Clinical Pharmacy and Therapeutics - Book 1

DYSLIPIDAEMIA 24

extensively in patients with homozygous FH and at a dosage of 1 3. Unfortunately, Mr DF’s father probably died of heart disease
mg/kg/day lowered LDL-C by 50.9% from baseline (Cuchel et al., at a time when the practice of detecting affected families and
2007). It is licensed for use only in patients with homozygous FH screening first-degree relatives was not widespread. The early,
and may have a role in preventing progression to LDL apheresis unrelated death of his brother and Mr DF’s previous good health
or, in those already receiving apheresis, to reduce the frequency of would not have given an opportunity to identify any underly-
sessions to minimise the impact on quality of life. It is an option for ing familial disorder. From population data it is known that the
a very small cohort of patients across the country and at a cost of prevalence of heterozygous FH is about 1 in 500. Consequently,
more than £200,000 per annum, usage will remain very low. 120,000 cases would be expected in the UK. However, far
fewer cases are known, and cascade screening programmes to
Lomitapide is initiated at a low 5 mg dose and increased gradu- track cases in affected families are now recommended once an
ally every 4 weeks to a maximum of 60 mg daily. It is contra- index case has been identified. A family history of elevated TC or
indicated where there is hypersensitivity to the active substance death from CHD before the age of 55 years in a first-degree male
or any excipients, in patients with moderate or severe hepatic relative, as in the case of Mr DF, is an important sign that should
impairment and those with unexplained persistent abnormal liver highlight the potential risk to other family members. The NHS
function tests, in patients with a known signiicant or chronic Health Checks programme in England will assist in the identifica-
bowel disease such as inlammatory bowel disease or malabsorp- tion of undetected FH. 
tion, where there is concomitant administration of greater than
40 mg simvastatin or strong or moderate CYP3A4 inhibitors and Case 24.2
in pregnancy. Adverse events include gastro-intestinal (mainly
diarrhoea), deranged liver function tests (increased levels of Mr PT is a 52-year-old active school teacher. Four years ago he was
aspartate transaminase and/or alanine transaminase and alka- found to have a raised TC and elevated blood pressure for which
line phosphatase) and increased hepatic fat content and possible he was started on 10 mg simvastatin and 2.5 mg ramipril. Over
steatohepatitis.  the years his dose of simvastatin has been gradually increased
to 40 mg/day, but apart from this his medication has remained
Case studies unchanged. He presents at the clinic complaining of aches and
pains in his legs over the past 10 days. On questioning he reveals
Case 24.1 that over recent months he has been eating fresh grapefruit and
consuming the occasional glass of grapefruit juice. A tentative
Mr DF is a 43-year-old man who has been relatively fit and well for diagnosis of myopathy is initially made.
the past 20 years during which he has rarely visited his primary
care doctor. Two weeks ago he was admitted to hospital having Questions
suffered an MI. On questioning it was revealed that his brother
had died in a road traffic accident at the age of 19 and his father 1. What is the likelihood that grapefruit juice has contributed to Mr
had died of CHD at age 54 years. PT’s problem?

Examination of Mr DF revealed a corneal arcus and tendon xan- 2. Are any additional biochemical tests warranted?
thomas. Blood drawn within 2 hours of the onset of his MI revealed 3. Would atorvastatin, rosuvastatin or pravastatin be a more appro-
TC 7.8 mmol/L, HDL-C 0.9 mmol/L and triglycerides 2.3 mmol/L.
priate statin to prescribe if Mr PT wanted to continue with the
Questions occasional glass of grapefruit juice? 

1. What is the likely diagnosis of Mr DF? Answers
2. What are the treatment options?
3. Mr DF wants to know why he was not identified as being at high 1. Grapefruit juice is known to interact with statins through its inhibi- 435
tion of the CYP3A4 enzyme. It has been suggested that it is the
risk of CHD before he suffered his MI.  furanocoumarin in the grapefruit juice which binds to CYP3A4 and
inactivates it in both the liver and the gastro-intestinal tract. As
Answers little as 200 mL of grapefruit juice may inhibit CYP3A4, thereby
prolonging the half-life of the statin and increasing serum levels.
1. Mr DF has the signs and family history of classic heterozygous FH, When taken on a regular basis this can increase the risk of dose-
most likely because of a genetic defect in the LDL receptor on related side effects such as rhabdomyolysis and increase the risk
hepatocytes. His presentation with an acute cardiac event at such of myopathy. Current advice is that grapefruit juice should be
an early age is indicative of the raised CV risk present for individu- avoided altogether when taking simvastatin, regardless of whether
als with FH. it is fresh grapefruit or grapefruit juice, grapefruit juice diluted
from concentrate or frozen grapefruit juice.
2. Mr DF has a high level of LDL-C, and action is required to reduce
it. Appropriate lifestyle advice is necessary, but a high-dose high- 2. A creatine kinase (CK) level should be checked in patients report-
intensity statin, such as atorvastatin 80 mg daily, will be required to ing significant muscle pain to exclude overt myopathy.
achieve the desired outcome of at least a 50% reduction in LDL-C. • If CK is raised significantly (>5 times upper normal level),
In addition, this patient has recently suffered an MI, which in itself temporary withdrawal of the statin is warranted. Once the CK
is an indication for a high-intensity statin first line. Mr DF should declines to normal levels, and in view of the suspicion that
be managed by a lipid specialist in the first instance and relatives, grapefruit intake was a precipitating factor, the statin could be
including any children, should be screened for the presence of FH reinitiated and the patient warned to avoid grapefruit and seek
to allow early initiation of lipid-lowering therapy. advice promptly should the muscle aches recur.
• If the CK is normal, then this is a simple myalgia. Grapefruit
should be avoided and hopefully the symptoms will resolve. If
the pain does not resolve this may have an impact on adher-
ence and an alternate statin should be considered. Of all the

24 THERAPEUTICS

agents currently on the UK market, simvastatin is most likely to 2. HDL-C is a major fraction of cholesterol in serum and an important
cause myalgia and myopathy. determinant of CV risk in men and women, even when the level
3. Atorvastatin is also metabolised by CYP3A4. Although the effect of TC appears to be within the normal range. The incidence of
is less dramatic than with simvastatin, the concurrent intake of MI is positively correlated with the cholesterol concentration and
large quantities of grapefruit juice with atorvastatin is not rec- inversely related to the concentration of HDL-C. The TC:HDL-C
ommended. Neither pravastatin nor rosuvastatin is substantially ratio is another way to represent this risk and has been shown to
metabolised by CYP450 and may be better alternatives. However, have good predictive capabilities in women. Until the menopause,
when there is a history of myopathy, the need for caution remains women generally have high levels of HDL-C as a result of the cir-
because the risk of recurrence is enhanced whatever lipid-lower- culating oestrogen. However, following the menopause, HDL-C
ing agent is prescribed. There are separate concerns regarding the levels fall rapidly. Lifestyle advice may improve the TC:HDL ratio,
muscle toxicity of rosuvastatin, especially when used at the higher especially via increased physical activity.
dose of 40 mg.
Because this patient is being treated with a statin for primary 3. With reference to the Qrisk2 CV risk calculator, it can be deter-
prevention, the NICE (2014) guidelines suggest that if a person is mined that with a TC:HDL-C ratio of 6.25 (5/0.8) and a sys-
not able to tolerate a high-intensity statin, then one should aim to tolic blood pressure of 140 mmHg Mrs MC has a 8.2% risk of
treat with the maximum tolerated dose. Patients should be reas- development of CVD over the next 10 years. This would not auto-
sured that any statin at any dose reduces CVD risk. Strategies for matically make her a candidate for treatment with a lipid-low-
dealing with adverse effects include: ering agent because her 10-year CV risk is not more than 10%.
• stopping the statin and trying again when the symptoms have Knowledge of Mrs MC’s BMI and blood glucose level would be
resolved to check whether the symptoms are related to the useful additional information, as would a more detailed insight
statin, into her family history of CVD. It is only when all the relevant
• reducing the dose within the same intensity group, or information has been gathered that a final decision on the use
• changing the statin to a lower intensity group.  of a lipid-lowering agent can be made. It would also be of inter-
est to determine whether the lifestyle support has brought about
Case 24.3 any improvement in Mrs MC’s lipid profile or blood pressure. It is
important to recognise that Mrs MC’s CV risk will increase as she
Mrs MC is a very active, 51-year-old Caucasian woman who for gets older; if nothing changes in 5 years’ time her CV risk will be
the past 6 months has been suffering from the classic symptoms 11.9%, which is over the threshold for offering statin therapy. She
of the menopause. Six months ago on a routine visit to her doctor should be offered advice and support to address all modifiable
she had her lipid profile measured and this revealed an HDL-C of risk factors for CVD including optimising her diet, undertaking
0.8 mmol/L and TC of 5 mmol/L. Her blood pressure was 140/80 regular physical activity and taking steps to control her blood
mmHg. She is currently prescribed no medication but is receiving pressure. 
intensive lifestyle support to lower her cholesterol. She has no
other medical history of note other than a record that her mother Case 24.4
died at the age of 66 years from a heart attack.
Mr EC is a 48-year-old Pakistani executive for a large, multina-
Mrs MC would like to be prescribed hormone replacement ther- tional company who works long hours and frequently has to
apy (HRT) to control her menopausal symptoms and reduce her travel abroad. He has a family history of CHD, and 9 months
risk of CVD. ago he attended a coronary screening clinic for a health check.
At the clinic he was found to have a normal blood pressure
Questions (132/84 mmHg) but a blood screen revealed a TC of 5.7 mmol/L
and triglycerides of 11.8 mmol/L. When he revisited the clinic
1. Is it appropriate to prescribe HRT to reduce Mrs MC’s CV risk? 4 weeks later after trying to follow dietary advice, a fasting
2. What is the value of measuring HDL-C? blood sample revealed a TC of 5 mmol/L and triglycerides of 2.7
3. Does Mrs MC have a risk of CVD that requires treatment with a mmol/L. Liver function tests were normal. He is a non-smoker
and claims never to drink more than 10 units of alcohol per
lipid-lowering agent?  week. His BMI is 27 kg/m2.

Answers After repeated requests to revisit the clinic he eventually
turned up stating he had been away from home for 6 months
436 1. The impact of HRT on CV risk has been a subject of much debate on a series of business trips. He was trying to keep to a low-fat
over many years. There are no compelling data to justify the use diet and his blood profile revealed TC 5.7 mmol/L, triglycerides
of HRT for the prevention or treatment of CVD in postmenopausal 4.3 mmol/L, HDL-C 0.7 mmol/L and LDL-C 3 mmol/L, non-HDL-C
women. In fact, current evidence indicates that HRT may increase 5 mmol/L.
the risk of breast cancer, ovarian cancer, CVD and thromboem-
bolic disease. NICE guideline NG23, “Menopause: Diagnosis Questions
and Management” (NICE, 2015), concluded that HRT does not
increase CVD risk when started in women younger than 60 years 1. Is Mr EC at high risk of CHD?
and does not affect the risk of dying of CVD. In addition, NICE 2. Is Mr EC a candidate for lipid-lowering therapy?
(2015) states that HRT with oestrogen alone is associated with no, 3. Should Mr EC’s children be screened for dyslipidaemia? 
or reduced, risk of CHD, whereas HRT with oestrogen and pro-
gestogen is associated with little or no increase in the risk of CHD. Answers
The presence of CV risk factors is not a contraindication to HRT as
long as they are optimally managed. If Mrs MC is to be prescribed 1. Mr EC has a TC:HDL-C ratio of 8.1 (5.7/0.7). Qrisk2 indicates a
HRT, then this should be based on the need to control her meno- CVD risk score of 12.3%, which indicates he should be considered
pausal symptoms and improve her quality of life. for statin therapy after other modifiable risk factors have been

DYSLIPIDAEMIA 24

addressed and if QRisk score remains ≥10. However, it should also 2. Options for Mr JT include:
be remembered that QRisk will underestimate the risk of CVD in • Reducing the dose of simvastatin: Mr JT has been receiving
those with familial hyperlipidaemia. Mr EC would appear to have a simvastatin for many years and a simple reduction in dosage
mixed lipidaemia, although it is difficult to interpret non-fasting tri- to 20 mg/day may improve tolerability without compromis-
glycerides because of the influence of food intake. The low HDL-C ing the lipid control substantially. Although an increase in
and raised BMI indicate he is overweight and/or has a non-ideal TC and LDL-C is expected with dose reduction, this is usu-
lifestyle. Exclusion of diabetes, high alcohol intake, liver and renal ally small (in the order of 6%) and should have little overall
impairment is necessary. The possibility of impaired glucose tol- impact on risk.
erance should not be overlooked and a haemoglobin A1c level • Substituting an alternative statin: Simvastatin causes more myal-
should be checked. gia and myopathy than other statins; therefore, an alternative
2. Given the elevated triglycerides and TC, Mr EC is certainly a can- agent may be better tolerated. Pravastatin is particularly well
didate for lifestyle advice. The use of a statin should be considered tolerated and may be a suitable alternative in this patient where
if the lifestyle changes do not bring about the necessary improve- potency is less of an issue. Where greater potency is required,
ments in the lipid profile. However, the dyslipidaemia may be sec- atorvastatin (starting at a dosage of 10–20 mg daily and increas-
ondary to obesity, alcoholism, diabetes or hypothyroidism. If any ing as required to control lipids) or rosuvastatin is a possibility.
of these disorders are present, appropriate treatment may correct • Switching to an alternative agent, such as ezetimibe: Non-
the underlying dyslipidaemia. statin agents could be used to lower cholesterol but should
3. The family history of CHD is important but is only significant if the be reserved for patients who are unable to tolerate statins.
age of onset in a parent or sibling was younger than 60 years. In Ezetimibe monotherapy may be a suitable alternative if Mr
this case, the children should have CV risk assessment undertaken JT cannot tolerate statin therapy after dose reduction and a
every 5 years from the age of 40 years. However, were a rare famil- change in agent.
ial disorder, for example, familial dysbetalipoproteinaemia, be • Using a low dose of statin plus an alternative agent, such as
identified as the causative factor, his children should be screened ezetimibe: This may be a suitable option if this patient can
after puberty because the offending gene may not express itself in tolerate only small doses of statins and the ezetimibe is intro-
the younger child. duced to increase the degree of cholesterol lowering achieved.
Mr EC was subsequently found to have diabetes for which he ini- This is a useful combination in some patients, but every effort
tially received metformin together with a statin. In this scenario should be made to maximise the statin dose before adding
where a patient is diagnosed with type 2 diabetes, it is also impor- ezetimibe to ensure maximal outcome benefits.
tant to consider advising children about lifestyle issues and the
need to control weight throughout life.  3. For Mr JT, a good starting point would be a reduction in the
dosage of simvastatin to 20 mg daily, providing he is willing
Case 24.5 to continue to take this drug. Myalgia appears to be dose
related, and the symptoms may resolve with the lower dose.
Mr JT is a 68-year-old man with stable angina. He is currently An alternative is to try pravastatin, perhaps at a starting dos-
receiving simvastatin 40 mg daily with well-controlled lipid levels age of 20 mg daily, to see whether it is better tolerated. The
(TC 3.8 mmol/L, LDL-C 1.8 mmol/L, HDL-C 0.9 mmol/L, triglycer- dosage will probably need increasing to give adequate control
ides 1.3 mmol/L, non-HDL-C 2.9 mmol/L). He has been receiving of lipid levels. The use of ezetimibe should be reserved as an
simvastatin for the past 7 years and has complained previously additional medicine if only low doses of statins can be toler-
about muscle aches, but on this visit he states that his muscle pain ated or for monotherapy if that patient cannot be persuaded
has become more troublesome, to the extent that he wishes to to take any statin at all. Mr JT should be reviewed regularly
stop taking the statin. He asks if there is anything else he can take over the next few months, until his concerns regarding his lipid-
to control his cholesterol. lowering therapy have been addressed, to encourage ongoing
adherence. 
Questions
Case 24.6
1. What action would you take immediately?
2. What options are available for Mr JT? Mrs RS is a 36-year-old care assistant from the Philippines with
3. What would you recommend to Mr JT?  heterozygous FH. She has diffuse, symptomatic coronary artery
disease and is currently taking rosuvastatin 20 mg daily and ezeti-
Answers mibe 10 mg daily. Her lipid levels are: TC 8.6 mmol/L (12.3 mmol/L
before statin therapy), non-HDL-C 7.7 mmol/L, HDL-C 0.9 mmol/L
1. A CK level should be checked to exclude myopathy in this and LDL-C 7.0 mmol/L.
patient, because this can occur at any time during statin treat-
ment. Assuming the CK is normal and this is myalgia, then it is still Questions
essential to address Mr JT’s concerns, because this muscle pain is
likely to impact on his adherence over time. An important issue is 1. What treatment options would you consider next for Mrs RS?
to ensure that the patient understands why he is taking a statin. 2. How would you monitor therapy?
The emphasis should be on the expected reduction in the risk of 3. What other issues should you consider? 
death, heart attack or stroke, rather than on achieving specific cho-
lesterol treatment targets. It may be worth temporarily stopping Answers
the statin to demonstrate the causal relationship. If the aches and
pains remain despite cessation of simvastatin, then this is unlikely 1. Mrs RS needs a significantly greater reduction in her lipid lev- 437
to be a statin-related issue. Many people report aches and pains, els than is currently being achieved with statin and ezetimibe.
particularly as they get older, and it is easy to blame the statin for A higher statin dose is contraindicated in view of the ethnicity of
all of these complaints. Mrs RS. Whilst other classes of oral lipid-lowering therapies could
be considered, they are unlikely to deliver a significant further

24 THERAPEUTICS

reduction in LDL. In this case, a lipid specialist may consider the the lipid specialist within 4–6 weeks of initiation to check she is
use of a PCSK9 inhibitor, because it is the only drug class able managing the injections and is not experiencing significant side
to deliver the significant drop in cholesterol required here. Mrs effects. Her lipid levels will fall rapidly on a PCSK9 inhibitor with
RS meets the NICE criteria for use of a PCSK9 inhibitor (NICE, a reduction in LDL-C of at least 30% expected within the first
2016b, 2016c); she has heterozygous FH and evidence of CVD, is 3 months of therapy. If this is not achieved, injection technique
at high risk of events and her LDL-C level remains greater than the and adherence should be checked initially, but if a poor response
3.5 mmol/L threshold for use, despite statin and ezetimibe therapy. persists, ongoing treatment should be reviewed.
2. Mrs RS will need to be willing to inject the PCSK9 inhibitor at two 3. Lifestyle issues, particularly diet and physical activity, should be
weekly intervals and will need adequate training to feel confident regularly reviewed with appropriate advice, support and/or sign-
in doing this procedure. In the UK, supplies of these drugs are posting to enable Mrs RS to make any necessary changes. In view
usually delivered by a homecare provider, and the companies offer of the presence of heterozygous FH, her first-degree relatives
nursing support to patients at home who require additional sup- should be screened for FH and offered appropriate advice and
port with the injections. Mrs RS should also be followed up by treatment.

