Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease
R. Andrew McIvor, MD, MSc, FRCPC
Introduction
Chronic obstructive pulmonary disease (COPD) is a systemic disease largely caused by smoking and
characterized by progressive, partially reversible airway limitation; systemic manifestations (e.g., altered
nutrition); and increasing frequency and severity of exacerbations. COPD is preventable and treatable.
The cardinal symptoms are shortness of breath and activity limitation.[1][2] Research suggests that
genetic variations may play a role in determining the presentation and severity of symptoms.[3]
The breathlessness experienced by people with COPD often causes them to restrict physical activity.
Restriction of activity is the beginning of a downward spiral of deconditioning and will result in further
restrictions of activity. Smoking cessation and optimal bronchodilation are key strategies in the
management of COPD to slow decline, relieve symptoms, reduce the risk of an acute exacerbation
(AE), and improve or maintain the patient’s activity level and quality of life.
Goals of Therapy
Prevent disease progression
Decrease or eliminate breathlessness and other respiratory symptoms through optimal
bronchodilation
Improve exercise tolerance
Reduce the frequency and severity of exacerbations
Improve health-related quality of life
Recognize and treat COPD comorbidities, e.g., cardiovascular disease, depression, osteoporosis
and smoking-related malignancies
Reduce impairment and disability
Reduce mortality
Investigations
History with particular attention to:[1][2]

symptoms and their pattern: dyspnea (insidious at onset and progressive), chronic cough,
sputum production, limitations to physical activity
degree of shortness of breath and disability, assessed using 1 of the following methods:
the modified Medical Research Council’s dyspnea scale (mMRC, see Table 1)[1][4]
the COPD Assessment Test (CAT): an online questionnaire for people with COPD
designed to measure the impact of COPD on a person’s life, and how it changes over
time.[5][6]
precipitating factors and triggers: tobacco smoking, heavy exposure to occupational dusts
and chemicals, air pollution
alpha1-antitrypsin deficiency, which has been associated with emphysema, liver disease,
panniculitis
signs/symptoms that suggest other comorbidities or systemic manifestations such as
cardiovascular disease, osteoporosis, skeletal muscle dysfunction, pulmonary embolism,
secondary polycythemia, depression, altered nutrition, pneumonia, malignancy, metabolic
syndrome
previous history of acute exacerbations of COPD: hospitalizations, emergency room visits,
use of oral corticosteroids and antibiotics
impact on daily life
social supports available
Physical examination is relatively insensitive for diagnosis:
signs of dyspnea, wheeze
late clinical findings: signs of hyperinflation, hypoxemia, pulmonary hypertension
Objective measurements needed to confirm diagnosis and assess severity:
spirometry, the gold standard for diagnosis and risk stratification of COPD.[2] Baseline
postbronchodilator FEV1 <80% of the predicted value is necessary to establish the diagnosis
along with a decreased FEV1/FVC.[1][2][7][8] Approximately 30% of patients thought to have
COPD will have an increase of 12% and >200 mL in FEV1 after salbutamol
guidelines have traditionally recommended using an FEV1/FVC <0.7 to diagnose
COPD;[9][10] however, a FEV1/FVC less than the Lower Limit of Normal (LLN) is more
accurate and will avoid overdiagnosing COPD.[11] LLN is the preferred measurement in
Canada
assessment of lung volumes and carbon monoxide diffusion
CBC to assess for polycythemia, which indicates chronic hypoxia or anemia that can worsen
dyspnea
chest x-ray to rule out lung cancer, bronchiectasis, tuberculosis
pulse oximetry ± arterial blood gases if FEV1 <1 L or <40% predicted or SaO2 <92% or
clinical signs of respiratory failure or right heart failure[1][2]
alpha1-antitrypsin level if patient <65 years of age presents with COPD, ≥20 pack-year
smoking history or a strong family history of COPD[2][12]
elevated eosinophils (>300 cells/mcL in blood or >3% in sputum), which may be a marker for
overlapping symptoms of asthma and COPD[10]
Table 1: Modified Medical Research Council (mMRC) Questionnaire for Assessing the Severity of
[a][a][b][b][2][4]
Breathlessness
Grade I only get breathless with strenuous exercise. □
0
Grade I get short of breath when hurrying on the level or walking up a slight hill. □
1
Grade I walk slower than people of the same age on the level because of □
2 breathlessness, or I have to stop for breath when walking on my own pace on
the level.
Grade I stop for breath after walking about 100 metres or after a few minutes on the □
3 level.
Grade I am too breathless to leave the house or I am breathless when dressing or □

4 undressing.
[a] Patient can tick only 1 response at a time.

[b] The mMRC questionnaire can be used on follow-up visits to monitor progress or response to therapy.
Spirometry is the gold standard for diagnosis of COPD.
Therapeutic Choices
Nonpharmacologic Choices
Recommend smoking cessation to reduce the risk of developing COPD,[1][2][13] stop COPD
progression[1][2][14][15][16] and decrease mortality.[17] Sustained smoking cessation (≥10 years)
is associated with a reduced risk of acute exacerbations, and the risk reduction is proportional
to the time the individual is smoke-free[18] (see Tobacco Use Disorder: Smoking Cessation).
Advise patients to minimize/eliminate exposure to air pollution and occupational dusts and
chemicals.[19][20]
Educate patients and their families to enhance patient outcomes and reduce costs by
improving self-management skills and the ability to cope with the illness and health status.[2][21]
[22]
Encourage physical activity to prevent decreased mobility and increased dyspnea. Patients
with a lower activity level at 1 month after hospital discharge were more likely to be readmitted
in the following year.[23] Formal exercise programs, with or without use of a pedometer, have
been found to improve endurance and quality of life.[24][25] Tai chi may improve exercise
tolerance and pulmonary function.[26]
Consider early referral of symptomatic patients to pulmonary rehabilitation programs providing
respiratory, physical and occupational therapy, exercise conditioning, nutritional assistance,
and psychosocial and vocational rehabilitation. Although pulmonary rehabilitation is a limited
resource, patients benefit in all stages of COPD.[27][28][29] After an acute exacerbation,
recommend initiation of pulmonary rehabilitation within 4 weeks to reduce the chances of
further exacerbations.[9][30]
The combination of patient education and case management that includes monthly access to a
health-care specialist has been shown to reduce hospitalizations. Patient education alone or
case management alone are not recommended methods of reducing the risk of acute
exacerbations.[9]
Written COPD action plans reduce acute exacerbations and risk of use of urgent care or
hospitalization when combined with education and case management. An action plan should
not be used alone.[9][31]
Oscillating positive expiratory pressure (OCEP) devices (e.g., Aerobika, which is available in
pharmacies, unlike many of the other products currently on the market) may provide some
improvement in lung function. The efficacy of OCEP devices in reducing COPD exacerbation
severity and improving lung function has been supported by some small studies;[32] however,
recommendations regarding their use have not yet been included in the Canadian guidelines
nor in the Global Initiative for Obstructive Lung Disease (GOLD) COPD strategy document.
Larger scale studies are required.
Pharmacologic Choices
Figure 1 depicts a stepwise approach to COPD management. See Table 4 and Table 5 for the
available agents for COPD treatment; care should be taken to avoid prescribing duplicate therapy
from the same class.
COPD Strategies and Guidelines
COPD is a global problem, and national and international bodies are reviewing the evidence and
suggesting various management strategies. Guideline development has advanced significantly;
precise criteria have been developed for reviewing evidence-based data for guidelines. The
Canadian Thoracic Society (CTS) produces guidelines[1] that are currently awaiting update, but
Canadian experts also acknowledge the GOLD COPD strategy.[1][2]
GOLD has evolved its recommendations beyond simply classifying COPD as mild, moderate,
severe or very severe based on the progressive impairment of FEV1.[2] It now categorizes
patients by combining the spirometric classification and/or the number of exacerbations or
hospitalizations in the preceding year with a symptomatic assessment (CAT score or mMRC
score) to stratify patients as Group A, B, C or D, where D is the most severe. GOLD has also
launched an app to facilitate integration of this approach into clinical practice.
The CTS and the American College of Chest Physicians (CHEST) have released joint guidelines
that assess the available evidence to support treatments and approaches for the prevention of
exacerbations and hospitalization.[9]
All medications used to treat symptoms in stable COPD also help to reduce the risk of acute
exacerbations of COPD. An acute exacerbation is a significant event in the life of a COPD
patient, often resulting in further decline in function or death. Careful selection of therapy for
patients with stable COPD can reduce the risk of requiring additional therapy or hospitalization.[9]
See Treatment of Acute Exacerbations of COPD for more information.
Stable COPD and Prevention of Acute Exacerbations
Optimal bronchodilation should be the main goal of pharmacologic therapy and should aim to
improve the patient’s functioning. Bronchodilators, the mainstay of pharmacotherapy, decrease
air trapping, improve FEV1, reduce symptoms (e.g., dyspnea), and improve exercise capacity
and quality of life in stable COPD and in acute exacerbations of COPD. Even a small
improvement in airflow may be of significant clinical benefit in COPD patients with severe
obstruction. Inhaled bronchodilators can be used as needed for occasional symptoms or
regularly for symptom prevention and/or reduction.
Initial therapy commences with short-acting beta2-adrenergic agonists (also known as short-
acting beta2 agonists, or SABAs) as needed to relieve dyspnea, which may be supplemented by
regular long-acting bronchodilators.[1][2][33] Maximum bronchodilation may be obtained with a
combination of long-acting beta2-agonists (LABAs) and long-acting muscarinic antagonists
(LAMAs).[1][2]
COPD is characterized by persistent inflammation, even in early disease.[1] However, compared

