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282 Chapter 11 Respiratory disease: asthma and COPD
of dissociated drug molecules. Tiotropium also has
anti-inammatory eects through antagonism of
muscarinic receptors on immune cells such as mast cells
(M1 receptors) and neutrophils (M4 and M5 receptors). It
has been shown to block the migration into airways of
neutrophils, the principal circulating white blood cell
type to initiate inammation (see Sections P3.1 and
P3.2.1 in the Introduction to Part 3 of this book).
Aclidinium has a faster onset of action than tiotropium. It
is metabolized rapidly, resulting in an extremely short
half-life in the circulation (2.4 minutes), thereby limiting
its systemic and CNS eects. e polar molecule also has
little propensity to cross the blood–brain barrier, further
reducing the likelihood of CNS-mediated eects. e
common adverse eects of LAMAs are dry mouth, throat
irritation, and headaches. Gastrointestinal disturbances,
bronchospasm, tachycardia, and palpitations are also
possible. As explored in Workbook 8 at the end of this
chapter, long-acting and short-acting muscarinic
antagonists should not be combined.
Measures of lung function, such as FEV1, should not be
the sole method used for assessing the ecacy of
bronchodilators in COPD; impact on the patient’s
functioning, such as ability to undertake daily activities,
must also be taken into account. It should be noted that
peak expiratory ow (PEF) readings used in asthma do
not have a role in monitoring COPD.
Corticosteroids
systemic side eects (see Section 11.4.2, and Chapter 9,
Section 9.3.2).
Mucolytics
A predominant feature of COPD is excessive production
of very viscous sputum, which is dicult to clear and can
add to breathing diculties. Mucolytics are agents which
break down the mucoprotein bres in sputum by
hydrolysing disulphide bonds. ey thereby decrease
mucus viscosity, making it easier to clear. ese drugs
have additional benecial anti-inammatory and
antioxidant properties which may modify the disease
processes in COPD. Mucolytics can be useful in COPD
patients who have a chronic productive cough. Drugs
include bromhexine, carbocisteine, erdosteine, and
acetylcysteine (also used as an antidote for
paracetamol poisoning). ey are usually administered
orally; acetylcysteine can also be given by nebulizer.
Evidence from clinical trials is mixed; some report an
improvement in pulmonary function and a signicant
reduction in exacerbations compared with placebo,
whereas others have been less conclusive. Where
reported, benet has been attributed to the antioxidant
and anti-inammatory properties of the drugs.
Mucolytics are very well tolerated with few side eects,
except gastrointestinal disturbances and occasional
bleeding due to interference with the gastric mucosa.
Bronchospasm has been reported with N-acetylcysteine.
Unlike in asthma, the inammation of the airways in
COPD does not generally respond well to inhaled
corticosteroids, although a trial at high dose may be
worthwhile. e long-term benet of these drugs has only
been documented in patients with moderate to severe
disease where FEV1 is less than 50% of the predicted
value. Such individuals may be given a combination
inhaler of LABA together with a corticosteroid (e.g.
formoterol plus budesonide, or salmeterol plus
uticasone). It is important to note that the use of inhaled
corticosteroids puts the patient at increased risk of
developing pneumonia due to the dampening down of
the immune response in the lungs. As an infection of this
kind would lead to an exacerbation of COPD, the inhaled
corticosteroids should be discontinued after a month if
benet is not seen.
Oral corticosteroids may produce a very small
improvement in the lung function of COPD patients, but
their long-term use is usually restricted because of their
Phosphodiesterase-4 inhibitors
Phosphodiesterase type 4 (PDE-4) is expressed in
inammatory cells, in particular macrophages,
neutrophils, and eosinophils where it is responsible for
the breakdown of cyclic AMP. Inhibition of PDE-4 results
in increased levels of cyclic AMP, which in turn decreases
release of cytokines. Inhibitors of PDE-4 for use in COPD
have been in clinical development for a number of years.
e rst to be marketed was roflumilast, an oral therapy
given once a day. It is licensed for treatment of severe
COPD associated with chronic bronchitis, as an adjunct
to bronchodilators where all other options have been
exhausted. Evidence suggests that roumilast produces
only a small improvement in FEV1 and a minimal
reduction in exacerbations. Its use is hampered by a
relatively high incidence of signicant side eects
including nausea, diarrhoea, headache, depression, and
weight loss. Despite this, roumilast may provide a less
toxic alternative to theophylline.
