THERAPEUTICS

25 Asthma Kelly Atack and Ian Clifton

Key points Epidemiology

• Asthma is a common chronic inflammatory disorder of the
Asthma is a common condition, with an estimated 300 million
airways.
people affected worldwide. The prevalence of the condition var-
• The common symptoms of asthma are breathlessness, wheeze
and cough.
ies widely in different populations, and it appears to lie in the
range of 1–18% (Global Initiative for Asthma, 2012). One of
• Reversible airflow obstruction is the main physiological mea-
sure used in the diagnosis of asthma. the reasons for this variation in prevalence would appear to be
• Asthma triggers should be identified and avoided where the lack of a strict deinition. There may also be overlap with
possible. other conditions, such as chronic obstructive pulmonary disease.
• Poorly controlled asthma remains a significant health burden During childhood, asthma tends to be commoner in boys; how-
despite effective therapy. ever, during adulthood, the condition tends to be more frequent in
• The keystone of pharmacological therapy in people with women (Global Initiative for Asthma, 2012).
asthma is the delivery of effective anti-inflammatory drugs. Within the UK, the prevalence of asthma is thought to amongst
• Well-established national and international guidelines should the highest in the world, with an estimated 5.4 million people
be used to direct therapy. receiving asthma treatment. Asthma is estimated to affect 1 in
• Asthma therapy should be titrated to the lowest effective dose 12 adults and 1 in 11 children in the UK. Approximately 900
to ensure control with minimal side effects. individuals die from asthma each year in the UK. The National
• Inhaler technique is crucial to ensure that drug delivery is Review of Asthma Deaths identiied that the majority of deaths
effective. occurred outside of the hospital environment, with only approx-
• People with asthma should be offered asthma education and imately a third (30%) occurring in hospital (Royal College of
self-management plans. Physicians, 2014). A common theme in many studies examin-
ing asthma deaths is the underuse of personal asthma action
plans (PAAPs), overuse of bronchodilators and underuse of
Introduction corticosteroids.␣

Asthma is a chronic inlammatory condition of the airways. The

airway inlammation is associated with hyper-responsiveness of
the airways and variable airlow obstruction (Global Initiative for Aetiology
Asthma 2012). These physiological changes result in the classic
symptoms of intermittent breathlessness, cough and wheeze. The aetiology of asthma is complex and not fully elucidated. It is
Asthma was irst formally described by Hippocrates approxi- recognised that there is a complex interaction between multiple
mately 2500 years ago. The term asthma is derived from the Greek genetic and environmental factors. There is evidence for a heredi-
word aazein, which describes panting or laboured breathing. tary component to asthma, and current data suggest that multiple
The modern treatment of asthma began with the use of epineph- genes are involved in the development of asthma. Numerous
rine at the turn of the 20th century, followed by the introduction of environmental factors have been identiied as potential fac-
xanthines, such as theophylline, in the 1920s. During the 1950s oral tors that inluence the risk of developing asthma. These include
corticosteroids were introduced, with subsequent introduction of exposure to allergens, infectious agents, occupational substances,
chromoglycate, inhaled corticosteroids and short-acting β-agonists air pollution and diet.
in the 1960s. Subsequently, during the 1980s and 1990s long-acting One hypothesis for the increasing prevalence of asthma is the
β-agonists and leukotriene antagonists were introduced, respec- ‘hygiene hypothesis’, which postulates that reduction in early
tively. Therapies, particularly for people with severe asthma, have childhood exposure to infectious agents increases the suscepti-
advanced during the early 21st century with the introduction of tar- bility to allergic diseases. There are other potential explanations
geted biological therapy such as omalizumab (anti-immunoglobulin for the increased incidence of asthma in the developing world,
E [IgE]) and mepolizumab (anti-interleukin-5 [IL-5]).␣ including air pollution.␣
440
 ASTHMA 25
Pathophysiology Table 25.1 Potential triggers for asthma symptoms

Asthma is an inlammatory disorder of the airways, and various Type of potential trigger Trigger
inlammatory cells and mediators have been identiied as playing
an important role in the pathophysiology of asthma. Allergens House dust mite
Animal dander
Bronchial hyper-reactivity is recognised as a key feature of
Moulds
asthma pathophysiology. This results in the airways of people with Pollens
asthma responding to exposure to particular triggers, which vary
from person to person. Exposure to triggers causes constriction Infectious agents Influenza
of the airway smooth muscle, resulting in bronchoconstriction. Rhinovirus
Bronchoconstriction is a result of activation of the parasym-
pathetic pathways of the autonomic nervous system. The release Drugs Non-steroidal anti-inflammatory drugs
Beta blockers
of acetylcholine by the postganglionic nerve ibres activates
Prostaglandins
the M3 muscarinic receptors within the airway smooth muscle.
Activation of these receptors results in contraction of the smooth Occupational Isocyanates
muscle and, consequently, constriction of the diameter the airway. Wheat flour
The inlammatory process follows the bronchoconstriction, Soy caster bean
resulting in the production of excess mucus and oedema within Latex
the airway. The combination of bronchoconstriction and inlam- Formaldehydes
Hair colourants
matory process leads to narrowing of the airway calibre and the
classic symptoms of breathlessness, wheeze and cough. Other Sulphites
Some people with asthma have brittle asthma, which is classi- Nitrogen oxides
ied into two types. Type I brittle asthma is deined by periods of Sulphur dioxide
prolonged peak low variability, whereas type II is characterised Exercise
by sudden deteriorations on a background of good control and Cold air
Stress
relatively normal lung function.
Over the last few years there has been a paradigm shift in the
understanding of asthma pathophysiology. This has led to asthma
no longer describing a single disease but a collection of multiple
subgroups referred to as phenotypes (Wenzel, 2012). There are a number of signs of acute asthma, including tachy-
The majority of people with asthma have an inlammatory pnoea (increased rate of respiration), wheeze on expiration and
process driven by TH2 processes that tend to be associated with use of accessory muscles of respiration. In children there may
atopy, allergy, type I hypersensitivity and eosinophilic inlamma- also be indrawing of the intercostal muscles.␣
tion. Asthma associated with an inlammatory process driven by
eosinophilic inlammation has long been recognised to be respon-
sive to treatment with corticosteroids (Brown, 1958). The under-
standing of non-TH2-driven asthma is much less established Investigations
than that of asthma driven by TH2 pathways. This subgroup of
people with asthma can be associated with a later age of onset, The diagnosis of asthma is a clinical one; there is no standardised
obesity and neutrophilic inlammation. Lack of response to treat- deinition of the type, severity or frequency of symptoms, nor
ment with corticosteroids tends to be a feature of non-TH2-driven of the indings on investigation (British Thoracic Society [BTS]
asthma.␣ and Scottish Intercollegiate Guidelines Network [SIGN], 2016).
A key part of the diagnostic process is to identify the character-
istic symptoms of asthma from the patient. Due to the long-term
nature of the condition, the history obtained from the patient is
Clinical signs and symptoms not suficient to make the diagnosis, and it is important to use
diagnostic tests to provide objective evidence of asthma.
Asthma can present with a number of different symptoms but
classically presents with cough, wheeze and breathlessness,
Lung function testing
often induced by exposure to a wide variety of trigger factors.
Individuals with asthma will commonly describe exposure to cer- Lung function testing is a key part of the diagnosis and monitor-
tain triggers resulting in an increase in symptoms (Table 25.1). ing for people with asthma. Lung function testing in asthma aims
The frequency and severity of these symptoms is highly vari- to demonstrate the presence of reversible airlow obstruction.
able between individuals and also within individuals. At times It can also provide a guide to response to treatment and detect
the person with asthma may be asymptomatic, whereas at other deterioration in asthma control. There are a number of different
times the person may have a high level of symptoms potentially methods for testing lung function, all of which have particular
requiring hospital admission. Asthma tends to demonstrate diur- strengths and weaknesses.
nal variation, generally with increased symptoms at night and Peak expiratory low rate (PEFR) is the maximum airlow 441
early in the morning. rate during forced expiration. A peak low meter can measure
 25 THERAPEUTICS

