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272 Chapter 11 Respiratory disease: asthma and COPD
Volume expired (litres)
FVC
Box 11.2
Obstructive versus restrictive lung disorders
Obstructive lung disorders are dened by diculty in
emptying the lungs because of either narrowing of the
airways or structural damage. ere is increased
airway resistance to the ow of air. Asthma and COPD
are both obstructive diseases.
Restrictive lung disorders are characterized by
diculty in lling the lungs which also have a reduced
capacity. Airway resistance is not increased.
Restrictive lung disease can be caused by such
conditions as pulmonary brosis and obesity.
Computerized spirometry measurements are useful in
distinguishing between obstructive and restrictive
disorders. Measurements are recorded using a
computerized spirometer in a clinical setting. e
patient stands, makes a maximal inspiration, and then
exhales forcefully and completely into a mouthpiece
5
FEV
1
4
Normal
(Norm)
connected to the spirometer. e values recorded are
compared with predicted values for the patient, which
take into account factors inuencing lung function,
such as race, gender and age. A number of lung
parameters are measured. e most revealing in the
diagnosis and monitoring of asthma and COPD are:
• forced vital capacity (FVC)—maximum volume of
air that is expelled after a maximal inspiration
• forced expiratory volume in one second (FEV1)—
volume of air that is expelled in the rst second
when measuring FVC.
e FEV1 value is expressed as a ratio of FVC, and in
healthy individuals should be greater than 0.7,
indicating that more than 70% of the air is expelled in
the rst second of forced expiration (Figure b).
Obstructive
3
(Obs)
FEV
1
(Res)
FEV
1
2
1
12
Figure b Typical spirometry traces for a healthy subject
compared with patients with obstructive and restrictive
disorders.
FVC, forced vital capacity; FEV1, forced expiratory volume in 1 second.
In obstructive disorders, where airways are narrowed
due to structural damage or inammation and
bronchoconstriction, air is expelled more slowly than
FVC
Restrictive
3
Time (seconds)
usual; this gives rise to a reduced FEV1. ere may be
air left in the lungs at the end of a full expiration and so
the FVC may also be reduced, although not to the
11.4 Treating asthma 273
Box 11.2 Obstructive versus restrictive lung disorders
same extent as the FEV1. Overall, the FEV1/FVC is
reduced to less than 0.7 (Figure b), indicating the
reduced proportion of air that is expelled in the rst
second of the forced expiration; this is a diagnostic
feature of obstructive disorders.
By contrast, in restrictive diseases there is an inability
to expand the lungs fully; FVC is consequently
reduced. As air is able to ow freely, the FEV1,
although also low, represents the normal 70% or more
of FVC (i.e. the FEV1/FVC ratio is normal).
e FEV1/FVC ratio is extremely important
diagnostically; where a reduced FEV1 is recorded, the
cause bronchoconstriction by antagonizing 2adrenoceptors on bronchiolar smooth muscle. 1Selective agents have a lower risk, but at high dose they
lose selectivity, and should be avoided in asthmatics (see
Chapter 5, Section 5.2.5). (It should be noted that these
agents are selective but not specic for -adrenoceptor
subtypes.)
Non-steroidal anti-inammatory drugs (NSAIDs), in
particular aspirin, can trigger asthma (‘aspirin-sensitive’
asthma). ese drugs block the conversion of arachidonic
acid into thromboxane A2 and prostaglandins by
inhibiting the enzyme cyclo-oxygenase (see Chapter 9,
Section 9.3.1, for more details). When this pathway is
ratio provides a means of distinguishing between
obstructive and restrictive disorders.
A further parameter of lung function measured during
spirometry investigations is peak expiratory ow
(PEF)—maximal airow rate on forced expiration
(usually referred to as peak ow). is can also be
measured with a simple hand-held device that can
easily be used at home. Such a device produces a less
reliable measure of lung function than spirometry, but
gives a useful indication of improvement or
deterioration. As such, this parameter is useful for
self-monitoring purposes in asthma (the progression
of COPD is not monitored in this way).
blocked, arachidonic acid is diverted into the biosynthesis
of a number of leukotrienes, mediators of inammation
implicated in the asthma disease process. e properties
of leukotrienes include bronchoconstriction, stimulation
of bronchial gland and mucus secretions, and recruiting
leucocytes (e.g. eosinophils) to the site of inammation.