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National Institute for Health and Care Excellence (NICE), 2016a. Ezetimibe Triglyceride Coronary Disease Genetics Consortium and Emerging Risk
for treating primary heterozygous-familial and non-familial hypercho-
lesterolaemia. Technology appraisal guidance (TA385). NICE, London. Factors Collaboration, 2010. Triglyceride-mediated pathways and coronary
Available at: https://www.nice.org.uk/guidance/ta385.
National Institute for Health and Care Excellence (NICE), 2016b. disease: collaborative analysis of 101 studies. Lancet 375, 1634–1639.
Evolocumab for treating primary hypercholesterolaemia and mixed
dyslipidaemia. Technology appraisal guidance (TA394). NICE, London. U.S. Food and Drug Adminsitration, 2015. FDA approves Praluent to treat

Available at: https://www.nice.org.uk/guidance/ta394. certain patients with high cholesterol. Available at: http://www.fda.gov/
National Institute for Health and Care Excellence (NICE), 2016c. Alirocum- NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm.
von Depka, M., Nowak-Göttl, U., Eisert, R., et al., 2000. Increased lipopro-
ab for treating primary hypercholesterolaemia and mixed dyslipidaemia.
Technology appraisal guidance (TA393) NICE, London. Available at: tein (a) levels as an independent risk factor for venous thromboembolism.
Blood 96, 3364–3388.
https://www.nice.org.uk/guidance/ta393. Widhalm, K., Binder, C.B., Kreissl, A., et al., 2011. Sudden death in a

National Organization of Rare Disorder (NORD), 2005. Hyperlipo- 4-year-old boy: a near-complete occlusion of the coronary artery caused

proteinemia type III. Available at: https://rarediseases.org/rare- by an aggressive low-density lipoprotein receptor mutation (W556R) in
homozygous familial hypercholesterolemia. J. Pediatr. 158, 167.
diseases/hyperlipoproteinemia-type-iii/. Wiggins, B.S., Saseen, J.J., Page, R.L., on behalf of the American Heart

Raal, F.J., Honarpour, N., Blom, D.J., et al.; TESLA Investigators, 2015. Association Clinical Pharmacology Committee of the Council on Clinical

Inhibition of PCSK9 with evolocumab in homozygous familial hypercho- Cardiology; Council on Hypertension; Council on Quality of Care and

lesterolaemia (TESLA Part B): a randomised, double-blind, placebo- Outcomes Research; Council on Functional Genomics and Translational
controlled trial. Lancet 385, 331–340.
Research Committee on Serum Lipid Level Survey 1990 in Japan, 1996. Biology, et al., 2016. Recommendations for management of clinically
signiicant drug-drug interactions with statins and select agents used
Current state of and recent trends in serum lipid levels in the general in patients with cardiovascular disease: a scientiic statement from the
American Heart Association. Circulation 134, e468–e495. https://doi.
Japanese population. J. Atheroscler. Thromb. 2, 122–132. org/10.1161/CIR.0000000000000456. Available at: http://circ.ahajournals.
Ridker, P.M., Danielson, E., Fonseca, F.A.H., 2008. Rosuvastatin to prevent
org/content/early/2016/10/17/CIR.0000000000000456.
vascular events in men and women with elevated C-reactive protein. N.
Woodward, M., Brindle, P., Tunstall-Pedoe, H., for the SIGN group on risk
Engl. J. Med. 359, 2195–2207.
estimation, 2007. Adding social deprivation and family history to car-
Robinson, J.G., Nedergaard, B.S., Rogers, W.J., et al.; LAPLACE-2 Investi-
diovascular risk assessment: the ASSIGN score from the Scottish Heart
gators, 2014. Effect of evolocumab or ezetimibe added to moderate- or high- Health Extended Cohort (SHHEC). Heart 93, 172–176.
World Health Organization, 2011. Waist circumference and waist-hip ratio.
intensity statin therapy on LDL-C lowering in patients with hypercholester- Report of a WHO expert consultation 2008. WHO, Geneva. Available at:
olemia: the LAPLACE-2 randomized clinical trial. JAMA 311, 1870–1882. http://apps.who.int/iris/bitstream/10665/44583/1/9789241501491_eng.pdf.
Yang, W., Xiao, J., Yang, Z., et al., 2012. Serum lipids and lipoproteins in

Chinese men and women. Circulation 125, 2212–2221.

Further reading Henderson, R., O’Kane, M., McGilligan, V., et al., 2016. The genetics and

Aronis, K.N., Blumenthal, R.S., Martin, S.S., 2016. Expert analysis. Sum- screening of familial hypercholesterolaemia. J. Biomed. Sci. 23, 39.
marizing the current state and evidence on eficacy and safety of statin
therapy. Available at: http://www.acc.org/latest-in-cardiology/articles/ Hendrani, A.D., Adesiyun, T., Quispe, R., et al., 2016. Dyslipidemia
2016/11/17/09/03/summarizing-the-current-state-and-evidence-on-
eficacy-and-safety-of-statin-therapy. management in primary prevention of cardiovascular disease: current
guidelines and strategies. World J. Cardiol. 8, 201–210.
Gonzalez, L., Helkin, A., Gahtan, V., 2016. Dyslipidemia part 2: review of Savarese, G., Gotto Jr., A.M., Paolillo, S., et al., 2013. Beneits of statins in
dyslipidemia treatment in patients with noncoronary vascular disease. elderly subjects without established cardiovascular disease: a meta-
Vasc. Endovascular Surg. 50, 119–135.
analysis. J. Am. Coll. Cardiol. 62, 2090–2099.
Helkin, A., Stein, J.J., Lin, S., et al., 2016. Dyslipidemia part 1: review of
lipid metabolism and vascular cell physiology. Vasc. Endovascular Surg.
50, 107–118.

Useful websites QRISK: https://www.qrisk.org
JBS3: www.jbs3risk.com
Cardiovascular risk calculators:
ASSIGN: http://assign-score.com 439
SCORE: https://www.escardio.org/Education/Practice-Tools/CVD-

prevention-toolbox/SCORE-Risk-Charts#

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

• Inhaler technique is crucial to ensure that drug delivery is Aetiology
effective.
The aetiology of asthma is complex and not fully elucidated. It is
• People with asthma should be offered asthma education and recognised that there is a complex interaction between multiple
self-management plans. genetic and environmental factors. There is evidence for a heredi-
tary component to asthma, and current data suggest that multiple
Introduction genes are involved in the development of asthma. Numerous
environmental factors have been identiied as potential fac-
Asthma is a chronic inlammatory condition of the airways. The tors that inluence the risk of developing asthma. These include
airway inlammation is associated with hyper-responsiveness of exposure to allergens, infectious agents, occupational substances,
the airways and variable airlow obstruction (Global Initiative for air pollution and diet.
Asthma 2012). These physiological changes result in the classic
symptoms of intermittent breathlessness, cough and wheeze. One hypothesis for the increasing prevalence of asthma is the
‘hygiene hypothesis’, which postulates that reduction in early
Asthma was irst formally described by Hippocrates approxi- childhood exposure to infectious agents increases the suscepti-
mately 2500 years ago. The term asthma is derived from the Greek bility to allergic diseases. There are other potential explanations
word aazein, which describes panting or laboured breathing. for the increased incidence of asthma in the developing world,
including air pollution. 
The modern treatment of asthma began with the use of epineph-
rine at the turn of the 20th century, followed by the introduction of
xanthines, such as theophylline, in the 1920s. During the 1950s oral
corticosteroids were introduced, with subsequent introduction of
chromoglycate, inhaled corticosteroids and short-acting β-agonists
in the 1960s. Subsequently, during the 1980s and 1990s long-acting
β-agonists and leukotriene antagonists were introduced, respec-
tively. Therapies, particularly for people with severe asthma, have
advanced during the early 21st century with the introduction of tar-
geted biological therapy such as omalizumab (anti-immunoglobulin
E [IgE]) and mepolizumab (anti-interleukin-5 [IL-5]). 
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 Allergens
an important role in the pathophysiology of asthma. 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- Drugs Non-steroidal anti-inflammatory drugs
pathetic pathways of the autonomic nervous system. The release 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
Soy caster bean
The inlammatory process follows the bronchoconstriction, Latex
resulting in the production of excess mucus and oedema within Formaldehydes
the airway. The combination of bronchoconstriction and inlam- Hair colourants
matory process leads to narrowing of the airway calibre and the
classic symptoms of breathlessness, wheeze and cough. Other Sulphites
Nitrogen oxides
Some people with asthma have brittle asthma, which is classi- Sulphur dioxide
ied into two types. Type I brittle asthma is deined by periods of Exercise
prolonged peak low variability, whereas type II is characterised Cold air
by sudden deteriorations on a background of good control and Stress
relatively normal lung function.
There are a number of signs of acute asthma, including tachy-
Over the last few years there has been a paradigm shift in the pnoea (increased rate of respiration), wheeze on expiration and
understanding of asthma pathophysiology. This has led to asthma use of accessory muscles of respiration. In children there may
no longer describing a single disease but a collection of multiple also be indrawing of the intercostal muscles. 
subgroups referred to as phenotypes (Wenzel, 2012).
Investigations
The majority of people with asthma have an inlammatory
process driven by TH2 processes that tend to be associated with The diagnosis of asthma is a clinical one; there is no standardised
atopy, allergy, type I hypersensitivity and eosinophilic inlamma- deinition of the type, severity or frequency of symptoms, nor
tion. Asthma associated with an inlammatory process driven by of the indings on investigation (British Thoracic Society [BTS]
eosinophilic inlammation has long been recognised to be respon- and Scottish Intercollegiate Guidelines Network [SIGN], 2016).
sive to treatment with corticosteroids (Brown, 1958). The under- A key part of the diagnostic process is to identify the character-
standing of non-TH2-driven asthma is much less established istic symptoms of asthma from the patient. Due to the long-term
than that of asthma driven by TH2 pathways. This subgroup of nature of the condition, the history obtained from the patient is
people with asthma can be associated with a later age of onset, not suficient to make the diagnosis, and it is important to use
obesity and neutrophilic inlammation. Lack of response to treat- diagnostic tests to provide objective evidence of asthma.
ment with corticosteroids tends to be a feature of non-TH2-driven
asthma.  Lung function testing 441

Clinical signs and symptoms Lung function testing is a key part of the diagnosis and monitor-
ing for people with asthma. Lung function testing in asthma aims
Asthma can present with a number of different symptoms but to demonstrate the presence of reversible airlow obstruction.
classically presents with cough, wheeze and breathlessness, It can also provide a guide to response to treatment and detect
often induced by exposure to a wide variety of trigger factors. deterioration in asthma control. There are a number of different
Individuals with asthma will commonly describe exposure to cer- methods for testing lung function, all of which have particular
tain triggers resulting in an increase in symptoms (Table 25.1). strengths and weaknesses.
The frequency and severity of these symptoms is highly vari-
able between individuals and also within individuals. At times Peak expiratory low rate (PEFR) is the maximum airlow
the person with asthma may be asymptomatic, whereas at other rate during forced expiration. A peak low meter can measure
times the person may have a high level of symptoms potentially
requiring hospital admission. Asthma tends to demonstrate diur-
nal variation, generally with increased symptoms at night and
early in the morning.

25 THERAPEUTICS

10 Predicted 8 Predicted

Baseline Baseline

8
6

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

4

2
2

00

12345 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
FVC% Percent of predicted FVC Calculated from normal values for gender, age, height and
ethnic origin
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
reversibility testing in individuals with normal or near-normal lung
Measurements of spirometry provide a measure of lung func- function is limited because there is limited scope for improvement.
tion that is more reproducible than PEFR. Spirometry is prefer- Salbutamol reversibility is assessed by repeating spirometry after
able to PEFR because it provides a more accurate measure of 20 minutes following the administration of 400 micrograms salbu-
airlow obstruction. When performing spirometry, an individ- tamol. Corticosteroid reversibility can be undertaken by using oral
ual inhales to maximal inspiration, then exhales maximally to prednisolone for 2 weeks or inhaled beclometasone for 6–8 weeks.
complete expiration. The spirometry provides a graphical rep-
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

Further investigations Testing of airway hyper-responsiveness has long been established
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
to demonstrate bronchoconstriction in response to administration
asthma, and further investigations are required.

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
with asthma but also would seem to predict an increased response (PEF) greater than 80% predicted or best,
rate to corticosteroids (Green et al., 2002a).  • minimal adverse effects from medication.

Other tests BTS guidelines recommend that treatment should begin at the
most appropriate step to improve symptoms and lung function as
Other tests that can be useful in supporting the diagnosis include quickly as possible (Fig. 25.2; BTS and SIGN, 2016).
measurement of blood eosinophil count, measurement of serum
IgE and testing for atopy through either skin-prick testing or IgE Treatment must be balanced against the risk of adverse effects
testing for speciic allergens. For individuals with atypical fea- and should be titrated down where possible whilst keeping good
tures, consideration should be undertaken for a chest X-ray (BTS control of asthma. Prior to moving treatment up a step, adherence
and SIGN, 2016).  and inhaler technique must be assessed and any triggers should be
removed.
Treatment
Inhaled corticosteroids
Chronic treatment
Corticosteroids bind to glucocorticoid receptors within the lung and
The aim of asthma management is to have complete control decrease the formation of cytokines, which produce IgE and pro-
and have no exacerbations of the disease. The BTS deines mote the expression of IgE receptors. They also inhibit the inlux
of eosinophils into the lung, therefore reducing overall inlamma-
tion. Inhaled corticosteroids (ICSs) are recommended as the sec-
ond step as a regular preventative therapy in the BTS guidelines

Asthma-suspected Asthma-diagnosed Summary of management in adults

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

lowestMcoovnetroulplintgo timheprraopvheycontrol as needed Continuous or
High-dose frequent use of oral

steroids

therapies

find and maintain

down to Additional add-on
therapies
Move

No response to LABA- Consider trials of: Use daily steroid tablet
Initial add-on therapy stop LABA and in the lowest dose
Increasing ICS up to providing adequate
consider increased high dose control
dose of ICS

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

consider trial
of other therapy-LTRA,

SR theophylline,
LAMA

Short acting β2 agonists as required – consider moving up if using three doses a week or more 443

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.
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-
lent in 24 hours. For adults, it is recommended that patients com- Additionally, oral SABAs are not recommended due their
mence treatment at a dose of 200–800 micrograms/day of BDP or higher risk of systemic side effects compared with administra-
equivalent. This can be increased to up to 2000 micrograms/day of tion via inhalation. 
BDP or equivalent as a fourth step if patients have no response to
the addition of a long-acting β-agonist (LABA) or a trial of alterna- Long-acting β-agonists
tive agents (BTS and SIGN, 2016). It should be noted, however,
that at doses of 800 micrograms/day of BDP or equivalent, this will LABAs act on the β2-receptors in the smooth muscle of the bron-
achieve 90% clinical beneit for the patient. At doses higher than chi, aiding bronchodilation. Inhaled LABAs are a irst-line addi-
this there is a signiicant increase in adverse effects (Holt et al., tion to ICSs and can be administered as an individual ingredient
2001). Budesonide, ciclesonide, luticasone and mometasone are or in a combination inhaler with an ICS. The addition of a LABA
other ICSs that are available and widely used. to a low-dose ICS has been shown to be as effective as increas-
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
micrograms/day of beclometasone or equivalent) are encouraged LABAs can exert an effect on β-receptors elsewhere and are
to carry a steroid card with them and should be educated of the not completely selective to β2-receptors. Consequently, they also
potential serious adverse effects (BTS and SIGN, 2016). ICSs can affect the β1-receptors in the cardiac muscle, increasing cardiac
cause oral candidiasis and dysphonia; hence, encouraging patients output and stimulation, leading to tachycardia and arrhythmias.
to rinse the mouth after use is important. Long-term, high-dose Additionally, they can cause tremor and hypokalaemia. LABAs
ICS use will result in some of the steroid being absorbed systemi- used alone have been associated with an increased risk of death
cally, potentially leading to adverse effects, including increased and therefore should not be used without an ICS (Royal College
blood glucose and susceptibility to diabetes. ICSs can also lead to of Physicians, 2014). The Medicines and Healthcare Products
osteoporosis, increasing the risk of fractures, muscle wasting and Regulatory Agency (MHRA) recommends that LABAs should
impaired wound healing. They can also cause psychiatric reac- ideally be administered in a combination inhaler to aid adherence
tions and mood disorders, as well as adrenal suppression, which (MHRA, 2008). There are not many interactions with LABAs,
may lead to the patient requiring steroid replacement therapy. but care must be taken when using LABAs with other agents that
Consequently, it is important to inform the patients of the risks cause hypokalaemia. Due to the cardiac risks associated with the
associated with ICSs and consider the risk versus beneit of them, use of LABAs, it is important to step down treatment where pos-
particularly in patients with medical conditions that may be exac- sible for safety.
erbated by the use of steroids.
The use of LABAs as monotherapy in asthma is associ-
ICSs are available in a variety of devices, in combination with ated with signiicantly worse asthma outcomes and increased
a LABA or as individual agents. In some circumstances they asthma mortality compared with treatment with ICSs. This
are used in conjunction with a LABA as a reliever, such as in increased mortality is not seen when LABAs and ICSs are used
the ‘Maintenance and Reliever Therapy’ regimen. Traditionally, concurrently. Consequently, national (BTS and SIGN, 2016)
there were few devices containing ICSs available to patients. and international (Global Initiative for Asthma, 2012) guide-
More recently there has been an inlux of new devices into the lines are very clear that long-acting relievers should not be
UK market. This gives patients and healthcare professionals more prescribed without an ICS and where possible should be pre-
choice with regard to selecting the most appropriate device. Care scribed as a combination ICS/LABA inhaler to prevent people
needs to be taken, however, when changing a patient’s inhaled inadvertently taking only the LABA. Table 25.5 demonstrates
therapy due to the variety of different devices and doses currently that there are a large number of ICS/LABA preparations and
available (Table 25.3). devices currently on the market and that it is important to
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
Short-acting β-agonists the LABA and the ICS.