10 Predicted 8 Predicted
Baseline Baseline
8
6

Volume (L)
Flow (L/s)
6
4
4

2
2

0 0
1 2 3 4 5 0 2 4 6 8 10
Volume (l) Time (s)
Fig. 25.1 Example flow–volume loop (A) and volume–time curve (B).
FEV1, Forced expiratory volume in 1 second; FVC, forced vital capacity.

Table 25.2 Spirometry parameters

Abbreviation Term Definition

FEV1 Forced expiratory volume in 1 second Volume of air forcibly expired in 1 second

FVC Forced vital capacity Total volume of air forcibly expired at maximum expiration

FEV1% Percent of predicted FEV1 Calculated from normal values for gender, age, height and
ethnic origin
FVC% Percent of predicted FVC

FEV1/FVC Ratio between FEV1 and FVC Normal ratio >0.7, if ratio <0.7, then spirometry in keeping
with airflow obstruction

FEV1, Forced expiratory volume in 1 second; FVC, forced vital capacity.

PEFR in a simple portable device that provides a simple and

Reversibility testing
useful method for patients to monitor their asthma. When using
a peak low meter, the patient undertakes three forced expira- Reversibility testing measures the response to bronchodilators or
tions through the device and records the highest of the three corticosteroids to determine whether there is an improvement in lung
values. function as demonstrated by a change in FEV1 or PEFR. The use of
Measurements of spirometry provide a measure of lung func- reversibility testing in individuals with normal or near-normal lung
tion that is more reproducible than PEFR. Spirometry is prefer- function is limited because there is limited scope for improvement.
able to PEFR because it provides a more accurate measure of Salbutamol reversibility is assessed by repeating spirometry after
airlow obstruction. When performing spirometry, an individ- 20 minutes following the administration of 400 micrograms salbu-
ual inhales to maximal inspiration, then exhales maximally to tamol. Corticosteroid reversibility can be undertaken by using oral
complete expiration. The spirometry provides a graphical rep- prednisolone for 2 weeks or inhaled beclometasone for 6–8 weeks.
resentation of the manoeuvre as a volume–time curve and/or a There are a number of deinitions of a positive reversibility trial.
low–volume loop (Fig. 25.1). Examination of the spirometry The European Respiratory Society/American Thoracic Society (ERS/
trace as well as review of the spirometry values is important ATS) guidelines deine a positive test as greater than 200 mL or 12%
to ensure that the procedure has been performed appropriately. improvement in FEV1 and/or FVC in response to treatment with bron-
When performing spirometry, the forced expiratory volume in chodilators or corticosteroids (Pellegrino et al., 2005). The National
1 second (FEV1) and forced vital capacity (FVC) are recorded Institute for Health and Care Excellence (NICE) uses a higher threshold
(see Table 25.2 for deinitions of spirometry parameters). This requiring greater than 400 mL improvement in FEV1 (NICE, 2010).␣
then allows for calculation of the FEV1/FVC ratio and also the
percentage of predicted values.␣
Measurement of airway hyper-responsiveness
Testing of airway hyper-responsiveness has long been established
Further investigations
as a research tool, and such testing is now starting to become more
Sometimes the combination of clinical assessment and measure- routine in clinical practice. These tests are generally more useful
442 ment of lung function is not suficient to conirm the diagnosis of in patients with normal or near-normal spirometry. The tests aim
asthma, and further investigations are required. to demonstrate bronchoconstriction in response to administration
 ASTHMA 25
of an inhaled challenge. A number of substances can be used as complete asthma control as the following (BTS and SIGN,
challenges, including histamine, methacholine and mannitol.␣ 2016):
• no daytime symptoms,
Measures of airway inflammation • no night-time wakening due to asthma symptoms,
• no requirement for rescue medication,
Eosinophilic airway inlammation can be determined using • no asthma attacks/exacerbations,
induced sputum differential counts or measurement of the frac- • no limitations on activity,
tion of exhaled nitric oxide (FeNO). Evidence of active eosino- • normal lung function – FEV1 and/or peak expiratory low
philic airway inlammation is seen more commonly in people (PEF) greater than 80% predicted or best,
with asthma but also would seem to predict an increased response • minimal adverse effects from medication.
rate to corticosteroids (Green et al., 2002a).␣ BTS guidelines recommend that treatment should begin at the
most appropriate step to improve symptoms and lung function as
Other tests quickly as possible (Fig. 25.2; BTS and SIGN, 2016).
Treatment must be balanced against the risk of adverse effects
Other tests that can be useful in supporting the diagnosis include and should be titrated down where possible whilst keeping good
measurement of blood eosinophil count, measurement of serum control of asthma. Prior to moving treatment up a step, adherence
IgE and testing for atopy through either skin-prick testing or IgE and inhaler technique must be assessed and any triggers should be
testing for speciic allergens. For individuals with atypical fea- removed.
tures, consideration should be undertaken for a chest X-ray (BTS
and SIGN, 2016).␣ Inhaled corticosteroids
Corticosteroids bind to glucocorticoid receptors within the lung and
Treatment decrease the formation of cytokines, which produce IgE and pro-
mote the expression of IgE receptors. They also inhibit the inlux
Chronic treatment
of eosinophils into the lung, therefore reducing overall inlamma-
The aim of asthma management is to have complete control tion. Inhaled corticosteroids (ICSs) are recommended as the sec-
and have no exacerbations of the disease. The BTS deines ond step as a regular preventative therapy in the BTS guidelines

Summary of management in adults

Asthma-suspected Asthma-diagnosed

Diagnosis and Evaluation: •assess symptoms, measure lung function, check inhaler technique and adherence
assessment •adjust dose •update self-management plan •move up and down as appropriate

d
ede
s ne
ntrol a
e co
rov
Continuous or
imp frequent use of oral
e u p to eraphy
h steroids
Mov olling t
ntr
st co High-dose therapies
lowe
tain
main
and
find
ow n to Additional add-on
Move d therapies

No response to LABA- Consider trials of: Use daily steroid tablet

Initial add-on therapy stop LABA and in the lowest dose
consider increased Increasing ICS up to providing adequate
dose of ICS high dose control
Regular preventer If benefit from LABA
Addition of a fourth Maintain high-dose
but control still ICS
drug, e.g. LTRA,
inadequate–continue
SR theophylline, beta
LABA and increase Consider other
agonist tablet, LAMA
ICS to medium dose treatments to minimise
use of steroid tablets
Consider monitored Low-dose ICS Add inhaled LABA to
initiation of treatment low-dose ICS If benefit from LABA
with low-dose ICS (normally as a but control still
combination inhaler) inadequate–continue
LABA and ICS and
consider trial
Infrequent, short-lived of other therapy-LTRA, Refer patient for Refer patient for
wheeze SR theophylline, specialist care specialist care
LAMA