to their effect in asthma, inhaled corticosteroids (ICS) have minimal effect on the neutrophilic
response in COPD. In addition, patients regularly using ICS for COPD treatment may be at
increased risk of pneumonia.[2] Furthermore, the TORCH study showed increased mortality with
ICS monotherapy.[34] The main role of ICS in COPD is in combination with a LABA in moderate
to severe disease (see Combination Inhaled Corticosteroids and Long-Acting Bronchodilators).[1]
Inhaled COPD Therapies
For a complete list of inhaled COPD therapies available in Canada, see Table 2; for dosing
information, see Table 4.
Table 2: Inhaled Agents Used to Treat COPD

Mechanism of Drug Class Drug
Action
Bronchodilators, SABA Salbutamol (Ventolin pMDI, Diskus and
short-acting Nebules)
Terbutaline (Bricanyl DPI)
SAMA Ipratropium (Atrovent pMDI and

Nebules)
SAMA/SABA Ipratropium/Salbutamol (Combivent

Combination(s) Respimat and UDV)
Bronchodilators, LABA Formoterol fumarate (Foradil DPI)

long-acting Formoterol fumarate dihydrate (Oxeze
Turbuhaler)
Indacaterol (Onbrez Breezhaler DPI)
Salmeterol (Serevent Diskhaler and
Diskus)
Mechanism of Drug Class Drug
Action
LAMA Aclidinium (Tudorza Genuair DPI)
Glycopyrronium (Seebri Breezhaler
DPI)
Tiotropium (Spiriva DPI and Respimat
SMI)
Umeclidinium (Incruse Ellipta DPI)
LAMA/LABA Aclidinium/formoterol fumarate

Combination(s) dihydrate (Duaklir Genuair DPI)
Glycopyrronium/formoterol fumarate
dihydrate (Bevespi pMDI)
Glycopyrronium/indacaterol (Ultibro
Breezhaler DPI)
Tiotropium/olodaterol (Inspiolto
Respimat SMI)
Umeclidinium/vilanterol (Anoro Ellipta
DPI)
Anti- ICS/LABA Budesonide/formoterol fumarate

inflammatory Combination(s) dihydrate (Symbicort Turbuhaler DPI)
agents Fluticasone/salmeterol (Advair pMDI
and Diskus DPI)
Fluticasone/vilanterol (Breo Ellipta DPI)
ICS/LAMA/LABA Fluticasone/umeclidinium/vilanterol
Combination(s) (Trelegy Ellipta DPI)
Abbreviations DPI = dry powder inhalation; ICS = inhaled corticosteroids; LABA = long-acting beta2-
adrenergic agonist; LAMA = long-acting muscarinic antagonist; pMDI = pressurized metered dose
inhaler; SABA = short-acting beta2-adrenergic agonist; SAMA = short-acting muscarinic
antagonist; SMI = soft mist inhaler; UDV = unit-dose vial
Short-Acting Bronchodilators
Recommend PRN use of a short-acting beta2-agonist (SABA) such as salbutamol or

terbutaline in all stages of disease severity for immediate symptom relief.[1] SABAs have
approximately equal efficacy, side effects, onset and duration of action (4–6 hours).[2]
Recommended doses of short-acting beta2-agonists result in less than maximal
bronchodilation; the dose may be doubled or tripled, although tachycardia, tremor and
potential hypokalemia must be recognized and monitored in patients at risk.
The short-acting muscarinic antagonist (SAMA) ipratropium has a slower onset of action
than inhaled beta2-adrenergic agonists but a longer duration of action (up to 8 hours).[2]
The recommended dose (40 mcg, 3–4 times/day), produces less than maximal
bronchodilation and may be doubled or tripled without notable side effects. The role of
ipratropium monotherapy is limited because it is less effective than tiotropium[37] and
has a slower onset of action than salbutamol.
The combination of ipratropium/salbutamol produces greater and more sustained

improvement in FEV1 and a greater degree of bronchodilation with a lower or similar
incidence of side effects compared with either drug alone.[2] The combination also confers
greater improvement in lung function than doubling the dose of either bronchodilator.[38]
[39][40]
Oral beta2-agonists offer few advantages and are associated with an increased incidence
of side effects; they have no role in the routine management of COPD.
Long-Acting Bronchodilators
There are 2 types of long-acting bronchodilators available, LAMAs (formerly referred to

as long-acting anticholinergics) and LABAs. Long-acting bronchodilators can be used in
patients with persistent symptoms and moderate to severe airflow obstruction. Studies
have shown that LAMAs and LABAs improve lung function and health status while
reducing exacerbation rates and dyspnea.[2]
Long-Acting Muscarinic Antagonists
The LAMA tiotropium is a first-line agent for managing persistent symptoms and
moderate to severe airflow obstruction, as it decreases exacerbations and
hospitalizations.[1][41] A single daily 18 mcg dose via a breath-activated DPI or two
2.5 mcg inhalations (total dose of 5 mcg) via SMI gives maximal anticholinergic
activity for a full 24 hours.[42] When compared with ipratropium, more sustained
effects on pulmonary function, activity-related dyspnea, and quality of life, as well as
fewer acute exacerbations, were noted.[37] When given in combination with pulmonary
rehabilitation, tiotropium improved treadmill walking endurance time.[43]
Retrospective studies have shown an increased risk of cardiovascular death, MI or