(Not surprisingly, the receptors for leukotrienes are
therapeutic targets in asthma; see Section 11.4.3). Aspirin
sensitivity is seen in approximately 10% of asthma
suerers; if previous use has precipitated asthma, rhinitis,
urticaria, or angioedema (swelling of the deeper dermal
layers of skin, often aecting the face), all NSAIDs should
be avoided.
11.4 Treating asthma
Asthma treatment involves two main classes of drugs,
bronchodilators and anti-inammatories.
Bronchodilators are useful in reversing the
bronchoconstriction experienced in the early phase of the
disease process, providing relief from symptoms.
Short-acting drugs with relatively fast onset of action are
often referred to as ‘reliever medication’. To eectively
manage asthma, the underlying inammation in the late
phase must also be tackled; anti-inammatory drugs are
known as ‘preventers/controllers’.
11.4.1 Bronchodilators
2-adrenoceptor agonists
As noted above, bronchiolar smooth muscle cells express
2-adrenoceptors and their activation leads to
bronchodilatation (Figure 11.3). Short-acting selective
2-adrenoceptor agonists (SABAs) such as salbutamol
and terbutaline are therefore used to relieve symptoms of
breathlessness in asthma. Similarities in the structures of
salbutamol and the physiological agonist adrenaline are
shown in Figure 11.6.
274 Chapter 11 Respiratory disease: asthma and COPD
OH
OH
HO
HO
HO
H
N
CH
Adrenaline Salbutamol
OH
H
N
HO
3
HO
O
H
N
CH
CH
3
CH
3
3
HO
Figure 11.6 Chemical structures of adrenaline, salbutamol, and salmeterol.
Structures of the endogenous agonist adrenaline, the short-acting 2-adrenoceptor agonist salbutamol, and the
long-acting 2-adrenoceptor agonist salmeterol. Differences between the molecules are shown in pink. The methyl group
of the secondary amine in adrenaline is replaced with a tertiary butyl group in salbutamol. This change alters the molecule
from a non-selective agonist that acts at all adrenoceptor subtypes to a selective 2-adrenoceptor agonist. In salmeterol,
this group is extended into a long lipophilic side chain, which enables the drug to intercalate into the plasma membrane,
increasing its duration of action.
Given by inhalation, SABAs have a rapid onset of action
within 5–10 minutes, with the maximum eect occurring
at about 30 minutes and lasting for 3–5 hours. ey are
used on an ‘as required’ basis and are the drug of choice
for acute exacerbations of asthma. ey are also used
prophylactically in patients with exercise-induced
asthma.
e duration of action of the long-acting inhaled 2adrenoceptor agonists (LABAs) salmeterol and
formoterol is extended to around 12 hours. Salmeterol
takes eect more slowly than salbutamol (around
10–20 minutes) and is used as preventer rather than
reliever medication. Formoterol, like salbutamol, is
eective within a few minutes, and can therefore be used
to relieve symptoms. Safety concerns have, however, been
raised over LABAs; their use as monotherapy has been
linked with an increase in asthma-related deaths through
a masking of ongoing airway inammation. ey are
recommended only where control is not achieved with
inhaled corticosteroids (see Section 11.4.2), and then
always alongside regular use of a steroid. In this respect,
combination inhalers containing both drugs are useful,
although they obviously restrict the ability to alter the
dose of each component.
Salmeterol
e longer duration of action of salmeterol and
formoterol reects their increased lipophilicity.
Salmeterol has a long lipophilic side chain (Figure 11.6)
which (it is postulated) intercalates into the plasma
membrane at an ‘exoreceptor site’, in close proximity to
the receptor. e remainder of the molecule can then
freely interact with the active site. Diusion of the
molecule away from the exoreceptor site is slow, hence
the long duration of action. Alternatively it has been
proposed that salmeterol enters the lipid bilayer and
binds to the receptor from within the membrane
(Figure 11.7). e reason for formoterol’s long duration of
action has not been established unequivocally, but may
involve accumulation of molecules close to the receptor
to form a reservoir, from where they slowly diuse to
activate the receptor from the outside. For both
salmeterol and formoterol, the increased duration of
action means they can be given twice a day, and also
makes them particularly useful for night-time
symptoms.