Short acting β2 agonists as required – consider moving up if using three doses a week or more

Fig. 25.2 Summary of stepwise management of asthma in adults (BTS and SIGN, 2016).
ICS, Inhaled corticosteroids; LABA, long-acting β-agonist; LAMA, long-acting antimuscarinics; LTRA,
leukotriene antagonists; SR, sustained release. 443
Reproduced from BTS/SIGN British Guideline on the management of asthma by kind permission of
the British Thoracic Society.
 25 THERAPEUTICS

(BTS and SIGN, 2016), for all people with asthma, except those (BTS and SIGN, 2016). Patients with very infrequent signs and
with very mild and occasional symptoms, where ‘as-required’ symptoms of asthma may require only a SABA. Excessive use of
symptomatic treatment with short-acting β2-agonists alone may SABAs, deined as more than one canister per month, has been
be suficient. Standard doses of ICSs are suggested as 200–400 associated with an increased risk of asthma death.
micrograms/day of beclometasone dipropionate (BDP) or equiva- Additionally, oral SABAs are not recommended due their
lent in 24 hours. For adults, it is recommended that patients com- higher risk of systemic side effects compared with administra-
mence treatment at a dose of 200–800 micrograms/day of BDP or tion via inhalation.␣
equivalent. This can be increased to up to 2000 micrograms/day of
BDP or equivalent as a fourth step if patients have no response to
Long-acting β-agonists
the addition of a long-acting β-agonist (LABA) or a trial of alterna-
tive agents (BTS and SIGN, 2016). It should be noted, however, LABAs act on the β2-receptors in the smooth muscle of the bron-
that at doses of 800 micrograms/day of BDP or equivalent, this will chi, aiding bronchodilation. Inhaled LABAs are a irst-line addi-
achieve 90% clinical beneit for the patient. At doses higher than tion to ICSs and can be administered as an individual ingredient
this there is a signiicant increase in adverse effects (Holt et al., or in a combination inhaler with an ICS. The addition of a LABA
2001). Budesonide, ciclesonide, luticasone and mometasone are to a low-dose ICS has been shown to be as effective as increas-
other ICSs that are available and widely used. ing the ICS dose and may be associated with fewer side effects.
Administering drugs via the inhalation route allows the drug to LABAs, such as salmeterol, formoterol fumarate and vilanterol,
be delivered directly into the lungs, allowing it to take action in the are designed to be used regularly but have different characteristics
target organ and reducing systemic absorption and therefore the in terms of onset and duration of action (Table 25.4). Indacaterol
risk of adverse effects. It is imperative to note, however, that using and olodaterol are LABAs designed for once-daily administra-
corticosteroids in the inhaled form is not without risk. Patients tion; however, they are not currently licensed for use in asthma.
on long-term, high-dose ICSs (i.e. at a dose of more than 1000 LABAs can exert an effect on β-receptors elsewhere and are
micrograms/day of beclometasone or equivalent) are encouraged not completely selective to β2-receptors. Consequently, they also
to carry a steroid card with them and should be educated of the affect the β1-receptors in the cardiac muscle, increasing cardiac
potential serious adverse effects (BTS and SIGN, 2016). ICSs can output and stimulation, leading to tachycardia and arrhythmias.
cause oral candidiasis and dysphonia; hence, encouraging patients Additionally, they can cause tremor and hypokalaemia. LABAs
to rinse the mouth after use is important. Long-term, high-dose used alone have been associated with an increased risk of death
ICS use will result in some of the steroid being absorbed systemi- and therefore should not be used without an ICS (Royal College
cally, potentially leading to adverse effects, including increased of Physicians, 2014). The Medicines and Healthcare Products
blood glucose and susceptibility to diabetes. ICSs can also lead to Regulatory Agency (MHRA) recommends that LABAs should
osteoporosis, increasing the risk of fractures, muscle wasting and ideally be administered in a combination inhaler to aid adherence
impaired wound healing. They can also cause psychiatric reac- (MHRA, 2008). There are not many interactions with LABAs,
tions and mood disorders, as well as adrenal suppression, which but care must be taken when using LABAs with other agents that
may lead to the patient requiring steroid replacement therapy. cause hypokalaemia. Due to the cardiac risks associated with the
Consequently, it is important to inform the patients of the risks use of LABAs, it is important to step down treatment where pos-
associated with ICSs and consider the risk versus beneit of them, sible for safety.
particularly in patients with medical conditions that may be exac- The use of LABAs as monotherapy in asthma is associ-
erbated by the use of steroids. ated with signiicantly worse asthma outcomes and increased
ICSs are available in a variety of devices, in combination with asthma mortality compared with treatment with ICSs. This
a LABA or as individual agents. In some circumstances they increased mortality is not seen when LABAs and ICSs are used
are used in conjunction with a LABA as a reliever, such as in concurrently. Consequently, national (BTS and SIGN, 2016)
the ‘Maintenance and Reliever Therapy’ regimen. Traditionally, and international (Global Initiative for Asthma, 2012) guide-
there were few devices containing ICSs available to patients. lines are very clear that long-acting relievers should not be
More recently there has been an inlux of new devices into the prescribed without an ICS and where possible should be pre-
UK market. This gives patients and healthcare professionals more scribed as a combination ICS/LABA inhaler to prevent people
choice with regard to selecting the most appropriate device. Care inadvertently taking only the LABA. Table 25.5 demonstrates
needs to be taken, however, when changing a patient’s inhaled that there are a large number of ICS/LABA preparations and
therapy due to the variety of different devices and doses currently devices currently on the market and that it is important to
available (Table 25.3). be aware of the different strengths when swapping between
Because there is some systemic absorption, ICSs also have inter- devices. Some patients may require a regimen requiring the
actions with other medicines. Itraconazole and ritonavir, in particu- separate components in separate inhaler devices, for example,
lar, interact signiicantly by inhibiting the metabolism of ICSs and if ciclesonide is prescribed as an alternative to other ICSs due
can increase levels enough to induce adrenal suppression.␣ to oropharyngeal side effects. However, patients in this situa-
tion must be made aware of the importance of adhering to both
the LABA and the ICS.
Short-acting β-agonists
When added to an existing ICS, LABAs are used in preference
Short-acting β-agonists (SABAs), such as salbutamol and ter- to leukotriene receptor antagonists because they provide greater
444 butaline, are the irst-line step and should be prescribed for all control and reduce exacerbation rates (Chauhan and Ducharme,
asthma patients and should be used on a when-required basis 2014).␣
 ASTHMA 25
Table 25.3 Equivalent steroid doses for inhaled corticosteroids

Equivalence to 400 micrograms of

Name Device beclometasone dipropionate

Beclometasone dipropionate

Asmabec Clickhaler 400 micrograms

Clenil pMDI 400 micrograms

Easyhaler beclometasone Easyhaler 200 micrograms

Fostair pMDI and Nexthaler 200 micrograms

Qvar Autohaler, Easi-Breathe and pMDI 200 micrograms

Budesonide

Budelin Novolizer 400 micrograms

DuoResp Spiromax 200 micrograms

Easyhaler budesonide Easyhaler 400 micrograms

Pulmicort Turbohaler 400 micrograms

Symbicort Turbohaler 400 micrograms

Ciclesonide

Ciclesonide pMDI 200–300 micrograms

Fluticasone furoate

Relvar Ellipta 200 micrograms

Fluticasone propionate

Flixotide Accuhaler and pMDI 200 micrograms

Flutiform pMDI 200 micrograms

Seretide Accuhaler and pMDI 200 micrograms

Sirdupla pMDI 200 micrograms

Mometasone furoate

Asmanex Twisthaler 200 micrograms

pMDI, Pressurised metered dose inhaler.

