theory and in practice; the most drug if regular therapy is needed and a β2 agonist if
prevalent treatments are acupuncture, aromatherapy, therapy as needed is all that is required. All groups
phytotherapy, homeopathy, reflexology, and chiro- discuss the value of combination therapy with a β2
practics. These alternative therapies are often perceived agonist and an anticholinergic drug compared with
as effective by those who use them, but their specific increasing the dose of a single drug. The GOLD
and nonspecific effects remain unclear. Nonspecific guidelines consider long-acting inhaled bronchodila-
effects can undoubtedly be an important part of the tors as more convenient; the ERS and the ATS suggest
total therapeutic effect of any treatment; however, a possible role in patients with nighttime or early
because safety is an essential precondition in any treat- morning symptoms, whereas the BTS recommends
ment, it should be stressed that although alternative limited use until more information is available, and
medicine is often promoted as entirely risk free, in fact, the CTS does not provide any mention of it. It is
there is no therapy that is totally devoid of risk. We worth noticing that the CTS guidelines were pub-
are uncertain about the benefits of most alternative lished in 1992, the ERS and ATS in 1995, and the
therapies and ignorant of their potential risks. Some of BTS in 1997, well before published studies had
the possible risks could be the following: (1) acupunc- reported information on the efficacy and potential
ture can cause trauma such as pneumothorax or infec- convenience of using long-acting bronchodilators. All
tions; (2) some herbal medicines are hepatotoxic; and guidelines place some value on the use of theo-


phylline, but owing to the high risk of drug interac- report at 1-year follow-up was slightly over 60%,
tion and its potential toxicity, inhaled bronchodila- declining to less than 50% at 5 years. In the same
tors are preferred. Theophylline is recommended study, compliance measured by canister weight was
when patients are still symptomatic despite combined about 10% below patient-reported compliance.
use of inhaled bronchodilators. However, these data may not be generalized since
The GOLD guidelines recommend that chronic patients with COPD participating in the Lung
treatment with systemic corticosteroids should be Health Study were largely non symptomatic. Per-
avoided because of an unfavorable benefit-to-risk haps we should not worry about underuse of drugs
ratio. When considering regular treatment with that have only symptomatic benefit.
inhaled corticosteroids, it should be prescribed only Compliance issues do not refer only to underuse
for symptomatic patients with COPD with a docu- but also to overuse and improper use of the drug or
mented spirometric response to corticosteroids. It device. Improper use of the inhaled drug devices is
can also be given to those with FEV1 less than 50% an extremely common and important issue. Most
predicted and with repeated exacerbations requiring commonly, improper patient techniques with
antibiotic and/or oral corticosteroid therapy. It is inhaled medication result in a suboptimal level of
worth mentioning that it has also been stated that drug delivery.45,46 Overcompliance in COPD has
the dose-response relationship and long-term safety also been observed.47 Overuse of inhaled drugs is
of inhaled corticosteroids in COPD are not known. often a consequence of improper use of the drug
Other guidelines emphasize the need to document delivery system and related drug inefficiency.
corticosteroid responsiveness before long-term use. Patients with severe COPD who often experience
Regarding the recommendations on using inhaled breathlessness on exertion may make excessive use
corticosteroids, they are of limited value considering of their inhaled β2 agonist when it is more appro-
that these national guidelines were produced prior to priate and efficient to implement their breathing
any real research on long-term treatment with techniques and appropriately pace their level of
inhaled corticosteroids.34–37 activity. It is also important to note that more than
Other drugs are generally not recommended, such one type of noncompliance is possible in the same
as mucokinetic drugs or the routine use of antibiotics patient. In patients with unfavorable outcomes, non-
and respiratory stimulants. The use of psychoactive compliance should always be considered before con-
drugs is suggested for the appropriate patients. cluding that a specific drug therapy is ineffective.
Alpha1-antitrypsin replacement therapy is recom-
mended for appropriate patients by the ATS but not
by the ERS and BTS. The GOLD guidelines suggest WHEN TO REFER
that young patients with severe hereditary α1-anti-
trypsin deficiency and established emphysema might When to Refer to a Pharmacist
be candidates for replacement therapy. Advice from a pharmacist may be useful when ques-
tions arise regarding adverse effects or compliance
with drug treatment. Adverse effects are uncommon
PATIENT NONCOMPLIANCE with most of the drugs used to treat COPD except
WITH THERAPY for theophylline. Theophylline presents a special case
whereby the patient’s metabolism and consequent
Successful pharmacologic management of COPD blood levels are subject to many drug interactions,
also involves monitoring and reinforcing effective including interactions with antibiotics (erythromycin,
compliance with drug therapy. Compliance can be ciprofloxacin) that may be used to treat exacerbations.
very poor and should be seen as a significant barrier It is essential to carefully review the therapy and non-
to improving clinical outcomes for those with pulmonary conditions of patients with COPD who
COPD. Even in the context of clinical trials, which are considered for theophylline therapy; moreover,
presumably involved more monitoring than standard consultation with a pharmacist may be of great value
care settings, compliance has been reported as low in in indicating whether these conditions, or drugs to
the past. In the Lung Health Study,7 patient com- treat comorbid conditions, need to be considered in
pliance with inhaled bronchodilator therapy by self- theophylline dosing and monitoring.