Several ultra-long-acting 2 adrenoceptor agonists have
been developed with even greater lipophilicity and with a
duration of action of around 24 hours. Of these only
vilanterol has been approved for use in asthma.
11.4 Treating asthma 275
Salbutamol
Formoterol
Salmeterol
Membrane
β
adrenoceptor
Binding site
Figure 11.7 Binding of short-acting and long-acting 2-adrenoceptor agonists.
The short-acting 2-adrenoceptor agonist salbutamol accesses the receptor’s binding site from outside the cell.
By contrast, the lipophilic structure of the long-acting agonist salmeterol allows it to accumulate within the
membrane close to the binding site, from where it stimulates the receptor. Formoterol also penetrates the
phospholipid bilayer to create a reservoir of drug. Unlike salmeterol, binding to the receptor is believed to be
achieved from the outside, once drug has been released from the membrane store.
2
As mentioned earlier (Section 11.1.2), 2-adrenoceptors
are expressed on a number of immune and inammatory
cells present in the asthmatic airways, including mast
cells and T-lymphocytes. Activation of these receptors
leads to a decrease in the release of histamine from
granules in mast cells, and decreased production of
interleukins by T-lymphocytes. Such eects may also
contribute to the therapeutic response of the asthmatic
airway to 2-adrenoceptor agonists.
e main side eect of inhaled 2-adrenoceptor agonists
is tremor, arising from stimulation of 2-adrenoceptors in
skeletal muscle. Hepatic glycogenolysis is also stimulated
by 2-adrenoceptor agonists and can lead to
hyperglycaemia. e drugs also stimulate the Na+/K
+
-ATPase, and can lead to decreased plasma levels of K+
(hypokalaemia) through enhanced cellular uptake of K+.
Hypokalaemia can induce serious arrhythmias; repeated
use of SABAs has been linked to deaths as a result. e
agonists are selective, but not specic for 2adrenoceptors, and so tachycardia and palpitations may
result from activation of cardiac 1-adrenoceptors.
Oral 2-adrenoceptor agonists have a limited role because
of the far greater risk of potential adverse eects than
when inhaled. Preparations of salbutamol, terbutaline,
and bambuterol are available for oral administration
where inhalation cannot be managed. Bambuterol is a
pro-drug of terbutaline with a longer duration of action.
Unlike the other two drugs, which are taken three or four
times daily, it can be taken once daily.
Antimuscarinic drugs
As noted above (Section 11.1.2) bronchoconstriction is
mediated by the M3 muscarinic receptor, providing a
rationale for the use of antimuscarinic agents in the
treatment of airway disease. However, 2-adrenoceptor
agonists, which are both faster acting and more eective
bronchodilators, are generally preferred. e only
antimuscarinic drug used to provide relief in chronic
asthma is the short-acting drug ipratropium. (Longacting antimuscarinics have a role in the management of
COPD, and are discussed later.) Ipratropium is used
second line, added to 2-adrenoceptor agonists in
patients where control has not been achieved by these
agents.
Ipratropium is a derivative of atropine, the naturally
occurring alkaloid derived from the deadly nightshade
plant (Atropa belladonna). Like atropine, it does not
distinguish between muscarinic receptor subtypes. e
276 Chapter 11 Respiratory disease: asthma and COPD
benecial eects are derived from the antagonism of M3
receptors on:
• bronchiolar smooth muscle to counteract
bronchoconstriction
• goblet cells to reduce secretions of mucus and their
viscosity, aiding mucociliary clearance.
In addition to blocking M3 receptors, ipratropium
antagonizes M2 autoreceptors on ACh-releasing nerve
terminals. is reduces their negative feedback inuence
on the further release of ACh, which is thereby increased;
this counteracts the antagonism of M3 receptors.
Ipratropium is used as a second-line agent, added to
2-adrenoceptor agonists in patients where these agents
have not achieved control. It is also used to reverse
bronchospasm precipitated by 2-adrenoceptor
antagonists (see Section 11.3.3). Its onset of action occurs
around 15 minutes after inhalation, peaks after about
1–2 hours, and lasts for 3–6 hours. Wide-ranging side
eects due to non-selective antagonism are largely
avoided when ipratropium is inhaled; distribution around
the body is limited by its high polarity and consequent
inability to penetrate plasma membranes to enter the
bloodstream. Ipratropium is generally well tolerated; its
most common adverse eects are dry mouth and throat
irritation.