11.5 Chronic obstructive pulmonary disease (COPD) 283
Key references and suggested reading
COPD-X Plan: Australian and New Zealand Guidelines for the
Management of Chronic Obstructive Pulmonary Disease,
2008. Version 2.44, 2015. http://www.copdx.org.au/.
Global Initiative for Asthma. Global Strategy for Asthma
Management and Prevention, 2015. http://www.ginasthma.
com/.
Moulton BC, Fryer AD. Muscarinic receptor antagonists, from
folklore to pharmacology; nding drugs that actually work in
asthma and COPD. Br J Pharmacol 2011; 163(1): 44–52.
National Collaborating Centre for Chronic Conditions. Chronic
obstructive pulmonary disease. National clinical guideline
on management of chronic obstructive pulmonary disease
in adults in primary and secondary care. orax 2004; 59
(Suppl 1): 1–232.
Strunk RC, Bloomberg GR. Omalizumab for asthma. New Engl J
Med 2006; 354: 2689–95.
SUMMARY OF DRUGS USED FOR ASTHMA AND COPD
284 Chapter 11 Respiratory disease: asthma and COPD
Therapeutic class Drugs Mechanism of action Common clinical uses Comments Common adverse drug
reactions
2-adrenoceptor agonists
Inhaled antimuscarinics Short-acting:
Methylxanthines Theophylline
Inhaled
Short-acting:
Salbutamol
Terbutaline
Inhaled
Long-acting:
Salmeterol
Formoterol
Ultra-long acting:
Vilanterol
Olodaterol
Indacaterol
Oral:
Bambuterol
Salbutamol
Terbutaline
Ipratropium
Long-acting:
Tiotropium
Aclidinium
Glycopyrronium
Aminophylline
Selectively stimulate 2-adrenoceptors
leading to bronchodilatation through
increased production of intracellular
cAMP and hence activation of PKA
Muscarinic receptor antagonists
(non-selective)
Block action of mAChR including M3
receptor on bronchial smooth muscle to
produce bronchodilatation, and on
goblet cells to reduce secretions of
mucus
Mechanism unclear
1) Non-selective inhibition of
phosphodiesterases, enzymes
responsible for breaking down cAMP
(unlikely in vivo)
2) Directly stimulate the respiratory
centre, resulting in increased respiratory
rate
3) Inhibit adenosine A1 and A2B
receptors on mast cells
Acute exacerbations of
asthma
COPD
Viral-induced wheeze
Prophylaxis of asthma
COPD
Acute exacerbation of
reversible airways obstruction
(where inhaled route not
possible, e.g. in elderly
patients or children)
Asthma
COPD
Asthma
COPD
Fast onset and short duration
of action
Salmeterol: delayed onset
Formoterol: quick onset; use
only in combination with
inhaled corticosteroid
Used rarely because of
systemic side effects
Ipratropium: slow onset and
short duration of action
Tiotropium, aclidinium, and
glycopyrronium are selective
for M3; longer duration of
action
Narrow therapeutic window
Metabolized by hepatic
CYP450 enzymes, leading to
interactions
Tremor
Headache
Muscle cramps
Palpitation
Tachycardia
Tachycardia
Tremor
Arrhythmia
Disturbances of sleep and
behaviour
Dry mouth
Nausea
Headache
Urinary retention
Glaucoma
Tachycardia
Palpitations
Corticosteroids Inhaled:
Beclometasone
Budesonide
Ciclesonide
Fluticasone
Bind to cytosolic receptors and
translocated to the nucleus to affect
gene expression; leads to reduced
transcription of pro-inflammatory genes,
and increased transcription of
anti-inflammatory genes
Prophylaxis of asthma
COPD
Less effective in COPD
Potencies variable
Fewer side effects than oral
(systemic) corticosteroids
High dose for prolonged
periods can induce adrenal
suppression (see Chapter 9)
11.5 Chronic obstructive pulmonary disease (COPD) 285
Inhaled drugs:
Oral thrush
Pneumonia (particularly in
elderly COPD patients)
Growth retardation in children
Oral:
Prednisone
Prednisolone
Leukotriene receptor
antagonists
Biologic agents Omalizumab Monoclonal antibody that binds
Mucolytics Bromhexine
PDE-4 inhibitors Roflumilast Inhibits PDE-4 in inflammatory cells
COPD, chronic obstructive pulmonary disease; GI, gastrointestinal; PDE-4, phosphodiesterase-4; PKA, protein kinase A.
