Pharmacotherapeutics I

PHAR 342

Lecture 12

Pharmacotherapy of COPD

By: Dr. Amal Galal

 COPD

• Chronic Obstructive Pulmonary Disease (COPD) is a progressive lung

disease characterized by airflow limitation that is not fully reversible. It
is caused by exposure to noxious particles or gases, most commonly
cigarette smoke. It is a major cause of morbidity & mortality.
• In order to standardize the care of patients with COPD, the National Heart,
Lung, and Blood Institute and the WHO launched the Global Initiative for
Chronic Obstructive Lung Disease (GOLD) in 2001. GOLD guidelines
are updated annually and aim to increase awareness of COPD and reduce
morbidity & mortality associated with the disease.
• COPD is differentiated from asthma in that the airflow limitation that is
present is not fully reversible; it is fixed with minimal improvement in
response to bronchodilators. However, it is preventable and treatable.

Epidemiology & Etiology

• In the USA, in 2000, 119,000 adults died from the disease; in 2001, 12.1
million people aged over 25 reported having COPD; in 2002, COPD was
estimated to cost the USA $32.1 billion; COPD represents the second
leading cause of disability (limiting physical activity and ability to work) and
is expected to be the third leading cause of death by 2020.
• Exposures & host factors play a role in the development of COPD:
Exposures Host factors

o Environmental tobacco smoke o Genetic susceptibility (AAT deficiency)

o Occupational dust & chemicals o Airway hyperresponsiveness
o Air pollution o Impaired lung growth

– Cigarette smoking is the primary cause of COPD and accounts for

80-90% of cases. Components of tobacco smoke activate inflammatory
cells, which release inflammatory mediators characteristic of COPD.
– However, only 15-20% of smokers develop COPD; this suggests that
genetic susceptibility (hereditary deficiency of AAT) plays a role.
– Exposure to multiple environmental toxins increases the risk of COPD;
for example, an individual who smokes and works in a textile factory (or
coal mining, or is exposed to asbestos or heating fires) has a higher
total burden of inhaled particles than an individual who smokes and
has no occupational exposure.

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 Pathophysiology
• COPD is characterized by chronic inflammation that leads to destructive
changes in the airways, lung parenchyma and pulmonary vasculature.
• The inflammation of COPD differs from that seen in asthma; therefore, the
use of anti-inflammatory medications & the response to those medications
are different: the inflammation of asthma is mediated through eosinophils
and mast cells, while in COPD the primary inflammatory cells are
neutrophils, macrophages & CD8+T-lymphocytes. Activated inflammatory
cells release leukotriene B4, interleukin-8, and tumor necrosis factor-α.
Various proteinases (e.g. elastase) are secreted by activated neutrophils
and are capable of damaging lung structures.
• An imbalance between proteinases & antiproteinases in the lung, and
oxidative stress are considered important in the pathogenesis of COPD:
– The imbalance of proteinase-antiproteinase activity in COPD is a result
of either increased production/activity of destructive proteinases or
reduced production/activity of protective antiproteinases.
– AAT (α
α1-antitrypsin) is an antiproteinase that inhibits trypsin,
elastase, and other proteolytic enzymes. Genetic deficiency of AAT
results in unopposed proteinase activity, which promotes destruction of
alveolar walls and lung parenchyma, leading to emphysema.

– Increased oxidative stress contributes to COPD in a variety of ways:

1. Oxidants (e.g., reactive oxygen species, superoxide and nitric oxide)
can react with a variety of molecules leading to cell dysfunction and
damage to the lung.
2. Oxidative stress promotes inflammation and contributes to the
proteinase-antiproteinase imbalance.
3. Oxidants constrict airway smooth muscle leading to airway narrowing.

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• In the central airways (the trachea, bronchi, and bronchioles greater than 2
to 4 mm in internal diameter), inflammatory cells and mediators stimulate
the increase in the number and size of mucus-secreting glands & mucus
hypersecretion. Mucus hypersecretion together with ciliary dysfunction
lead to chronic cough and sputum production. The major site of airflow
obstruction is the peripheral airways (small bronchi & bronchioles with an
internal diameter less than 2 mm).Three mechanisms are involved in
narrowing of these small airways and fixed airflow obstruction:
1. Airways may be blocked by inflammatory exudates and mucus
hypersecretion.
2. Loss of elasticity and destruction of alveolar attachments leads to loss
of support and closure of small airways during expiration.
3. Infiltration of inflammatory cells, increased smooth muscle tissue, and
fibrosis cause thickening of airway walls.