Methylxanthine drugs
Theophylline and its salt aminophylline
(ethylenediamine salt) are the main methylxanthines
used in lung disease. Caeine is a methylxanthine,2 and
has been used in medicine for its bronchodilator
properties for centuries; nowadays it is used only as a
respiratory stimulant in premature babies. eophylline
is a bronchodilator, and it too directly stimulates the
respiratory centre, resulting in increased respiration
which may be of benet to patients with COPD (see
below); this property is also exploited in treatment of
premature babies with hypoventilation.
Methylxanthines are known to non-selectively inhibit
phosphodiesterases (PDE), the family of enzymes
responsible for breaking down cyclic AMP and cyclic
GMP. is eect, though, is only seen at concentrations
which far exceed therapeutic levels of theophylline; the
mechanism of action in vivo is not understood.
2 eobromine, found in chocolate, is also a methylxanthine.
ere are ve main isoforms of PDE, with PDE3 and PDE4
selective for cyclic AMP. PDE4 is expressed in
inammatory cells (e.g. eosinophils) and is one of the
targets for novel asthma treatments.
Methylxanthines are non-selective antagonists of
adenosine receptors. Activation of A1 and A2B adenosine
receptors on mast cells enhances the release of
inammatory mediators. Antagonism of these receptors
by theophylline may explain some of this drug’s benecial
action in asthma.
Evidence for the long-term ecacy of theophylline is
lacking. It is generally only used as add-on therapy for
patients whose asthma is not adequately managed with
corticosteroids.
eophylline has a narrow therapeutic window which
seriously limits its usefulness. Toxic eects arise at plasma
concentrations only just over the therapeutic range.
Toxicity involves stimulation of the CNS, cardiovascular
system, and gastrointestinal tract, leading to a range of
adverse eects including insomnia, palpitations,
tachycardia, nausea, and vomiting. (Allergy to
ethylenediamine can lead to additional problems such as
urticaria and dermatitis when administering
aminophylline.) At high doses theophylline can produce
serious and potentially fatal cardiac and central eects
such as cardiac arrhythmias and seizures. Its use
therefore requires therapeutic drug monitoring. Trough
(pre-dose) levels should be between 10 and 20 mg/l
(55 and 110 mol/l); levels at the lower end appear to be
eective and may not require monitoring. (is is also
explored in Chapter 3, Section 3.4.1.)
eophylline is metabolized in the liver by cytochrome
P450 enzymes, but the rate varies greatly between
individuals. Metabolism is decreased in liver disease,
heart failure, and viral infections, in elderly patients,
and by a number of drugs that inhibit CYP enzymes,
including some macrolide antibiotics (e.g. erythromycin
and clarithromycin) and the H2 antihistamine cimetidine;
increased theophylline levels result. e interaction with
antibiotics is clinically relevant, as a severe asthma attack
precipitated by a chest infection may require antibiotic
treatment. If the patient is taking theophylline and the
dose is not altered, toxicity could ensue.
Metabolism of theophylline is increased, and hence
plasma concentrations decreased, by inducers of CYP450
enzymes. A number of drugs, including phenytoin and
11.4 Treating asthma 277
carbamazepine, have this eect, as does alcohol
consumption and smoking cigarettes. e half-life of
theophylline may be decreased by as much as 60% in
heavy smokers. is is an important consideration for
patients who stop smoking whilst on theophylline;
metabolism will be reduced and plasma concentrations
may reach toxic levels.
11.4.2 Corticosteroids
Corticosteroids (glucocorticoids) are the cornerstone of
therapy for everyone with asthma, with the exception of
those with mild intermittent symptoms which can be
eectively managed by a short-acting 2-adrenoceptor
agonist. Corticosteroids tackle the underlying
inammation in asthma and are central to the
management of the condition. e mode of action of
these drugs is covered in detail in Chapter 9, Section 9.3.2
and Box 9.2. In essence, they target nuclear receptors for
the endogenous glucocorticoids, of which cortisol is the
primary example. ese receptors are expressed by
virtually every cell type in the body and mediate wideranging eects on immunity, as well as on the
metabolism of carbohydrates and proteins.