Compliance with drug regimens should always changes in drug therapy are contemplated and
be a consideration in patients with chronic diseases. whenever a patient does not respond to treatment
A dangerous and difficult scenario occurs when a as anticipated. Furthermore, they should be con-
patient with severe disease overuses his/her drugs. sulted if a patient appears to be so ill that hospital-
This can occur with bronchodilators, corticosteroids, ization or an emergency department visit may be
or antibiotics and can cause problems with drug required. Indicators of this kind of severity include
reimbursement plans. In such cases, the clinic and fever and extreme dyspnea, cyanosis, or altered
the pharmacist should cooperate to make sure that mentation, but no list is completely comprehen-
the appropriate inhaler technique is employed and sive. Physicians should also be consulted whenever
that proper education is available to the patient in a patient with COPD is suspected of developing a
terms of the expectations and effects of these agents. nonpulmonary disease.
With this in mind, it must be acknowledged that
inhaled bronchodilators are given to relieve symp- When to Refer to a Respirologist
toms and that if they successfully accomplish this, This decision varies with the degree of comfort and
overuse may be occasionally tolerable. However, experience that the practitioner and health care team
overuse of corticosteroids or antibiotics can also have have in dealing with COPD. Uncertain diagnosis
serious consequences, and every effort should be should be an absolute indication for respirologist
made to prevent mistakes; the pharmacist can help referral. Although there is no concrete evidence to
by providing the necessary information and educa- support this view, it has been suggested that all
tion. On the one hand, patients with relatively mild patients with COPD should see a respirologist at
COPD can also fail to comply with drug regimens some point in their disease. It is certainly true that
by under using prescribed therapy. This case, how- patients with COPD should undergo periodic
ever, is considered less serious since most treatments (roughly annual) spirometric testing that is often
are aimed at improving symptoms, and one can infer available only through specialists. Other indications
that if the patient chooses not to take a particular for referral could include patients with cor pul-
drug, it is likely owing to the fact that the drug is monale, bullous disease, rapid decline in FEV1, or
reducing symptoms. disease in relatively young people, such as those
under 40 years, and patients who cannot be with-
When to Refer to a Physician drawn from their oral corticosteroids. Essentially all
Generally speaking, physicians should always symptomatic patients with COPD should be given
supervise the care of patients with COPD. Super- the opportunity to undergo pulmonary rehabilita-
vision does not always require direct contact tion under the supervision of established specialists
between the patient and the physician but does and their programs. Finally, many patients with
require that the physician know what is going on. COPD have such severe symptoms and such a
Thus, groups of patients with COPD can receive restricted quality of life that consultation with a spe-
their front-line health care from nonphysicians; this cialist may be beneficial in serving to reassure both
is routine in most clinical research. However, peri- the patient and the person making the referral that
odic meetings with the responsible physicians and everything possible is being done. The vast majority
key members of the team are essential so that of daily care plans for patients with COPD are suc-
progress can be monitored. As is always the case in cessfully delivered by a team of health care workers
medicine, decisions regarding health care and per- that does not always include respirologists.
sonal maintenance have to be individualized.
Whereas some patients are stable and require little
physician input, others need more guidance and SUMMARY
supervision. The most comprehensive rule of
thumb states that the physician be consulted when- All patients with COPD should be offered treatment
ever other caregivers are uncomfortable with the using inhaled bronchodilators with the understand-
status of a particular patient, which is something ing that the benefits of these agents are confined to
that varies according to the individuals involved. the relief of symptoms. The choice of the particular
Physicians should always be consulted whenever bronchodilator agent is less important than the ini-