Montelukast
Zafirlukast
Carbocisteine
Erdosteine
acetylcysteine
Antagonists at the CysLT1 receptor for
cysteinyl leukotrienes: inflammatory
mediators and bronchoconstrictors
released by mast cells and eosinophils
circulating IgE and prevents it activating
mast cells
Break disulphide bonds in mucus
decreasing its viscosity and making it
easier to clear
leading to reduced release of cytokines
Allergies
Asthma
Severe asthma Long half-life of 26 days
COPD Limited evidence of efficacy
Last-line treatment for COPD Limited evidence of efficacy Nausea
Reserved for short-term use
of severe exacerbations in
asthma
Metabolized by hepatic CYP
enzymes leading to
interactions
IgE levels measured before
treatment commenced
Use with caution if history of
gastric ulcers
Diabetes
Osteoporosis (risk of
fractures)
Muscle wasting
See also Drug summary table
in Chapter 9
GI effects
Headache
Insomnia
Malaise
Headache
Injection site reactions
Nausea
Diarrhoea
GI disturbance including
bleeding
Headache
Diarrhoea
Psychiatric disturbances
Weight loss
WORKBOOK 8
Chronic obstructive pulmonary disease
and asthma
The patient: a simplified case history
Once again Den has been admitted to hospital as his heart failure has deteriorated. In the
cardiacwardhisconditionisstabilized,andheisencouragedtotakesomegentleexercise.
While wandering the hospital corridors he runs into Ian, an old friend whom he has not seen for
10 years.
Den remembers Ian as a person who was very active and very funny, but also a very heavy
smoker. Ian is in hospital because he has chronic obstructive pulmonary disease (COPD) and is
struggling to breathe. He has been admitted to the respiratory ward.
A table of clinical clerking abbreviations is given on page xviii.
CLINICAL CLERKING FOR IAN WRIGHT
Age: 68 years
Weight and height: 98 kg, 170 cm
PC: Worsening shortness of breath, and productive cough with increased sputum production.
HPC: Six-year history of COPD (dominated by symptoms of chronic bronchitis) and hypertension.
Exercise tolerance has been good until recent months. He also wheezes.
To wheeze means to breathe with difficulty, producing a high-pitched whistling sound or rattle in
the chest as a result of obstruction in the airways.
Shortness of breath can be a sign of many conditions including heart failure, but in Ian’s case it is
due to a respiratory problem: chronic obstructive pulmonary disease (COPD). The working definition
of COPD, according to the UK’s National Institute for Health and Care Excellence (NICE), is a chronic
disease of the lungs ‘characterized by airflow obstruction that is not fully reversible. The airflow
obstruction does not change markedly over several months and is usually progressive in the long
term. COPD is predominantly caused by smoking. Other factors, particularly occupational exposures,
may also contribute to the development of COPD. Exacerbations often occur, where there is a rapid
and sustained worsening of symptoms beyond normal day-to-day variations.’
COPD encompasses a number of distinct conditions; the main ones are chronic bronchitis and
emphysema. These two conditions have distinct underlying pathophysiologies, and can give rise to
different characteristics in the sufferer. In most COPD patients, however, the two conditions coexist.
An understanding of the balance between the two may be useful in directing the most effective
individualized treatment. For example, patients with dominant chronic bronchitis tend to have a
productive cough, and mucolytics may therefore be of benefit.
WORKBOOK 8 Chronic obstructive pulmonary disease and asthma 287
DH:
• Ipratropium bromide 20 mcg/puff inhaler (two puffs four times a day)
• Salbutamol inhaler 100 mcg (two puffs four times daily)
No known drug allergies.
Ipratropium and salbutamol are bronchodilators with different receptor targets. They can be used in
combination to alleviate breathlessness.
SH:
• Ex-smoker, stopped 3 years ago. Smoked 30/day for ~45 years.
• Married, lives with wife.
For COPD patients who smoke, the biggest factor in influencing prognosis is giving up smoking. To
help patients do this, nicotine replacement therapy and support should be offered at every
opportunity.
O/E:
• Ian is breathless
• Swollen ankles and bluish tinge to skin (signs of oedema and hypoxaemia)
Investigations:
1) Relevant blood results:
• white blood cells (WBC): 18.1 × 109/l () (normal range 3.5–9.5 × 109/l)
• C-reactive protein (CRP): 56 mg/l (normal range <5 mg/l)
• Haemoglobin (Hb): 15.6 g/dl (normal range 13.5–17 g/dl for males; 11.5–14.8 g/dl for females).