Short-acting β-agonists (SABAs), such as salbutamol and ter- When added to an existing ICS, LABAs are used in preference
444 butaline, are the irst-line step and should be prescribed for all to leukotriene receptor antagonists because they provide greater
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

Name Device Equivalence to 400 micrograms of
Beclometasone dipropionate beclometasone dipropionate
Asmabec Clickhaler
Clenil pMDI 400 micrograms
Easyhaler beclometasone Easyhaler 400 micrograms
Fostair pMDI and Nexthaler 200 micrograms
Qvar Autohaler, Easi-Breathe and pMDI 200 micrograms
Budesonide 200 micrograms
Budelin Novolizer
DuoResp Spiromax 400 micrograms
Easyhaler budesonide Easyhaler 200 micrograms
Pulmicort Turbohaler 400 micrograms
Symbicort Turbohaler 400 micrograms
Ciclesonide 400 micrograms
Ciclesonide pMDI
Fluticasone furoate 200–300 micrograms
Relvar Ellipta
Fluticasone propionate 200 micrograms
Flixotide Accuhaler and pMDI
Flutiform pMDI 200 micrograms
Seretide Accuhaler and pMDI 200 micrograms
Sirdupla pMDI 200 micrograms
Mometasone furoate 200 micrograms
Asmanex Twisthaler
pMDI, Pressurised metered dose inhaler. 200 micrograms

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

Drug Onset of action (min) Duration of action (h)
Formoterol 2–3 12
12
Salmeterol 10–14 24

Vilanterol 5–15

445

25 THERAPEUTICS

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

Name and device Active ingredients Low dose (micrograms Medium dose (micro- High dose (micro-
DuoResp Spiromax Budesonide and formoterol per dose) grams per dose) grams per dose)
320/9
160/4.5 1 puff BD 160/4.5 2 puffs BD 2 puffs BD
320/9 1 puff BD 250/10 2 puffs BD
200/6 2 puffs BD
Flutiform pMDI Fluticasone and formoterol 50/5 2 puffs BD 125/5 2 puffs BD
200/6 2 puffs BD
Fostair pMDI Beclometasone and for- 100/6 1 puff BD 100/6 2 puffs BD
moterol 200/6 1 puff BD 184/22 1 puffs OD
500/50 1 puff BD
Fostair NEXThaler Beclometasone and for- 100/6 1 puff BD 100/6 2 puffs BD 250/25 2 puff BD
moterol 200/6 1 puff BD 250/25 2 puffs BD
400/12 1–2 puffs BD
Relvar Ellipta Fluticasone and vilanterol 92/22 1 puff OD

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

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

Sirdupla pMDI Fluticasone and salmeterol 125/25 2 puffs BD

Symbicort Turbohaler Budesonide and formoterol 100/6 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-
ity of life as well as reduce exacerbation frequency in patients
Leukotriene antagonists work by reducing the inlammation in with severe asthma (Rodrigo and Castro-Rodriguez, 2015). The
the bronchi, by inhibiting leukotriene receptors in the respiratory other currently marketed LAMAs – aclidinium, glycopyrronium
mucosa and reducing sputum eosinophilia. Leukotriene antago- and umeclidinium – are not currently licensed for use in asthma.
nists such as montelukast and zairlukast are recommended for It should be noted that they have antimuscarinic side effects
use in the UK when patients are not responding to a LABA or throughout the body and can cause dry mouth, constipation, uri-
as an addition to an ICS/LABA combination inhaler in someone nary retention and angle-closure glaucoma. 
with persistent poor control.
Theophylline preparations
There is some evidence for their use in addition to ICSs, and
they have been shown to be particularly useful for people with Theophylline and aminophylline are methylxanthines and work
exercise-induced asthma (Malmstrom et al., 1999) and poten- as bronchodilators and stimulate respiration. The exact mecha-
tially for patients with allergic rhinitis (Nathan, 2003). They can nism of action is unclear, and their effect is not speciic to the
be taken orally, and there are a number of preparations available, lung. Oral theophylline and aminophylline can be used as an
including granules if patients have problems with swallowing alternative in the same way as the leukotriene antagonists when
solid oral dosage forms. patients are unresponsive to LABAs or as an addition to an ICS/
LABA combination inhaler (BTS and SIGN, 2016).
Leukotriene antagonists are commonly associated with rela-
tively mild side effects of headaches and gastro-intestinal side Methylxanthines have a narrow therapeutic window and require
effects. However, they are also rarely associated with the more close monitoring of serum theophylline levels to ensure a therapeu-
serious eosinophilic granulomatosis with polyangiitis (previ- tic dose and avoid toxicity. Levels should be taken 5 days after com-
ously known as Churg-Strauss syndrome). This is characterised mencing treatment or changing doses and annually, with the aim of
by vasculitis and eosinophilia, and care should be taken to inform achieving a serum level of 10–20 mg/L. At toxic levels methylxan-
patients of this rare adverse effect. There are minimal drug inter- thines have effects on the central nervous system, causing tremor
actions associated with the leukotriene antagonists.  and action on cardiac muscle α-receptors that results in increased
cardiac output and tachycardia, as well as constricting cerebral
Long-acting antimuscarinics blood vessels. Because theophylline may also cause convulsions,
care must be taken when prescribing for people with epilepsy. The
Long-acting antimuscarinics (LAMAs) work by binding to the use of theophylline should be reviewed regularly. The risk of car-
muscarinic M3 receptors in the smooth muscle of the lung to aid diotoxicity and high plasma concentrations should be taken into
bronchodilation. LAMAs may also be trialled in patients who consideration to ensure that the beneit outweighs the risk.
have not responded to an ICS/LABA combination in the fourth
446 step of the BTS guidelines (BTS and SIGN, 2016). Tiotropium

ASTHMA 25

Table 25.6 Drug interactions with theophylline year (NICE, 2013). It has been shown to signiicantly reduce the
number of exacerbations in patients with severe asthma who have
Drug Interaction not improved on standard treatments.
May increase theophylline levels
Azole antifungals (itracon- Omalizumab is administered as a subcutaneous injection two
azole, fluconazole) to four times weekly, and it can take up to 12–16 weeks before an
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
Carbamazepine May decrease theophylline targets IL-5, which is responsible for activating eosinophils, and
levels is used for patients with severe refractory eosinophilic asthma.
It has recently been approved for use in the UK for people with
Cimetidine May increase theophylline levels severe eosinophilic asthma requiring frequent or daily oral corti-
costeroids (NICE, 2017).
Fluvoxamine May increase theophylline levels
Because biological therapies are not metabolised, there are
Isoniazid May increase theophylline levels minimal drug interactions, although there are concerns regard-
ing the possibility of an anaphylactic reaction during therapy.
Lithium carbonate Increased lithium levels Patients are therefore expected to have these injections adminis-
tered in a specialist hospital setting (BTS and SIGN, 2016).
Macrolide antibiotics (azithro- May increase theophylline levels
mycin, clarithromycin, More biological therapies targeted at speciic parts of the
erythromycin) inlammatory response are being developed to reduce the need
for oral steroids and their associated side effects. However, such
Phenytoin May reduce theophylline and therapies are likely to be expensive and therefore only used in
phenytoin levels specialist centres. 

Primidone Decreased theophylline levels Oral corticosteroids

Quinolone antibiotics (cipro- May increase theophylline levels Oral corticosteroids, such as prednisolone, can be used for the
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
should be checked to assess the risk of toxicity.  Care must also be taken to consider interactions with oral corti-
costeroids because they can increase the risk of gastro-intestinal
Biological therapies bleeding. Other medicines that increase the risk of this (e.g. non-
steroidal anti-inlammatory drugs [NSAIDs] and selective sero-
Biological therapies are slowly being introduced into the UK for tonin re-uptake inhibitors [SSRIs]) should be used with caution. 
treatment of allergic asthma. Omalizumab is a humanised mono-
clonal anti-IgE antibody. It works to reduce the amount of circu- Steroid-sparing agents
lating IgE and reduce the inlammatory response. Omalizumab
is being more widely used in particular and is licensed for use in Steroid-sparing agents, such as methotrexate, ciclosporin and 447
patients with uncontrolled asthma where their asthma is medi- oral gold, have been used in some patients with dificult-to-treat
ated by the presence of IgE. In the UK, it is approved for people asthma to reduce the risk of adverse effects from prolonged use
with allergic asthma who need continuous or frequent treatment of corticosteroids, despite a limited evidence base (Davies et al.,
with oral corticosteroids and had at least four courses in the last 1998; Evans et al., 2000a,b). When used, they are prescribed on a
3-month trial after discussion with the patient about the potential

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 Characteristics • People younger than 18 years
exacerbation • Poor adherence to medication
Increased symptoms • Person living alone
Moderate PEFR 50–75% of best or predicted • Psychological problems, such as depression, and alcohol or
asthma No features of acute severe asthma
drug misuse
Acute severe Any one of the following features: • Physical or learning disability
asthma • PEFR 33–50% of best or predicted • Previous near-fatal attack or brittle asthma
• ≥25 breaths/min • Persistent exacerbation despite an adequate dose of oral
• Heart rate ≥110 beats/min
• Inability to complete sentences in one breath corticosteroids before presentation
• Presentation at night or in the afternoon
Life-threatening One of the following features in a patient with • Pregnancy
asthma acute severe asthma:
• PEFR <33% of best or predicted hospital. Patients with life-threatening or near-fatal asthma should
• PaO2 ≤8 kPa be admitted to hospital for assessment and treatment. Patients
• Normal PaCO2 (4.6–6.0 kPa) with acute severe asthma who have responded to initial therapy
• sO2 <92% and have no other concerning features do not need to be admit-
• Altered consciousness level ted to hospital. Patients should be assessed for a number of other
• 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 Treatment
• Cyanosis
• Silent chest Acute asthma can be life-threatening, and treatment aims to relieve
immediate symptoms, improve bronchoconstriction and address
Near-fatal One of the following features: airway inlammation. Acute asthma is stratiied according to clini-
asthma cal observations and investigations (see Table 25.7). Acute severe
PaCO2 >6.0 kPa asthma is deined as the patient’s peak low reduced to between
Need for mechanical ventilation with raised 33–50% of the patient’s best or predicted, increased respiratory
rate of more than 25 breaths per minute, heart rate of more than
inflation pressures 110 beats per minute and the patient is unable to complete a sen-
tence in one breath. Life-threatening asthma is deined as the peak
PaCO2, Partial pressure of carbon dioxide in arterial blood; PaO2, partial low being less than 33% of the patient’s best or predicted, oxygen
pressure of oxygen in arterial blood; PEFR, peak expiratory forced reserve. saturation of less than 92%, silent chest, reduced respiratory effort,
hypotension and an altered state of consciousness. Suficient treat-
risks. It is recommended they are only used under the supervision ment with steroids and monitoring of the patient’s condition are
of a specialist severe asthma service (BTS and SIGN, 2016).  key factors in ensuring the patient’s recovery. Overuse of β-agonist
therapy has been associated with asthma death; therefore, care
Cromones must be taken and monitoring undertaken.

Inhaled sodium cromoglicate and nedocromil have a limited Oxygen. Patients with severe or life-threatening acute asthma
role in the management of asthma, and they are signiicantly should have their oxygen saturation maintained at 94–98% to
less effective than ICS therapy (BTS and SIGN, 2016). They are treat hypoxia. These patients should be administered oxygen
rarely used in current practice.  via a face mask, Venturi mask or nasal cannulae as a matter of
urgency. Pulse oximetry should be used to measure oxygen satu-
Acute treatment ration where possible; however, this should not be a barrier to the
use of oxygen in this situation if unavailable (BTS and SIGN,
When assessing a person with an acute exacerbation of asthma, it 2016; O’Driscoll et al., 2008). 
is important to ask about possible trigger factors, such as recent
allergen exposure or upper respiratory tract viral infections Bronchodilators. Inhaled β-agonists should also be adminis-
(Green et al., 2002b). An acute exacerbation of asthma needs tered in emergency situations to treat bronchoconstriction. High
prompt assessment and appropriate treatment because it repre- doses should be given via the nebulised route where possible.
sents a potentially life-threatening condition. However, if the patient is at home, they can administer 4–6 puffs
at one time of a SABA into a large-volume spacer and take mul-
Risk stratification and assessment tiple breaths in and out of this device. Patients should have their
potassium and heart rate monitored due to the potential adverse
The severity of an acute exacerbation of asthma is determined by effects of hypokalaemia and tachycardia associated with nebu-
a number of different clinical factors and is categorised as moder- lised β-agonist use (BTS and SIGN, 2016).
ate, acute severe, life-threatening or near-fatal (Table 25.7). This
448 risk stratiication provides guidance on the need for admission to

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 No loading dose required
M3 receptors to relax the smooth muscle of the bronchi to induce Adult already taking oral
bronchodilation. theophylline/aminophylline

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 Elderly adult/adult with heart Maintenance dose
β-agonists via an inhaled route (BTS and SIGN, 2016; Travers failure 0.3 mg/kg/h
et al., 2012). 
Nonsmoking adult 0.5 mg/kg/h
Corticosteroids. Oral corticosteroids should be adminis-
tered after an acute asthma attack at the earliest stage possible Smoking adult 0.7 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 to the risks involved with intravenous aminophylline and also
and aid recovery time, as well as decrease mortality (Rowe the monitoring involved, this should not be commenced with-
et al., 2007). Oral prednisolone should be administered at a out specialist medical input. 
dose of 40–50 mg daily, preferably in the morning to mimic
the body’s natural cortisol production and reduce adverse Antibiotics. Acute asthma exacerbations are mostly caused by
effects, including insomnia. If the oral route is unavailable, exposure to allergens or viruses. Consequently, antibiotics are not
then intravenous hydrocortisone may be administered at a indicated and should not be commenced without clear evidence
dose of 100 mg four times daily until the oral route is avail- of a bacterial cause (Graham et al., 2001). 
able again.
Patient care
Corticosteroid therapy should be continued for at least 5 days
but can be extended until the patient’s condition has improved. Structure of an asthma review
Additionally, corticosteroids can be stopped without needing to
wean down the dose unless they have been prescribed for longer There are a number of issues that should be addressed during
than 2 weeks or if the patient is already taking maintenance corti- an asthma review to ensure that it is as effective as possible.
costeroids because this poses a risk of adrenal suppression. The Firstly the degree of asthma control needs to be assessed. If
shortest course length possible should be used to protect patients the person’s asthma symptoms are controlled, then poten-
from the adverse effects of corticosteroids (BTS and SIGN, tially a step down in therapy may be indicated. Conversely,
2016).  when the person’s asthma is not at the appropriate level of
control, a number of factors will need to be assessed prior to
Intravenous magnesium. Patients who have not responded stepping up pharmacological therapy. These include assess-
well to initial bronchodilator therapy can be administered a ment of trigger factors, concordance and inhaler technique
dose of intravenous magnesium at a dose of 1.2–2 g over 20 (Fig. 25.3).
minutes. This can aid bronchodilation and reduce the require-
ment for admission to hospital (Rowe et al., 2000). It has mini- Assessment of asthma control 449
mal adverse effects unless repeated doses are administered
and hypermagnesaemia develops. Blood pressure, respiratory One key aspect of an asthma review is determining the level of
rate and urine output should be monitored whilst intravenous control. The degree of asthma control can be assessed using a
magnesium is administered. Signs of toxicity, including weak- number of different methodologies.
ness, nausea, drowsiness and slurred speech, should also be
monitored.  There are several different deinitions used to report symptoms
in clinical practice. These include:
Intravenous aminophylline. Intravenous aminophylline • Global Initiative for Asthma deinition (Global Initiative for
may be commenced in severe acute asthma to aid with bron-
chodilation, although evidence suggests it does not provide Asthma, 2012; Table 25.9),
additional bronchodilation compared with SABAs (Travers • Royal College of Physicians 3 questions (Pearson and
et al., 2012). Care should be taken with regards to the dos-
ing of intravenous aminophylline. A loading dose should be Bucknall, 1999),
administered to patients who are not taking oral theophylline • Asthma Control Questionnaire (Juniper et al., 1999),
or aminophylline already. Smoking status also needs to be • Asthma Control Test (Nathan et al., 2004).
obtained because patients who smoke require a higher main- Other physiological tests can be useful to help to monitor
tenance dose; conversely, patients with heart failure require asthma control, including lung function (PEFR or FEV1) or
lower loading doses as per Table 25.8. The risk of arrhyth- measures of eosinophilic airway inlammation (Green et al.,
mias and toxicity due to high plasma concentrations should 2002a). 
be taken into consideration before commencement. Patients
require daily plasma concentration levels to ensure safety. Due