Table 25.4 Pharmacokinetic characteristics of different long-acting β-agonists

Drug Onset of action (min) Duration of action (h)

Formoterol 2–3 12

Salmeterol 10–14 12

Vilanterol 5–15 24

445
 25 THERAPEUTICS

Table 25.5 Approximate equivalent dose of combination inhaled corticosteroids/long-acting β-agonist inhalers

Low dose (micrograms Medium dose (micro- High dose (micro-

Name and device Active ingredients per dose) grams per dose) grams per dose)

DuoResp Spiromax Budesonide and formoterol 160/4.5 1 puff BD 160/4.5 2 puffs BD 320/9
320/9 1 puff BD 2 puffs BD

Flutiform pMDI Fluticasone and formoterol 50/5 2 puffs BD 125/5 2 puffs BD 250/10 2 puffs BD

Fostair pMDI Beclometasone and for- 100/6 1 puff BD 100/6 2 puffs BD 200/6 2 puffs BD
moterol 200/6 1 puff BD

Fostair NEXThaler Beclometasone and for- 100/6 1 puff BD 100/6 2 puffs BD 200/6 2 puffs BD
moterol 200/6 1 puff BD

Relvar Ellipta Fluticasone and vilanterol 92/22 1 puff OD 184/22 1 puffs OD

Seretide Accuhaler Fluticasone and salmeterol 100/50 1 puff BD 250/50 1 puff BD 500/50 1 puff BD

Seretide pMDI Fluticasone and salmeterol 50/25 2 puffs BD 125/25 2 puffs BD 250/25 2 puff BD

Sirdupla pMDI Fluticasone and salmeterol 125/25 2 puffs BD 250/25 2 puffs BD

Symbicort Turbohaler Budesonide and formoterol 100/6 1–2 puffs BD 400/12 1–2 puffs BD
200/6 1–2 puffs BD

BD, Twice daily; OD, once daily; pMDI, pressurised metered dose inhaler.

Leukotriene antagonists
has been demonstrated to improve asthma control and qual-
Leukotriene antagonists work by reducing the inlammation in ity of life as well as reduce exacerbation frequency in patients
the bronchi, by inhibiting leukotriene receptors in the respiratory with severe asthma (Rodrigo and Castro-Rodriguez, 2015). The
mucosa and reducing sputum eosinophilia. Leukotriene antago- other currently marketed LAMAs – aclidinium, glycopyrronium
nists such as montelukast and zairlukast are recommended for and umeclidinium – are not currently licensed for use in asthma.
use in the UK when patients are not responding to a LABA or It should be noted that they have antimuscarinic side effects
as an addition to an ICS/LABA combination inhaler in someone throughout the body and can cause dry mouth, constipation, uri-
with persistent poor control. nary retention and angle-closure glaucoma.␣
There is some evidence for their use in addition to ICSs, and
they have been shown to be particularly useful for people with
Theophylline preparations
exercise-induced asthma (Malmstrom et al., 1999) and poten-
tially for patients with allergic rhinitis (Nathan, 2003). They can Theophylline and aminophylline are methylxanthines and work
be taken orally, and there are a number of preparations available, as bronchodilators and stimulate respiration. The exact mecha-
including granules if patients have problems with swallowing nism of action is unclear, and their effect is not speciic to the
solid oral dosage forms. lung. Oral theophylline and aminophylline can be used as an
Leukotriene antagonists are commonly associated with rela- alternative in the same way as the leukotriene antagonists when
tively mild side effects of headaches and gastro-intestinal side patients are unresponsive to LABAs or as an addition to an ICS/
effects. However, they are also rarely associated with the more LABA combination inhaler (BTS and SIGN, 2016).
serious eosinophilic granulomatosis with polyangiitis (previ- Methylxanthines have a narrow therapeutic window and require
ously known as Churg-Strauss syndrome). This is characterised close monitoring of serum theophylline levels to ensure a therapeu-
by vasculitis and eosinophilia, and care should be taken to inform tic dose and avoid toxicity. Levels should be taken 5 days after com-
patients of this rare adverse effect. There are minimal drug inter- mencing treatment or changing doses and annually, with the aim of
actions associated with the leukotriene antagonists.␣ achieving a serum level of 10–20 mg/L. At toxic levels methylxan-
thines have effects on the central nervous system, causing tremor
and action on cardiac muscle α-receptors that results in increased
Long-acting antimuscarinics
cardiac output and tachycardia, as well as constricting cerebral
Long-acting antimuscarinics (LAMAs) work by binding to the blood vessels. Because theophylline may also cause convulsions,
muscarinic M3 receptors in the smooth muscle of the lung to aid care must be taken when prescribing for people with epilepsy. The
bronchodilation. LAMAs may also be trialled in patients who use of theophylline should be reviewed regularly. The risk of car-
have not responded to an ICS/LABA combination in the fourth diotoxicity and high plasma concentrations should be taken into
446 step of the BTS guidelines (BTS and SIGN, 2016). Tiotropium consideration to ensure that the beneit outweighs the risk.
 ASTHMA 25
year (NICE, 2013). It has been shown to signiicantly reduce the
Table 25.6 Drug interactions with theophylline
number of exacerbations in patients with severe asthma who have
Drug Interaction not improved on standard treatments.
Omalizumab is administered as a subcutaneous injection two
Azole antifungals (itracon- May increase theophylline levels to four times weekly, and it can take up to 12–16 weeks before an
azole, fluconazole)
effect is felt. The dose of omalizumab is calculated according to
Calcium-channel antagonists May increase theophylline levels
the individual’s weight and serum IgE levels.
(diltiazem, verapamil) Mepolizumab is another humanised monoclonal antibody. It
targets IL-5, which is responsible for activating eosinophils, and
Carbamazepine May decrease theophylline is used for patients with severe refractory eosinophilic asthma.
levels It has recently been approved for use in the UK for people with
severe eosinophilic asthma requiring frequent or daily oral corti-
Cimetidine May increase theophylline levels
costeroids (NICE, 2017).
Fluvoxamine May increase theophylline levels
Because biological therapies are not metabolised, there are
minimal drug interactions, although there are concerns regard-
Isoniazid May increase theophylline levels ing the possibility of an anaphylactic reaction during therapy.
Patients are therefore expected to have these injections adminis-
Lithium carbonate Increased lithium levels tered in a specialist hospital setting (BTS and SIGN, 2016).
More biological therapies targeted at speciic parts of the
Macrolide antibiotics (azithro- May increase theophylline levels
inlammatory response are being developed to reduce the need
mycin, clarithromycin,
erythromycin) for oral steroids and their associated side effects. However, such
therapies are likely to be expensive and therefore only used in
Phenytoin May reduce theophylline and specialist centres.␣
phenytoin levels