stroke associated with both ipratropium and tiotropium.[44][45] This was not confirmed
in a 4-year randomized controlled trial that evaluated efficacy of tiotropium and also
included safety parameters as secondary endpoints.[46] The FDA and others have
extensively reviewed available data and have concluded there is no increased risk of
stroke, MI or death associated with tiotropium DPI.[47][48] However, ipratropium
appears to be associated with an increase in cardiovascular events.[49][50]
Glycopyrronium is a rapid-onset LAMA delivered via DPI. It has a faster onset of

action than tiotropium. The currently licensed dose is 50 mcg once daily. Phase III
studies have established improvement in dyspnea and quality of life and reduced risk
of exacerbation compared with placebo; when compared with tiotropium, similar
efficacy and safety data were observed.[51][52][53] The bronchodilation effect is seen
on day 1 of administration. Improvements in exercise endurance and quality of life are
seen over time.
The LAMA aclidinium is dosed at 400 mcg twice daily and has effects similar to those
of tiotropium and glycopyrronium on lung function.[54][55][56]
Umeclidinium is a once daily LAMA delivered via DPI. A Cochrane review found that
it reduced the likelihood of developing moderate exacerbations requiring oral steroids
and/or antibiotics (NNT = 18); however, a reduction in exacerbations requiring
hospitalization was not observed. This therapy also reduced the frequency of rescue
inhaler use while improving quality of life, COPD-related symptoms and lung function.
[57]
All LAMAs have been found to reduce the rate of acute exacerbations leading to
hospitalization.[2][9][51][52][58]
Long-Acting Beta2-agonists
The inhaled LABAs salmeterol and formoterol offer sustained improvements in

pulmonary function, dyspnea and quality of life compared with SABAs.[1][59] Unlike
salmeterol, formoterol has the advantage of rapid onset of bronchodilation (<3 min vs.
20–120 min in COPD) in addition to the 12-hour duration of action.[60][61]
Indacaterol and olodaterol are once-daily, ultra-long-acting beta2-adrenergic

agonists with rapid onset of action. Indacaterol has shown bronchodilation similar to
tiotropium, and has been shown in a short-term trial to be noninferior to
salmeterol/fluticasone with respect to changes in FEV1 in patients with moderate
COPD who were at low risk of exacerbation.[62][63][64][65] Olodaterol, only available in
combination with a LAMA, is an effective bronchodilator as a single agent, provides
similar bronchodilation to formoterol and has shown additive bronchodilation when
combined with tiotropium.[66][67][68] The role in therapy for indacaterol and olodaterol
is for the treatment of COPD patients who either cannot tolerate a muscarinic
antagonist due to adverse effects or demonstrate poor adherence with twice-daily
LABA regimens.
LABAs have been found to reduce the risk of moderate and severe acute
exacerbations compared with placebo and are safe for long-term use.[9][69] When
comparing LAMAs with LABAs, LAMAs appear to be more effective in reducing the
incidence of acute exacerbations and hospitalizations.[2][9][70]
Combination Long-Acting Bronchodilators
When selecting bronchodilator therapy, choose LAMA/LABA over ICS/LABA to

maximize bronchodilation and reduce incidence of exacerbations.[2]
For symptom control, offer the combination of a LAMA and LABA if disability persists
despite monotherapy; for prevention of acute exacerbations, offer either a
LAMA/LABA combination or LAMA monotherapy.[9][71][72] Compared with
monotherapy, the combination of LAMA and LABA maximizes bronchodilation and
lung deflation, thus improving FEV1 while reducing symptoms and exacerbation rates.
[2]LAMA/LABA combination is recommended in moderate to severe disease with
persistent symptoms, in those with poor health status despite monotherapy with LAMA
or LABA, and/or in those with frequent exacerbations (≥2 moderate exacerbations or
≥1 exacerbation requiring hospitalization).[2][10]
Several combination products containing a LAMA and a LABA in a single inhaler are
now available (see Table 2). Studies show an acceptable safety profile and superior
bronchodilation of combination products when compared with both placebo and
individual components.[73][74][75][76][77] Cardiovascular safety was acceptable in
studies up to 52 weeks.[74][78][79]
The combination of LAMA/LABA (glycopyrronium/indacaterol) was compared with

ICS/LABA (fluticasone/salmeterol) in the FLAME study and a Cochrane review.[80]
[81] The LAMA/LABA combination was found to be superior to ICS/LABA in terms of
delaying time to first exacerbation as well as decreasing the rate of exacerbations and
incidence of pneumonia.[80][81]
Combination Inhaled Corticosteroids and Long-Acting Bronchodilators
Prior to initiating ICS, it is best to assess inhaler technique and ensure optimal
bronchodilation using LAMA/LABA.
ICS monotherapy is not recommended in the management of COPD symptoms;[1][9]

however, several ICS/LABA combination products are available in Canada (see Table 4).
The combination of ICS plus LABA may improve lung function and reduce the risk of
exacerbations.[9] ICS/LABA combinations are more effective than either drug alone in
terms of exercise endurance, symptom control, lung function and exacerbation rates in
patients with moderate to very severe COPD.[9][82][83][84][85] These combinations are
especially useful in patients with overlapping asthma and COPD symptoms.[2][10]
In comparison with LABA monotherapy, the use of ICS/LABA increases the risk of
pneumonia without expected increases in mortality.[34][85][86] The risk of pneumonia may
be most elevated in regimens using fluticasone (both propionate and furoate). Regimens
using budesonide may be associated with a lower risk than fluticasone, although direct
comparisons have not been conducted.[86][87] Budesonide appears to increase the risk of
pneumonia in comparison with placebo.[88]
ICS therapy may also increase the risk of contracting or reactivating tuberculosis.[89]
While less of a concern in Canada, patients at high risk of tuberculosis may warrant
closer monitoring and consideration of withdrawal of the ICS when the patient is
considered stable (see Tuberculosis). The risk of contracting influenza in patients treated
with ICS is unclear. Strongly recommend that all patients with COPD receive the annual
influenza vaccine[89] (see Vaccines).
Due to the risk of adverse effects, experts recommend reserving the use of triple therapy
for patients with moderate to severe COPD and repeated exacerbations (≥2 per year or
≥1 requiring hospitalization). In these patients, the use of a LAMA, LABA and ICS may
prevent exacerbations and improve lung function.[2]
The combination of ICS/LABA plus tiotropium improves bronchodilation and lung

deflation, reduces frequency and severity of exacerbations, improves health, and reduces
hospitalization.[1][9][34][90] Triple therapy with ICS/LABA plus glycopyrronium was found
to be noninferior to ICS/LABA plus tiotropium in a 12-week study in terms of
bronchodilation and quality of life.[91][92]
Consider tapering inhaled corticosteroids in patients with severe to very severe COPD
who are otherwise stable. The WISDOM study examined a 12-week tapering withdrawal
of inhaled fluticasone in patients with severe or very severe COPD who were also
receiving salmeterol and tiotropium. No difference was found in the time to first
exacerbation, symptoms or quality of life between subjects who continued inhaled
fluticasone and those who were tapered to dual therapy.[93]
Finally, if triple therapy is required, it is preferable for it to be provided as a single entity