25 THERAPEUTICS

Patient education in inhaler technique have been associated with reduced asthma
control (Giraud and Roche, 2002). Inhaler technique should be
It is important to provide high-quality and accurate information reassessed during regular asthma reviews and should also be reas-
to people with asthma. This information is crucial for achieve- sessed after an exacerbation. Inhaler devices should be chosen
ment of adherence with therapy and improving patient outcomes. based on patient choice and the patient’s ability to use them (BTS
There are a number of organisations that can help provide infor- and SIGN, 2016). It should be appreciated that every inhaler has
mation for patients (see Box 25.2).  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

Incorrect Therapy step-up Check:
Correct Minimal
Check inhaler No Symptoms
technique
Leading a
Assess compliance normal life
and aggravating
factors Taking usual
exercise

Low inhaled β-
agonist use

No additional
treatment

Yes

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
>2 per week 3 or more characteristics of
Daytime symptoms <2 per week Any partly controlled asthma
Any present in any week
Limitations of daily activity None
<80%
Night-time symptoms or awakening None
from sleep >2 per week

Lung function as measured by PEFR Normal
or FEV1

Use of reliever inhaler <2 per week

450 FEV1, Forced expiratory volume in 1 second; PEFR, peak expiratory flow rate.
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.
Additionally, using inhalers correctly will reduce waste, improve Inhaler devices can be split into pMDIs, DPIs, breath-actuated
patient outcomes and reduce the risk of adverse effects such as metered-dose inhalers (BA-MDIs) and soft-mist inhalers (SMIs),
oral candidiasis (Basheti et al., 2007; Capstick and Clifton, 2012). with each device requiring a different technique (Table 25.10).
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
dose of corticosteroid to be used, and these have been shown to DPIs may involve the loading of a single capsule manually by
have improved lung deposition compared with standard pMDIs the patient or be multiple-dose devices, which may require other
(Basheti et al., 2007; Capstick and Clifton, 2012). manipulation by the patient to load the dose. The only SMI device
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
pMDIs require a slower inspiratory low. Failing to achieve the Prior to prescribing an inhaler, healthcare professionals must
desired inspiratory low for any device increases the likelihood check the patient’s inspiratory low and inhaler technique. The
that the drug will deposit into the mouth and oropharynx rather In-Check Dial Inspiratory Flow Meter or inhaler device whis-
than the lungs, leading to a lack of eficacy and an increased risk tles can be used to test inspiratory low. Placebo inhalers are
of oral side effects. The inspiratory low is determined by the also available to help train patients on how to use new devices
effort of the patient during inspiration and the resistance to air- (Capstick and Clifton, 2012). 
low within the device. pMDIs have a low resistance to airlow,
meaning they require less effort on inhalation, whereas DPIs Different inhaler devices

Box 25.2 Organisations that provide educational material for Pressurised metered dose inhaler
people with asthma
The pMDI (Fig. 25.4) is a cost-effective device used widely. It is
• Asthma UK: http://www.asthma.org.uk a pressurised aerosol device and can be used with spacer devices
• British Lung Foundation: http://www.lunguk.org if needed. It is available for several drugs, although a popular
• Allergy UK: http://www.allergyuk.org choice can be dificult to use due to the coordination required.
• Global Initiative for Asthma: http://www.ginasthma.org Inhalation should be slow and deep for this device; if patients
• European Lung Foundation: http://www.europeanlung.org inhale too quickly using this device, the aerosol will hit the back
• 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. 451
Adapted from Voshaar et al. (2001).

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
T. Capstick.)
Ellipta. The Ellipta is a new, simple DPI that is primed by
opening the cover completely until a click is heard. It has a dose Spiromax. The Spiromax is a DPI and requires loading by
counter; however, doses may be wasted if the cap is opened mul- opening the cap. It requires strong and deep inhalation, has a dose
tiple times or if the device is not held upright. It requires deep and counter and patients cannot multi-dose when using this device. 
strong inhalation to achieve drug deposition into the lungs. 
Turbohaler. The Turbohaler device is another DPI (Fig. 25.6)
Nexthaler. The Nexthaler is a new DPI device (Fig. 25.5) that requires strong and deep inhalation to achieve deposition of
that also requires priming by opening the cap completely. It the dose into the lungs. It has a dose counter and requires priming
requires strong and deep inhalation, and if this is achieved, by twisting the bottom of the device to load it prior to inhalation.
a click should be heard. It has a dose counter and cannot be Fortunately, patients are unable to multi-dose because the counter
multi-dosed.  will continue to count down but will not actually load multiple doses. 

Novolizer. The Novolizer device is a DPI that requires prim- Twisthaler. The Twisthaler device is a DPI requiring strong
ing by pressing the button down until it clicks. It has a coloured and deep inhalation. It is primed by twisting the cap anticlockwise
control window that patients may ind useful; it changes from red to remove it and ensuring the pointers on the device and the coun-
to green as the inhaler is primed, then back to red once the dose is ter are aligned. It has a dose counter, which will count down with
452 inhaled. It requires deep and strong inhalation, and patients can- multiple actuations; however, the dose is not loaded multiple times. 
not multi-dose using this device. 

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. 

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

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?
Case studies 4. Because she is failing to improve, what two other therapies could

be considered, and at what dose? 

Case 25.1 Answers

Mr DM is a 25-year-old man with a history of asthma since child- 1. Mrs ES has a life-threatening exacerbation as determined by her
hood. He has a background of poor asthma control; he uses his oxygen saturation and PEFR. Her oxygen saturation is ≤92%, and
reliever most days and wakes at night approximately twice per her PEFR is less than 33% of her normal value.
week. He works full-time in a garage, smokes 10 cigarettes per
day and has a pet dog at home. He has been admitted to hospital 2. Mrs ES should be started on nebulised salbutamol 5 mg and
in January with an acute severe exacerbation of asthma. During ipratropium 500 micrograms as an immediate response. If she
his hospital stay his regular inhalers were changed from Symbicort fails to respond clinically to the initial therapy, then repeated (or
200/6 Turbohaler two puffs twice a day to Seretide 500/50 ‘back-to-back’) administration of salbutamol can be used until
Accuhaler one puff twice a day. clinical improvement is seen in terms of routine observations and/
or PEFR. Once she is more stable, the nebulised bronchodilators
Questions should be administered 6 hourly and stopped 24 hours prior to
discharge from hospital.
1. What asthma reviews should Mr DM have following this exacerba-
tion of his asthma? 3. She should receive 40–50 mg of oral prednisolone immediately,
then once daily for a minimum of 5 days. Because her asthma
2. What components are key to each asthma review? exacerbation is life-threatening, she should be monitored in hos-
3. What are the potential causes of Mr DM’s poor asthma control? pital until clinically stable for discharge. If she is unable to take
4. What is the increase in Mr DM’s inhaled steroid dose?  the tablets orally, then an alternative would be hydrocortisone 100
micrograms intravenously. Once she is able to take medication
Answers orally, then the intravenous hydrocortisone should be swapped to
oral prednisolone as previously described.
1. Mr DM should be reviewed by a respiratory specialist prior to
discharge from hospital. He should also be seen by his primary 4. Mrs ES could be considered for intravenous magnesium 1.2–2 g
care doctor or specialist primary care nurse two days following dis- over 20 minutes. Alternatively, she could receive intravenous ami-
charge. Subsequent to this he should be seen in a hospital asthma nophylline. Aminophylline would require a loading dose of 5 mg/
clinic 4 weeks following discharge. kg (380 mg) over 20 minutes, followed by a maintenance infusion
of 0.5 mg/kg/h (38 mg/h). If Mrs ES received intravenous ami-
2. At each review Mr DM’s asthma control should be assessed, nophylline, then therapeutic drug monitoring would need to be
adherence with therapy should be reviewed, aggravating factors undertaken daily. 
identified and inhaler technique checked.
Case 25.3
3. Mr DM has a number of factors that may be worsening his asthma,
including his smoking and exposure to pets. In view of the time Mr CM is a 56-year-old man with a history of asthma over the
of the year, the most likely cause of his exacerbation may be a preceding 5 years. His height is 177 cm and weight is 80 kg. He
viral infection. More information about his job should be elicited had one exacerbation of his asthma 3 years ago that required hos-
because exposure to isocyanates in car-paint fumes can be an pital admission, and he is currently prescribed Symbicort 200/6
asthma trigger. Turbohaler two puffs twice daily. At his asthma review today, Mr
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- Questions
grams beclometasone per day. 
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? 
454 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- Answers
scribed a Fostair 100/6 pMDI two puffs twice a day and salbutamol
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.

ASTHMA 25

2. Mr CM’s asthma treatment should be considered for a step down Questions
in treatment because he meets the current guideline definition
for asthma control. He is currently on step 3 of the BTS guideline 1. What is the likely diagnosis?
treatment. 2. What investigations should be undertaken?
3. What treatment should be started?
3. Mr CM is currently taking Symbicort 200/6 two puffs twice daily. 4. What non-pharmacological measures should be considered? 
This is a medium-dose combination inhaled steroid and LABA
inhaler. Potential changes to his therapy would be either to con- Answers
tinue the LABA and reduce his ICS dose (i.e. change to Symbicort
100/6 Turbohaler two puffs twice a day) or, alternatively, to change 1. Miss CM’s history is suggestive of a diagnosis of asthma. The inter-
his inhaler to an equivalent ICS dose as monotherapy.  mittent symptoms, diurnal variation and previous atopy (seasonal
allergic rhinitis) would all be supportive of this diagnosis.
Case 25.4
2. Miss CM should undertake a lung function test to confirm the
Miss CM is 45 years old. She presents with a 6-month history of presence of airflow obstruction. Ideally this should be spirometry
intermittent breathlessness, wheeze and cough. Miss CM has measurements, although an alternative would be serial peak flow
found that she gets symptoms at least three or four times each measurements. These measurements should be taken morning
week. She has also noticed that her symptoms are worse first and evening for 2 weeks. If these investigations were not conclu-
thing in the morning, also significantly during the winter when she sive, then Miss CM may need to proceed to reversibility testing
had a minor upper respiratory tract infection. or be considered for referral to a hospital specialist for further
investigation.
She is currently taking no regular medication. Apart from sea-
sonal allergic rhinitis, Miss CM has no other health problems. 3. Initial therapy would be a regular ICS at a starting dose equivalent
to beclometasone 400 micrograms per day.

4. The other key non-pharmacological interventions are to provide
Miss CM with a PAAP. She should also receive education regarding
her condition and training in the use of her inhaler device.

References Holt, S., Suder, A., Weatherall, M., et al., 2001. Dose–response relation of
inhaled luticasone propionate in adolescents and adults with asthma:
Basheti, I., Reddel, H.K., Armour, C.L., et al., 2007. Pharmacists’ under- meta-analysis. Br. Med. J. 323, 253–256.
standing of patient education on metered-dose inhaler technique. Ann.
Pharmacother. 34, 1249–1256. Juniper, E.F., O’Byrne, P.M., Guyatt, G.H., et al., 1999. Development and
validation of a questionnaire to measure asthma control. Eur. Respir. J.
British Thoracic Society (BTS) and Scottish Intercollegiate Guidelines 14, 902–907.
Network (SIGN), 2016. British Guideline on the Management of Asthma.
SIGN, Edinburgh (QRG 153). Available at http://www.sign.ac.uk. Lanes, S.F., Garrett, J.E., Wentworth, C.E., et al., 1998. The effect of adding
ipratropium bromide to salbutamol in the treatment of acute asthma: a
Brown, H.M., 1958. Treatment of chronic asthma with prednisolone; signii- pooled analysis of three trials. Chest 114, 365–372.
cance of eosinophils in the sputum. Lancet 2, 1245–1247.
Lenney, J., Innes, J.A., Crompton, G.K., 2000. Inappropriate inhaler use:
Capstick, T.G., Clifton, I.J., 2012. Inhaler technique and training in people assessment of use and patient preference of seven inhalation devices.
with chronic obstructive pulmonary disease and asthma. Expert Rev. EDICI Resp. Med. 94, 496–500.
Respir. Med. 6, 91–101.
Malmstrom, K., Rodriguez-Gomez, G., Guerra, J., et al., 1999. Oral mon-
Chauhan, B.F., Ducharme, F.M., 2014. Addition to inhaled corticosteroids telukast, inhaled beclomethasone, and placebo for chronic asthma. A
of long-acting beta2-agonists versus anti-leukotrienes for chronic asthma. randomized, controlled trial. Montelukast/Beclomethasone Study Group.
Cochrane Database Syst. Rev. 2014 (1), Art. No. CD003137. https://doi. Ann. Intern. Med. 130, 487–495.
org/10.1002/14651858.CD003137.pub5.
Medicines and Healthcare Products Regulatory Agency, 2008. Review on
Crompton, G.K., Barnes, P.J., Broeders, M., et al., 2006. The need to long-acting β2 agonists for asthma. Available at https://www.gov.uk/
improve inhalation technique in Europe: a report from the Aerosol Drug drug-safety-update/review-on-long-acting-2-agonists-for-asthma.
Management Improvement Team. Resp. Med. 100, 1479–1494.
Nathan, R.A., 2003. Pharmacotherapy for allergic rhinitis: a critical review
Davies, H., Olson, L., Gibson, P., 1998. Methotrexate as a steroid sparing of leukotriene receptor antagonists compared with other treatments. Ann.
agent for asthma in adults. Cochrane Database Syst. Rev. 1998 (3), Art. Allergy Asthma Immunol. 90, 182–190.
No. CD000391. https://doi.org/10.1002/14651858.CD000391.
Nathan, R.A., Sorkness, C.A., Kosinski, M., et al., 2004. Development of
Evans, D.J., Cullinan, P., Geddes, D.M., 2000a. Cyclosporin as an oral corti- the asthma control test: a survey for assessing asthma control. J. Allergy
costeroid sparing agent in stable asthma. Cochrane Database Syst. Rev. 2000 Clin. Immunol. 113, 59–65.
(4), Art. No. CD002993. https://doi.org/10.1002/14651858.CD002993.
National Institute for Health and Care Excellence (NICE), 2010. Chronic
Evans, D.J., Cullinan, P., Geddes, D.M., 2000b. Gold as an oral corticoster- obstructive pulmonary disease in over 16s: diagnosis and management
oid sparing agent in stable asthma. Cochrane Database Syst. Rev. 2000 (CG101). Available at https://www.nice.org.uk/guidance/cg101.
(4), Art. No. CD002985. https://doi.org/10.1002/14651858.CD002985.
National Institute for Health and Care Excellence (NICE), 2013. Omalizum-
Giraud, V., Roche, N., 2002. Misuse of corticosteroid metered-dose inhaler ab for treating severe persistent allergic asthma (review of Technology
is associated with decreased asthma stability. Eur. Respir. J. 19, 246–251. Appraisal Guidance 133 and 201). Available at https://www.nice.org.
uk/guidance/ta278.
Global Initiative for Asthma, 2012. Global strategy for asthma management
and prevention. Available at http://ginasthma.org. National Institute for Health and Care Excellence (NICE), 2017. Mepoli-
zumab for treating severe eosinophilic asthma. Available at https://www.
Graham, V., Lasserson, T., Rowe, B.H., 2001. Antibiotics for acute asthma. nice.org.uk/guidance/ta431.
Cochrane Database Syst. Rev. 2001 (2), Art. No. CD002741. https://doi.
org/10.1002/14651858.CD002741. O’Driscoll, B.R., Howard, L.S., Davison, A.G., 2008. BTS guideline for
emergency oxygen use in adult patients. Thorax 63 (Suppl. 6), 1–68.
Green, R.H., Brightling, C.E., McKenna, S., et al., 2002a. Asthma exacerba-
tions and sputum eosinophil counts: a randomised controlled trial. Lancet Pearson, M., Bucknall, C., 1999. Measuring Clinical Outcomes in Asthma:
360, 1715–1721. A Patient Focused Approach. Royal College of Physicians, London.

Green, R.M., Custovic, A., Sanderson, G., et al., 2002b. Synergism between 455
allergens and viruses and risk of hospital admission with asthma: case-
control study. Br. Med. J. 324, 763.

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Pellegrino, R., Viegi, G., Brusasco, V., et al., 2005. Interpretative strategies Royal College of Physicians, 2014. Why Asthma Still Kills: The National
for lung function tests. Eur. Respir. J. 26, 948–968. Review of Asthma Deaths (NRAD) Conidential Enquiry Report. Royal
College of Physicians, London.
Rodrigo, G.J., Castro-Rodriguez, J.A., 2015. What is the role of tiotropium
in asthma? A systematic review with meta-analysis. Chest 147, 388–396. Travers, A.H., Jones, A.P., Camargo, C.A., et al., 2012. Intravenous beta2-
agonists versus intravenous aminophylline for acute asthma. Cochrane
Rowe, B.H., Bretzlaff, J.A., Bourdon, C., et al., 2000. Magnesium sulfate Database Syst. Rev. 2012 (12), Art. No. CD010256. https://doi.org/
for treating exacerbations of acute asthma in the emergency department. 10.1002/14651858.CD010256.
Cochrane Database Syst. Rev. 2000 (1), Art. No. CD001490. https://doi.
org/10.1002/14651858.CD001490. Voshaar, T., App, E.M., Berdel, D., et al., 2001. Recommendations for the
choice of inhalatory systems for drug prescription. Pneumologie 55,
Rowe, B.H., Spooner, C., Ducharme, F.M., et al., 2007. Early emergency 579–586.
department treatment of acute asthma with systemic corticosteroids.
Cochrane Database Syst. Rev. 2007 (3), Art. No. CD000195. https://doi. Wenzel, S.E., 2012. Asthma phenotypes: the evolution from clinical to
org/10.1002/14651858.CD000195.pub2. molecular approaches. Nat. Med. 18, 716–725.