Primidone Decreased theophylline levels Oral corticosteroids

Oral corticosteroids, such as prednisolone, can be used for the
Quinolone antibiotics (cipro- May increase theophylline levels
floxacin, norfloxacin) treatment of both exacerbations and chronic asthma. A mainte-
nance dose of oral corticosteroids is occasionally used for chronic
Rifampicin Decreased theophylline levels asthma treatment for individuals requiring multiple courses of
oral steroids who are on the ifth step of treatment (BTS and
Ritonavir May increase theophylline levels SIGN, 2016). Individuals who may require long-term oral cor-
ticosteroids should be referred to a specialist clinic for review
St John’s wort May reduce theophylline levels
of their asthma and treatment plan. These drugs should be used
at the lowest dose possible and regularly reviewed, and patients
Theophylline is metabolised using the cytochrome P450 should be monitored for risk of adverse effects. Corticosteroids
pathway; therefore, its plasma concentration can be decreased will reduce lung inlammation; however, they also have systemic
by enzyme inducers and increased by drugs that inhibit cyto- adverse effects. The risk of these serious adverse effects must be
chrome P450 (Table 25.6). Unfortunately, antimicrobials that thoroughly considered to ensure that patients are gaining beneit
may be used for the treatment of respiratory tract infections, such from oral corticosteroid use. Patients should be fully informed
as ciproloxacin and clarithromycin, inhibit cytochrome P450. of the risks of long-term oral steroids. Other treatments, such as
Therefore, patients should be informed to halve the dose of the- calcium and vitamin D, bisphosphonates for bone protection and
ophylline whilst taking these medicines, to ensure levels are not medicines for gastric protection, may also be required when the
increased and cause toxicity. Care should be taken when prescrib- patient is prescribed oral corticosteroids.
ing medicines concurrently with theophylline, and interactions Care must also be taken to consider interactions with oral corti-
should be checked to assess the risk of toxicity.␣ costeroids because they can increase the risk of gastro-intestinal
bleeding. Other medicines that increase the risk of this (e.g. non-
steroidal anti-inlammatory drugs [NSAIDs] and selective sero-
Biological therapies
tonin re-uptake inhibitors [SSRIs]) should be used with caution.␣
Biological therapies are slowly being introduced into the UK for
treatment of allergic asthma. Omalizumab is a humanised mono-
Steroid-sparing agents
clonal anti-IgE antibody. It works to reduce the amount of circu-
lating IgE and reduce the inlammatory response. Omalizumab Steroid-sparing agents, such as methotrexate, ciclosporin and
is being more widely used in particular and is licensed for use in oral gold, have been used in some patients with dificult-to-treat
patients with uncontrolled asthma where their asthma is medi- asthma to reduce the risk of adverse effects from prolonged use
ated by the presence of IgE. In the UK, it is approved for people of corticosteroids, despite a limited evidence base (Davies et al.,
with allergic asthma who need continuous or frequent treatment 1998; Evans et al., 2000a,b). When used, they are prescribed on a
with oral corticosteroids and had at least four courses in the last 3-month trial after discussion with the patient about the potential 447
 25 THERAPEUTICS

Table 25.7 Classification of acute asthma severity (BTS and Box 25.1 Factors lowering the threshold for admission to
SIGN, 2016) hospital

Severity of • People younger than 18 years

exacerbation Characteristics • Poor adherence to medication
• Person living alone
Moderate Increased symptoms • Psychological problems, such as depression, and alcohol or
asthma PEFR 50–75% of best or predicted drug misuse
No features of acute severe asthma • Physical or learning disability
• Previous near-fatal attack or brittle asthma
Acute severe Any one of the following features: • Persistent exacerbation despite an adequate dose of oral
asthma • PEFR 33–50% of best or predicted corticosteroids before presentation
• ≥25 breaths/min • Presentation at night or in the afternoon
• Heart rate ≥110 beats/min • Pregnancy
• Inability to complete sentences in one breath