Corticosteroid drugs act by directly entering cells and
interacting with these glucocorticoid receptors. e
ligand–receptor complexes form dimers which are
translocated to the nucleus, where they alter the
expression of an array of genes. e consequences of
altered gene transcription are decreased activation of
inammatory cells and mediators, and a dampening
down of the immune response. Amongst the benecial
actions of glucocorticoids in asthma are:
• reduced transcription of the gene for IL-2, the
interleukin which promotes the clonal proliferation of
T-helper cells (see Section P3.2.2 and Figure P3.2 in the
Introduction to Part 3 of this book)
• reduced recruitment of eosinophils into lung tissue and
reduction in their activity
• increased expression of 2-adrenoceptors
• reduced number of mast cells in respiratory lining with
long-term treatment.
As the therapeutic eect relies upon changes in rates of
protein synthesis, it develops slowly, requiring weeks or
months for full development.
In addition to the well-recognized eects of
corticosteroids on gene transcription, it has recently
become apparent that some of their actions are mediated
by more rapidly activated pathways involving protein
kinases or phosphatases. So, for instance, PKC-mediated
phosphorylation and activation of annexin-1, a protein
with potent anti-inammatory actions, occurs within
minutes of glucocorticoid treatment (see Chapter 9,
Box 9.2).
Most commonly, corticosteroids are inhaled, allowing the
delivery of potent agents directly to the lung tissue,
thereby reducing potential systemic eects.
Beclometasone and budesonide were the rst inhaled
corticosteroids to be developed; newer agents include
ciclesonide and fluticasone. Ciclesonide is an inactive
pro-drug, which is converted in the lungs by esterases to
the active form desisobutyryl-ciclesonide. is local
conversion may be advantageous in further reducing
both systemic and local side eects. e equivalent doses
of the commonly used oral and inhaled corticosteroids
are given in Table 11.2.
Although administration through inhalation reduces the
likelihood of adverse systemic eects, the use of inhaled
corticosteroids long term, or in high dose, is associated
with increased risk of a number of side eects, including
adrenal suppression, decreased bone mineral density,
cataracts, and skin thinning. Use in children has been
linked with early growth retardation through a negative
feedback eect of corticosteroids on hypothalamic output
of growth hormone-releasing factor (GHRF), and
therefore of growth hormone (GH); normal adult height
will probably still be reached. Other eects include
increased risk, particularly in the elderly, of respiratory
tract infections including pneumonia. To minimize the
Table 11.2 Comparative potency of common oral and
inhaled corticosteroids
Corticosteroid Equivalent doses
Oral Inhaled
Hydrocortisone 100 mg N/A
Prednisolone 25 mg N/A
Prednisone 25 mg N/A
Beclometasone N/A
Budesonide N/A
Fluticasone N/A
Ciclesonide N/A
100 g
200 g
100 g
80 g
278 Chapter 11 Respiratory disease: asthma and COPD
possibility of such adverse eects, most management
guidelines recommend restricting the use of inhaled
corticosteroids to the lowest dose that achieves
satisfactory relief from symptoms. It is important to note
that inhaled corticosteroids have a fairly at dose–
response curve; increasing the dose above a daily 250 g
uticasone/beclometasone produces little therapeutic
benet, whilst substantially increasing the risk of side
eects.
e most common adverse eect is the development of
oral thrush, caused by the deposition of corticosteroids
on the back of the throat and mouth. e local
suppression of anti-infective mechanisms allows
colonization by the fungus Candida albicans, which
therefore thrives, and candidiasis develops. e risk is
lessened through use of a spacer which reduces
oropharyngeal deposition, and/or rinsing and gargling
with water and spitting out after inhalation. is practice
will also reduce the risk of systemic side eects: drug
deposited in the mouth or throat will be swallowed, and
then absorbed into the blood.
Combination inhalers of corticosteroids and longacting 2-adrenoceptor agonists
As noted above, inhalers are available which combine
corticosteroids with LABAs. ese reduce the number of
devices needed and may therefore improve adherence.
ey also address the recommendation that LABAs are
only administered with concomitant inhaled
corticosteroid therapy (see Section 11.4.1).
11.4.3 Other drugs used for asthma
treatment
A number of other agents can be introduced as second or
third line in the management of asthma, usually when
maximal doses of inhaled corticosteroids have been
reached.