Further reading Wenzel, S.E., 2012. Asthma phenotypes: the evolution from clinical to
molecular approaches. Nat. Med. 18, 716–725.
Barnes, P.J., Rodger, I.W., Thomson, N.C., 1998. Asthma: Basic Mecha-
nisms and Clinical Management, third ed. Academic Press, London.

Mahmoudi, M., 2016. Allergy and Asthma: Practical Diagnosis and Man-
agement, second ed. Springer International Publishing, New York.

Useful websites Global Initiative for Asthma: http://www.ginasthma.org
European Lung Foundation: http://www.europeanlung.org
Asthma UK: http://www.asthma.org.uk NHS Choices: http://www.nhs.uk/conditions/asthma
British Lung Foundation: http://www.blf.org.uk
Allergy UK: http://www.allergyuk.org

456

THERAPEUTICS

26 Chronic Obstructive
Pulmonary Disease
Trevor Rogers and Helen Meynell

Key points Epidemiology

• Chronic obstructive pulmonary disease (COPD) is a leading COPD is a leading cause of morbidity and mortality. In the UK
cause of morbidity and mortality worldwide. an estimated 3 million people have the condition (a prevalence
of about 5%), of whom only about 900,000 have been diag-
• Reducing exposure to tobacco smoke as well as other recre- nosed; a substantial majority, an estimated 2 million people,
ational drugs, including cannabis, cocaine and heroin; occupa- have not. The diagnosis is usually not made before patients
tional dusts; chemicals and pollutants is an important goal to reach their 50s, with prevalence increasing with age. Worldwide
prevent the onset and progression of COPD. prevalence is likely to vary between about 5% and 10%, with
estimates varying according to the methods employed in iden-
• Smoking cessation is the single most important intervention tifying disease. 
to reduce the risk of developing COPD and slow disease
progression. Aetiology

• Risk factors for COPD include host factors (α1-antitrypsin Whilst smoking is overwhelmingly the commonest cause, it
deficiency and airway hyper-responsiveness) and exposure is now well established that dust and fume exposure can also
to tobacco smoke as well as socio-economic status. cause the condition. In the developed world this is most often
seen in subjects exposed occupationally, as in mining, steel
• Pulmonary rehabilitation, incorporating exercise and working and similar occupations. Globally, cooking using
education, is the intervention that has the greatest impact biomass in poorly ventilated houses is an important cause,
on quality of life. especially in women. The rare homozygous α1-antitrypsin
deiciency predisposes to early-onset emphysema, mostly in
• Drugs have an important role in maximising lung function and smokers, revealing the importance of the balance between
reducing exacerbations. neutrophil-derived proteases and anti-proteases in the develop-
ment of the condition. The major risk factors are summarised
Definitions in Table 26.1. 

Chronic obstructive pulmonary disease (COPD) is deined Pathology and pathophysiology
on the basis of airlow obstruction that is not fully reversible.
Certainly, this clinical entity is highly prevalent and familiar, The two pathological components of COPD are chronic bronchi- 457
usually in older patients with a signiicant smoking history. It tis and emphysema, existing in the individual in greater or lesser
is associated with largely irreversible damage to the airways proportions. Emphysema means dilatation of the airways distal
and lung parenchyma (emphysema). However, based as it is to the terminal bronchiole, with loss of alveolar walls and conse-
on physiology, this deinition is likely also to include other quent reduction in the surface area of the alveolar membrane. This
pathologies. For example, there is a subset of patients who impairs gas transfer and can be measured in the laboratory by a
meet this deinition who have varying degrees of eosinophilia
and who share the important characteristic of corticosteroid reduction in the carbon monoxide gas transfer coeficient (DLCO).
responsiveness with the other highly prevalent condition in Another effect of this tissue damage is a reduction in the traction
which airlow obstruction is a key feature: asthma. A diag- on airways, increasing lung compliance and making airways prone
nostic label is only of use if it is helpful in practice, and in to collapse during expiration. The tendency is for emphysema-
this important aspect of corticosteroid responsiveness, the use tous areas to coalesce, which can lead to the formation of large air
of the unqualiied terms of COPD, and indeed asthma, fail. cysts, called bullae. These are most commonly located in the upper
Relecting this, there has recently been a move away from
these umbrella terms, instead identifying ‘treatable traits’,
such as eosinophilic, steroid-responsive airway disease and
those in which it is absent when the emphasis is on broncho-
dilatation. The term COPD is so irmly entrenched that its use
will undoubtedly continue for the foreseeable future, but its
limitations do need to be borne in mind. 

26 THERAPEUTICS

Table 26.1 Risk factors for the development of chronic their eficiency. Hyperinlation can be exacerbated by exercise,
obstructive pulmonary disease leading to further reduction in eficiency of the respiratory pump,
a process known as dynamic hyperinlation.
Risk factor Comment
The syndrome known as hypoxic cor pulmonale is widely mis-
Smoking (including Risk increases with increasing consumption, understood. It refers to peripheral oedema occurring in COPD
with type 2 respiratory failure. It is not, as widely thought, due to
tobacco, heroin, but there is large inter-individual variation simple right ventricular failure and pressure overload: pulmonary
artery pressures are similar to those tolerated by many millions
cannabis) in susceptibility. of people living at high altitude without dificulty over lifetimes,
and right ventricular hypertrophy is rarely found at autopsy. In
Age Lung function impairment progresses with fact, cardiac output increases during acute episodes. It is likely
age. that the systemic vasodilation caused by elevated carbon dioxide
levels causes blood pressure to fall. Renal salt and luid reten-
Gender Male gender was previously thought to be tion mediated by neurohumoral mechanisms are utilised by the
a risk factor, but this may be due to histori-
cal higher rates of smoking in men. body to maintain blood pressure, as in other forms of high-output
cardiac failure. The onset of oedema is an important milestone in
Occupation Development of COPD is associated with the natural history of COPD, suggesting a poor prognosis, albeit
occupational dust and fume exposure, much improved by long-term oxygen therapy (LTOT). Whilst
including coal mining, farming, loop diuretics are necessary to control oedema, the improvement
grain-handling and the cement and in gas exchange by optimal medical management is the real key
cotton industries. to its treatment. 

Genetic factors Alpha-1 antitrypsin deficiency is the stron- Clinical manifestations
gest single genetic risk factor, accounting
for 1–2% of COPD. Symptoms, signs and natural history

Air pollution Death rates are higher in urban areas than The earliest symptoms of COPD are cough and expectoration of
in rural areas. Indoor air pollution from sputum. These develop insidiously, often being disregarded as a
burning biomass fuel is also a risk factor, ‘smoker’s cough’. Acute infections may lead to episodic breath-
particularly in the developing world. lessness and increased expectoration, frequently with wheezing,
which may be appreciated by the patient and by the clinician
Socio-economic COPD has increased prevalence in individu- on auscultation of the chest. Lung function usually continues to
status als of low socio-economic status. decline at an accelerated rate, particularly whilst smoking con-
tinues, although it is likely that many COPD patients start from
COPD, Chronic obstructive pulmonary disease. a lower baseline with reduced lung function from an early age.
Due to the substantial reserve of respiratory function, which is
zones, whereas in α1-antitrypsin deiciency, emphysematous areas only called on at times of stress, such as heavy exertion or respi-
are more basally distributed. Occasionally giant bullae can develop ratory tract infection, more persistent symptoms of breathless-
and occupy over half of the volume of a lung. ness only occur when large amounts of lung have been destroyed.
This is the explanation for the gross underdiagnosis of the condi-
The other pathological component is chronic bronchitis. This tion, especially in its earlier stages. When pulmonary reserve is
has been deined clinically, largely in epidemiologic studies, as a exhausted, patients often perceive that they have fairly suddenly
chronic cough with sputum production for at least 3 months per developed a problem with persistent breathlessness. Thus, iden-
year for 2 consecutive years. Pathologically, chronic bronchitis tiication of early intermittent symptoms and performing spirom-
refers to hypertrophy of the mucus-secreting goblet cells in air- etry to identify and quantify airlow obstruction can be helpful in
concentrating efforts on smoking cessation, at a time when severe
way walls. This in turn leads to worsening airlow obstruction disability is completely avoidable.
by luminal obstruction of small airways, epithelial remodelling
and alteration of airway surface tension, predisposing to collapse. If emphysema is prominent, the chest becomes visibly hyper-
inlated, which can also be appreciated by a hyper-resonant per-
At a microscopic level the inlammation is predominantly neu- cussion note, as part of the clinical examination.
trophilic, and as is usual, this is not responsive to corticosteroids.
A relatively small proportion of COPD patients, however, have Other symptoms that may be experienced are sleep disturbance,
a signiicant eosinophilic component to their disease, which is dry mouth, lethargy and weight loss, the last of which is a poor
steroid responsive (see later discussion). prognostic sign, independent of lung function but more common
in advanced disease. If respiratory failure develops, ankle oedema
Repeated bronchial infections can cause damage to bronchial appears, comprising the clinical syndrome of hypoxic cor pulmo-
nale. This may be associated with headache and drowsiness and
walls, leading to loss of elasticity, and dilatation, a condition is clinically associated with a bluish complexion (‘cyanosis’),
called bronchiectasis, which develops in a proportion of COPD warm peripheries, a bounding pulse and lapping tremor.
patients. This tends to be associated with copious sputum produc-
tion, with repeated infective exacerbations and frequently with
the emergence of pathogens more resistant to irst-line antibiotics.

Both emphysema and bronchitis combine to impair the abil-

ity to expel air from the lungs, leading to hyperinlation of the
thorax. The consequent overstretching of intercostal muscles and
458 diaphragm places them at a mechanical disadvantage, reducing

CHRONIC OBSTRUCTIVE PULMONARY DISEASE 26

Table 26.2 Assessment of severity of airflow obstruction Table 26.3 Modified Medical Research Council dyspnoea scale

FEV1 Severity Grade Degree of breathlessness related to activities
Greater than 80% predicted GOLD stage 1: Mild
1 Not troubled by breathlessness except on strenuous
50–79% predicted GOLD stage 2: Moderate exercise

30–49% predicted GOLD stage 3: Severe 2 Short of breath when hurrying or walking up a slight hill

<30% predicted GOLD stage 4: Very severe 3 Walks slower than contemporaries on level ground be-
cause of breathlessness, or has to stop for breath when
FEV1, Forced expiratory volume in 1 second. walking at own pace
Adapted from GOLD (2017).
4 Stops for breath after walking about 100 m
Two COPD stereotypes have been recognised, the so-called or after a few minutes on level ground
‘pink puffer’ and ‘blue bloater’. Pink puffers tend to have a more
emphysematous phenotype, with marked hyperinlation. They 5 Too breathless to leave the house, or breathless when
maintain normal blood gases at the expense of a high work of dressing or undressing
breathing and severe breathlessness. These patients are typi-
cally thin. The blue bloater, in contrast, tends to have less obvi- Adapted from Fletcher et al. (1959).
ous hyperinlation and slips into respiratory failure and hypoxic
cor pulmonale. These patients are less breathless and tend to be respiratory symptoms, this is an important differential diagnosis
obese. It should be emphasised that whilst these caricatures do in which the chest X-ray is useful. In COPD the chest X-ray can
exist, they are opposite ends of a spectrum, with many patients be normal but often shows hyperinlated lungs, increased lung
having elements of both. Interestingly, pathologically, the lungs markings due to bronchial wall thickening and regions of lucency
of these two stereotypes are very similar, suggesting that the corresponding to areas of emphysema/bullae.
cause for the difference lies in the central respiratory control of
Symptoms can be quantiied with differing levels of precision.
breathing.  One of the simplest is the modiied Medical Research Council
(mMRC) dyspnoea score (Table 26.3), which is readily usable in
Investigations clinical practice.

Airlow obstruction is readily measured by spirometry, now con- More complex and multidimensional instruments exist, gen-
ventionally performed, in the assessment of COPD, 10–20 min- erating indices of quality of life, the most widely used of which
utes after bronchodilator treatment. Airlow obstruction is present is the St George Respiratory Questionnaire (SGRQ), which was
when the ratio of the volume expired in the irst second (FEV1) to developed speciically for COPD and is mostly used in clinical
the total volume expired (FVC) falls below 70%. The severity of trials (Jones et al., 1991). Functional assessments can also be
airlow obstruction is assessed by the post-bronchodilator FEV1 used, including exercise tests, including the 6-minute walk and
expressed as the percentage of the predicted, according to age shuttle walks. Body mass index (BMI) is also prognostically
and height, and can be graded as shown in Table 26.2. important, with weight loss and cachexia being associated with
a poor prognosis. Indeed, a combination of BMI, the severity of
More detailed physiological evaluation is not usually required, airlow obstruction, severity of breathlessness and walking dis-
tance can be used to assess prognosis having been incorporated
but lung volume measurements and carbon monoxide gas trans- into the Body-Mass Index, Airlow Obstruction, Dyspnoea, and
fer (DLCO) can more precisely quantify the severity of air trap- Exercise (BODE) index (Celli et al., 2004). 
ping and emphysema, respectively. When the diagnosis remains
in doubt, including when lung function testing reveals features Classification
that may indicate interstitial lung disease (pulmonary ibrosis),
computed tomography (CT) scanning can be helpful in identi- COPD has historically been graded in severity according to the 459
fying emphysema, and this is also useful when lung volume
reduction treatment is being considered, including the surgical degree of airlow obstruction (see Table 26.2). Symptom severity
correlates poorly with lung function. The Global Strategy for the
removal of giant bullae. CT scanning can also be useful in iden- Diagnosis, Management, and Prevention of Chronic Obstructive
tifying the not infrequent co-existence of bronchiectasis. Plain
chest radiography has both poor sensitivity and speciicity for Pulmonary Disease guidelines (GOLD, 2017) have been updated
COPD but is recommended when the diagnosis is irst being con- to introduce the ‘ABCD’ algorithm. This is the irst classiication
sidered to exclude other pathologies. COPD is a strong risk fac- to combine risk assessment with symptoms to help determine the
tor for lung cancer, even after correction for smoking has been most effective treatments. This generates a 2 × 2 matrix (Fig.
included. Therefore, when a smoker presents with persistent new 26.1). It is important to note that there are two ways of qualifying
as high risk: higher GOLD score (equating to poor lung function)
or frequent exacerbations. 

26 THERAPEUTICS

Spirometrically Assessment of Assessment of
confirmed airflow limitation symptoms/risk of
diagnosis
exacerbations
Post-bronchodilator FEV1 Exacerbation
FEV1/FVC < 0.7 (% predicted) history CD

GOLD 1 ≥80 ≥2 AB
or
GOLD 2 50–79 ≥1 leading
to hospital
GOLD 3 30–49 admission

GOLD 4 <30 0 or 1
(not leading
to hospital
admission)

mMRC 0–1 mMRC ≥ 2
CAT < 10 CAT ≥ 10

Symptoms

Fig. 26.1 GOLD refined ABC assessment tool. For mMRC definitions, see Table 26.3. The CAT score
refers to the COPD Assessment Test (GlaxoSmithKline, 2009).
COPD, Chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced
vital capacity; mMRC, Modified Medical Research Council.
(GOLD, 2017; with kind permission from GOLD.)

