Review Article: A review of bronchodilators for chronic obstructive pulmonary disease

A review of bronchodilators for chronic

obstructive pulmonary disease
Haley Smith, BPharm
Amayeza Info Services
Correspondence to: Haley Smith, e-mail: haley@amayeza-info.co.za
Keywords: bronchodilators, chronic obstructive pulmonary disease

Abstract
Chronic obstructive pulmonary disease (COPD) is a progressive lung disease that is associated with airway obstruction.
COPD is a major cause of chronic morbidity and mortality throughout the world. It is a progressive condition, but is partially
reversible through treatment, especially when diagnosed early in its clinical course. Bronchodilators are important in treating
the symptoms of COPD. Long-acting bronchodilators provide sustained symptom relief and are usually preferred in patients
with COPD. Combining bronchodilators with different mechanisms of action appears to improve efficacy.
Medpharm

Reprinted with permission from S Afr Pharm J 2013;80(7):9-12

Introduction

responsiveness.3 Rarely, a genetic condition called alpha1antitrypsin deficiency may play a role in causing COPD.3,5

Chronic obstructive pulmonary disease (COPD) is the fourth

leading cause of death in the world and represents an
important public health challenge. Many people may suffer
from this disease for years, and die prematurely from it or
its complications. Globally, the COPD burden is projected to
increase in coming decades because of continued exposure
to COPD risk factors and ageing of the population.1

Symptoms
Initially, in the early stages of COPD, the patient may
experience no symptoms or only mild symptoms.3 However,
as the disease progresses, the symptoms of COPD may
worsen.3 Characteristic symptoms of COPD are a chronic
cough, sputum production and dyspnoea (breathlessness).
The most common early symptom is exertional dyspnoea.
Other symptoms may include chest tightness, wheezing,
fatigue, morning headaches and an increase in respiratory
infections, such as colds and flu.1,3,6,7

Chronic obstructive pulmonary disease

COPD is associated with chronic inflammation of the
airways.2 As the lungs become more damaged over time,
it becomes increasingly difficult to breathe.3 The damage to
the lungs causes less air to flow in and out of the airways in
COPD, because of one or more of the following factors:4,5
The walls of the airways become thick and inflamed
The airways in the lungs can become scarred and
narrowed
The airways and air sacs lose their elastic quality
The walls between many of the air sacs are destroyed
The airways may become clogged with mucus

Diagnosis
The diagnosis of COPD is based upon the presence of
symptoms associated with COPD, such as a cough with
or without sputum production, dyspnoea at rest or during
exertion, and progressive limitation of activity.The hallmark
for the diagnosis of COPD is spirometry showing airflow
limitation that is incompletely reversible with an inhaled
bronchodilator. 1,3,6

Risk factors

Management

Across the world, cigarette smoking is the most commonly

encountered risk factor for COPD, but in developing
countries, biomass fuel smoke and tuberculosis are
important additional causes.1,2 The amount and duration of
smoking contributes to COPD severity.6 However, there is
consistent evidence from epidemiological studies that nonsmokers may also develop COPD.1,3 Exposure to secondhand smoke and air pollution may also increase the risk of
developing COPD, as well as an abnormal sensitivity and
exaggerated response to inhaled substances, called airway

Currently, there is no cure for COPD. However, lifestyle

changes and treatments may help to relieve symptoms, slow
the progression of the disease, improve exercise tolerance
and prevent and treat possible COPD complications.5,7

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Lifestyle changes
The best method for cigarette smokers to prevent or keep
COPD from worsening is to quit smoking.1,5 Second-hand
smoke, dust, fumes or other toxic substances which may
be inhaled should also be avoided.5

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Review Article: A review of bronchodilators for chronic obstructive pulmonary disease

Treatment with bronchodilators

because of its rapid onset of action.2 Indacaterol is a new

once-daily inhaled beta 2 agonist with a duration of action
of 24 hours.1,11 The bronchodilator effect is significantly
greater than that of formoterol and salmeterol and similar
to tiotropium.1

Bronchodilators are medication that is used to relax and

expand the bronchial muscles. By relaxing these muscles,
the airways become wider, which helps to improve airflow
through the lungs, making breathing easier for patients with
COPD.5,7-10 Bronchodilators are important in treating the
symptoms of COPD, such as breathlessness, coughing and
sputum production.8 Many different kinds of bronchodilators
are available. They can be grouped according to the method
by which they dilate the airways. Therefore, it is possible
to combine bronchodilators of different pharmacological
classes in order to achieve maximal benefit.1,8

Side-effects of b2-agonists
Side-effects of b2-agonists are often dose-related. They
include the following:1,10
Tremors
Palpitations
Tachycardia (a rapid heart rate)
Premature ventricular contractions
Hypokalaemia (decreased potassium levels)
Sleep disturbances