tiation of inhaled therapy, which should be guided they may reduce the frequency and severity of exacer-
by issues of symptom relief, adverse effects, and cost bations and should thus be considered only in patients
in individual patients. Combining bronchodilators with frequent exacerbations. It is important to
may improve efficacy and decrease the risk of adverse remember, however, that COPD exacerbations are
effects as compared with increasing the dose of a sin- very difficult to measure, and further validation of this
gle agent. Many symptomatic patients will derive approach is needed. Other than in treating infectious
further symptomatic benefit from theophylline, but exacerbations of COPD and other bacterial infections,
some care must be taken with these agents to avoid the use of antibiotics is not established.
overdoses and toxicity. When a patient is not responding to pharmaco-
Chronic treatment with oral corticosteroids should logic treatment, it is also essential to consider non-
be avoided because of an unfavorable benefit-to-risk compliance. This is especially a concern as improper
ratio. Inhaled corticosteroids do not modify the long- patient techniques with inhaled medication result
term decline in FEV1 in patients with COPD, but in a suboptimal level of drug delivery.

CASE STUDY chodilator and 5.00 L postbronchodilator, and
the FEV1/FVC ratio is 63%.
Mr. Cope, a 45-year-old male civil servant, arrives
for a check-up. Questions and Discussion
Mr. Copd has mild airway obstruction, which is
Medical History, Physical Examination, most likely owing to his smoking habit. Alhough he
and Test Results regards himself as asymptomatic, he does, in fact,
have COPD. Bronchodilator medication might
Medical History improve his function, but he is unlikely to comply
• Morning cough and phlegm production have with treatment. He must be convinced to stop
been present for many years, but he has no smoking; ideally, his motivation to quit might be
wheezing or breathlessness. increased with the reception of the news on his
• He smoked approximately 20 cigarettes a day abnormal pulmonary function. Although this may
for about 30 years. take several visits, considerable effort should be
• He has “chest colds,” but not every winter, and made to persuade him that quitting smoking is
he does not miss work because of them; they both necessary and urgent. Influenza vaccines can
are characterized by increased cough and puru- also be recommended for administration in the
lent sputum, which have been treated with autumn of every year.
antibiotics. At each encounter, the practicalities of quit-
• He has never been hospitalized for respiratory ting should be discussed; these include drug ther-
disease and did not have childhood asthma. apy, group programs available in the community,
• He is not known to have any medical or surgical modifying behaviors associated with cigarettes,
condition. and dealing with smokers in the home and the
workplace. It is very important that the patient feel
Physical Examination that the physician is genuinely interested and con-
• Physical examination and chest radiography are cerned. The physician should offer to work with the
normal. patient throughout the quitting process.
But what if this same patient has already devel-
Test Results oped symptoms such as breathlessness on activi-
• He has spirometry compatible with mild airflow ties at work? A long period of asymptomatic airway
obstruction without significant reversibility; obstruction is followed by a gradual worsening of
spirometry pre- and postbronchodilators: FEV1 is symptoms, such as breathlessness on daily activ-
3.11 L (75% of predicted normal) prebron- ities. Mr. Copd’s FEV1 would be less than 70% of
chodilator and 3.30 L postbronchodilator, (FVC) predicted normal, and he would be experiencing
is 4.95 L (101% of predicted normal) prebron- dyspnea on exertion or perhaps even at rest if it is