• As airflow obstruction worsens, the rate of

lung emptying is slowed, and the interval
between inspirations does not allow expiration
to the relaxation volume of the lungs, thus
leading to air trapping resulting in pulmonary
(thoracic) hyperinflation, which initially only
occurs during exercise, but later is also seen
at rest. Hyperinflation contributes to the
discomfort associated with airflow obstruction
by making the diaphragm flattened (normally dome-shaped) and less
efficient in ventilation.
• For patients with COPD who exhibit thoracic hyperinflation, there is an
increase in the amount of air left in the lung after exhalation (also known as
functional residual capacity, FRC). This increased FRC limits the
amount of air that the patient can inhale to fill the lungs as well as the
duration of inhalation time, and this is responsible for the patient
complaints from dyspnea (i.e. difficult breathing). Therefore, by reducing
airflow obstruction, bronchodilators can reduce thoracic hyperinflation.
• In advanced COPD, airflow obstruction, damaged bronchioles and alveoli,
and pulmonary vascular abnormalities lead to impaired gas exchange,
resulting in hypoxemia & hypercapnia.
• Pulmonary hypertension develops late in the course of COPD, usually
secondary to the development of severe hypoxemia (which causes
vasoconstriction of pulmonary arteries). Pulmonary hypertension is the
most common CV complication of COPD and can result in cor pulmonale
(right-sided heart failure) and pulmonary embolism.
• Another important systemic effect is the progressive loss of skeletal
muscle mass, which leads to exercise limitation & declining health status.

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 Diagnosis
• The diagnosis of COPD is based on the patient’s symptoms (cough,
sputum production, and dyspnea) and/or history of exposure to risk factors.
• Spirometry is required to confirm the diagnosis:
– When blowing out forcefully, individuals with normal lungs can exhale
most of the air in their lungs in one second.
– However, in patients with COPD the FEV1:FVC ratio is less than 70%
(which indicates airway obstruction) and the post-bronchodilator
FEV1 is less than 80% of predicted (which confirms airflow limitation
that is not fully reversible).

FEV1 = Forced Expiratory Volume in 1 second (in L)

FVC = Forced Vital Capacity i.e. the total exhaled breath (in L)

– According to the Spirometry results, the GOLD guidelines previously

suggested the following four-stage classification of COPD severity:

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• Recently, the GOLD guidelines included a modified system for classifying
COPD severity based on numerous factors that have a significant impact
on the patient, including:
1. Degree of airflow obstruction, where the patient is first classified
according to spirometric results into grades ranging from 1 to 4.
2. Frequency & severity of symptoms, where the patient is placed into
a group (A, B, C, or D) based on the impact of symptoms and the risk
for future exacerbations (the extent of symptoms is assessed using a
validated symptom assessment tool, e.g., MMRC; Modified Medical
Research Council dyspnea scale, or CAT; COPD Assessment Test).
3. Frequency of exacerbations, where the patient is categorized based
on a history of less than two annual exacerbations, or two or more.

• Prognosis:
– In patients with COPD, the combination of impaired lung function and
recurrent exacerbations promotes dyspnea, reduced exercise tolerance
and physical activity. These factors lead to disease progression, poor
quality of life, possible disability, and premature mortality. COPD is
ultimately a fatal disease. The primary causes of death of patients with
COPD include respiratory failure, cardiovascular diseases, and lung
cancer.
– Since the FEV1 is the most important prognostic indicator for a
patient with COPD, spirometry should be performed at least annually
to assess disease progression.
– The average rate of decline in FEV1 for healthy, non-smoking patients
due to age alone is 25 to 30 ml/year. The rate of decline for smokers is
steeper, especially for heavy smokers.
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 – The rate of decline of blood gases is not a useful parameter to assess
progression of the disease.
– The survival rate of patients with COPD is highly correlated to the
initial level of impairment in the FEV1: a rapid decline in pulmonary
function tests indicates a poor prognosis; where the median survival is
approximately 10 years when the FEV1 is 1.4 L, 4 years when the
FEV1 is 1 L, and about 2 years when the FEV1 is 0.5 L.
– The BODE index is a validated predictor of mortality better than FEV1
alone; it is a composite score derived from the body mass index or BMI
(B), FEV1 or degree of airflow obstruction (O), Modified Medical
Research Council Dyspnea scale (D), and 6-minute walking distance
exercise capacity (E).
• It is important to distinguish COPD from asthma because treatment and
prognosis differ. Differentiating factors include age of onset, smoking
history, triggers, occupational history, and degree of reversibility measured
by pre- and post-bronchodilator spirometry.
• Other lung diseases (e.g. tuberculosis & cystic fibrosis) are distinguished
from COPD by chest radiography or high-resolution computed tomography
(CT) along with clinical presentation.

Clinical Presentation
• Patients with COPD are initially asymptomatic.
The disease is usually not diagnosed until
declining lung function leads to significant
symptoms and prompts the patients to seek
medical care.