Bronchodilators are most commonly given in an inhaled

form, using a metered dose inhaler, dry powder inhaler or
nebuliser. It is important to use the inhaler properly to ensure
that the correct dose of medication is delivered to the lungs.
If the inhaler is not used correctly, little or no medicine will
reach the lungs.4

Anticholinergics
The most important effect of anticholinergic medication
in patients with COPD appears to be blockage of
acetylcholines effect on the muscarinic receptors.1 They are
able to cause bronchodilation with minimal side-effects and
may be of particular benefit to patients who are not able to
use inhaled b2-agonists.10

The three main groups of bronchodilators are beta 2 agonists,

anticholinergics and theophyllines.1,8 It is recommended to
commence treatment in symptomatic patients with COPD
using an inhaled short-acting bronchodilator (beta 2 agonist
or anticholinergic) on an as-needed basis. Thereafter,
treatment should be increased stepwise to include inhaled
long-acting bronchodilators, slow-release theophylline and
inhaled corticosteroids.2

Anticholinergic medications can be either short- or

long-acting.

Short-acting anticholinergics
The bronchodilating effect of short-acting inhaled
anticholinergics lasts longer than that of short-acting
b2-agonists, with some bronchodilator effect apparent
up to eight hours after administration.1 Short-acting
anticholinergics, e.g. ipratropium, improve lung function
and COPD symptoms. If symptoms are mild and infrequent,
a short-acting anticholinergic may be recommended on an
as-needed basis.4

b2-agonists
The principle action of the b2-agonists is to stimulate b2
adrenergic-receptors, which increase cyclic adenosine
monophosphate
and
functional
antagonism
to
bronchoconstriction. This results in relaxation of the smooth
muscle of the airways.1 b2-agonists can either be short- or
long-acting.1,4,5

Long-acting anticholinergics

Short-acting b2-agonists

Long-acting anticholinergic medication, e.g. tiotropium,

is administered once daily, and improves lung function
while decreasing shortness of breath and flares of COPD
symptoms. Long-acting anticholinergics are recommended
if COPD symptoms are not adequately controlled with the
short-acting bronchodilators.4 Tiotropium has a duration of
action of more than 24 hours.1 Tiotropium may be used as
a first-line long-acting bronchodilator, or may be used in
combination with a long-acting beta 2 agonist because of
their different mechanisms of action.1

Short-acting b2-agonists, or rescue inhalers, are used to

relieve shortness of breath and should only be used on
an as-needed basis.4,5 The bronchodilator effects of shortacting b2-agonists usually wear off within 4-6 hours.1
Examples of short-acting b2-agonists include salbutamol,
fenoterol and terbutaline.1

Long-acting beta 2 agonists

Long-acting b2-agonists are recommended for patients with
COPD who need to use medication on a regular basis to
control their symptoms.4 Long-acting b2-agonists have been
shown to have a duration of action of 12 hours or longer.
Examples include salmeterol, formoterol and indacaterol.1
Their use as monotherapy, without inhaled corticosteroids,
appears to be safe (in contrast to asthma).2 Long-acting
b2-agonists improve symptoms, reduce exacerbations
and rescue therapy requirements, and increase exercise
capacity.2 Formoterol may also be used as reliever treatment

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Side-effects of anticholinergics
Anticholinergics are poorly absorbed which may limit
troublesome systemic effects.1 The most commonly
reported side-effect of anticholinergeric agents is dryness of
the mouth. Some patients using ipratropium have reported
a bitter metallic taste after inhalation.1,10 An unexpected
small increase in cardiovascular events in patients with
COPD who are regularly treated with ipratopium bromide
has been reported, which requires further investigation.1

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Review Article: A review of bronchodilators for chronic obstructive pulmonary disease

Acute glaucoma has been noted when using solutions with

a face mask, probably from a direct effect of the solution on
the eye.1,10

Table I details bronchodilators that are used in stable

chronic obstructive pulmonary disease.1

Complications

Methylxanthines
The mechanism that underlies the beneficial effect of the
methylxanthines in treating COPD is not well defined,
but may include an improvement in respiratory muscle
strength.10 However, controversy remains about the exact
effects of the xanthine derivatives.1 Theophylline is the
most commonly used methylxanthine. All studies that have
shown the efficacy of theophylline in COPD were performed
using slow-release preparations.1 Theophylline is not
commonly used, but may be beneficial to some people with
more severe, but stable COPD. The dose of theophylline
must be monitored carefully using blood tests because of
its potential toxic effects.4 Theophylline is less effective and
less well tolerated when compared to inhaled long-acting
bronchodilators, and is not recommended if these agents
are available and affordable.1

Complications that may be associated with COPD

include:7,12
COPD exacerbations
Worsening of pre-existing conditions, such as
cardiovascular disease, osteoporosis, diabetes and
mood disorders
Heart failure
Nutritional deficiencies
Skeletal muscle wasting
An increased susceptibility to lung diseases, such as
pneumonia, respiratory failure and end-stage lung
disease

Side-effects

Unfortunately, the symptoms of COPD cannot be completely

eliminated with treatment and the condition usually
worsens over time. However, correct diagnosis of COPD is
important because appropriate management can decrease
symptoms (especially dyspnoea), reduce the frequency and
severity of exacerbations, improve health status, develop
exercise capacity and prolong the survival of the patient.
Bronchodilators are central to the management of COPD
and may be used alone or in combination, depending on the
severity of the patients disease.