Life-threatening One of the following features in a patient with

asthma acute severe asthma: hospital. Patients with life-threatening or near-fatal asthma should
• PEFR <33% of best or predicted be admitted to hospital for assessment and treatment. Patients
• PaO2 ≤8 kPa with acute severe asthma who have responded to initial therapy
• Normal PaCO2 (4.6–6.0 kPa) and have no other concerning features do not need to be admit-
• sO2 <92%
ted to hospital. Patients should be assessed for a number of other
• Altered consciousness level
• Exhaustion or poor respiratory effort
factors because these may inluence the threshold for referral for
• Haemodynamic instability as defined by admission to hospital (see Box 25.1).␣
cardiac arrhythmias or hypotension
• Cyanosis
• Silent chest
Treatment
Acute asthma can be life-threatening, and treatment aims to relieve
Near-fatal One of the following features:
immediate symptoms, improve bronchoconstriction and address
asthma PaCO2 >6.0 kPa
Need for mechanical ventilation with raised airway inlammation. Acute asthma is stratiied according to clini-
inflation pressures cal observations and investigations (see Table 25.7). Acute severe
asthma is deined as the patient’s peak low reduced to between
PaCO2, Partial pressure of carbon dioxide in arterial blood; PaO2, partial 33–50% of the patient’s best or predicted, increased respiratory
pressure of oxygen in arterial blood; PEFR, peak expiratory forced reserve.
rate of more than 25 breaths per minute, heart rate of more than
110 beats per minute and the patient is unable to complete a sen-
risks. It is recommended they are only used under the supervision tence in one breath. Life-threatening asthma is deined as the peak
of a specialist severe asthma service (BTS and SIGN, 2016).␣ low being less than 33% of the patient’s best or predicted, oxygen
saturation of less than 92%, silent chest, reduced respiratory effort,
hypotension and an altered state of consciousness. Suficient treat-
Cromones
ment with steroids and monitoring of the patient’s condition are
Inhaled sodium cromoglicate and nedocromil have a limited key factors in ensuring the patient’s recovery. Overuse of β-agonist
role in the management of asthma, and they are signiicantly therapy has been associated with asthma death; therefore, care
less effective than ICS therapy (BTS and SIGN, 2016). They are must be taken and monitoring undertaken.
rarely used in current practice.␣ Oxygen. Patients with severe or life-threatening acute asthma
should have their oxygen saturation maintained at 94–98% to
treat hypoxia. These patients should be administered oxygen
Acute treatment
via a face mask, Venturi mask or nasal cannulae as a matter of
When assessing a person with an acute exacerbation of asthma, it urgency. Pulse oximetry should be used to measure oxygen satu-
is important to ask about possible trigger factors, such as recent ration where possible; however, this should not be a barrier to the
allergen exposure or upper respiratory tract viral infections use of oxygen in this situation if unavailable (BTS and SIGN,
(Green et al., 2002b). An acute exacerbation of asthma needs 2016; O’Driscoll et al., 2008).␣
prompt assessment and appropriate treatment because it repre- Bronchodilators. Inhaled β-agonists should also be adminis-
sents a potentially life-threatening condition. tered in emergency situations to treat bronchoconstriction. High
doses should be given via the nebulised route where possible.
However, if the patient is at home, they can administer 4–6 puffs
Risk stratification and assessment
at one time of a SABA into a large-volume spacer and take mul-
The severity of an acute exacerbation of asthma is determined by tiple breaths in and out of this device. Patients should have their
a number of different clinical factors and is categorised as moder- potassium and heart rate monitored due to the potential adverse
ate, acute severe, life-threatening or near-fatal (Table 25.7). This effects of hypokalaemia and tachycardia associated with nebu-
448 risk stratiication provides guidance on the need for admission to lised β-agonist use (BTS and SIGN, 2016).
 ASTHMA 25
If their response to nebulised β-agonists is poor, or in cases
Table 25.8 Dosing of intravenous aminophylline
of severe exacerbations, then there is evidence for the addition
of nebulised ipratropium for increased bronchodilation (Lanes Patient characteristics Loading dose
et al., 1998). Ipratropium is an antimuscarinic and works on the
M3 receptors to relax the smooth muscle of the bronchi to induce Adult already taking oral No loading dose required
theophylline/aminophylline
bronchodilation.
Intravenous salbutamol and terbutaline have also been used; Adult not taking oral 5 mg/kg over 20 min
however, these are no longer recommended because nebulised theophylline/aminophylline
salbutamol is a safer option. The only scenario where they could
be considered would be where a patient was not responding to Maintenance dose
β-agonists via an inhaled route (BTS and SIGN, 2016; Travers
Elderly adult/adult with heart 0.3 mg/kg/h
et al., 2012).␣ failure
Corticosteroids. Oral corticosteroids should be adminis-
tered after an acute asthma attack at the earliest stage possible Nonsmoking adult 0.5 mg/kg/h
for the most benefit (Rowe et al., 2007). There is much evi-
dence suggesting they will reduce the risk of another attack Smoking adult 0.7 mg/kg/h
and aid recovery time, as well as decrease mortality (Rowe
et al., 2007). Oral prednisolone should be administered at a
dose of 40–50 mg daily, preferably in the morning to mimic to the risks involved with intravenous aminophylline and also
the body’s natural cortisol production and reduce adverse the monitoring involved, this should not be commenced with-
effects, including insomnia. If the oral route is unavailable, out specialist medical input.␣
then intravenous hydrocortisone may be administered at a Antibiotics. Acute asthma exacerbations are mostly caused by
dose of 100 mg four times daily until the oral route is avail- exposure to allergens or viruses. Consequently, antibiotics are not
able again. indicated and should not be commenced without clear evidence
Corticosteroid therapy should be continued for at least 5 days of a bacterial cause (Graham et al., 2001).␣
but can be extended until the patient’s condition has improved.
Additionally, corticosteroids can be stopped without needing to
wean down the dose unless they have been prescribed for longer Patient care
than 2 weeks or if the patient is already taking maintenance corti-
Structure of an asthma review
costeroids because this poses a risk of adrenal suppression. The
shortest course length possible should be used to protect patients There are a number of issues that should be addressed during
from the adverse effects of corticosteroids (BTS and SIGN, an asthma review to ensure that it is as effective as possible.
2016).␣ Firstly the degree of asthma control needs to be assessed. If
Intravenous magnesium. Patients who have not responded the person’s asthma symptoms are controlled, then poten-
well to initial bronchodilator therapy can be administered a tially a step down in therapy may be indicated. Conversely,
dose of intravenous magnesium at a dose of 1.2–2 g over 20 when the person’s asthma is not at the appropriate level of
minutes. This can aid bronchodilation and reduce the require- control, a number of factors will need to be assessed prior to
ment for admission to hospital (Rowe et al., 2000). It has mini- stepping up pharmacological therapy. These include assess-
mal adverse effects unless repeated doses are administered ment of trigger factors, concordance and inhaler technique
and hypermagnesaemia develops. Blood pressure, respiratory (Fig. 25.3).
rate and urine output should be monitored whilst intravenous
magnesium is administered. Signs of toxicity, including weak-
Assessment of asthma control
ness, nausea, drowsiness and slurred speech, should also be
monitored.␣ One key aspect of an asthma review is determining the level of
Intravenous aminophylline. Intravenous aminophylline control. The degree of asthma control can be assessed using a
may be commenced in severe acute asthma to aid with bron- number of different methodologies.
chodilation, although evidence suggests it does not provide There are several different deinitions used to report symptoms
additional bronchodilation compared with SABAs (Travers in clinical practice. These include:
et al., 2012). Care should be taken with regards to the dos- • Global Initiative for Asthma deinition (Global Initiative for
ing of intravenous aminophylline. A loading dose should be Asthma, 2012; Table 25.9),
administered to patients who are not taking oral theophylline • Royal College of Physicians 3 questions (Pearson and
or aminophylline already. Smoking status also needs to be Bucknall, 1999),
obtained because patients who smoke require a higher main- • Asthma Control Questionnaire (Juniper et al., 1999),
tenance dose; conversely, patients with heart failure require • Asthma Control Test (Nathan et al., 2004).
lower loading doses as per Table 25.8. The risk of arrhyth- Other physiological tests can be useful to help to monitor
mias and toxicity due to high plasma concentrations should asthma control, including lung function (PEFR or FEV1) or
be taken into consideration before commencement. Patients measures of eosinophilic airway inlammation (Green et al.,
require daily plasma concentration levels to ensure safety. Due 2002a).␣ 449
 25 THERAPEUTICS

Patient education
in inhaler technique have been associated with reduced asthma
It is important to provide high-quality and accurate information control (Giraud and Roche, 2002). Inhaler technique should be
to people with asthma. This information is crucial for achieve- reassessed during regular asthma reviews and should also be reas-
ment of adherence with therapy and improving patient outcomes. sessed after an exacerbation. Inhaler devices should be chosen
There are a number of organisations that can help provide infor- based on patient choice and the patient’s ability to use them (BTS
mation for patients (see Box 25.2).␣ and SIGN, 2016). It should be appreciated that every inhaler has
a different number of steps that need to be achieved to allow the
drug to be accurately delivered. Simplifying information is a
Inhaler technique
good approach to helping patients retain the correct technique.
Good inhaler technique is imperative in optimising asthma treat- The most common inhaler device prescribed in the UK is the
ment. Many new devices are now available. This allows for pressurised metered dose inhaler (pMDI), which contains an aero-
more patient choice but also requires healthcare professionals to sol, yet it has been shown that only 21% of patients are able to use
be trained in their use so that they can provide accurate patient pMDIs correctly even after expert training (Lenney et al., 2000).
training. Optimal inhaler technique is paramount in ensuring the In stable patients, their inhaler technique should be checked at
drug is delivered into the lung for it to exert its action. Errors every asthma review. Patients should also be checked after an

Consider inhaler Fix next

Step down therapy
change appointment

Check:
Incorrect Therapy step-up Minimal
Symptoms
Leading a
normal life
Taking usual
exercise
Check inhaler
Correct Low inhaled β-
technique
agonist use
No additional
treatment

Assess compliance
and aggravating No Yes
factors

Fig. 25.3 Structure of an asthma review. (Adapted from Crompton et al., 2006.)