ICS/LAMA/LABA inhaler or as a LAMA inhaler in combination with a ICS/LABA inhaler
(see Table 2). The availability of new bronchodilators and combination LAMA/LABA
therapy may reduce the use of triple therapy.
Delivery Systems
The choice of delivery device for patients with COPD depends on the patient’s ability to
correctly use the device as well as convenience, ease of use and affordability.[94][95]
Inhaled bronchodilators are delivered via pressurized metered-dose inhaler (pMDI) with or
without a spacer device, dry powder inhaler (DPI), soft mist inhaler (SMI or Respimat) or
nebulizer.[94] If pMDI technique is inadequate or ineffective, a spacer device is
recommended to improve deposition of the medication to the lower respiratory tract and
to avoid problems in coordinating the time of inhaler actuation with inhalation. DPIs do not
present the problems with hand-breath coordination seen with pMDIs. Appropriate use of
pMDIs (with or without spacer devices), DPIs or SMIs provides optimal drug delivery and
should be encouraged over nebulizers. Nebulizers may be used in patients who remain
symptomatic despite maximal treatment with handheld inhalers.
The proper use of inhalers is not intuitive. Careful instruction and demonstration of correct
inhaler technique is essential before therapy is initiated and should be reinforced at each
visit. Several studies have found that many people with COPD were in need of technique
correction, never received training on their device or could not recall having their
technique reassessed by a health-care practitioner.[96][97][98] Observation and correction
of technique can help to improve technique for both MDIs and DPIs as well as reduce
exacerbations and hospitalizations.[99] Various manufacturers of DPIs have been
developing their own “trademarked” devices to deliver their proprietary medications;
patients and health-care practitioners will need to become familiar with the individual
requirements of multiple devices to optimize the clinical benefits.
Long-term adherence to inhaled medications for COPD is poor but improves with less
frequent administration (e.g., 1 vs. 2 or more daily doses).[100] Poor adherence is
associated with higher rates of hospitalization, lower quality of life and lower productivity.
[101] Adherence may improve in patients who use one type of inhaler for all medications,
but this is not always practical.[98]
Initially, there was concern over potentially increased mortality with the SMI formulation
based on several meta-analyses and systematic reviews.[102][103][104] A large,
randomized trial and a systematic review allayed these concerns by demonstrating no
increased mortality with tiotropium administered via SMI compared with DPI
administration.[105][106]
Oral COPD Therapies
See Table 4 for dosing information related to oral COPD therapies.
Phosphodiesterase 4 (PDE4) Inhibitors
Roflumilast is an oral medication that suppresses the release of inflammatory mediators

through inhibition of cyclic AMP breakdown. It is indicated as add-on therapy with
bronchodilators for the maintenance treatment of severe COPD associated with chronic
bronchitis (history of chronic cough and sputum) in adult patients with a history of frequent
exacerbations.[107]
Roflumilast has demonstrated a significant improvement in prebronchodilator FEV1

(48–80 mL increase) along with a small reduction in exacerbations requiring systemic
corticosteroids (8%), even for patients who were also taking a LABA.[108][109][110][111] A
Cochrane review found that patients were 23% less likely to experience an exacerbation
over the study period (≤1 year) with an NNT of 20; however, quality of life and symptoms
scores were not greatly improved.[112] Data support addition of roflumilast to foundation
bronchodilatory therapy to reduce exacerbations, either before or in addition to
introduction of ICS/LABA, particularly in patients with frequent or severe exacerbations.
Roflumilast may be considered for add-on therapy to existing triple therapy

(ICS/LAMA/LABA or LAMA + ICS/LABA) for people with COPD who have had at least
1 exacerbation in the past year.[9][111][113]
Methylxanthines
Clinically, theophylline exerts little bronchodilator effect beyond that of optimal inhaled
bronchodilators. Due to theophylline’s narrow therapeutic index and complex
pharmacokinetics, serum levels should be measured and adjusted to the low therapeutic
range (55–85 mcmol/L) to minimize adverse effects.[9] Theophylline has significant drug
interactions, e.g., its levels may be doubled if the patient stops smoking or with the
addition of medications commonly used during acute exacerbations of COPD such as
clarithromycin.
Long-acting preparations of theophylline (see Table 5) may be used in patients with

severe symptoms of COPD despite use of triple therapy;[1] consult a specialist when a
patient reaches this stage of disease.
Mucolytics
N-acetylcysteine (NAC) is a mucolytic agent with antioxidant properties. The mechanism

of action of NAC in COPD is not clearly understood. High-dose NAC (600 mg orally twice
daily) may be of benefit in reducing acute exacerbations in people with moderate to
severe COPD who have experienced 2 or more exacerbations in the previous 2-year
period.[9][114][115] The optimal dose of NAC has not been determined. The injectable
solution is administered orally, usually diluted in a cola beverage to reduce nausea and
vomiting.
Vitamin D3
One prospective study found supplementation with vitamin D3 (cholecalciferol) 3 mg

(120 000 units) every 2 months helped to reduce the incidence of exacerbations only in
patients with low baseline vitamin D levels (<50 nmol/L). Those with higher baseline
vitamin D levels did not benefit from supplementation; however, for patients with low
baseline vitamin D levels, supplementation may help to reduce risk of exacerbations.[116]
[117] Further studies are required to better define the role of vitamin D in COPD.
Antibiotics
Long-term macrolide therapy can help to reduce the number of patients experiencing
exacerbations as well as the frequency of exacerbations experienced by each patient.[118]
For patients with moderate to severe COPD who have experienced ≥1 moderate or
severe exacerbation in the previous year while on optimal therapy, consider a long-term
course of macrolide antibiotic therapy. The ideal length of therapy has not been
established. Consideration needs to be given to the individual patient’s risk of QTc
prolongation, risk of ototoxicity including hearing loss, and the risk of antibiotic resistance
to both the individual and the community.[9] Current evidence does not support pulsed
antibiotic therapy for prevention of exacerbations; however, intermittent prophylactic
therapy (three times weekly) clinically reduced exacerbations in COPD patients.[118]
Azithromycin may be most effective at preventing exacerbations requiring treatment with

both antibiotics and corticosteroids. Patients who are older and who have milder COPD
may be more likely to respond to long-term azithromycin therapy. Current smokers appear
to receive no benefit from long-term azithromycin. Use of azithromycin in current smokers
should be carefully considered.[119]
Oxygen Therapy
Oxygen therapy reduces the risk of death in select patients. In COPD patients with severe
hypoxemia (PaO2 ≤55 mm Hg or SaO2 <88%), long-term oxygen therapy may prolong life by
6–7 years.[2] Improved survival has been seen only when oxygen is administered for
≥15 hours per day.[120] Continuously administered oxygen provides the greatest survival
benefit. A patient whose PaO2 is between 55 and 59 mm Hg may benefit from oxygen
therapy if there is evidence of bilateral ankle edema, cor pulmonale or a hematocrit greater
than 56%.[1] Oxygen therapy is usually administered via Venturi facemask or nasal prongs at
a flow rate sufficient to produce a resting PaO2 between 65 and 80 mm Hg. Flow rates are
often increased by 1 or 2 L/min during exercise and sleep. If hypoventilation (PaCO2
>45 mm Hg) is present, the titration of oxygen may worsen hypercarbic hypoxia, thus
monitoring is advised.
Vaccines
Ensuring COPD patients have currently recommended vaccines will help to reduce their risk
of infection and exacerbation.
Vaccinate against influenza annually, early in the fall. Influenza vaccine reduces
exacerbations and death in patients with COPD (see Influenza).[1][2][121][122]
Recommend pneumococcal vaccination to all patients with COPD who have no