Treatment Box 26.1 Treatment aims for patients with chronic obstructive
pulmonary disease
Managing stable chronic obstructive pulmonary
disease • Prevent disease progression
• Relieve symptoms
The National Institute for Health and Care Excellence (NICE, 2010) • Improve exercise tolerance
guidance for the management of COPD has largely been superseded • Improve quality of life and health status
• Prevent and treat complications such as hypoxaemia
by the body of evidence that is outlined in the GOLD (2017) guide- • Prevent and treat exacerbations
lines. As such, NICE is no longer favoured for the management of • Reduce mortality
COPD, and GOLD (2017) is a comprehensive document that respi-
ratory professionals should be referring to when managing these therapy to a dual LABA-LAMA combination should symptoms
patients. The rate of progression of COPD does not change despite continue. GOLD (2017) guidelines also give the lexibility to ini-
medication or rehabilitation, but the measures in the guidance can sig- tiate treatment straight away with a LABA-LAMA combination.

niicantly improve a patient’s quality of life and reduce the symptom Group C patients are those who are not particularly symptom-
burden. If the treatment plan is optimised, then this is likely to reduce atic but have experienced more than two exacerbations requiring
symptoms, exacerbations and admissions to hospital. The aims of antibiotics and/or steroids or more than one exacerbation requir-
treatment with the pharmacological agents are shown in Box 26.1. ing hospital admission in the previous year. For these patients,
GOLD (2017) guidelines recommend a LAMA, escalating to a
Fig. 26.1 outlines assessment of COPD dependent on symptom LABA-LAMA combination if further exacerbations occur. In this
burden and exacerbation frequency. group, there is an option to add in a LABA/inhaled corticosteroid
(ICS), but this is not the preferred choice of agent.
A group A patient is one who is relatively symptom-free (mMRC
0–1 or CAT score <10) with no exacerbations in the previous year. Group D patients are those with frequent exacerbations and
For these patients, who are most likely to present in primary care, severe symptoms. For these patients, the options are very lexible
a bronchodilator should be prescribed. An as-required broncho- and would be based on individual patients. Ultimately, for these
dilator would only be recommended for those patients with very patients, so-called ‘triple therapy’ may be appropriate (i.e. LAMA
occasional breathlessness: it is preferable to use a long-acting plus LABA/ICS). Rolumilast has recently been approved by NICE
bronchodilator in these circumstances. Once initiation with a bron- (2017) as an add-on bronchodilator in this group of patients. It is
chodilator has occurred, the patient should be re-assessed and an generally thought that ICSs should be reserved for these patients
with very debilitating symptoms and frequent exacerbations.
alternative bronchodilator prescribed if symptoms remain an issue.
Group B patients are those patients who are more symptomatic Pharmacological treatments do not change the underlying
pathology. The common therapeutic problems associated with
(mMRC >2 or CAT score >10) who also have not exacerbated in COPD are shown in Box 26.2.
the previous year. For these patients, GOLD (2017) guidelines
recommend the use of a long-acting β-agonist (LABA) or long-
acting anti-muscarinic antagonists (LAMAs). This is very simi-
460 lar to the management of category A patients, with a step up in

CHRONIC OBSTRUCTIVE PULMONARY DISEASE 26

Box 26.2 Common therapeutic problems associated with improve exercise tolerance. GOLD (2017) guidance recommends 461
chronic obstructive pulmonary disease that the once the diagnosis of COPD is conirmed, the patient
is assessed for symptom severity, either using the CAT score or
• Failure of patient to stop smoking mMRC dyspnoea score. In addition, the number of exacerbations
• Inadequate inhaler technique, leading to subtherapeutic dos- in the past year should also be determined. Once these have been
assessed, the patient can be initiated on appropriate treatment
ing and medicine wastage
• Poor adherence to the treatment regimen using the modiied ABCD algorithm (see Fig. 26.1). Patients
• Inappropriate prescribing (or lack of prescribing) of antibiotics should be provided with a short-acting β2-agonist (SABA) for
use when required. Salbutamol and terbutaline are the principal
in an acute exacerbation of chronic obstructive pulmonary SABAs available, although formoterol, which is long-acting,
disease has an equally swift onset of action of approximately 5 minutes.
• Failure to properly assess a patient for home nebulisation Ipratropium, the only short-acting anti-muscarinic available
• Failure to properly assess adherence to at least 15 h/day of (SAMA), is another option, provided the patient is not taking a
oxygen therapy LAMA, although its rate of onset is slower. 
• Failure to discontinue current inhalers when switching to new
devices/regimens Long-acting bronchodilators. LAMAs and LABAs are
the mainstay of treatment for patients with stable COPD. The
Surgical treatments evidence base is rapidly growing, and the role of bronchodila-
tors and their position in therapy is also rapidly changing. The
Intervention to reduce lung volume can improve lung function recent FLAME study (Jadwiga et al., 2016) has demonstrated
and breathlessness in appropriately selected patients, with severe that a combination product of indacaterol and glycopyrronium is
air trapping. This can be achieved by surgical removal of emphy-
sematous regions, especially when these are located primarily in superior to salmeterol plus luticasone for all exacerbations, lung
the upper zones, or more recently by the placement of endobron- function and health-related quality of life in patients with a his-
chial valves. tory of exacerbations. In addition, there was a lower incidence of
pneumonia in the LABA/LAMA arm.
Lung transplantation is an option when lung function and qual-
ity of life become severely impaired, but the rigorous criteria Long-acting muscarinic antagonists. Tiotropium has been a
applied in selection and the paucity of donor organ availability cornerstone of treatment and provides the most robust evidence
limit this to a very small proportion of patients. 
of eficacy. The landmark trial UPLIFT showed that treatment
Smoking cessation with tiotropium in mild to severe disease can signiicantly sus-
tain improvements in lung function over 4 years. It was also
Smoking is the most important and modiiable factor in the devel- shown to delay time to irst exacerbation, reduce the number of
opment of COPD. Smoking cessation interventions are effective exacerbations per year and reduce the risk of exacerbations lead-
in reducing ill health and prolonging life. All COPD patients who ing to hospital admission (Tashkin et al., 2008).
continue to smoke, regardless of age, should be given encour-
agement to stop smoking and be offered help to do so at every There was controversy over the cardiovascular safety of
opportunity (GOLD, 2017). Even brief conversations between Tiotropium Respimat, which has been largely discounted fol-
the patient and the healthcare professional can lead to quitting lowing publication of TIOSPIR in 2013 (Wise et al., 2013), a
and, as a result, are one of the most cost-effective of all health- randomised, double-blind, parallel group trial of around 17,000
care interventions. Once a quit date has been determined, it is patients. Patients were randomised to either tiotropium Respimat
the level of dependence rather than the motivation that inluences 2.5 micrograms, tiotropium Respimat 5 micrograms or tiotropium
the success rate, and this is where having professional support 18 micrograms in the HandiHaler device. End points were risk
can help the individual to maintain his or her smoke-free status. of death and time to irst exacerbation, but cardiovascular safety
For example, in the irst few days after quitting, the cough and was also assessed. The trial showed that 2.5-microgram and
sputum production increase as the cilia start to recover from their 5-microgram doses via the Respimat device had a similar safety
paralysis due to the toxic effects of the smoke.
proile and exacerbation rate to the HandiHaler mode of delivery.
Fig. 26.2 summarises how lung function and symptoms are Other, newer LAMAs include aclidinium, umeclidinium and gly-
believed to be affected by continuing to smoke or stopping at any copyrronium, and new trial data are emerging regarding quality
age. Estimates suggest that stopping smoking leads to a sustained of life, exacerbations and improvement in lung function (Jones
50% reduction in the rate of lung function decline; however, it et al., 2012; Kerwin et al., 2012; Trivedi et al., 2014). Choice of
should be remembered that the damage already sustained cannot LAMA is made by consideration of the patient’s ability to use the
be reversed.  device, adherence and tolerability. 

Bronchodilators Long-acting β2-adrenergic agonists. Salmeterol, inda-
caterol, olodaterol and formoterol are all available in the UK
Short-acting β-agonists and short-acting antimuscarin- in a range of different inhaler devices and in combination with
ics. Bronchodilators in COPD are used to reverse airlow limita- LAMAs or ICSs. There is emerging evidence that LABAs are
tion. They are useful for easing symptoms such as wheeze and also effective in reducing exacerbations and improving symp-
toms; however, asthma must be conidently excluded before ini-
tiating a LABA without an ICS. The TORCH study (Calverley
et al., 2007) demonstrated that salmeterol signiicantly reduced
exacerbation frequency. 

26 THERAPEUTICS

FEV, (% of value at age 25) 100 Never smoked or not
susceptible to smoke
75
Smoked regularly Stopped
and susceptible to its effects smoking at
45
50
Disability Stopped
smoking at
25 65
Death

0
25 50 75
Age (years)

Fig. 26.2 Diagrammatic representation of the effects of smoking and smoking cessation in a man who
is likely to develop COPD if he smokes. (Reproduced from Fletcher and Peto, 1977, with permission.)

Nebulised bronchodilator therapy. For those patients who of therapy redundant. This also stratiies the treatment according
suffer debilitating breathlessness, a home nebuliser has tradi- to inhaler device rather than changing devices at each step of the
guideline.
tionally been offered for SABA and/or ipratropium bromide
therapy. However, with the evidence of longer-term beneits There is some concern around the use of these agents in patients
conferred by the newer long-acting inhaler-delivered drugs, who may have an asthmatic component to their disease. This is
there has been a marked reduction in long-term nebuliser use. because the use of a LABA without an ICS increases the risk of
Very occasionally patients do seem to beneit from high-dose death in asthma (Spitzer et al., 1992). It is, therefore, imperative
nebuliser treatment, and motivated patients are generally loaned that a irm diagnosis of COPD is made when considering these
agents. The absence of eosinophilia may be helpful in identifying
a device to explore this aspect. Further consideration should be patients who are unlikely to require inhaled steroids, although the
given to the very time-consuming nature of regular nebulisation role of blood eosinophils has yet to be irmly established in clini-
cal practice. Evidence for the so-called ‘triple therapy’ (LABA-
on the patient’s social well-being and itness.  LAMA-ICS) is limited, and cost per quality-adjusted life-year
Combination long-acting β-agonist and long-acting musca- (QALY) is very high. 

rinic antagonist therapy. Numerous LABA-LAMA combina- Long-acting β2-adrenergic agonists and inhaled
tions have been introduced into the UK market. Available options corticosteroid therapy
are Anoro (umeclidinium/vilanterol), Spiolto (tiotropium/olo-
daterol), Duaklir (aclidinium/formoterol) and Ultibro Breezhaler Several preparations are now available on the UK market and
(glycopyrronium/indacaterol). SPARK was a 64-week, double- include Relvar Ellipta (vilanterol and luticasone furoate),
blind, randomised, parallel group study comparing glycopyr- Seretide Accuhaler and AirFluSal Forspiro (salmeterol and
luticasone propionate), Symbicort Turbohaler and DuoResp
ronium/indacaterol versus tiotropium versus glycopyrronium Spiromax (formoterol and budesonide), and Fostair (formoterol
and ultraine beclometasone). One of the pivotal trials was the
(Wedzicha et al., 2013). SPARK showed that the dual combina- TORCH study (Calverley et al., 2007), which compared sal-
tion decreased moderate to severe exacerbations compared with meterol to luticasone to salmeterol/luticasone and placebo.
both tiotropium and glycopyrronium alone. The LABA-LAMA The primary end point of reduced mortality was not reached,
combinations offer value for money in comparison to the sepa- despite a non-signiicant trend toward beneit. This was also
important as being the irst study to identify an increased risk
rate components and short-acting drugs, so it is reasonable to of pneumonia in patients using ICSs, whether as monotherapy

use a LABA-LAMA combination inhaler from the outset rather
than to use monotherapy and add in a different inhaler at a later

date. Thus, the availability of these LABA-LAMA combinations
along with recognition that an identiiable (non-eosinophilic)
majority do not beneit from inhaled steroids has effectively
462 made the previous complex NICE (2010) guidance on escalation

CHRONIC OBSTRUCTIVE PULMONARY DISEASE 26

or in combination with a LABA. At this time, trials had not Withdrawal of inhaled corticosteroids in patients
been designed to assess the risk of pneumonia, and where with chronic obstructive pulmonary disease
pneumonia was reported, there was variation in methods for
diagnosis and how it was distinguished from COPD exacerba- From the emerging literature (Magnussen et al., 2014), there is
tions. Patient demographics (e.g. smoking or vaccination sta- increasing conidence that there is overuse of ICSs in the COPD
tus, concurrent or previous use of oral corticosteroids) were patient population. It is far easier to change the therapy strategy
not recorded. It has now become clear that ICSs, alone or in in those patients newly diagnosed. How this is managed in the
combination with a LABA, can increase the number of seri- existing population is more challenging because of the evidence
ous pneumonias that require hospitalisation. Because patients suggesting bronchodilation rather than suppression of inlam-
receiving an ICS are no more likely to die overall compared mation is important in patients with a low eosinophil count. The
with controls, the clinical implication of these indings is yet recent WISDOM study by Magnussen et al. (2014) showed that
to be established (Kew and Seniukovich, 2014). There is also in a severe to very severe COPD population without a tendency
debate whether the increased risk of pneumonia is a class to exacerbate, gradual withdrawal of ICS did not increase exac-
effect or if a particular ICS is implicated. An increased risk of erbation rates or result in loss of symptom control. Although the
pneumonia with Relvar Ellipta of approximately double com- evidence is beginning to point toward ICS withdrawal in this phe-
pared with the LABA monotherapy arm (6% vs 3%) has been notype, the practicalities of how this should be undertaken are yet
identiied (Dransield et al., 2013). The trial was designed to to be determined, and there are many factors to be considered: for
example, how this would be communicated across the primary/
detect pneumonia as a primary end point and used radiographic secondary care interface; how the patient would be counselled
when being switched from one inhaler type to another; whether
techniques for diagnosis, which means that the diagnosis was the patient should be switched to a LABA-LAMA device and a
robustly established. More information was also available with monotherapy (off-license) ICS to gradually reduce the steroid.
regard to participants’ smoking status, pneumonia history and The WISDOM study does provide a basis on which withdrawal
body mass index (which is a risk factor for pneumonia). regimens can be based (Magnussen et al., 2014), but it should be
noted that the role of ICSs in these patients is currently very much
It is advised that the corticosteroid dose prescribed is the debated within the respiratory community. 
minimum to maintain symptom control and/or decrease exac-
erbations. A recent review by the European Medicines Agency Roflumilast
(EMA) Pharmacovigilance Risk Assessment Committee
(EMA, 2016) has concluded that ICSs in the treatment of Rolumilast is a PDE-4 inhibitor recommended by NICE (2017)
COPD do signiicantly increase the risk of pneumonia, but for use in patients with severe or very severe COPD with a
the beneits of using ICSs continue to outweigh the risks over- chronic bronchitic phenotype. These patients should have had
all. The committee also concludes that there is insuficient evi- two or more exacerbations in the last 12 months despite receiving
dence to distinguish between different ICSs with regard to risk treatment with triple inhaled therapy, that is, LABA/LAMA/ICS
of pneumonia. during that period. The evidence considered by NICE was based
on two clinical trials REACT (Martinez et al., 2015) and RE(2)
Triple therapy combination inhalers. Trimbow pMDI (ultra- SPOND (Martinez et al., 2016). The primary endpoints, rates of
ine beclometasone/formoterol/glycopyrronium) and Trelegy moderate or severe exacerbations, did not reach statistical signii-
(luticasone furoate/vilanterol/umeclidinium) have recently been cance versus placebo in the intention to treat analysis. However,
licensed for the management of COPD in patients who continue it did in a pre-deined sensitivity analysis using negative binomial
to experience symptoms despite treatment with ICS/LABA. regression and approval has been given by NICE (2017).

Two eficacy studies using Trimbow have been completed. The Rolumilast may have a role in those patients who are obese
TRILOGY study compared Trimbow to Fostair 100/6 over a 26 and of a chronic bronchitic phenotype. Currently rolumilast is
week period. This study identiied that Trimbow improved pre- considered to generally provide only a modest beneit in a small
and post-dose FEV1 compared to Fostair and also reduced the cohort of patients, rather than the whole population as recom-
annual rate of exacerbations by 23% as a secondary end point mended by NICE (2017). Moreover, not only is there small clini-
(Singh et al., 2016). The TRINITY study compared Fostair plus cal beneit, rolumilast is associated with signiicant side effects:
tiotropium to Trimbow over a 52 week study period. As expected, notably weight loss, diarrhoea and nausea. These would not be
Trimbow was superior to tiotropium alone for reduction in exac- appropriate in an already cachectic patient meeting the treat-
erbations and improvement in FEV1. Trimbow was shown to be
non-inferior (or equivalent) to the triple combination with regard ment criteria. In addition, more patients taking rolumilast with-
to exacerbations and FEV1 (Vestbo et al., 2017). In these studies drew in both trials due to adverse effects (Martinez et al., 2015,
pneumonia was seen in a small proportion of patients, similar to 2016). There is also an increased risk of psychiatric disorders in
other ICS studies. patients with or without a history of depression, including sui-
cidal ideation.
These combination inhalers may offer a simpliied regimen for
those patients that beneit from ICS, combined with a signiicant Controversy with the NICE (2017) guidance lies with the deini-
cost saving. It is important to recognise that existing patients on tion of triple therapy. To be eligible for rolumilast, a patient must
so-called triple therapy need a therapeutic review before switch- demonstrate that triple therapy is entirely clinically appropriate.

ing to a combination inhaler device to assess inhaler technique

and to review whether the ICS can be withdrawn safely from
therapy for that individual. 

463

26 THERAPEUTICS

There is a view that ICS is overused and that maximal broncho- exacerbation rates from 1.83 per patient-year in the placebo
dilation is suficient for symptom management and reduction in group to 1.48 per patient-year (Albert et al., 2011). However,
exacerbation rates for many patients. In addition, a patient has azithromycin has been associated with prolonged QT intervals
to have been adherent with the triple therapy for 12 months to and ventricular arrhythmias. Probably more importantly, there
be eligible. In the UK there are practical problems implement- is real concern regarding antibiotic resistance and the effect on
ing the guidance because of challenges associated with assessing
adherence to the triple therapy. This is coupled with dificulties in the microbial lora in the community. Unfortunately, azithro-
assessment of the number of exacerbations, particularly in those mycin appears to be particularly prone to causing transmissible
patients who have rescue packs at home. This, together with the
equivocal evidence and side effect proile for rolumilast reduces antibiotic resistance, even when compared to other macrolides.
the incentive for secondary care prescribers to adopt the NICE Whilst the routine use of prophylactic azithromycin is not rec-
(2017) guidance. There is also debate about when to stop rolu- ommended, it may be considered in very severe patients who
milast, if the patient still exacerbates. Currently NICE has not have a history of frequent exacerbations, whose medication
provided practical advice on this management aspect.  regimens have been fully optimised, who are not at risk of
ventricular arrhythmias and who have a normal QT interval on
electrocardiography. 