Cromolyns
Inhaled sodium cromoglicate or nedocromil are
occasionally used in asthma and can reduce the extent of
the early and late phases, as well as hyper-reactivity of the
airways; they do not aect bronchodilatation. eir
mechanism of action is not clearly understood; they are
sometimes referred to as ‘mast cell stabilizers’, but this
does not underlie their action in asthma. e eect on
airway hyper-reactivity may be mediated through
reduced activation of TRPV1 receptors on sensory nerves
and the subsequent inhibition of the neuronal reexes
(see Section 11.1.1). Cromolyns are less eective than
inhaled corticosteroids, but may be useful where they are
not tolerated. ey are only useful prophylactically; their
lack of bronchodilator action means they are not eective
in an acute attack.
Inhaled cromolyns are generally well tolerated with few
side eects except mouth and throat irritation, and
occasionally bronchospasm and headache. Because of
their short duration of action they have to be given four
times a day.
Cysteinyl leukotriene receptor antagonists
Oral corticosteroids
e risk of the wide-ranging and potentially serious side
eects associated with corticosteroids as set out above is
obviously far greater when these drugs are administered
orally. is route is therefore usually reserved for short
courses in severe asthma exacerbations where symptoms
cannot be controlled with maximal inhaled
corticosteroids and bronchodilators, or where rapid
deterioration is seen.
Prednisolone and prednisone are used most commonly;
prednisone is inactive until converted in the body to
prednisolone. Corticosteroids do not need to be tapered
o at the end of a short course, as the hypothalamic–
pituitary–adrenal (HPA) axis is not signicantly
suppressed (see Chapter 9, Section 9.3.2, for more
discussion of HPA suppression).
e cysteinyl leukotrienes C4, D4, and E4 are powerful
bronchodilators and mediators of inammation which
are released from activated inammatory cells such as
mast cells and eosinophils which inltrate asthmatic
airways. ese mediators have a central role in the
pathogenesis of asthma, exerting their eects through
activation of the CysLT1 receptor expressed on
bronchiolar smooth muscle cells. ey also stimulate
increased mucus secretions. e CysLT1 receptor subtype
is also expressed by eosinophils themselves, providing an
example of autocrine signalling; leukotrienes act on the
same cells that release them, to encourage their further
release. CysLT1 receptors are Gq-coupled GPCRs, whose
activation leads to increased cytosolic Ca
(see Chapter 2, Section 2.2.4).
Two selective CysLT1 receptor antagonists (LTRAs),
montelukast and zafirlukast, are used in clinical
2 +
concentration
11.5 Chronic obstructive pulmonary disease (COPD) 279
practice. Trials have shown that when used alone they are
less eective bronchodilators than salbutamol. In
combination with inhaled corticosteroids, though, they
can have a useful steroid-sparing function. ey also
appear to be eective in aspirin-induced asthma where
leukotrienes play a central role.
Montelukast has a long duration of action and can be
given once a day, while zarlukast is given twice a day.
Both drugs are well tolerated, with gastrointestinal upset
and headache the main side eects.
IgE antagonists
Omalizumab is a monoclonal anti-IgE antibody. It binds
and inactivates IgE to prevent allergen-mediated release
of inammatory mediators from mast cells so as to inhibit
both early and late phases of asthma. Its use is reserved
for patients with severe persistent asthma with high levels
of circulating IgE levels, whose symptoms are not
controlled by other treatments. Clinical trials have shown
that omalizumab reduces symptoms, improves quality of
life, and reduces required doses of inhaled corticosteroids
in such individuals. Administered by subcutaneous
injection, it is an expensive option. It acts to reduce IgE
levels within hours, although a full eect is not seen for
several days. It has a long duration of action and is usually
administered every 2–4 weeks, at a dose informed by IgE
levels.
Omalizumab is generally well tolerated, with injection
site reactions being the main adverse eect. However, like
any protein, it has the potential to cause anaphylactic
reactions.