contraindications.[123] Efficacy studies of pneumococcal vaccine in patients with COPD
yield conflicting results;[124][125] however, pneumococcal vaccination is recommended
because patients with COPD are at increased risk of hospitalization and mortality from
pneumonia.[1][2][123] Consider repeating the pneumococcal polysaccharide vaccine (Pneu-P-
23) as a one-time booster in high-risk patients (COPD plus ≥1 other risk factor) in 5 years.[1]
[2][123] Additional boosters are not recommended.[123]
One small study suggests an additive protective effect against acute exacerbations in COPD
patients who received both the pneumococcal and influenza vaccines compared with receipt
of influenza vaccine alone.[126] Further studies are needed to confirm this finding.
For more information related to vaccines in patients with COPD, consult the Canadian
Immunization Guide.
Treatment of Acute Exacerbations of COPD
COPD exacerbations become more frequent and more severe as a patient’s disease worsens.
The strongest predictor of future exacerbations and mortality is a prior history of exacerbation,
irrespective of disease severity. This suggests that the “frequent exacerbator” is a distinct
subgroup (or phenotype) of patients who could be identified and targeted with specific
exacerbation-prevention strategies.[127][128] Several other factors are associated with
exacerbations and increased mortality: female gender, advanced age, low FEV1, high number of
comorbidities and low physical activity.[127][129][130][131][132] Cold weather is associated with an
increase in the number of patients experiencing acute exacerbations.[133][134] Two-thirds of
exacerbations are related to acute respiratory infections, while one-third have no clear cause.[9]
A combination of prevention of infectious diseases (e.g., appropriate immunization) and good
symptomatic control may help to prevent exacerbations.
Acute exacerbations are the most frequent cause of medical visits, hospital admissions and
death among COPD patients. Characterized by sustained worsening of dyspnea, cough and/or
sputum production, acute exacerbations of COPD contribute to the accelerated rate of decline in
lung function.[1][2][9] In addition, acute exacerbations lead to an increase in the use of
maintenance medications and/or initiation of systemic corticosteroids and/or inhaled oxygen.[1][2]
In acute exacerbations of COPD, bronchodilation is optimized by increasing the dose and/or
frequency of existing bronchodilator treatment.[2] Treat dyspnea with a SABA and ipratropium.
In addition to optimized bronchodilator therapy, patients with purulent acute exacerbations
benefit from antibiotics.[1][2] Severe COPD patients gain additional benefit from a short course of
systemic corticosteroids.[1][2]
Systemic Corticosteroids
Oral corticosteroids (see Table 5) improve lung function and shorten length of hospital stay
in all patients and reduce risk of early relapse or hospitalization for subsequent acute
exacerbations.[1][2][9] They should be given within 30 days of an acute exacerbation to
reduce the risk of further exacerbations. Administration beyond 30 days is not recommended.
[9]
A 5-day course of oral prednisone 30–40 mg/day or equivalent is sufficient and has shown
outcomes comparable to a 10- to 14-day course.[2][135][136] Tapering is unnecessary for oral
corticosteroid courses that last <2 weeks. There is no role for oral corticosteroid maintenance
therapy for patients with COPD. There is no advantage to using IV corticosteroids.
Antibiotics
Viruses are the most common infectious agents in exacerbations. Consider rapid virology
and antivirals for influenza during influenza season (see Influenza). Routine use of antibiotics
in acute exacerbations of COPD is not recommended because of inconsistent study results in
nonsevere exacerbations and concerns about increasing prevalence of antimicrobial
resistance.[137] Antibiotics are indicated in all patients with severe exacerbations requiring
invasive mechanical ventilation or if the exacerbation is accompanied by 2–3 of the following
cardinal signs: increased dyspnea, increased sputum or increased sputum purulence (see
Table 3).[2][138]
The common bacterial pathogens causing acute exacerbations of COPD are

and .[1][2][139] In complicated
patients, species and other gram-negative organisms including
may also be involved.[139]
Empiric choice of an antibiotic should take into account individual risk stratification, previous
antibiotic use and the prevalence of antimicrobial resistance in the area (see Table 3).
Consider a change in antibiotic class if the same class has been used within the previous
3 months. Re-evaluate patients who do not respond within 24–36 hours. See Table 6 for
antibiotic dosing information.
Table 3: Empiric Antibiotic Therapy for Acute Exacerbation of COPD

Risk
Symptoms Factors Probable Pathogens Antibiotic of First Choice[a][b]
Risk
Symptoms Factors Probable Pathogens Antibiotic of First Choice[a][b]
At least 2 of: <4 spp. Amoxicillin × 5–7 days
Increased exacerbations Doxycycline × 5–7 days
sputum in the past
year Sulfamethoxazole/trimethoprim
purulence × 5–7 days
Increased
sputum ≥4 Organisms listed above Preferred:
volume exacerbations Amoxicillin/clavulanate
Worsening in the past
spp. × 5–10 days
dyspnea year
in these cases, there is a Cefuroxime axetil × 5–10 days
higher probability of resistance Levofloxacin × 5 days
Failure of 1 of
the agents Alternative:
listed Azithromycin × 3 days
above[b] Clarithromycin × 5–10 days
Antibiotics in
the past 3
months[b]
[a]
See Table 6 for dosing information
[b] If an antibiotic has been used within the past 3 months if treatment failure occurs (clinical
deterioration after 72 h of antibiotic therapy no symptom improvement after completion of
antibiotic therapy), use an antibiotic from a different therapeutic class.
Adapted with permission from Bugs and Drugs ©2019 Alberta Health Services (AHS). [Mobile application software].
(Version 2.0.17). Edmonton: Alberta Health Services [2018]. Retrieved from https://googleplay.com. AHS is not
responsible for any inaccuracies in content different from the content of the original English edition. All acts of copyright
infringement including reproduction, translation, transmission, republication and distribution of this material without written
permission of the Canadian Pharmacists Association and AHS are prohibited. These materials are intended for general
information only and are provided on an “as is, where is” basis. Although reasonable efforts were made to confirm the
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use of these materials, and for any claims, actions, demands or suits arising from such use.
Oxygen Therapy
Arterial blood gas determination is the gold standard for assessing oxygenation and
ventilation during an exacerbation.
Therapeutic Tips
Perform spirometry with bronchodilator assessment in the following patients:[7]
all smokers ≥35 years of age
past smokers with a ≥20 pack-year (number of packs smoked per day х number of years
smoked) history of smoking, whether or not the patient complains of symptoms
patients with recurrent or chronic respiratory symptoms including cough and breathlessness
on exertion
patients with a family history of COPD
patients who have significant occupational exposure to respiratory irritants
Ensure vaccines are up to date.
Review inhaler technique at each visit.
Promote smoking cessation at each visit (see Tobacco Use Disorder: Smoking Cessation).
Encourage physical activity to prevent a cycle of decreasing mobility and increasing dyspnea.
Encourage adherence to therapy by using a stepwise approach to treatment with positive
reinforcement at all stages.
Ensure patient and family are aware of warning signs of a COPD exacerbation and have a written
action plan for initial management. A COPD action plan has been developed and is available from
the COPD Action Plan website.
Recommend helpline groups including the Canadian Lung Association (New Patient Information
number 1-866-717-COPD [2673]).
Algorithms
[1][2][9]
Figure 1: Pharmacologic Management of COPD
[a]
A patient with frequent exacerbations is classified as: ≥2 exacerbations requiring antibiotics and/or
systemic corticosteroids ≥1 exacerbation requiring hospitalization in the past year.
Abbreviations: CAT = COPD Assessment Test; COPD = chronic obstructive pulmonary disease; FEV1
= forced expiratory volume in 1 second; ICS = inhaled corticosteroids; LABA = long-acting beta2-
agonist; LAMA = long-acting muscarinic antagonist/anticholinergic; mMRC = Modified Medical Research
Council; PDE4 = phosphodiesterase 4; SABA = short-acting beta2-agonist; SABD = short-acting
bronchodilator
Drug Tables
Table 4: Inhaled Drugs Used for the Treatment of COPD
Drug/Cost[a] Dosage Adverse Effects
Drug Class: Beta2-adrenergic Agonists, short-acting (SABA)