Table 25.9 Definition of asthma control

Characteristic Controlled asthma Partly controlled asthma Uncontrolled

All characteristics present Any characteristic present

Daytime symptoms <2 per week >2 per week

Limitations of daily activity None Any

3 or more characteristics of
Night-time symptoms or awakening None Any partly controlled asthma
from sleep present in any week

Lung function as measured by PEFR Normal <80%

or FEV1

Use of reliever inhaler <2 per week >2 per week

FEV1, Forced expiratory volume in 1 second; PEFR, peak expiratory flow rate.
450 Adapted from Global Initiative for Asthma (2012).
 ASTHMA 25
exacerbation and each time there is a decision made to switch have a high resistance to airlow, requiring more effort on inhala-
inhalers. Inhalers should not be changed or the dose increased tion (Capstick and Clifton, 2012).
without ensuring that the patient can use the inhaler optimally. Inhaler devices can be split into pMDIs, DPIs, breath-actuated
Additionally, using inhalers correctly will reduce waste, improve metered-dose inhalers (BA-MDIs) and soft-mist inhalers (SMIs),
patient outcomes and reduce the risk of adverse effects such as with each device requiring a different technique (Table 25.10).
oral candidiasis (Basheti et al., 2007; Capstick and Clifton, 2012). Many patients using pMDIs ind the coordination of pressing
Particle size, inspiratory low and resistance all affect lung the canister down to deliver the dose whilst inhaling dificult.
deposition of the inhaled drug. The particle size of the drug BA-MDIs or DPIs may be more appropriate for use in these
decides the location in which it will be deposited. Ideally, inhaled patients, or the use of a spacer may be beneicial. These strategies
drugs should have a particle size of 1–5 micrometres for them remove the need for coordination. Additionally, spacer devices
to be deposited within the airways and have an effect on the reduce the amount of resistance and decrease particle size, thus
receptors within the bronchi. There are some pMDIs that have allowing improved drug deposition (Capstick and Clifton, 2012).
been developed with extra-ine particles, allowing a reduced DPIs may involve the loading of a single capsule manually by
dose of corticosteroid to be used, and these have been shown to the patient or be multiple-dose devices, which may require other
have improved lung deposition compared with standard pMDIs manipulation by the patient to load the dose. The only SMI device
(Basheti et al., 2007; Capstick and Clifton, 2012). available in the UK is the Respimat device. This device requires
Inspiratory low also has an impact on lung deposition, and multiple steps to prepare the dose and administer the drug, but it
each device requires a different level. Dry powder inhalers removes the reliance on the patient’s inspiratory low to deliver
(DPIs) require a quick inspiratory low so that the dose is broken the drug (Capstick and Clifton, 2012).
up into small enough particles to penetrate the airways, whereas Prior to prescribing an inhaler, healthcare professionals must
pMDIs require a slower inspiratory low. Failing to achieve the check the patient’s inspiratory low and inhaler technique. The
desired inspiratory low for any device increases the likelihood In-Check Dial Inspiratory Flow Meter or inhaler device whis-
that the drug will deposit into the mouth and oropharynx rather tles can be used to test inspiratory low. Placebo inhalers are
than the lungs, leading to a lack of eficacy and an increased risk also available to help train patients on how to use new devices
of oral side effects. The inspiratory low is determined by the (Capstick and Clifton, 2012).␣
effort of the patient during inspiration and the resistance to air-
low within the device. pMDIs have a low resistance to airlow,
Different inhaler devices
meaning they require less effort on inhalation, whereas DPIs
Pressurised metered dose inhaler
Box 25.2 Organisations that provide educational material for
people with asthma The pMDI (Fig. 25.4) is a cost-effective device used widely. It is
a pressurised aerosol device and can be used with spacer devices
• Asthma UK: http://www.asthma.org.uk if needed. It is available for several drugs, although a popular
• British Lung Foundation: http://www.lunguk.org choice can be dificult to use due to the coordination required.
• Allergy UK: http://www.allergyuk.org Inhalation should be slow and deep for this device; if patients
• Global Initiative for Asthma: http://www.ginasthma.org
inhale too quickly using this device, the aerosol will hit the back
• European Lung Foundation: http://www.europeanlung.org
• NHS Choices: http://www.nhs.uk/Conditions/Asthma of the pharynx rather than travel to the lungs and deposit in the
desired area.␣

Table 25.10 Guide to suitability of inhaler devices according to the patient’s inspiratory flow and ability to coordinate inhaler actuation
and inhalation

Good actuation–inhalation coordination Poor actuation–inhalation coordination

Inspiratory flow >30 L/min <30 L/min >30 L/min <30 L/min

pMDI ! ! ! !

BA-MDI ! !

pMDI + spacer ! ! ! !

Dry powder inhaler ! !

Soft-mist inhaler ! ! !

Nebuliser ! ! ! !

BA-MDI, Breath-actuated metered dose inhaler; pMDI, pressurised metered dose inhaler.
Adapted from Voshaar et al. (2001). 451
 25 THERAPEUTICS

Fig. 25.5 Nexthaler device. (Reproduced by kind permission of

T. Capstick.)

Fig.25.4 Pressurised metered dose inhaler. (Reproduced by kind

permission of T. Capstick.)

Breath-actuated metered dose inhaler

Easi-Breathe. The Easi-Breathe device is a BA-MDI and is
an aerosol inhaler. The Easi-Breathe device may be favourable
for those patients who struggle with the coordination aspect of
the pMDI. This device again requires slow and deep inhalation.␣
Autohaler. The Autohaler device is another type of breath-
actuated inhaler that requires priming by pushing a lever into the
vertical position prior to inhalation. Slow and steady inhalation is
required for this device.␣

Dry powder inhalers

Fig. 25.6 Turbohaler device. (Reproduced by kind permission of
Ellipta. The Ellipta is a new, simple DPI that is primed by T. Capstick.)
opening the cover completely until a click is heard. It has a dose
counter; however, doses may be wasted if the cap is opened mul- Spiromax. The Spiromax is a DPI and requires loading by
tiple times or if the device is not held upright. It requires deep and opening the cap. It requires strong and deep inhalation, has a dose
strong inhalation to achieve drug deposition into the lungs.␣ counter and patients cannot multi-dose when using this device.␣
Nexthaler. The Nexthaler is a new DPI device (Fig. 25.5) Turbohaler. The Turbohaler device is another DPI (Fig. 25.6)
that also requires priming by opening the cap completely. It that requires strong and deep inhalation to achieve deposition of
requires strong and deep inhalation, and if this is achieved, the dose into the lungs. It has a dose counter and requires priming
a click should be heard. It has a dose counter and cannot be by twisting the bottom of the device to load it prior to inhalation.
multi-dosed.␣ Fortunately, patients are unable to multi-dose because the counter
Novolizer. The Novolizer device is a DPI that requires prim- will continue to count down but will not actually load multiple doses.␣
ing by pressing the button down until it clicks. It has a coloured Twisthaler. The Twisthaler device is a DPI requiring strong
control window that patients may ind useful; it changes from red and deep inhalation. It is primed by twisting the cap anticlockwise
to green as the inhaler is primed, then back to red once the dose is to remove it and ensuring the pointers on the device and the coun-
452 inhaled. It requires deep and strong inhalation, and patients can- ter are aligned. It has a dose counter, which will count down with
not multi-dose using this device.␣ multiple actuations; however, the dose is not loaded multiple times.␣
 ASTHMA 25

Fig. 25.7 Accuhaler device. (Reproduced by kind permission of

T. Capstick.)

Fig. 25.9 Respimat device. (Reproduced by kind permission of

T. Capstick.)

Soft-mist metered dose inhaler

Respimat. Respimat is a soft-mist metered dose inhaler
(Fig. 25.9) that requires multiple steps to use eficiently. It
requires slow and steady inhalation. Those with dexterity issues
may ind this device dificult to use due to the cartridge requiring
insertion into the device and the requirement to then turn the base
of the device and push the button during inhalation.␣