Conclusion

Serious side-effects include a rapid heart rate or irregular

heart rhythm. Side-effects that indicate toxicity include
convulsions and heart dysrhythmias. Other side-effects
include headaches, heartburn, nausea, vomiting, diarrhoea
and insomnia. These may occur within the therapeutic
range of theophylline.1,10

Combination bronchodilator therapy

Combining bronchodilators with different mechanisms of
action may increase the degree of bronchodilation with
the same or a lesser side-effect profile.1,10 Combination
inhalers may be used when needed or regularly, depending
on the frequency and severity of COPD symptoms.4 The
combination of a b2-agonists, an anticholinergic and/or
theophylline may produce additional improvements in lung
function and health status in patients with COPD.1

References
1.

Global initiative for chronic obstructive lung disease. Global strategy for the diagnosis,
management, and prevention of chronic obstrcutive pulmonary disease. The Global
Initiative for Chronic Obstructive Lung Disease (GOLD) [homepage on the Internet].
2013. Available from: http://www.goldcopd.org
2. Raising awareness of chronic obstructive pulmonary disease. South African COPD
Edu-Group [homepage on the Internet]. c2013. Available from: http://www.copd.co.za
3. Rennard SI. Chronic obstructive pulmonary disease, including emphysema. UpToDate
[homepage on the Internet]. 13 2013. c2013. Available from: http://www.uptodate.
com
4. Rennard SI. Chronic obstructive pulmonary disease treatments. UpToDate [homepage
on the Internet]. 2013. c2013. Available from: http://www.uptodate.com
5. Chronic obstructive pulmonary disease. National Heart, Lung and Blood Institute
[homepage on the Internet]. c2013. Available from: http://www.nhlbi.nih.gov/health/
health-topics/copd
6. Rennard SI. Chronic obstructive pulmonary disease: definition, clinical manifestations,
diagnosis, and staging. UpToDate [homepage on the Internet]. 2013. c2013. Available
from: http://www.uptodate.com
7. Chronic obstructive pulmonary disease: overview. FamilyDoctor.org [homepage on
the Internet]. 2012. Available from: http://www.familydoctor.org/familydoctor/en/
diseases-conditions/chronic-obstructive-pulmonary-disease.html
8. What are bronchodilators? American Thoracic Society [homepage on the Internet].
2013. c2013. Available from: http://www.thoracic.org/clinical/copd-guidelines/forpatients/what-are-bronchodilators.php
9. Chronic obstructive pulmonary disease: medications. WebMD [homepage
on the Internet]. 2011. Available from: http://www.webmd.com/lung/copd/tc/
chronic-obstructive-pulmonary-disease-copd-medications
10. Leader D. A closer look at bronchodilators in treatment of COPD. About.com
[homepage on the Internet]. c2013. Available from: http://www.copd.about.com/od/
emphysema/a/bronchodilators.htm
11. Onbrez Breezhaler package insert. 7 June 2012. Novartis South Africa (Pty) Ltd.
12. Medifocus guidebook on chronic obstructive pulmonary disease. Medifocus
Guidebooks [homepage on theInternet]. 2013. c2013. Available from: http://www.
copd-guidebook.com/2009/landingp.php

The following combinations are effective:1

Short-acting b2-agonists and ipratropium.
Long-acting anticholinergic and short-acting b2-agonists.
Long-acting anticholinergic and long-acting b2-agonists.
Long-acting b2-agonists and ipratropium.
Table I: Bronchodilators in stable chronic obstructive pulmonary disease1

Bronchodilator medication is central to symptom management in

chronic obstructive pulmonary disease.
Inhaled therapy is preferred.
The choice between b2-agonists, anticholinergics, theophylline or
combination therapy depends on availability and individual patient
response in terms of symptom relief and side-effects.
Bronchodilators are prescribed on an as-needed basis, or on a
regular basis to prevent or reduce symptoms.
Long-acting inhaled bronchodilators are convenient and more
effective at maintaining symptom relief than short-acting
bronchodilators.
Combining bronchodilators of different pharmacological classes
may improve efficacy and decrease the risk of side-effects,
compared to increasing the dose of a single bronchodilator.

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