pMDI 100 mcg/puff: Tremor, nervousness,

Airomir, Ventolin Diskus, Ventolin 1–2 puffs inhaled hypokalemia, tachycardia,
HFA, Ventolin Nebules P.F., TID–QID PRN; palpitations.
generics maximum 8 puffs
(800 mcg)/day
$
Diskus
200 mcg/actuation:
1 actuation inhaled
TID–QID PRN;
maximum
800 mcg/day
Nebules: 2.5–5 mg
inhaled QID PRN
Individualize dose Tremor, nervousness,

Bricanyl Turbuhaler DPI hypokalemia, tachycardia,
0.5 mg/actuation: palpitations.
$
1 actuation inhaled
Q4–6H PRN;
maximum
6 actuations/day
Drug Class: Muscarinic Antagonists,[b] short-acting (SAMA)
Individualize dose; Dry mouth, metallic taste,

Atrovent HFA, generics may use PRN or mydriasis and glaucoma if
regularly scheduled released into eye; urinary
$ retention.
pMDI 20 mcg/puff:
2–4 puffs inhaled Possible increased risk of
Q6–8H up to cardiovascular events.
6–8 puffs inhaled
Q6–8H, if tolerated;
maximum
12 puffs/day
Nebules:
250–500 mcg
inhaled TID–QID
Drug Class: Muscarinic Antagonist[b]/Beta2-adrenergic Agonist Combinations, short-

acting (SAMA/SABA)
Individualize dose Dry mouth, metallic taste,

Combivent Respimat, Combivent SMI 20/100 mcg mydriasis and glaucoma if
UDV, generics per actuation; released into eye; urinary
1 actuation inhaled retention.
$
QID; additional Possible increased risk of
doses PRN; cardiovascular events.
maximum Tremor, nervousness,
6 doses/day hypokalemia, tachycardia,
UDV nebules palpitations.
0.5/2.5 mg per
2.5 mL: 2.5 mL
inhaled Q6H PRN
Drug Class: Beta2-adrenergic Agonists, long-acting (LABA)

DPI Tremor, nervousness,

Foradil 12 mcg/capsule: hypokalemia, tachycardia,
1 capsule inhaled palpitations.
$$ BID; maximum
48 mcg/day (as
2 capsules inhaled
BID)
DPI 6 or Tremor, nervousness,

Oxeze Turbuhaler 12 mcg/actuation: hypokalemia, tachycardia,
1 actuation inhaled palpitations.
$$ Q12H; maximum
48 mcg/day
DPI Tremor, nervousness,

Onbrez Breezhaler 75 mcg/capsule: hypokalemia, tachycardia,
1 capsule inhaled palpitations.
$$ once daily
Diskhaler Tremor, nervousness,

Serevent 50 mcg/blister: hypokalemia, tachycardia,
1 blister inhaled palpitations.
$$ BID
Diskus
50 mcg/actuation:
1 actuation inhaled
BID
Drug Class: Muscarinic Antagonists,[b] long-acting (LAMA)
DPI Dry mouth, metallic taste,

Tudorza Genuair 400 mcg/actuation: mydriasis and glaucoma if
1 actuation inhaled released into eye; urinary
$$ BID retention.

Seebri Breezhaler 50 mcg/capsule: mydriasis and glaucoma if
1 capsule inhaled released into eye; urinary
$$ once daily retention.

Spiriva, Spiriva Respimat 18 mcg/capsule: mydriasis and glaucoma if
SMI
2.5 mcg/actuation:
2 actuations
inhaled once daily

Incruse Ellipta 62.5 mcg/actuation: mydriasis and glaucoma if
Drug Class: Inhaled Corticosteroid/Beta2-adrenergic Agonist Combinations, long-acting

(ICS/LABA)
DPI 100/6 mcg or Corticosteroid: oropharyngeal

[c] 200/6 mcg per candidiasis and hoarseness
Symbicort Turbuhaler actuation: (can be prevented by using a
2 actuations spacer with pMDI or by using
$$$ inhaled BID; DPI, and by rinsing mouth after
maximum use); skin bruising;[35] posterior
8 actuations/day subcapsular and nuclear
cataracts,[36] possible worsening
of glaucoma. May decrease
bone mineral density and
increase fracture risk. Consider
monitoring bone mineral density
in individuals at high risk, e.g.,
osteoporosis.
LABA: tremor, nervousness,
hypokalemia, tachycardia,
palpitations.
pMDI 125/25 mcg Corticosteroid: oropharyngeal

Advair, Advair Diskus or 250/25 mcg per candidiasis and hoarseness
puff: 2 puffs inhaled (can be prevented by using a
$$$$$ BID spacer with pMDI or by using
Diskus DPI DPI, and by rinsing mouth after
100/50 mcg, use); skin bruising;[35] posterior
250/50 mcg or subcapsular and nuclear
500/50 mcg per cataracts,[36] possible worsening
actuation: of glaucoma. May decrease
1 actuation inhaled bone mineral density and
BID increase fracture risk. Consider
osteoporosis.
palpitations.
DPI 100/25 mcg Corticosteroid: oropharyngeal

Breo Ellipta per actuation: candidiasis and hoarseness
1 actuation inhaled (can be prevented by using a
$$$ once daily spacer with pMDI or by using
DPI, and by rinsing mouth after
use); skin bruising;[35] posterior
subcapsular and nuclear
osteoporosis.
palpitations.
Drug Class: Muscarinic Antagonist[b]/Beta2-adrenergic Agonist Combinations, long-

acting (LAMA/LABA)
DPI 400/12 mcg LAMA: dry mouth, metallic taste,

per actuation: mydriasis and glaucoma if
Duaklir Genuair 1 actuation inhaled released into eye; urinary
BID retention.
$$$
palpitations.
DPI 50/110 mcg LAMA: dry mouth, metallic taste,