Ian’s Hb level is normal. Reduced Hb levels, combined with other indices of red blood cell function,
can indicate anaemia. This condition can lead to breathlessness and inability of the patient to
function normally.
The raised WBC count and CRP level indicate the presence of infection. (CRP is secreted by the liver
in response to inflammatory mediators. A raised level is an indicator of infection.)
2) Spirometry
Ian previously had a recorded FEV1 of 50% of the predicted value, indicating a moderate degree of airflow
obstruction.
Lung function tests (spirometry) are used to detect airflow obstruction in the diagnosis of COPD.
The results should be interpreted in combination with the patient’s ability to function.
Patients perform a forced expiration, maximally filling the lungs before blowing out forcefully and
completely into a mouthpiece attached to a spirometer. The volume of expired air is plotted against
time. The measurements derived are normalized by comparing with predicted values for the patient;
these take into account factors that influence lung function, such as sex, age, and race (see Box
11.2). Measurements are recorded after administration of bronchodilator (usually salbutamol via
inhaler), and repeated once the patient is stable (6 weeks post-exacerbation).
In COPD patients the volume of air expired in the first second of the forced expiration (FEV1) is
reduced. The total volume of air expired, the forced vital capacity (FVC), is also measured and used
in combination with FEV1. Airflow obstruction is confirmed when FEV1/FVC ratio is <0.7.
288 Chapter 11 Respiratory disease: asthma and COPD
Assessing the severity of COPD is based on FEV1 measurements (post-bronchodilator):
FEV1 (% of predicted) Severity (according to NICE 2010)
80%
50–79% Moderate
30–49% Severe
<30%
*In combination with symptoms indicative of COPD.
Mild*
Very severe
Diagnosis: Infective exacerbation of COPD, based on blood results and symptoms.
Plan: Admit.
Commence:
• Intravenous amoxicillin
• Salbutamol inhaler via spacer (Volumatic® device)
• Tiotropium inhaler
• Oxygen therapy
• Oral steroid, prednisolone.
A spacer or Volumatic® is a clear plastic chamber into which inhaler is dispensed whilst the patient
breathes deeply. Recent evidence has indicated that metered dose inhalers (MDIs) used with such a
deviceareaseffectiveas,andmuchlesscostlythan,administrationbynebulizer—thisusedtobe
the preferred route of administration in urgent situations.
Oxygen is considered as drug therapy and should be prescribed. In COPD patients, oxygen is
recommended to prevent hypoxaemia, so as to improve survival.
Exploring Ian’s condition
The doctor tells Ian that he has a respiratory tract infection which has led to the exacerbation of
his COPD. He recommends that from now on Ian uses a spacer with his bronchodilator therapy
to improve access of the drug to the lungs. He will also be given intravenous antibiotics and a
course of oral steroids.
1) What is COPD? In your answer identify which parts of the respiratory tract are affected.
2) In emphysema the walls between adjacent alveoli break down. What are the physiological
consequences of this?
3) What is the main cause of COPD?
4) Explain why COPD can be described as irreversible, whereas asthma is reversible.
5) List the main types of bronchodilator used in obstructive airway disease.
6a) Salbutamol is the most common bronchodilator used. At which type of receptor does salbutamol
act, and what is/are the physiological agonist(s)?
6b) Where in the respiratory tract are these receptors?
WORKBOOK 8 Chronic obstructive pulmonary disease and asthma 289
6c) What is the effect of stimulating these receptors? How is this brought about?
7) One of the main side effects of 2-adrenoceptor agonists is tremor. Explain why.
Some time later the ward pharmacist notices that Ian is now using two inhaled antimuscarinic
bronchodilators: the newly prescribed tiotropium as well as the ipratropium he was already
taking. The pharmacist explains to the junior doctor and Ian that the two drugs should not be
used simultaneously, and that ipratropium should have been discontinued when he started
using tiotropium.
Antimuscarinic bronchodilators have a greater effect in COPD than asthma and are commonly used.
8a) At which class of receptor do ipratropium and tiotropium act? Why are these receptors so termed?
8b) What are the differences between ipratropium and tiotropium? Which subtypes of receptor do they
block, and where are these located in the respiratory tract?
8c) How does blocking these receptors benefit patients like Ian with COPD?
9) What are the main side effects of antimuscarinic agents?
Ian asks the pharmacist why he has been given oral steroids but has never been prescribed a
steroid inhaler.