more advanced. Besides making the commitment bronchodilator therapy for every patient should be
to stop smoking and administering influenza vac- based on the overall assessment of benefit, with
cines in the autumn of every year, this patient the additional goals of achieving compliance with
should be treated with inhaled bronchodilators. the medication while maintaining a low or tolera-
The usual regimen is a regular dose of ipratropium ble level of adverse effects and an acceptable cost.
plus an as-needed short-acting β2 agonist. If the In addition to his chronic symptoms, the patient
patient regularly uses ipratropium plus a short- described acute exacerbation of COPD once or twice
acting β2 agonist to relieve symptoms, prescribing over the past 5 years. He has required antibiotics but
a single metered-dose inhaler that produces both no oral corticosteroid therapy, and he has never been
anticholinergic and β 2 -agonist bronchodilating hospitalized for his respiratory condition. Knowing
effects could be more convenient. Patients could that treatment with inhaled corticosteroids does not
sometimes benefit from a long-acting β2 agonist modify the long-term decline in FEV1 in patients with
combined with ipratropium, although an as- COPD, the use of regular treatment with inhaled cor-
needed short-acting β2 agonist should still be pro- ticosteroids would not be required for this patient
vided as a rescue medication. In any case, and should, in fact, be considered inappropriate.

KEY POINTS Advice for Patients and Their Families
• Follow the inhalation technique as recommended.
Pharmacologic Therapy • Encourage use of a spacing device (spacer) for
• None of the existing medications for COPD have improved therapeutic effects and reduced inci-
been shown to prevent further decline in lung dence of adverse effects.
function; therefore, drug therapy should be used • Rinse mouth after use if tremors or palpitations
to improve symptoms and/or decrease complica- occur (β2 agonists).
tions. • Rinse mouth after use to prevent dry mouth and
• Successful management of COPD also involves attenuate bad taste (anticholinergic agents).
monitoring and reinforcing effective compliance • Advise patients of the maximum number of
with therapy. inhalations in 1 day.

Inhaled Bronchodilators Oral Bronchodilators
• Inhaled therapy is preferred.
• The choice depends on the availability and cost of Methylxanthines
the medication, the patient’s response, and the • Methylxanthines may be indicated for severe
adverse effects involved. pulmonary obstruction despite optimal use of
inhaled bronchodilators.
β2 Agonists • Methylxanthines may produce therapeutic bene-
• β agonists are effective for reversal (short-acting fits unrelated to bronchodilation.
β2 agonists) and prevention of bronchospasm. • Dose adjustments may be necessary because
• β agonists are the most commonly used rescue metabolic clearance is affected by several diseases,
medication (short-acting β2 agonists). liver dysfunction, and drug interactions.

Anticholinergic Agents (Ipratropium Bromide) Advice for Patients and Their Families
• Anticholinergic agents have proven value for • Take theophylline-based preparations at the same
patients with COPD with chronic symptoms. time every day with food.
• Anticholinergic agents have at least an equal • Avoid taking the medication at bedtime.
bronchodilation effect in patients with COPD • Advise the local pharmacist of any changes in
versus β2 agonists. drug regimen (withdrawal or addition of a drug,
• Anticholinergic agents have an excellent side- over-the-counter purchases, new lifestyle changes
effect profile regardless of dose administered. such as smoking cessation, etc) because of the