Theophylline and aminophylline Pharmacological management of exacerbations
of chronic obstructive pulmonary disease
Methylxanthines are weak bronchodilators with a narrow ther-
apeutic index. It appears that the beneits of these compounds Exacerbations of COPD are an acute deterioration beyond the
in COPD may involve other mechanisms, including increasing day-to-day variation in symptoms, often precipitated by viral or
respiratory drive and exercise tolerance as well as some steroid- bacterial infection. This can result in episodes of respiratory fail-
sparing and anti-inlammatory effects. These drugs are now being ure and may require admission to hospital, although patients can
superseded due to their relative lack of effect and poor tolerabil- often be safely managed at home, with appropriate support and
ity. If used, patients should be given a therapeutic trial of 6–8 self-management plans.
weeks to see if there is any clinical beneit. Treatment should be
discontinued if there is no improvement in breathlessness or lung Bronchodilators
function testing.
These are used to treat the acute wheeze and breathlessness.
Care must be taken to ensure theophylline levels are measured, After acute admission, hand-held inhalers plus spacer device is
particularly if the patient is prescribed interacting medications recommended where possible, but in practice, it is more prag-
such as ciproloxacin or clarithromycin. Other comorbidities that matic from a nursing workload perspective to administer bron-
can also affect the clearance of theophylline include heart failure chodilators via a nebuliser at least for the irst day. Salbutamol
and smoking.  2.5 mg four times daily is usually adequate with the addition
of ipratropium 500 micrograms four times daily as an adjunct.
Mucolytics Doses above 1 mg of salbutamol confer small additional beneits
and increase cost and side effects. It is usually preferable to use
Carbocysteine, the most commonly prescribed mucolytic, pro- a mouthpiece for delivery of nebules where possible to decrease
vides some symptomatic beneit in those patients with a pro- adverse effects and to improve lung deposition. This is particu-
ductive cough. Upon initiation, the carbocysteine should be larly important with the use of ipratropium in patients with glau-
trialled for 6–8 weeks and then assessed for clinical improve- coma. LAMAs and LABA-LAMAs should be suspended whilst
ment (e.g. reduction in cough frequency and/or sputum pro- on nebuliser therapy. 
duction). If there is no perceived beneit, then the mucolytic
should be stopped. A systematic review has shown that patients Antibiotics
who take mucolytics are less likely to exacerbate (Poole et al.,
2015). The beneit appears to be greatest in those patients who Acute infective exacerbations may be bacterial or viral in origin.
exacerbate frequently and/or who have prolonged exacerba- If the exacerbation is bacterial in origin, suggested by purulent
tions. There is little evidence to support the initiation of muco- sputum, then antibiotics should be prescribed. Common bacteria
lytics in the acute phase.  include Streptococcus pneumoniae, Haemophilus inluenzae and
Moraxella catarrhalis. First-line antibiotics include amoxicil-
Prophylactic antibiotics lin, doxycycline and clarithromycin, but local antibiotic policy
should be followed. Antibiotic therapy is not indicated if sputum
Currently, prophylactic antibiotic therapy with azithromycin is is non-purulent (or similar in colour to normal) unless there is
not currently recommended in the GOLD (2017) guidance unless other evidence or infection, such as infective consolidation, high
the patient is a former smoker with recurrent exacerbations fever or acute-phase response (i.e. a markedly raised C-reactive
despite optimal pharmacological therapy. Macrolide antibiot- protein [CRP] or erythrocyte sedimentation rate [ESR]). Patients
ics appear to have immunomodulatory and anti-inlammatory admitted to hospital should have sputum sent for culture and
effects. One study has shown that azithromycin in a dose of sensitivity to optimise therapy. Usually a 5- to 7-day course is
250 mg daily (in addition to usual COPD medication) reduced
464

CHRONIC OBSTRUCTIVE PULMONARY DISEASE 26

Table 26.4 Comparison of type 1 and type 2 respiratory failure

PaO2 level Type 1 respiratory failure Type 2 respiratory failure
PaCO2 level Low Low
Pathophysiological cause
Low or normal Raised

Impaired gas exchange (ventilation/perfusion Hypoventilation (may also be impaired gas
mismatch) exchange)

Common associated diseases ‘Pink-puffer’ variant of COPD ‘Blue-bloater’ variant of COPD
Pneumonia Morbid obesity
Pulmonary embolism Neuromuscular diseases including respiratory
Asthma (unless moribund) muscle weakness, kyphoscoliosis

Treatment Whatever concentration of oxygen needed (FiO2) Controlled oxygen to achieve SaO2 88–92%

to achieve SaO2 of 94–98% If PaCO2 climbs, causing pH to fall below 7.35,

Treatment of the underlying cause consideration of non-invasive ventilation

COPD, Chronic obstructive pulmonary disease; FiO2, fraction of inspired oxygen; PaCO2, arterial carbon dioxide tension; PaO2, arterial oxygen tension; SaO2,
percentage of oxygen saturation of arterial blood.

effective. It is prudent to monitor sputum volume and colour and Physiotherapy
temperature to ensure resolution of infection prior to discontinu-
ing antibiotics. If the exacerbation follows inluenza, then there When bronchiectasis complicates COPD, physiotherapy instruc-
is a risk of Staphylococcal aureus infection, when an agent with tion on daily sputum clearance exercise is the mainstay of control,
anti-staphylococcal properties should be used (e.g. lucloxacillin along with antibiotics for infective exacerbations. Otherwise, the
or co-amoxiclav).  input of the physiotherapist is generally limited to pulmonary
rehabilitation, which is now widely available. 
Corticosteroids
Management of acute respiratory failure in 465
GOLD (2017) recommends a course of prednisolone 30 mg for chronic obstructive pulmonary disease
5–7 days only. There is evidence to suggest that a shorter course
of steroids does not increase the risk of relapse and minimises The type of respiratory failure is important in the management
risk to the patient. Many clinicians favour the use of a 5-day of the acute exacerbation: patients with type 1 respiratory failure
course (Leuppi et al., 2013). ICSs are usually continued during (that is, a low oxygen level without an increased carbon dioxide
this phase. Increasingly, an absence of eosinophilia is used to level) are not at risk of developing elevated carbon dioxide lev-
identify patients who may not beneit, but this is not presently els when receiving supplemental oxygen therapy and can safely
supported by guidelines.  be treated with whatever oxygen concentration is required to
achieve normal oxygen saturation (94–98%). In contrast, patients
Aminophylline with type 2 respiratory failure (when the carbon dioxide level
is increased) can develop severe carbon dioxide retention with
On occasion, intravenous aminophylline may be used if there attendant narcosis, especially if treated with injudicious concen-
is an inadequate response to bronchodilators. If the patient is trations of oxygen; a target of 88–92% is suficient. These two
already on a theophylline compound, then the loading dose is forms of respiratory failure are compared in Table 26.4.
not required. If the patient is unsure if he or she is on a theophyl-
line and that information is not available, then it is best to omit Some patients live with undiagnosed type 2 respiratory failure,
the loading dose and give the maintenance dose only. Smoking and its longstanding nature can be identiied when the pH is nor-
status should be established because smoking increases the mal. The respiratory acidosis is fully compensated by a metabolic
metabolism of theophylline. Once smoking stops, then continu- alkalosis, relected by a high standard bicarbonate level observed
ing a patient on his or her usual theophylline dose will likely on arterial blood gas analysis.
result in toxicity. 
When patients present acutely with a respiratory acidosis (i.e.
Thromboprophylaxis the pH is less than 7.35 despite appropriate oxygen and bronchodi-
lator therapy), the introduction of non-invasive ventilation (NIV)
All acutely unwell medical patients admitted to hospital should can be life-saving and may obviate invasive positive pressure ven-
receive a prophylactic dose of low-molecular-weight heparin if
there is no known contraindication.  tilation (IPPV). It is important that a ceiling of escalation of treat-
ment is established in the acute setting because severely disabled

patients are unlikely to survive or beneit from IPPV and indeed
would often decline this when its implications are explained.

26 THERAPEUTICS

Doxapram, a respiratory stimulant, has largely been superseded signiicant inluencing factor is the habit of putting a cigarette
by NIV and is no longer recommended as a routine treatment. to the lips, and the use of some of the products that mimic this
Doxapram must be infused at a rate of 1.5–4 mg/min in those action can also be helpful, especially in social situations. NRT
patients where NIV is contraindicated and in patients with hyper- does not completely eliminate the effects of withdrawal because
capnic respiratory failure who are comatosed. It can sometimes none of the available products can accurately reproduce the rapid
enable the patient to become more rousable and more able to and high levels of nicotine obtained from cigarettes.
cooperate with therapy. Clinicians should be aware that doxapram
can also be harmful in respiratory failure because it stimulates There is no clear evidence that one formulation is more effective
both respiratory and nonrespiratory muscles. As a consequence it than another, and the effectiveness of any of these products will lie
must only be used under expert medical advice and in a suitably with the individual and his or her trigger points and habits. Choices
supervised clinical area to minimise risk. Overall, the recommen- are inluenced by the number of cigarettes smoked, personal pref-
dation is to avoid doxapram due to its very limited beneits.  erence/previous/experience and tolerance of side effects. Another
factor to consider, although unlikely with a diagnosis of COPD, is
Patient care if the patient is pregnant. Patches should be avoided where pos-
sible due to the continuous level of nicotine in the plasma. As with
Pulmonary rehabilitation any pharmacological therapy, the beneits should always outweigh
the risks, and the use of nicotine patches is not contraindicated in
The most effective treatment for improving quality of life and pregnancy if the patient is able to maintain her smoke-free status
ameliorating breathlessness is pulmonary rehabilitation. It is as a result of using the product. For information on formulations
composed of multiple interventions, not just exercise training. available and their usage/side effects, please see Table 26.5. 
Thus, subjects receive education on self-management, nutrition,
home exercise and medication use. Programmes typically run Bupropion
from 6–8 weeks, usually with two visits per week. Pharmacists
are well placed to contribute to this programme of education Bupropion (amfebutamone hydrochloride) is licensed for smok-
regarding pharmacological management, including introducing ing cessation and works by inhibiting uptake of noradrenaline
the concept of medicines in the palliation of symptoms.  and dopamine within the neuronal synapses. This reduces the
withdrawal symptoms by increasing synaptic dopamine levels.
Vaccination Treatment is started 2 weeks prior to the quit date, and cigarettes
should be stopped in the second week of treatment. If abstinence
Whilst pneumococcal and inluenza vaccinations are not 100% is not achieved or maintained by week 7 of treatment, it should
effective, all patients diagnosed with COPD should be offered be discontinued. Bupropion is contraindicated in epilepsy, acute
them. Inluenza vaccination is annual, and a single pneumococcal alcohol or benzodiazepine withdrawal, bipolar disorder, cen-
inoculation is advised unless there is another reason to be vacci- tral nervous system (CNS) tumour, eating disorders and hepatic
nated more frequently (e.g. nephrotic syndrome). Patients should cirrhosis. The main side effects include agitation, anxiety, dry
be reassured that the inluenza vaccine is inactive and that they mouth, allergic reactions and insomnia. 
are not able to contract the illness from the vaccination itself. 
Varenicline
Stopping smoking
Varenicline is a selective nicotine receptor partial agonist at the
The effects of smoking on health are well known and well pub- a4b2 acetylcholine receptor. It alleviates the craving and with-
licised. As described previously, stopping smoking is the most drawal whilst reducing the rewarding and reinforcing effects of
important intervention patients can achieve no matter their age or smoking by preventing binding of nicotine to a4b2 receptors if a
how advanced their lung disease is. There are a number of thera- cigarette is smoked. A recent trial, EAGLES, compared vareni-
peutic options to aid a quit attempt. cline with bupropion, NRT patches and placebo. The trial showed
that at weeks 12 and 24, varenicline provided superior abstinence
Nicotine replacement therapy rates in both psychiatric and nonpsychiatric patients (Anthenelli
et al., 2016). Varenicline is usually started 1–2 weeks before quit-
Nicotine replacement therapy (NRT) can be used to aid abrupt ting smoking and comprises a 12-week course. Medicines and
smoking cessation (e.g. whilst on a ward as an in-patient) or, Healthcare Products Regulatory Agency (MHRA)/Commission
alternatively, to reduce the number of cigarettes smoked in the on Human Medicines (CHM) advice states that varenicline may
lead-up to a speciied quit date. be associated with increased risk of suicide, and patients should
be counselled to discontinue treatment if they develop agitation,
There are many different formulations available that can be depression or suicidal thoughts. Any patient with a history of psy-
prescribed. Many of these are now licensed to be used in combi- chiatric illness should be monitored closely. 
nation with other NRT products with or without smoking and also
in pregnancy. These are shown in Table 26.5. Electronic cigarettes

The mode of action is directly on nicotine receptors in the The use of electronic cigarettes has also received attention,
brain, which release dopamine. This has the effect of reduc- with controversy over effectiveness and regulation. Initially, the
466 ing the nicotine withdrawal symptoms (e.g. agitation). Another

CHRONIC OBSTRUCTIVE PULMONARY DISEASE 26

Table 26.5 Comparison of nicotine replacement products

Formulation Use and comments Specific side-effects

Patch Apply on waking to dry, clean and non-hairy skin on the hip, trunk or upper arm Local skin irritation and
24 h: 7, 14, 21 mg and held in position for 10–20 s. Remove the 16-h patch prior to bed. Place rash, insomnia. Do not
16 h: 5, 10, 15, 25 mg next patch on a different area and avoid using the same site for several days. use on broken skin or
Licensed for use over 12 years of age. Patch therapy can be useful in in patients with skin
pregnancy if patient vomiting, otherwise intermittent therapy is preferable. disorders.

Chewing gum: Chew one piece of gum when urge to smoke occurs or to prevent cravings. No Gum may stick to den-
2, 4 mg more than 15 pieces of 4 mg gum should be used in one day. The gum should tures. Jaw ache, headache
be chewed until the taste becomes strong then should be rested between gum and mild burning in mouth
and cheek until taste has faded. The gum should then be chewed again. Repeat and throat may occur.
for 30 min or until taste dissipates. Avoid acidic drinks (e.g. coffee, fruit juice) for
15 min before and during treatment.

Sublingual tablets: Place tablet under the tongue and allow to dissolve. Acidic drinks should be Gastritis, oesophagitis
2 mg avoided for 15 min before and during treatment. Maximum 40 tablets and peptic ulcers can be
per day. aggravated by swallowing
nicotine

Inhalator: Inhale as required up to 5 min per session. Helps to satisfy the hand-to-mouth Caution with asthmatics
10, 15 mg cartridge habit. The nicotine is absorbed through the oral mucosa rather than the lungs. because can cause bron-
No more than 12 cartridges of the 10 mg strength or 6 cartridges of the 15 mg chospasm. Nasal irritation,
strength per day. A 10 mg cartridge lasts approximately 20 min of intense use; a rhinorrhea, sneezing,
15 mg cartridge lasts approximately 40 min of intense use. throat irritation and cough
may occur.

Lozenges: One lozenge every 1–2 h as required. Slowly allow the lozenge to dissolve in the Gastritis, oesophagitis
1, 1.5, 2, 4 mg mouth; periodically move the lozenge from one side of the mouth to the other. and peptic ulcers can be
Lozenges last 10–30 min depending on their size. Maximum of 15 lozenges per aggravated by swallowing
day. Patients who smoke less than 20 cigarettes per day should use the lower- nicotine. Nasal irritation,
strength lozenges; patients who smoke more than 20 cigarettes per day or who rhinorrhea, sneezing,
have failed to quit on the low-strength should use the high-strength lozenge. throat irritation and cough
Avoid acidic drinks for 15 min before and during treatment. may occur.

Oromucosal spray: One to two sprays when cravings occur, do not exceed 2 sprays per episode. Gastritis, oesophagitis
500 micrograms and 1 mg Maximum 64 sprays per day. Avoid acidic drinks for 15 min before and during and peptic ulcers can be
per actuation treatment. Spray should be released into the mouth by holding the spray as aggravated by swallowing
close to the mouth as possible and avoiding the lips. Do not inhale while spray- nicotine.
ing and avoid swallowing for a few seconds after use.

Intranasal spray One spray as required; can spray into each nostril when craving occurs. Maxi- Caution in asthma,
mum 64 sprays per day. More rapidly absorbed than other forms of nicotine nasal/sinus conditions or
replacement therapy. allergies.

Orodispersible film: Suitable for smokers who have their first cigarette of the day more than 30 min Gastritis, oesophagitis
2.5 mg after waking up. Place one film on the tongue. Close the mouth and press the and peptic ulcers can be
tongue gently to the roof of the mouth until the nicotine film dissolves (approxi- aggravated by swallowing
mately 3 min). The film should not be chewed or swallowed whole. Users should nicotine.
not eat or drink while a nicotine film is in the mouth.

Information taken from British National Formulary (2017).

stance from the professional bodies such as the MHRA was that with no evidence that they encourage children or nonsmokers 467
electronic cigarettes could not be recommended due to the varia- to start smoking tobacco. However, there is no long-term infor-
mation about the solvents used in the process of ‘vaping’ and
tion in product quality, although anecdotal reports do suggest
that these are effective in helping to support a quit programme. the long-term clinical impact that this may have on the patient.
Subsequently, there have been several papers published that There are also very real concerns around the risk of ire if the
appear to endorse the use of e-cigarettes (Public Health England, electronic cigarette is left charging, particularly with a noncom-
2015a). Public Health England (2015b) issued a press release that patible charger from a different brand. The use of an electronic
concluded that e-cigarettes are 95% less harmful than tobacco cigarette is not considered safe in patients on long-term oxygen

26 THERAPEUTICS

therapy (LTOT), and so electronic cigarettes are not permitted on exacerbations, measured by pulse oximetry, of 88–92% in such
hospital premises or in any area that may be oxygen enriched, for patients, whereas those with normal or low carbon dioxide levels
example, in the home of a patient with LTOT in place.  should have a normal target of 94–98%.