Corticosteroids are the cornerstone of asthma therapy, but are not as effective in COPD. They have
been shown to reduce the number of exacerbations, and to slow the rate of decline only in moderate
to severe COPD (FEV1 < 50%).
Inhaled steroids are only licensed for use in COPD when combined with long-acting
adrenoceptor
2
agonists.
Oral steroids, such as prednisolone, are used for acute exacerbations.
10a) Considering the information above, if Ian is to start using an inhaled corticosteroid, which type of
inhaler is likely to be recommended?
10b) Explain why corticosteroids appear to be less effective in COPD than in asthma.
On day 2 after admission Ian shows improvement and his antibiotics are changed to oral form.
On day 4 he is discharged.
Discharge plan:
• Completecoursesoforalantibioticsandoralsteroid
• Continueontiotropium(oncedaily)viaHandihaler®andsalbutamol(asrequired),usinga
spacer to administer
• Seretideaccuhaler,compoundpreparationofuticasoneandsalmeterol
The pharmacist counsels Ian on the correct use of the seretide accuhaler. Its benefit will be
assessed by his GP over the course of the next 12 months.
290 Chapter 11 Respiratory disease: asthma and COPD
As Ian is leaving hospital, accompanied by his daughter Rose, they spot one of her colleagues,
Chris, who works with her in the local nursery. Chris is asthmatic. She is experiencing an
exacerbation of her asthma and is being admitted to the respiratory ward. Rose can see that
Chrisisnotwell;shehasamaskaroundhernoseandmouthwhichRoserealizesistosupply
oxygen.SheremembersChriscomplainingofwheezing, which she attributed to a chest
infection.
Chris has two young children who have been very excited in recent days as they have got a
new kitten called Felix.
CLINICAL CLERKING FOR CHRISTINE JONES
Age: 32 years
PC: Has become very breathless over the previous few hours; confused and disorientated.
HPC: Severe eczema as a child which she outgrew. Asthma for more than 20 years, controlled with
regular use of inhalers.
Asthma is a chronic inflammatory disorder of the airways which leads to reversible airflow
obstruction and increased airway sensitivity to a variety of stimuli.
The most common type of asthma is atopic, triggered by allergic reactions in hypersensitive
individuals; atopy often shows an inherited tendency.
DH:
Salbutamol: one or two puffs, three to four times a day as required.
Beclometasone: Clenil® Modulite® odulite 100 mcg, two puffs, twice a day regularly.
SH: 32-year-old mother of two small children.
Diagnosis: Acute exacerbation of atopic asthma due to exposure to allergen.
Plan: Admit:
• High-dose salbutamol via spacer
• High flow oxygen therapy
• Oral prednisolone
OnceherbreathinghasstabilizedChrisistransferredtotherespiratorywardtocontinueher
therapy. She knows that asthma can be a very serious condition which, if uncontrolled, can lead
to life-threatening acute attacks. She has allergic/atopic asthma; the current exacerbation has
been triggered by exposure to an allergen.
WORKBOOK 8 Chronic obstructive pulmonary disease and asthma 291
11a) Chris’s asthma has been very well controlled. What is likely to have been the triggering factor for
her current attack?
11b) List five other typical triggering stimuli for atopic/allergic asthma.
The process which initiates inflammation in allergic asthma is known as a type I hypersensitivity
reaction. It can be localized to the bronchial tree (asthma), the nose (hay fever), or the skin (eczema
or atopic dermatitis). The inflammatory response is mediated by a number of immune cells and
chemical mediators.
12) Complete the table below using ticks to indicate the differences between atopic (allergic) and nonatopic (non-allergic) asthma.
Atopic asthma Non-atopic
Family history
Responds well to inhaled corticosteroids
IgE type I hypersensitivity reaction is involved
13) Complete the flow chart below showing the processes leading to the development of asthma
symptoms.
Asthma risk factors
1. _________________________________________
2. _________________________________________
Bronchial
____________________
Bronchial
____________________
Bronchial
_____________________
Asthma symptoms include:
____________________________________
____________________________________
____________________________________
In an acute asthma attack there are two phases: an early/immediate phase and a late phase.
The early phase is dominated by bronchospasm. It is the result of the priming reaction that occurred
on first exposure to the allergen, when IgE antibodies were generated against it. Upon re-exposure
to the allergen, its interaction with mast-cell-fixed IgE causes the release of substances known as
spasmogens which stimulate the contraction of bronchiolar smooth muscle.
The late phase is dominated by airway inflammation and hyper-reactivity which further aggravate
bronchospasm, wheezing, and cough.