very high potential for drug interactions. disease. Pulm Pharmacol Ther 1997;10:129–44.
• Make patients aware of the importance of 3. Calverly PMA. Symptomatic bronchodilator treatment.
requested blood tests to prevent drug toxicity. In: Calverly PMA, Pride NB, eds. Chronic obstruc-
tive lung disease. London: Chapman and Hall,
1995:419–45.
Corticosteroids
4. Barnes PJ. Bronchodilators: basic pharmacology. In:
• There is no clinical evidence that long-term oral Calverly PMA, Pride NB, eds. Chronic obstructive
administration is justifiable in COPD. lung disease. London: Chapman and Hall, 1995:
• There is demonstrated efficacy for suppressing 391–417.
5. Anthonisen NR, Wright EC. Bronchodilator response in
inflammatory response and decreasing bronchial chronic obstructive pulmonary disease. Am Rev
hyperreactivity in asthmatics only. Respir Dis 1986;133:814–9.
• Inhaled steroids may reduce the frequency and 6. Eliasson O, Degraff AC Jr. The use of criteria for
severity of COPD exacerbations and may be of reversibility and obstruction to define patient groups
value in patients with frequent exacerbations for bronchodilator trials. Influence of clinical diag-
nosis, spirometric, and anthropometric variables. Am
requiring antibiotic and/or systemic cortico- Rev Respir Dis 1985;132:858–64.
steroid therapy. 7. Anthonisen NR, Connet JE, Kiley JP, et al. Effects of
smoking intervention and the use of an inhaled bron-
Advice for Patients and Their Families chodilator on the rate of decline of FEV1: the Lung
Oral Corticosteroid Therapy Health Study. JAMA 1994;272:1497–505.
8. Shim CS, Williams MH. Bronchodilator response to
• Encourage patients to take the drug as a single oral aminophylline and terbutaline versus aerosol
dose in the morning with food. albuterol in patients with chronic obstructive lung
• Refer elderly patients to a physician or pharmacist disease. Am J Med 1983;75:697–701.
for vitamin D and calcium supplements. 9. van Schayck CP, Folgering H, Harbers H, et al. Effects
• Refer postmenopausal women to a physician for of allergy and age on responses to salbutamol and
ipratropium bromide in moderate asthma and
an evaluation of estrogen therapy. chronic bronchitis. Thorax 1991;46:355–9.
• Evaluate parameters that require monitoring to 10. Boyd G, Morice AH, Pounsford JC, et al. An evaluation
prevent or control the possibility of numerous of salmeterol in the treatment of chronic obstructive
adverse effects. pulmonary disease (COPD). Eur Respir J 1997;10:
815–21.
11. Jaeschke R, Guyatt G, Cook D, et al. The effect of
Inhaled Corticosteroid Therapy increasing doses of β-agonists on airflow in patients
• Follow the inhalation technique as recommended. with chronic airflow limitation. Respir Med 1993;
• Encourage use of a spacing device for improved 87:433–8.
therapeutic effects and reduced incidence of 12. COMBIVENT Inhalation Aerosol Study Group. In
adverse effects. chronic obstructive pulmonary disease, a combina-
tion of ipratropium and albuterol is more effective
• Rinse mouth after use to prevent irritation of the than either agent alone. An 85-day multicenter trial.
upper respiratory airways or Candida infections; Chest 1994;105:1411–9.
do not swallow. 13. Barnes P. Chronic obstructive pulmonary disease. N Engl
• Advise patients of the maximum number of J Med 2000:343:219–280.
inhalations in 1 day. 14. Murciano D, Auclair MH, Pariente R, Aubier M. A ran-
domized, controlled trial of theophylline in patients
• Refer elderly patients to a physician or pharmacist with severe chronic obstructive pulmonary disease.
for calcium and vitamin D supplements when on N Engl J Med 1989;320:1521–5.
high doses of inhaled corticosteroids. 15. Moxham J. Aminophylline and the respiratory muscles:
an alternative view. Clin Chest Med 1988;9:325–36.
16. McKay SE, Howie CA, Thomson AH, et al. The value
of theophylline treatment in patients handicapped
REFERENCES by chronic obstructive lung disease. Thorax
1993;48:227–32.
1. Guyatt GH, Townsend M, Pugsley SO, et al. Bron- 17. Mahon JL, Laupacis A, Hodder RV, et al. Theophylline
chodilators in chronic air-flow limitation. Effects on for irreversable chronic airflow limitation. A ran-
airway function, exercise capacity, and quality of life. domized study comparing “n of 1” trials to standard
Am Rev Respir Dis 1987;135:1069–74. practice. Chest 1999;115:38–48.
2. Cazzola M, Spina D, Matera MG. The use of bron- 18. Easton PA, Jadue C, Dhingra S, Anthonisen NR. A
chodilators in stable chronic obstructive pulmonary comparison of the bronchodilating effects of a beta-