Adherence
Good adherence to asthma treatment is imperative in improving
asthma outcomes and reducing exacerbations. A concordant deci-
sion must be made between the healthcare professional and the
Fig. 25.8 Easyhaler device. (Reproduced by kind permission of
patient with regards to prescribing medicines. Adherence to treat-
T. Capstick.)
ment for any long-term condition has been shown to be poor, and
there are a number of barriers to adherence. Consequently, patient
Accuhaler. The Accuhaler is a DPI (Fig. 25.7) that does not adherence should be monitored regularly and interventions made
require coordination. It has a dose counter; therefore, it can aid if patients are having dificulty adhering to their medicines. Time
patients in ensuring they do not run out of their inhaler. It has should be taken to discuss barriers with patients, whether these
increased lung deposition compared with a pMDI and is useful are physical or psychological, intentional or unintentional, and
for patients with poor dexterity. The Accuhaler does require load- concordant decisions made with regards to overcoming these.
ing by pushing down a lever; however, if this dose is loaded sev- Treatment should not be stepped up with regard to treating asthma
eral times, there is potential to waste the dose if these doses are without assessing and improving adherence where possible.␣
not inhaled. There is also potential to take too many doses if the
lever has been pushed down multiple times. Inhalation should be
Management plans
strong and deep with this device.␣
Clickhaler. The Clickhaler device is a DPI and is primed by Self-management is a long-established practice in the care of
pushing the button down prior to inhaling; it does not require people with asthma. When self-management is delivered to
coordination. There is a risk of multi-dosing with this device if people (and/or their carers) with asthma, there is good evi-
the button is pushed multiple times prior to inhalation.␣ dence for reduced emergency healthcare utilisation, particu-
Easyhaler. The Easyhaler is a DPI (Fig. 25.8) very similar to larly emergency department attendance, hospital admission
the Autohaler. It requires priming by pushing the button down in and unscheduled primary care consultations. From a patient
the upright position; however, patients are unable to load multiple perspective, self-management has been demonstrated to
doses, as with the Clickhaler. The dose may be lost if the device improve asthma control and quality of life, as well as reducing
is not kept upright.␣ absenteeism from work and school (BTS and SIGN, 2016). 453
 25 THERAPEUTICS

The key aspects of self-management are education that is She is started on nebulised bronchodilators and a steroid but
strengthened by written PAAPs. The PAAPs include advice about fails to improve.
recognising the loss of asthma control as deined by symptoms
and peak low. In response to recognition of deteriorating asthma Questions
control, there are then two or three action points. These action
points can include increasing ICS dose, starting an oral cortico- 1. What severity of asthma exacerbation does Mrs ES have?
steroid and seeking immediate medical attention.␣ 2. What bronchodilators and at what dose would be recommended?
3. What dose of steroid would be recommended?
4. Because she is failing to improve, what two other therapies could
Case studies be considered, and at what dose?␣

Case 25.1 Answers

1. Mrs ES has a life-threatening exacerbation as determined by her
Mr DM is a 25-year-old man with a history of asthma since child- oxygen saturation and PEFR. Her oxygen saturation is ≤92%, and
hood. He has a background of poor asthma control; he uses his her PEFR is less than 33% of her normal value.
reliever most days and wakes at night approximately twice per 2. Mrs ES should be started on nebulised salbutamol 5 mg and
week. He works full-time in a garage, smokes 10 cigarettes per ipratropium 500 micrograms as an immediate response. If she
day and has a pet dog at home. He has been admitted to hospital fails to respond clinically to the initial therapy, then repeated (or
in January with an acute severe exacerbation of asthma. During ‘back-to-back’) administration of salbutamol can be used until
his hospital stay his regular inhalers were changed from Symbicort clinical improvement is seen in terms of routine observations and/
200/6 Turbohaler two puffs twice a day to Seretide 500/50 or PEFR. Once she is more stable, the nebulised bronchodilators
Accuhaler one puff twice a day. should be administered 6 hourly and stopped 24 hours prior to
discharge from hospital.
3. She should receive 40–50 mg of oral prednisolone immediately,
Questions then once daily for a minimum of 5 days. Because her asthma
exacerbation is life-threatening, she should be monitored in hos-
1. What asthma reviews should Mr DM have following this exacerba-
pital until clinically stable for discharge. If she is unable to take
tion of his asthma?
the tablets orally, then an alternative would be hydrocortisone 100
2. What components are key to each asthma review?
micrograms intravenously. Once she is able to take medication
3. What are the potential causes of Mr DM’s poor asthma control?
orally, then the intravenous hydrocortisone should be swapped to
4. What is the increase in Mr DM’s inhaled steroid dose?␣
oral prednisolone as previously described.
4. Mrs ES could be considered for intravenous magnesium 1.2–2 g
Answers over 20 minutes. Alternatively, she could receive intravenous ami-
nophylline. Aminophylline would require a loading dose of 5 mg/
1. Mr DM should be reviewed by a respiratory specialist prior to kg (380 mg) over 20 minutes, followed by a maintenance infusion
discharge from hospital. He should also be seen by his primary of 0.5 mg/kg/h (38 mg/h). If Mrs ES received intravenous ami-
care doctor or specialist primary care nurse two days following dis- nophylline, then therapeutic drug monitoring would need to be
charge. Subsequent to this he should be seen in a hospital asthma undertaken daily.␣
clinic 4 weeks following discharge.
2. At each review Mr DM’s asthma control should be assessed,
adherence with therapy should be reviewed, aggravating factors Case 25.3
identified and inhaler technique checked.
3. Mr DM has a number of factors that may be worsening his asthma, Mr CM is a 56-year-old man with a history of asthma over the
including his smoking and exposure to pets. In view of the time preceding 5 years. His height is 177 cm and weight is 80 kg. He
of the year, the most likely cause of his exacerbation may be a had one exacerbation of his asthma 3 years ago that required hos-
viral infection. More information about his job should be elicited pital admission, and he is currently prescribed Symbicort 200/6
because exposure to isocyanates in car-paint fumes can be an Turbohaler two puffs twice daily. At his asthma review today, Mr
asthma trigger. CM reported minimal symptoms from his asthma and could not
4. Mr DM was initially taking Symbicort 200/6 Turbohaler two puffs remember the last time he used his reliever inhaler. His peak flow
twice daily. This is equivalent to 800 micrograms of beclometa- was 580 L/min, which is at his best.
sone per day. His dose has been increased to Seretide 500/50
Accuhaler one puff twice daily, which is equivalent to 2000 micro-
grams beclometasone per day.␣ Questions
1. Is Mr CM’s asthma controlled?
Case 25.2 2. Should Mr CM’s asthma treatment be altered?
3. What potential alterations could be used in Mr CM’s treatment?␣
Mrs ES is 36 years old. She weighs 76 kg, and her height is 170 cm.
Her usual PEFR is 440 L/min. She does not smoke. Mrs ES is pre-
scribed a Fostair 100/6 pMDI two puffs twice a day and salbutamol
Answers
100 micrograms/dose pMDI two puffs to be taken as required. She 1. Mr CM’s asthma is controlled because he is reporting minimal
is admitted to hospital with an exacerbation of asthma. Mrs ES’s symptoms, has not had an exacerbation in the last 12 months and
initial observations demonstrate a PEFR of 100 L/min, respiratory has a normal peak flow. He would fulfil the Global Initiative for
rate of 30 breaths/min and sO2 of 92% on room air. Asthma (2012) definition of controlled asthma.
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