• Symptoms:
– The onset of symptoms does not occur until the FEV1 has fallen to
approximately 50% of predicted.
– Most patients of COPD demonstrate both chronic bronchitis and
emphysema.
– Chronic bronchitis is a recurrent excessive mucus secretion into the
bronchial tree with cough that is present on most days for at least 3
months of the year for at least 2 consecutive years in a patient in whom
other causes of chronic cough are excluded.
– Dyspnea is first observed on exertion, then as COPD progresses, it
develops at rest, and the ability to perform daily activities declines.

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• Signs:
– Observation of the patient may reveal the use of accessory muscles of
respiration manifested as paradoxical movements of the chest and
abdomen, in a see-saw–type motion, pursed-lips breathing, and
hyperinflation of the chest (barrel chest).

See-saw chest Barrel chest

Pursed-lips breathing

– On auscultation of the lungs, patients may have wheezing & prolonged

expiratory phase of respiration.
– In advanced COPD, signs of hypoxemia may include cyanosis and
tachycardia.
– Signs of cor pulmonale include increased jugular venous distention,
lower extremity edema, and hepatomegaly.

• Lab tests
– Arterial blood gases (ABGs) should be obtained in patients with FEV1
less than 40% of predicted, or signs or symptoms suggestive of cor
pulmonale or respiratory failure.
– An α1-antitrypsin (AAT) level should be obtained in younger patients
(less than 45 years old) presenting with COPD signs and symptoms,
especially if there is a strong family history of emphysema.

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 Treatment

Desired Outcomes

• The goals of COPD management include:

– Prevent disease progression
– Relieve symptoms
– Improve exercise tolerance
– Improve overall health status
– Prevent and treat exacerbations
– Prevent and treat complications
– Reduce morbidity and mortality

• There are 4 primary components of COPD management:

– Assess and monitor the condition.
– Avoid or reduce exposure to risk factors.
– Manage stable disease.
– Treat exacerbations.

• These components are addressed through a variety of non-pharmacologic

and pharmacologic approaches.

Non-Pharmacological Therapy

• Smoking cessation:
– It is a critical part of any treatment
plan for patients with COPD.
– It is the only intervention known to
slow the rate of decline in pulmonary
function in patients with COPD.
– Stopping smoking can also reduce
cough and sputum production and
decrease airway reactivity.
– Patients who are ready to quit should be treated with a combination of
counseling on behavioral strategies and pharmacotherapy (nicotine
replacement therapy, sustained-release bupropion, or varenicline).

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• Pulmonary rehabilitation:
– It includes exercise training, nutrition counseling, and education.
– It should cover a range of non-pulmonary problems including lost
exercise fitness, altered mood, muscle wasting, and weight loss.

• Long-Term Oxygen Therapy:

– Long-term administration of oxygen (greater
than 15 hours per day) to patients with chronic
respiratory failure has been shown to reduce
mortality and improve quality of life.
– Oxygen therapy should be initiated in stable
patients with very severe COPD (GOLD stage
IV) and should be continued indefinitely.
– Withdrawal of oxygen because of improved
PaO2 in such a patient may be detrimental.

• Immunization:
– Because influenza is a common complication in COPD that can lead
to exacerbations and respiratory failure, an annual vaccination with the
inactivated intramuscular influenza vaccine is recommended.
– Immunization against influenza can reduce serious illness and death by
50% in COPD patients.

• Surgery:
– Lung volume reduction surgery (bullectomy)
and lung transplantation are surgical options for
very severe COPD.

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 Pharmacological Therapy of stable COPD

Medications available for COPD are effective for reducing or relieving

symptoms, improving exercise tolerance, reducing the number and severity of
exacerbations, and improving quality of life. No medications presently
available have been shown to slow the rate of decline in lung function.

Bronchodilators
• They are the mainstay of treatment for symptomatic COPD.
• They can be used as needed for symptoms or on a scheduled basis to
prevent or reduce symptoms.
• Bronchodilators used in COPD include β2-agonists, anticholinergics, and
theophylline. The choice depends on availability, individual response, and
preferences.
• The inhaled route is preferred.
• Long-acting inhaled bronchodilators are more effective and convenient
but more expensive than short-acting inhaled bronchodilators.
• Combination therapy is preferred over increasing the dose of a single
agent, since the dose-response relationship using FEV1 as the outcome is
flat for single-agent therapy.