2 adrenergic agent (albuterol) and an anticholinergic of inhaled budesonide in mild and moderate
agent (ipratropium bromide), given by aerosol alone chronic obstructive pulmonary disease: a ran-
or in sequence. N Engl J Med 1986;315:735–9. domised controlled trial. Lancet 1999;353:
19. Higgins BG, Powell RM, Cooper S, Tattersfield AE. 1819–23.
Effect of salbutamol and ipratropium bromide on 35. Pauwels RA, Lofdahl C-G, Laitinen LA, et al. Long-term
airway calibre and bronchial reactivity in asthma and treatment with inhaled budesonide in persons with
chronic bronchitis. Eur Respir J 1991;4:415–20. mild chronic obstructive pulmonary disease who con-
20. Colice GL. Nebulized bronchodilators for outpatient tinue smoking. N Engl J Med 1999;340:1948–53.
management of stable chronic obstructive pul- 36. Burge PS, Caverley PM, Jones PW, et al. Randomised,
monary disease. Am J Med 1996;100 Suppl 2A: double blind, placebo controlled study of fluticas-
11S–8S. one propitionate in patients with moderate to
21. Mahler DA, Donohue JF, Barbee RA, et al. Efficacy of severe chronic obstructive pulmonary disease. The
salmeterol xinafoate in the treatment of COPD. ISOLDE trial. BMJ 2000;320:1297–303.
Chest 1999;115:957–65. 37. The Lung Health Study Research Group. Effect of
22. Jones P, Bosh T. Quality of life changes in COPD inhaled triamcinolone on the decline in pulmonary
patients treated with salmeterol. Am J Respir Crit function in chronic obstructive pulmonary disease.
Care Med 1997;155:1283–9. N Engl J Med 2000;343:1902–9.
23. Casaburi R, Serby CW, Menjoge SS, et al. The spiro- 38. American Thoracic Society. Standards for the diagnosis
metric efficacy of once daily dosing with tiotropium and care of patients with chronic obstructive pul-
in stable COPD. Am J Respir Crit Care Med monary disease (COPD). Am J Respir Crit Care
1999;159:A254. Med 1995;152:S77–120.
24. Van Noord JA, Bantje T, Eland M, et al. Superior effi- 39. Wewers MD, Casolaro MA, Sellers SE, et al. Replace-
cacy of tiotropium (TIO) compared to ipra-tropium ment therapy for alpha1-antitrypsin deficiency asso-
(IpBr) as a maintenance treatment bronchodilator ciated with emphysema. N Engl J Med 1987;
in COPD. Am J Respir Crit Care Med 1999;159: 316:1055–62.
A525. 40. Seersholm N, Wencker M, Banik N, et al. Does alpha1-
25. Filuk RB, Easton PA, Anthonisen NR. Responses to antitrypsin augmentation therapy slow the annual
large doses of salbutamol and theophylline in decline in FEV1, in patients with severe hereditary
patients with chronic obstructive pulmonary disease. alpha1 -antitrypsin deficiency? Eur Respir J 1997;10:
Am Rev Respir Dis 1985;132:871–4. 2260–3.
26. Mahler DA, Matthay RA, Snyder PE, et al. Sustained- 41. Chapman KR, Bowie DM, Goldstein RS et al. Guide-
release theophylline reduces dyspnea in non- lines for the assessment and management of chronic
reversible obstructive airway disease. Am Rev Respir obstructive pulmonary disease. Can Med Assoc J
Dis 1985;131:22–5. 1992;147:420–8.
27. Guyatt GH, Berman LB, Townsend M. Long-term out- 42. Siafakas NM, Vermeire P, Price NB, et al. Optimal
come after respiratory rehabilitation. Can Med Assoc assessment and management of chronic obstructive
J 1987;137:1089–95. pulmonary disease (COPD): the European Respira-
28. Kirsten D, Wegner R, Jorres R, Magmussen H. Effects tory Society Task Force. Eur Respir J 1995;8:
of theophylline withdrawal in severe chronic 1398–420.
obstructive pulmonary disease. Chest 1993;104: 43. British Thoracic Society. Guidelines for the manage-
1101–7. ment of chronic obstructive pulmonary disease: the
29. Ziment I. Pharmacologic therapy of obstructive airway COPD Guideline Group of the Standards of Care
disease. Clin Chest Med 1990;11:461–86. Committee of the BTS. Thorax 1997;52 Suppl:
30. Decramer M, Lacquet LM, Fagard R, Rogiers P. Corti- S16–28.
costeroids contribute to muscle weakness in chronic 44. Pauwels RA, Buist AS, Calverley PMA, et al., on behalf
airflow obstruction. Am Rev Respir Dis 1994;150: of the GOLD Scientific Committee. National
11–6. Heart, Lung, and Blood Institute/WHO Global Ini-
31. Rice KL, Rubins JB, Lebahn F, et al. Withdrawal of tiative for Chronic Obstructive Lung Disease
chronic systemic corticosteroids in patients with (GOLD) workshop summary: global strategy for
COPD. Am J Respir Crit Care Med 2000;162: the diagnosis, management, and prevention of
174–8. chronic obstructive lung disease. Am J Respir Crit
32. Bourbeau J, Rouleau MY, Boucher S. Randomized con- Care Med 2001;163:1256–76.
trolled trial of inhaled corticosteroids in patients 45. Goodman DE, Isreal E, Rosenberg M, et al. The influ-
with chronic obstructive pulmonary disease. Thorax ence of age, diagnosis and gender on proper use of
1998;53:477–82. metered-dose inhalers. Am J Respir Crit Care Med
33. Paggiaro PL, Dahle R, Bakran I, et al. Multicentre ran- 1994;150:1256–61.
domized placebo-controlled trial of inhaled flutica- 46. McFadden ERJ. Improper patient techniques with
sone propionate in patients with chronic obstructive metered dose inhalers: clinical consequences and
pulmonary disease. Lancet 1998;351: 773–80. solutions to misuse. J Allergy Clin Immunol 1995;
34. Vestbo J, Sorensen T, Lange P, et al. Long-term effect 96:278–83.