Ultibro Breezhaler per capsule: mydriasis and glaucoma if
$$$ once daily retention.
palpitations.
SMI 2.5/2.5 mcg LAMA: dry mouth, metallic taste,

Inspiolto Respimat per actuation: mydriasis and glaucoma if
2 actuations released into eye; urinary
$$$ inhaled once daily retention.
palpitations.
DPI 62.5/25 mcg LAMA: dry mouth, metallic taste,

Anoro Ellipta per actuation: mydriasis and glaucoma if
$$$ once daily retention.
palpitations.
Drug Class: Inhaled Corticosteroid/Muscarinic Antagonist[b]/Beta2-adrenergic Agonist

Combinations, long-acting (ICS/LAMA/LABA)
DPI Corticosteroid: oropharyngeal

Trelegy Ellipta 100/62.5/25 mcg candidiasis and hoarseness
per actuation: (can be prevented by using a
$$$$$ 1 actuation inhaled spacer with pMDI or by using
once daily DPI, and by rinsing mouth after
use); skin bruising;[35] posterior
subcapsular and nuclear
osteoporosis.
palpitations.
Dry mouth, metallic taste,
mydriasis and glaucoma if
released into eye; urinary
retention.
[a] Cost of inhaled agents is per unit; cost of inhaled solutions is per 20 vials; includes drug cost only.
[b] Also referred to as anticholinergics.
[c]
Not approved for the relief of acute bronchospasm in COPD.
Abbreviations: DPI = dry powder inhaler; ICS = inhaled corticosteroids; LABA = long-acting beta2-adrenergic
agonists; LAMA = long-acting muscarinic antagonists; pMDI = pressurized metered dose inhaler; SABA = short-
acting beta2-adrenergic agonists; SAMA = short-acting muscarinic antagonists; SMI = soft mist inhaler; UDV
= unit-dose vial
Legend: $ < $30 $$ $30–60 $$$ $60–90 $$$$ $90–120 $$$$$ 120–150
Table 5: Oral Drugs Used in the Treatment of COPD
Drug/Cost[a] Dosage Adverse Effects Drug

Interactions
Drug Class: Corticosteroids, systemic
For acute GI upset, fluid/electrolyte imbalance, Increased GI

generics exacerbation pituitary-adrenal suppression, ulceration with
of COPD: hypertension, cutaneous effects NSAIDs.
$ 30–40 mg (dermal thinning, easy bruising, acne), Decreased
once daily hyperglycemia, glycosuria, peptic efficacy of
PO ulcer, behavioural disturbances prednisone with
× 5–14 days (insomnia, euphoria), posterior barbiturates,
subcapsular cataracts, glaucoma, phenytoin,
myopathy, decreased bone mineral rifampin.
density, cushingoid, avascular
necrosis of bone including hip (rare). Increased levels
with CYP3A4
inhibitors, e.g.,
clarithromycin,
erythromycin,
ketoconazole.
Hypokalemia with
concomitant
diuretics, e.g.,
thiazides.
Prednisone
decreases
response to
vaccines.
Drug Class: Methylxanthines

Drug/Cost[a] Dosage Adverse Effects Drug
Interactions
Initial: Nausea, vomiting, abdominal cramps, Many drugs can

Uniphyl, Apo- 400–600 mg headache, nervousness, tremor, affect theophylline
Theo LA, once daily insomnia, tachycardia. serum levels.
other PO with Decreased
generics food, usually theophylline
with the serum levels may
$ evening occur with
meal. alcohol,
Monitor and carbamazepine,
adjust based phenobarbital,
on serum phenytoin,
levels rifampin, tobacco
smoking.
Increased
theophylline
serum levels may
occur with
amiodarone,
cimetidine,
ciprofloxacin,
clarithromycin,
erythromycin,
fluvoxamine,
isoniazid,
mexiletine,
verapamil.
Drug Class: Mucolytics
600 mg BID Nausea, vomiting, stomatitis, May enhance

injectable rhinorrhea. vasodilation of
generics solution nitroglycerin.
administered
$$$$ PO mixed
with cola or
other
beverage to
reduce
nausea and
vomiting
Drug Class: Phosphodiesterase 4 (PDE4) Inhibitors
500 mcg Nausea, vomiting, diarrhea, Strong CYP450

Daxas once daily decreased appetite, weight decrease, inducers (e.g.,
PO abdominal pain, headache, insomnia, carbamazepine,
$$$ anxiety, depression. Avoid the use of phenobarbital,
this medication in patients with a phenytoin,
history of depression with suicidal rifampin) may
ideation. reduce the
therapeutic effect
of roflumilast and
are not
recommended in
combination with
roflumilast.
[a] Cost of 14-day supply; includes drug cost only.

Abbreviations: COPD = chronic obstructive pulmonary disease; GI = gastrointestinal; NSAID = nonsteroidal
anti-inflammatory drug
Legend: $ < $15 $$ $15–30 $$$ $30–45 $$$$ $45–60

Table 6: Oral Antibiotics for Treatment of Acute Exacerbations of COPD
Drug/Cost[a] Dosage[b] Adverse Drug

Effects Interactions
Drug Class: Penicillins
1000 mg TID PO Rash, May increase

generics × 5–7 days anaphylaxis serum levels of
(rare). methotrexate.
$ May enhance
anticoagulant
effect of warfarin.
875 mg BID PO Anaphylaxis, GI May increase

Clavulin, generics × 5–10 days upset, diarrhea. serum levels of
Alternative: 500 mg TID methotrexate.
$$ PO × 5–10 days May enhance
anticoagulant
effect of warfarin.
Drug Class: Sulfonamide Combinations
800/160 mg (2 regular- Nausea, skin May increase

strength tablets or rash, Stevens- warfarin effect;
generics 1 double-strength tablet) Johnson may increase
BID PO × 5–7 days syndrome phenytoin levels;
$ (rare). may increase
methotrexate
toxicity.
Drug Class: Tetracyclines
200 mg PO × 1 dose then GI upset, Iron or antacids

generics 100 mg BID PO photosensitivity. decrease
× 5–7 days doxycycline
$ absorption.
Carbamazepine,
phenytoin,
rifampin, may
decrease
doxycycline
levels.
Drug Class: Cephalosporins
500 mg BID PO GI intolerance, No major drug

Ceftin, generics × 5–10 days anaphylaxis interactions but
(rare), rash. enhanced
$$$ anticoagulant
effect of warfarin
possible.
Drug Class: Fluoroquinolones

Patients at risk of Usually well Antacids,

Cipro, generics : tolerated. sucralfate, metal
500–750 mg BID PO Headache, cations decrease
$$ × 7–21 days dizziness may fluoroquinolone
occur. absorption.
Peripheral May increase
neuropathy, theophylline
tendon rupture levels; may
(rare). increase warfarin
May worsen effect.
symptoms of Avoid using with
myasthenia drugs that
gravis and prolong the QTc
should not be
interval such as
used in this
Class IA or Class
population.
III
QTc antiarrhythmics.
prolongation.
750 mg once daily PO Usually well Antacids,

generics × 5 days tolerated. sucralfate, metal
Alternative: 500 mg once Headache, cations decrease
$$ daily PO × 7 days dizziness may fluoroquinolone
occur. absorption.
May worsen effect.
should not be
interval such as
used in this
Class IA or Class
population.
III
prolongation.
Cases of
severe liver
injury including
liver failure
have been
reported.
400 mg once daily PO Usually well Antacids,