Beta2-Agonists.
• Short-acting β2-agonists (albuterol, levalbuterol, terbutaline & pirbuterol)
are used as rescue therapy for acute symptom relief.
• Most COPD patients need continuous bronchodilator therapy on a
scheduled basis every day. For these patients, short-acting β2-agonists
are inconvenient because of the need for frequent dosing. In addition,
short-acting β2-agonists lose effectiveness when used regularly for more
than 3 months (tachyphylaxis).
• Long-acting β2-agonists (salmeterol & formoterol) have bronchodilator
effects that last at least 12 hours (allowing for twice-daily dosing) and are
superior to scheduled short-acting bronchodilators regarding clinical
outcomes (i.e. frequency of exacerbations, degree of dyspnea, etc …).
• Therefore, for symptomatic patients, long-acting β2-agonists are preferred
over short-acting agents for maintenance therapy; patients should also
have a short-acting β2-agonist available as a rescue medication.

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Anticholinergics.
• Ipratropium & tiotropium are inhaled anticholinergic drugs commonly
used for COPD, producing bronchodilation & decreasing mucus secretion.
• Tiotropium dissociates from receptors extremely slowly resulting in a t1/2
longer than 36 hours, which allows for once-daily dosing. Ipratropium has
an elimination t1/2 of about 2 hours, necessitating dosing every 6 to 8 hours.
• Tiotropium is superior to ipratropium & salmeterol in improving lung
function, and superior to ipratropium in relieving symptoms, reducing
exacerbation frequency, and improving health status. It is therefore
considered first-line therapy for all COPD patients with persistent
symptoms (e.g., dyspnea, need for rescue medication more than twice a
week, and night waking).
• The largest drawback of tiotropium is the high cost of therapy.
• Patients using tiotropium as maintenance therapy should be prescribed
albuterol as their rescue therapy.

Theophylline.
• It has a modest bronchodilator effect in patients with COPD.
• Its use is limited due to its narrow therapeutic index, multiple drug
interactions, and adverse effects.
• Theophylline should be reserved for patients who cannot use inhaled
medications or who remain symptomatic despite appropriate use of inhaled
bronchodilators.

Combination of bronchodilators.
• Patients with COPD usually need maintenance treatment with 2 or 3
bronchodilators; these combinations produce greater change in spirometry
than either drug alone; examples include:
– Albuterol + ipratropium
– Long-acting β2-agonist + theophylline
– Long-acting β2-agonist + tiotropium
– β2-agonist + anticholinergic + theophylline

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 Corticosteroids
• In symptomatic patients with severe COPD (FEV1 less than 50%
predicted) and frequent exacerbations, regular treatment with inhaled
corticosteroids decreases the number of exacerbations per year and
improves health status; however, corticosteroids do not slow the long-
term decline in pulmonary function.
• Patients should be reassessed 6 to 8 weeks after initiating inhaled
corticosteroids to determine whether there is a positive response, indicated
by an increase in FEV1 of 15% or more, improvement in symptoms, and/or
improvement in 6-minute walking distance.
• Treatment should be discontinued if no clinical improvement is seen.
Upon discontinuation of inhaled corticosteroids, some patients may show
deterioration in lung function, increase in dyspnea and mild exacerbations;
in these patients, corticosteroids should be reinstituted.

Alpha1-Antitrypsin augmentation therapy

• Intravenous augmentation therapy for individuals with AAT deficiency and
severe airflow obstruction (FEV1 35 - 60% predicted) is recommended to
reduce overall mortality and slow the decline in FEV1.
• Augmentation therapy consists of weekly transfusions of pooled human
AAT with the goal of maintaining adequate plasma levels of the enzyme.

Other Pharmacological Therapies

• Leukotriene modifiers (e.g., zafirlukast and montelukast) have not been
adequately evaluated in COPD patients and are not recommended for
routine use.
• N-acetylcysteine has antioxidant & mucolytic activity, which makes it a
promising agent for COPD treatment, but clinical trials have produced
conflicting results.
• Prophylactic, continuous use of antibiotics has no effect on the frequency
of exacerbations; antibiotics should only be used for treating infectious
exacerbations.
• Antitussives are contraindicated because cough has a protective role.
• Opioids may be effective for dyspnea in terminal patients.

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 Pharmacological Therapy of COPD exacerbations

• An exacerbation is a sustained worsening of the patient symptoms from

the usual stable state that is beyond normal day-to-day variations. It is
acute in onset and sufficient to make a change in management.
• Exacerbation symptoms are: worsening of dyspnea, increased sputum
production, and change in sputum color.
• The most common causes of an exacerbation are respiratory infection and
air pollution.
• Treatment depends on the symptoms & severity of the exacerbation:
– Mild exacerbations can be treated at home with an increase in
bronchodilator therapy with or without oral corticosteroids. Antibiotics
are indicated only if there are clinical signs of airway infection (e.g.,
increased volume and change in color of sputum and/or fever).
– Moderate-to-severe exacerbations require management in the
emergency department or hospital. Management should consist of
oxygen therapy, bronchodilators, oral or intravenous corticosteroids,
antibiotics if indicated, and consideration of mechanical ventilation.

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