47. Dolce JJ, Crisp C, Manzolla B, et al. Medication adher- physician and health professional to understand, detect,
ence patterns in chronic obstructive pulmonary dis- and improve compliance. A health decision model that
ease. Chest 1991;99:837–41. combines decision analysis, behavioral decision theory,
and health belief is proposed.
Pauwels RA, Buist AS, Calverley PMA, et al., on behalf
SUGGESTED READINGS of the GOLD Scientiﬁc Committee. National Heart,
Lung, and Blood Institute/WHO Global Initiative
Barnes PJ. New therapies for chronic obstructive for Chronic Obstructive Lung Disease (GOLD)
pulmonary disease. Thorax 1998;53:137–47. This workshop summary: global strategy for the diagnosis,
is a review of new therapies for COPD: new bron- management, and prevention of chronic obstructive
chodilators, anti-inﬂammatory treatments, antipro- lung disease. Am J Respir Crit Care Med 2001;163:
teases, mediator antagonists, pulmonary vasodilators, 1256–76. The GOLD guidelines present a COPD
mucoregulators, and drugs affecting remodeling. It management plan with four components: (1) assess and
presents some recent advances in the therapy of COPD monitor disease, (2) reduce risk factors, (3) manage sta-
and several new drugs now in development that may ble COPD, and (4) manage exacerbations. It has been
be useful in preventing disease progression. developed by individuals with expertise in COPD
Eraker SA, Kirscht JP, Becker MH. Understanding and research and patient care and reviewed by many experts
improving patient compliance. Ann Intern Med and national societies. Levels of evidence are assigned to
1984;100:258–68. This review article presents the statements, where appropriate, using a system developed
problem of patient compliance and the ability of the by the NHLBI.

Ch05

Recommended

Recommended

More Related Content

What's hot

What's hot (18)

Viewers also liked

Viewers also liked (20)

Similar to Ch05

Similar to Ch05 (20)

Recently uploaded

Recently uploaded (20)

Ch05