11.4.4 Guidelines for treating asthma
Most guidelines, including GINA, recommend a stepwise
additive approach to choosing therapy based on asthma
severity and symptom control. e GINA
recommendations are shown in Box 11.3.
e drugs available for the treatment of asthma are
eective in all but a few refractory cases, and yet it
remains a poorly controlled disease and leads to many
avoidable deaths. Enabling patients to appreciate the
inammatory basis of the disease, and the impact of
bronchodilators on airways resistance, will in turn aid
appropriate and correct use of medication; its benets
will be maximized and exacerbations of their condition
thereby avoided.
11.5 Chronic obstructive pulmonary disease (COPD)
COPD is one of the leading causes of death worldwide,
and is likely to rise in the near future. It is most usually,
although not always, caused by the damage done to the
lungs by smoking cigarettes. Like asthma, COPD is an
obstructive pulmonary disorder; FEV1 is reduced, as is the
FEV1/FVC ratio (see Box 11.2, and also Workbook 8 at the
end of this chapter). Unlike asthma, however, the
obstruction is not reversible; COPD is nearly always
progressive (see Figure 11.8).
COPD is a disease state rather than a single disease. It
mainly comprises chronic bronchitis and emphysema,
and while these can exist independently, most suerers of
COPD have both. Chronic bronchitis is inammation
throughout the airways, and involves a range of cells and
mediators, although these are not as well characterized as
they are in asthma. Importantly, this inammation is not
eectively dampened down by the anti-inammatory
actions of corticosteroids.
Emphysema aects the alveoli. When healthy, the
alveolar walls are elastic and they expand and return to
their original size with each breath, like a new balloon. In
emphysema, elastin bres in the walls are broken down
by the action of elastases released during the
inammatory response. e alveolar walls become hard
and resistant, more like blowing up a paper bag!
Eventually individual alveoli are destroyed and coalesce
into larger spaces. e consequent loss of surface area
limits gas exchange, and is responsible for the respiratory
failure seen in COPD.
e exact symptoms of COPD experienced by the patient
depend on the relative contribution of emphysema or
chronic bronchitis to his/her condition. Each of these
diseases is associated with characteristic features which
are reected in the appearance of the suerer. is is
explored in Workbook 8 where Ian’s COPD is dominated
by chronic bronchitis and this is reected in his
appearance on examination. As noted earlier though, for
most patients the pathophysiology of COPD is a mixture
of the two conditions.
Bronchial secretions are increased in COPD as bronchial
glands enlarge and goblet cells proliferate, leading to
increased mucus production. Ciliary function is also
280 Chapter 11 Respiratory disease: asthma and COPD
Box 11.3
Adapted GINA guidelines on asthma management
Step-up if control is not achieved
6
Consider step-down once control is achieved
5
+ Anti IgE
4
+ LTRA
or
3
LD-ICS + LTRA
or
2
LTRA LABA
1
Mild
intermittent
asthma
Figure c Stepwise management of asthma in adults. Preferred treatments are shown in coloured boxes;
alternative options are given in grey boxes.
Step 1 Use inhaled short-acting 2-adrenoceptor agonists (salbutamol or terbutaline) as required. If needed more than twice a
week, prophylactic treatment should be considered.
Step 2 Add regular preventer therapy—standard low dose inhaled corticosteroids, considered equivalent to 100–400 g
budesonide, twice daily (see Table 11.2 for equivalent doses of inhaled corticosteroids). An LTRA may be considered as an
alternative.
Step 3 Add regular inhaled LABA. Inhaled corticosteroids can be increased up to maximum of standard dose range (400 g
budesonide, twice daily). As alternatives, if LABA is deemed to be ineffective, patient can be given an LTRA or modified-release
theophylline.
Step 4 Increase inhaled corticosteroids to medium-high dose, equivalent to 400–1000 g budesonide, twice daily. The
addition of an LTRA or theophylline may be considered to spare the use of corticosteroids.
Step 5 A serious exacerbation of asthma necessitates the addition of oral corticosteroids at the lowest possible dose to
provide adequate control; other treatment options should be considered to minimize their use. The patient should be referred
for specialist care. Anti-IgE therapy should only be instigated where IgE levels are shown to be high.
Once control is achieved, stepping down to the previous level should be considered. For mild persistent asthma, the dose of
inhaled corticosteroid should be the lowest possible to maintain control.
Anti IgE, anti-immunoglobulin E therapy; ICS, inhaled corticosteroids; LABA, long-acting 2-adrenoceptor agonist; LD-ICS, low dose inhaled
corticosteroid; LTRA, leukotriene receptor antagonist; Theo, theophylline.