Avelox, generics × 5 days tolerated. sucralfate, metal
Headache, cations decrease
$ dizziness may fluoroquinolone
occur. absorption.
May worsen effect.
should not be
interval such as
used in this
Class IA or Class
population.
III
prolongation.
Cases of
severe liver
injury including
liver failure
have been
reported.
Drug Class: Macrolides, extended spectrum
500 mg once daily PO GI intolerance, Coadministration

Zithromax, generics × 3 days QTc with pimozide is
Alternative: 500 mg PO prolongation. contraindicated.
$
× 1 day then 250 mg once Use cautiously
daily × 4 days with other drugs
that cause QTc
prolongation
such as Class IA
or Class III
antiarrhythmics.
May increase
effects of digoxin
and warfarin.
Biaxin BID: 500 mg BID Bitter taste, GI Coadministration

Biaxin BID, Biaxin XL, PO × 5–10 days intolerance, with pimozide is
generics Biaxin XL: 1000 mg once QTc contraindicated.
daily PO × 5–10 days prolongation. Use cautiously
$$ with other drugs
that cause QTc
prolongation
such as Class IA
or Class III
antiarrhythmics.
May increase
effects of digoxin
and warfarin.
Inhibitor of
CYP3A4
enzymes;
therefore, many
potential
interactions, e.g.,
atorvastatin,
some
benzodiazepines,
buspirone,
carbamazepine,
colchicine,
cyclosporine,
ergots, glyburide,
lovastatin,
simvastatin,
sirolimus,
tacrolimus,
theophylline.
Inhibitor of Pgp
and may
therefore
increase levels of
Pgp substrates,
e.g., colchicine,
dabigatran.
[a] Cost is for 1 course of therapy; includes drug cost only.

[b] [140] [141]
See references Blondel-Hill and Anti-infective Review Panel.
Dosage adjustment may be required in renal impairment; see Dosage Adjustment in Renal Impairment.
Abbreviations: GI = gastrointestinal; Pgp = P-glycoprotein
Legend: $ < $10 $$ $10–25 $$$ $25–50
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Dougall S, Bolt J, Semchuk W et al. Inhaler assessment in COPD patients: a primer for pharmacists.
2016;149(5):268-73.
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis,
Management and Prevention of Chronic Obstructive Lung Disease. . Available from:
goldcopd.org.
Hurst JR, Vestbo J, Anzueto A et al. Susceptibility to exacerbation in chronic obstructive pulmonary
disease. 2010;363(12):1128-38.
Jones PW, Harding G, Berry P et al. Development and first validation of the COPD Assessment Test.
2009;34(3):648-54.
O'Donnell DE, Hernandez P, Kaplan A et al. Canadian Thoracic Society recommendations for
management of chronic obstructive pulmonary disease–2008 update–highlights for primary care.
2008;15(Suppl A):1A-8A.
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Chronic Obstructive Pulmonary Disease

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Chronic Obstructive Pulmonary Disease

R. Andrew McIvor, MD, MSc, FRCPC

History with particular attention to:[1][2]

Grade I am too breathless to leave the house or I am breathless when dressing or □

[a] Patient can tick only 1 response at a time.

COPD Strategies and Guidelines

Stable COPD and Prevention of Acute Exacerbations

COPD is characterized by persistent inflammation, even in early disease.[1] However, compared

Inhaled COPD Therapies

Table 2: Inhaled Agents Used to Treat COPD

SAMA Ipratropium (Atrovent pMDI and

SAMA/SABA Ipratropium/Salbutamol (Combivent

Bronchodilators, LABA Formoterol fumarate (Foradil DPI)

LAMA/LABA Aclidinium/formoterol fumarate

Anti- ICS/LABA Budesonide/formoterol fumarate

Recommend PRN use of a short-acting beta2-agonist (SABA) such as salbutamol or

The combination of ipratropium/salbutamol produces greater and more sustained

There are 2 types of long-acting bronchodilators available, LAMAs (formerly referred to

Long-Acting Muscarinic Antagonists

Retrospective studies have shown an increased risk of cardiovascular death, MI or

Glycopyrronium is a rapid-onset LAMA delivered via DPI. It has a faster onset of

The inhaled LABAs salmeterol and formoterol offer sustained improvements in

Indacaterol and olodaterol are once-daily, ultra-long-acting beta2-adrenergic

Combination Long-Acting Bronchodilators

When selecting bronchodilator therapy, choose LAMA/LABA over ICS/LABA to

The combination of LAMA/LABA (glycopyrronium/indacaterol) was compared with

Combination Inhaled Corticosteroids and Long-Acting Bronchodilators

ICS monotherapy is not recommended in the management of COPD symptoms;[1][9]

The combination of ICS/LABA plus tiotropium improves bronchodilation and lung

Finally, if triple therapy is required, it is preferable for it to be provided as a single entity

but this is not always practical.[98]

See Table 4 for dosing information related to oral COPD therapies.

Phosphodiesterase 4 (PDE4) Inhibitors

Roflumilast is an oral medication that suppresses the release of inflammatory mediators

Roflumilast has demonstrated a significant improvement in prebronchodilator FEV1

Roflumilast may be considered for add-on therapy to existing triple therapy

Long-acting preparations of theophylline (see Table 5) may be used in patients with

N-acetylcysteine (NAC) is a mucolytic agent with antioxidant properties. The mechanism

One prospective study found supplementation with vitamin D3 (cholecalciferol) 3 mg

Azithromycin may be most effective at preventing exacerbations requiring treatment with

Recommend pneumococcal vaccination to all patients with COPD who have no

Treatment of Acute Exacerbations of COPD

The common bacterial pathogens causing acute exacerbations of COPD are

Table 3: Empiric Antibiotic Therapy for Acute Exacerbation of COPD

Drug/Cost[a] Dosage Adverse Effects

Drug Class: Beta2-adrenergic Agonists, short-acting (SABA)

pMDI 100 mcg/puff: Tremor, nervousness,

Individualize dose Tremor, nervousness,

Drug Class: Muscarinic Antagonists,[b] short-acting (SAMA)

Individualize dose; Dry mouth, metallic taste,

Drug Class: Muscarinic Antagonist[b]/Beta2-adrenergic Agonist Combinations, short-

Individualize dose Dry mouth, metallic taste,

Drug Class: Beta2-adrenergic Agonists, long-acting (LABA)

DPI Tremor, nervousness,

DPI 6 or Tremor, nervousness,

DPI Tremor, nervousness,

Diskhaler Tremor, nervousness,

Drug Class: Muscarinic Antagonists,[b] long-acting (LAMA)

DPI Dry mouth, metallic taste,

DPI Dry mouth, metallic taste,

DPI Dry mouth, metallic taste,

DPI Dry mouth, metallic taste,

Drug Class: Inhaled Corticosteroid/Beta2-adrenergic Agonist Combinations, long-acting

DPI 100/6 mcg or Corticosteroid: oropharyngeal