Low dose ICS
Short-acting
Mild
persistent
asthma
β
-adrenoceptor agonist on an ‘as needed’ basis
2
LD-ICS + Theo
Low dose ICS
+ Theo
LABA LABA
Medium or
high dose ICS
Oral
corticosteroids
High dose ICS
Lung function
11.5 Chronic obstructive pulmonary disease (COPD) 281
function in patients with COPD. ey are used on an ‘as
required’ basis, providing relief from bronchoconstriction
for around 4 hours. If breathlessness persists or
Asthma
exacerbations continue, a long-acting 2-adrenoceptor
agonist (LABA) can be introduced. In addition to the
LABAs used in asthma (see Section 11.4.1), three
ultra-long-acting 2-adrenoceptor agonists (ULABAs)
COPD
have been approved for use in COPD: olodaterol,
indacaterol, and vilanterol. All three drugs have a rapid
onset of action, similar to that of salbutamol. e
Exacerbations
prolonged duration of action allows once-daily dosing. In
trials, these drugs have been shown to improve quality of
Time
life of COPD patients when added to their usual
medication. e benecial eects of ULABAs may be
Figure 11.8 Comparison of lung function over time for
asthma and COPD.
Exacerbations, or flare-ups, are experienced in both conditions,
but in asthma lung function returns to a normal baseline
between attacks; the underlying obstruction is reversible. In
contrast, in COPD lung function deteriorates progressively; the
disease process is not reversible.
additive with those of long-acting muscarinic antagonists
(LAMAs); a combined inhaler of vilanterol and
umeclidinium (see below) has recently been licensed for
use in adult COPD patients in the UK.
Inhaled antimuscarinic drugs
Antagonists at muscarinic acetylcholine receptors
(mAChRs) have a more central role in the management of
compromised and therefore the mucus tends to build up,
blocking the alveoli and reducing gas exchange. e
patient is additionally at increased risk of viral or bacterial
infection because of the reduced eectiveness of the
defensive mechanisms. Overall, COPD patients tend to
have slowly declining lung function interspersed with
exacerbations, often caused by lung infections
(Figure 11.8).
COPD compared with asthma, and have a signicant
bronchodilator eect. e short-acting muscarinic
antagonist (SAMA) ipratropium, given on an ‘as required’
basis, can be used to provide short-term relief in mild
COPD. It is a non-selective antagonist, acting at all
muscarinic subtypes. M1, M2, and M
3
present at dierent locations in the respiratory tract (see
Section 11.1.2). e consequences of antagonizing the
dierent subtypes are considered in Section 11.4.1; not all
11.5.1 Management of COPD
Smoking cessation
e most signicant intervention to slow COPD
progression and the decline in lung function is to stop
smoking. Patients should be oered help in achieving this
goal through psychological as well as pharmacological
means. Drugs which combat nicotine addiction directly
target the nicotinic acetylcholine receptor (nAChR). ey
include nicotine replacement therapy (e.g. patches,
chewing gum, and inhalers), the antagonist bupropion,
and the partial agonist varenicline. (Nicotine addiction
and its treatment are explored in Chapter 21,
are benecial.
Long-acting muscarinic antagonists (LAMAs) include
tiotropium, glycopyrronium, umeclidinium, and
aclidinium; as bronchodilators they are as eective in
COPD as LABAs. LAMAs have a similar anity for all
muscarinic subtypes. However, they show functional
selectivity for the M3 receptor by virtue of the fact that
they dissociate much more quickly from the M2 receptor
than from the M3 receptor.3 e exact reason for the
prolonged duration of action of LAMAs is as yet unclear,
but may reect the slow diusion of drug away from the
micro-environment of the receptor, allowing re-binding
Section 21.4.)
3 e prolonged duration of action of LAMAs has been attributed in a
Bronchodilators
Inhaled short-acting 2-adrenoceptor agonists (SABAs;
see Section 11.4.1) have been shown to improve lung
number of studies to extended receptor occupancy and very long
dissociation half-lives (e.g. 35 hours for tiotropium at the M3 receptor).
is has been refuted by others, who claim the results reect the
non-physiological conditions under which these experiments were
conducted.