Effect of smoking on concomitant medications Acute episodes of type 2 respiratory failure may occur, with
development of a respiratory acidosis as acute elevations of car-
When smoking is discontinued, this can have signiicant impact bon dioxide overtake the relatively slow process of compensation
on how concomitant medications are metabolised. Areas of high by renal metabolic alkalosis. Oxygen and drug therapy alone are
risk include the previously common respiratory medication the- often insuficient; indeed, even low low rates of oxygen may
ophylline. Theophylline is a narrow-therapeutic-index medication make acidosis worse. It has been shown that non-invasive ven-
that interacts with antibiotics such as clarithromycin and cipro- tilation can be life-saving and can avoid the need for invasive
loxacin, causing the theophylline levels to signiicantly increase. ventilation in the relatively small proportion of patients who are
It is imperative that an accurate smoking history is taken for otherwise it enough to be eligible. It is recommended when the
patients prescribed theophylline because smoking increases its pH is less than 7.35. During the irst 48 hours of therapy, the
metabolism. Admission to hospital for an exacerbation of COPD patient is encouraged to adhere to the therapy for as long as pos-
means the patient is no longer able to smoke whilst an in-patient; sible to maximise the effectiveness of the intervention.
therefore, theophylline metabolism is reduced, and the theophyl-
line levels will become raised. Tachycardia and tremor are often Some patients are prone to recurrent severe episodes of type 2
attributed to salbutamol nebuliser therapy, but these should be respiratory failure despite long-term oxygen therapy. They often
recognised as a potential sign of likely theophylline toxicity. have severe nocturnal hypoventilation and sleep poorly. Such
For patients who smoke, theophylline levels should be taken on patients may beneit from long-term domiciliary non-invasive
admission to hospital and the doses reduced as appropriate.  ventilation as well as LTOT. 

Oxygen therapy Antidepressants

Large studies in the USA and Britain performed in the 1970s It is widely recognised that depression is prevalent within the COPD
showed an important improvement in prognosis when LTOT is population. It is also recognised that it is underdiagnosed, as it is
used for substantial proportions of the day in patients with stable in many chronic medical conditions. The selection of antidepres-
hypoxaemia (Cooper et al., 1987; Medical Research Council sant should be made according to comorbidities, side-effect proile,
Working Party, 1981; Nocturnal Oxygen Therapy Trial Group, interaction proile and patient choice. For example, for a cachectic
1980). The accepted criteria are as follows: patients with stable patient, mirtazapine may be preferable because it can cause appe-
COPD and a resting PaO2 ≤7.3 kPa or patients with stable COPD tite stimulation. Likewise, if insomnia is a problem, then tricyclic
with a resting PaO2 ≤8 kPa plus evidence of peripheral oedema, antidepressants, trazodone or mirtazapine are good choices. For
polycythaemia or pulmonary hypertension (British Thoracic patients with a cardiac history, sertraline is the safest option. 
Society [BTS], 2015). Oxygen is delivered via an oxygen con-
centrator, which is usually piped to the living room and bedroom Palliative care
so that the patient can use oxygen for at least 15 hours/day at a
low rate suficient to raise PaO2 above 8 kPa. Palliative care is deined by the World Health Organization
(WHO, 2015) as follows:
Outside this setting, oxygen is usually unhelpful: there is no
evidence that short-burst oxygen therapy improves breathless- an approach that improves the quality of life of patients and their
ness, despite its powerful placebo effect. Occasionally patients families facing the problem associated with life-threatening illness,
are suficiently motivated and beneit from portable oxygen to through the prevention and relief of suffering by means of early
enable increased exercise capacity, but these are exceptions. identiication and impeccable assessment and treatment of pain
and other problems, physical, psychosocial and spiritual.
Patients with the typical ‘pink-pufing’ form of COPD tend to
maintain normal blood gases until very late in the disease and Palliative care for COPD patients should start at the point of
so rarely meet the criteria for LTOT. Neither are they at risk of diagnosis: it is a progressive disease, and most patients con-
adverse effects from high concentrations of oxygen. In contrast, tinue to deteriorate despite maximising pharmacological and
the ‘blue-bloating’ patients develop type 2 respiratory failure, non-pharmacological treatments. COPD contributes to the
meaning that that they develop elevated carbon dioxide levels increasing population of patients diagnosed with life-limiting
and accommodate to surprisingly low oxygen levels. This group illnesses not related to malignancy. Any patient deemed to be
is the one that tends to beneit from LTOT. They are also, how- in the last year of life is entitled to be managed symptomati-
ever, susceptible to developing acute rises in carbon dioxide cally through the palliative route, but resources are currently
levels in response to acute exacerbations, especially when high limited for these patients. Often the most debilitating symptoms
concentrations of oxygen are administered. This life-threatening are breathlessness, depression and anxiety. It is seen as best
complication can cause initial headache and drowsiness, lead- practice to discuss preferred place of care, resuscitation status
ing on to coma and ultimately respiratory arrest. As a result, and the patient wishes as they approach the last year of life. For
the BTS (2008) emergency oxygen guidelines recommend rela- example, the patient’s wish to have antibiotics and/or invasive
468 tively low target oxygen saturation in the management of acute

CHRONIC OBSTRUCTIVE PULMONARY DISEASE 26

and non-invasive ventilation in the event of a future severe reported anecdotally that they are effective, and there is a trend
exacerbation should be determined.
towards beneit (Simon et al., 2010). Opioids would be irst line,
Management of breathlessness but benzodiazepines are used particularly in patients who suf-
fer with panic/anxiety during an acute episode of breathlessness.
Breathlessness is the primary symptom in the patient with COPD, Lorazepam is widely used, 0.5 mg when required up to a maxi-
reported in 90–95% of the COPD population. Breathlessness is mum of 4 mg daily in divided doses. 
not always related to exertion and correlates poorly with lung
function. Other causes of breathlessness also frequently coexist. Case studies
Heart failure, angina and dysfunctional breathing/panic should be
diagnosed and treated appropriately. Unfortunately, the dyspnoea Case 26.1
of COPD can be refractory to conventional treatment in up to
50% of patients. Mr B is a 67-year-old retired miner who presents to hospital as an
emergency with acute shortness of breath and a cough produc-
Non-pharmacological methods are outlined as follows: tive of green sputum. Mr B has a past medical history of COPD
• addressing fear and anxiety through education and psycho- and had a myocardial infarction 10 years ago. He smokes 35 ciga-
rettes per day and has done so for the last 45 years. Spirometry
logical support; has shown that his FEV1 is 58% of predicted. He weighs 45 kg.
• use of a hand-held fan, or sitting near an open window, to When he is well his CAT score is 8. There are no known drug
allergies.
stimulate the second and third trigeminal nerves, which
reduces the sensation of breathlessness; Mr B’s regular medication is:
• activity-pacing advice; • aspirin 75 mg daily,
• breathing exercises (e.g. pursed-lip breathing); • bisoprolol 10 mg daily,
• complementary therapies (e.g. acupuncture, hypnosis, massage). • simvastatin 20 mg at night,
Opioids are the mainstay of treatment for breathlessness. The • salmeterol 25 microgram pressurised metered dose inhaler
evidence base for the management of dyspnoea is not as estab-
lished as for pain management, but patients do derive beneit. A (pMDI) two puffs twice daily.
Cochrane review has concluded that opioids can reduce dyspnoea On examination:
irrespective of route of administration (Jennings et al., 2002). The • blood pressure (BP) 130/75 mmHg,
mechanism is believed to be a central action on the respiratory • temperature 38.6 °C,
control centre: it is well known that in higher doses opioids can • pulse 98 bpm,
reduce minute ventilation. They can reduce the perception of • respiratory rate 28 breaths/min.
breathlessness in the same way as the perception of pain. It seems Investigations:
paradoxical to be giving a medication known to depress respira- • white blood cell count 20.8 × 109 L,
tory drive to a patient with an already-compromised respiratory • creatinine 140 mmol/L – his baseline was 93 mmol/L 3 months
function, but it is understood that the response to chronic hypoxia ago,
results in an abnormal perception of the symptom of breathless- • Hb – normal,
ness. This practice is also regarded as safe. No reports of respira- • oxygen saturation 84% on 28% oxygen via Venturi mask,
tory depression were found in a study of the use of opioids for • chest X-ray – no consolidation seen.
relief of dyspnoea in heart failure (Oxberry et al., 2011). To initi- Arterial blood gases on 28% oxygen:
ate opioids, the irst-line choice is morphine sulfate. Often, very
small doses are effective (e.g. 1.25–2.5 mg at night) initially, but pH 7.30 (7.35–7.45)
it is also entirely appropriate to follow the NICE (2012) guidance 7.26 kPa (10–13 kPa)
for the management of pain (i.e. 2.5–5 mg every 4–6 hours or pO2 8.3 kPa (4.7–6.0 kPa)
morphine sulfate MR 10 mg twice a day with 2.5 mg as required). pCO2 24 mmol/L (22–26 mmol/L)
There is no upper limit for dosing, provided relief is obtained HCO3
and there are no signs of opiate toxicity, such as myoclonus, pin-
point pupils or respiratory depression. As with the initiation of Questions
any medication, it is very important that the patient understands
the reason for prescribing opiates and that any misperceptions are 1. What is the diagnosis, and how was this determined?
explored. Patient should also be advised that drowsiness, espe- 2. What do the arterial blood gases show, and how would you sug-
cially when these drugs have recently been started, may affect
itness to drive; however, there is no restriction on driving in the gest this is managed?
UK (Department for Transport, 2013). 3. What would you expect to see on Mr B’s prescription chart for

Benzodiazepines acute management of his condition?
Mr B shows no clinical improvement and appears to be tiring.
There is a paucity of evidence to support the use of benzodi-
azepines for management of breathlessness, but it has been He is transferred to the intensive care unit (ICU) in case ventilation
(invasive or non-invasive) may be needed. In the ICU, the intensiv-
ists wish to increase his medical treatment.
4. What options are there?
5. How should aminophylline be administered?
6. What treatment options would you recommend for Mr B once he
has recovered from his acute illness?
7. Are there any other medications that require optimisation? 

469

26 THERAPEUTICS

Answers is running through. The infusion should then immediately be
restarted. It is not necessary to wait for the result before restart-
1. Mr B has an infective exacerbation of COPD. The patient has ing the infusion.
a cough productive of green sputum and elevated tempera- • The rate should be adjusted according to level obtained.
ture and white blood cell count. He is also tachypnoeic and 6. Because Mr B has exacerbated, he would benefit from a full medi-
has deranged arterial blood gases. Other potential diagnoses cation review. Mr B has continued to be symptomatic despite
include anaemia, which has been excluded because his hae- demonstrated adherence to his salmeterol therapy. GOLD (2017)
moglobin level is normal, community-acquired pneumonia and guidelines suggest that a LAMA should be added to his current
acute heart failure, which have also been excluded because the prescription. Mr B would fall in GOLD group C because he has
chest X-ray is currently clear. The patient has also developed an had an exacerbation requiring hospital admission and his CAT
acute kidney injury, which should be considered when prescrib- score is less than 10 when he is feeling well. Alternatively, once
ing any new medications. inhaler technique has been assessed and recorded, a LABA-LAMA
combination could be prescribed to maintain cost-effectiveness,
2. The low PaO2 indicates significant hypoxia. The reduced pH and for example, Anoro, Spiolto, Duaklir or Ultibro. Mr B’s salmeterol
raised carbon dioxide constitute a respiratory acidosis and indi- should be discontinued, and this should be communicated to him
cate hypoventilation. The normal bicarbonate indicates there has and his primary care doctor.
not yet been any metabolic compensation and that the condition Whilst Mr B is an in-patient, it would be a good opportunity to
has deteriorated in the last 1–2 days. offer him smoking cessation advice and pharmacological interven-
The acidosis indicates a need for non-invasive ventilation. tion to support his quit attempt. He should also be referred into
Administering higher concentrations of oxygen alone will exacer- the pulmonary rehabilitation service and be seen by a dietician, as
bate carbon dioxide retention and may precipitate narcosis. His he is underweight at 45 kg.
arterial blood gases should be checked every 30–60 minutes after Mr B should be offered a routine pneumococcal and annual flu vac-
any change in oxygen therapy, and the carbon dioxide levels should cination and be given a self-management plan with reserve anti-
be closely monitored. If there is any increase in the carbon dioxide biotics and steroids with clear instruction on when to start these.
concentration, then this may indicate a clinical deterioration. Finally, at least 12 hours prior to discharge, he should be weaned
from the oxygen and nebulisers and converted back to regular
3. In the acute phase, the aim of treatment is to optimise oxygen inhalers.
levels, bronchodilate to improve symptoms and treat any underly- 7. Mr B suffered a myocardial infarction 10 years ago. His medica-
ing infection. Other interventions include thromboprophylaxis at tion could be reviewed. His simvastatin should be increased to a
appropriate doses and frequencies according to local policy. minimum of 40 mg at night. β-Blockers are not contra-indicated in
The prescription should therefore include oxygen at a flow rate to COPD, and indeed, there is evidence to suggest that β-blockers
maintain oxygen saturation between 88% and 92%. A salbutamol may decrease mortality in patients with this condition, so this med-
nebuliser 2.5 mg four times daily (or 10 puffs of salbutamol 100 icine should be continued. Addition of an angiotensin-converting
micrograms/actuation via a spacer device four times daily) plus enzyme (ACE) inhibitor should be considered once the acute kid-
ipratropium 500 micrograms nebuliser four times daily will provide ney injury has resolved. 
bronchodilation. An appropriate antibiotic such as amoxicillin or
doxycycline should be prescribed for a total of 5–7 days (or as per Case 26.2
local policy) given the green sputum and 30 mg oral prednisolone
for a total of 5 days. There is no benefit in giving i.v. hydrocorti- Ms M is a 54-year-old woman who presents to hospital as an
sone if the patient is able to swallow; therefore, oral steroids will emergency, with shortness of breath and coughing up green
suffice. sputum. She has a history of COPD and an FEV1 of 44% of pre-
dicted. She smokes 50 cigarettes per day and has done so for
4. The dose of nebulised salbutamol can be increased, but the the past 34 years. She normally finds it difficult to get herself
main limitation is the side effects, including tremor, tachycardia dressed in the morning without becoming breathless. She is
and hypokalaemia. Ordinarily, if there has been an inadequate allergic to penicillin, which causes her tongue to swell. She has
response to bronchodilators, then intravenous aminophylline may had antibiotics and steroids from her primary care doctor 5 times
be considered. in the past 8 months.

5. Aminophylline is available in 250 mg/10 mL vials. The loading Her usual medication is:
dose required is 5 mg/kg (i.e. 225 mg in his case). To make the • Anoro Ellipta 55/22 micrograms one puff daily, started 6
dose practical for administration it should be rounded to the near-
est millilitre. In this case, either 250 mg (10 mL) or 200 mg (9 mL) months ago;
should be added to a 50 to 100 mL bag of either sodium chlo- • salbutamol 100 micrograms pMDI two puffs when required
ride 0.9% or glucose 5% and given over 20 minutes. Immediately
after giving the loading dose, the maintenance infusion must be (has been using this every 2 hours in the past 2 days);
started. • Uniphyllin 600 mg twice daily.
• To calculate the maintenance dose = 500 microgram/kg/h.
Convert to milligrams first so that everything is in the same The doctor diagnoses Ms M with an infective exacerbation of
units (i.e. 0.5 mg/kg/h). Dose to be given is therefore 22.5 COPD and prescribes:
mg/h. • oxygen – target saturation 88–92%;
• Check if the is patient fluid restricted because this may dictate • dalteparin 5000 units daily;
which fluid volume to use. In Mr B’s case there is no evidence • doxycycline 200 mg as a single stat dose followed by 100 mg
that fluid restriction is required. Add 500 mg of aminophylline daily, total course 5 days;
to a 500 mL bag of compatible i.v. fluid. This gives a 1 mg/mL • salbutamol nebules 5 mg four times daily;
solution, which should be infused at 22.5 mL/h through an infu- • ipratropium 500 micrograms four times daily;
sion pump. • Anoro Ellipta 55 micrograms/22 micrograms one puff daily;
• To check aminophylline levels, the infusion should be stopped • Uniphyllin 600 mg twice daily;
after 4–6 hours. After waiting 20 minutes a blood sample can • Prednisolone 30 mg daily for 5 days.
be taken from a cannula different from the one the infusion

470

CHRONIC OBSTRUCTIVE PULMONARY DISEASE 26

Questions can be considered if severe tachycardia persists. Monitor theophyl-
line levels every 2 to 4 hours to ensure they are falling. Activated
1. What is Ms M’s MRC dyspnoea score? charcoal is not usually indicated if theophylline levels are less than
2. What monitoring parameters would need to be measured, and 40 mg/L, but treatment of theophylline toxicity should be consid-
ered if symptoms do not resolve rapidly. Toxbase (www.toxbase.org)
why? should be accessed for more detailed information.
Ms M is admitted to a respiratory ward and appears to be Ondansetron is an alternative antiemetic should cyclizine be
ineffective; therefore, 8 mg when required should be prescribed
doing well. On day 2, she starts to vomit, and the medical team proactively.
prescribes i.v. cyclizine 50 mg three times daily to try to control 4. Smoking cessation should be discussed with Ms M. She should
this. Her BP has dropped to 90/52 mmHg, and her pulse is ele- be offered advice on support available and the pharmacological
vated at 135 bpm. She is tremulous, and her respiratory rate has therapies that may aid her quit attempt. She should be referred
increased to 40 breaths/min. to the smoking cessation team. If Ms M decides to quit, then the
3. What is the cause of Ms M’s vomiting, how can this be managed theophylline dose will need to be adjusted. Initially the theoph-
and why has this occurred? ylline dose should be halved to 300 mg twice daily and a level
taken within a week, 4–6 hours post-dose. Ms M should also be
Potassium levels come back as 3.0 mmol/L with no electro- offered pulmonary rehabilitation. She has also had five courses of
cardiogram (ECG) changes other than sinus tachycardia. After oral prednisolone in the last 8 months, which increases the risk
giving Ms M a bolus of 250 mL sodium chloride 0.9%, her for osteoporosis. Osteoporosis prophylaxis should therefore be
BP improves to 110/60 mmHg. The medical team prescribes considered. For a patient of 54 years of age, a bone scan would
40 mmol/L potassium in 1 litre sodium chloride 0.9% over usually need to be arranged. Ms M is already on Anoro, but due to
4 hours via an infusion pump with a plan to recheck potassium her exacerbation history, she may benefit from ICS/LABA, particu-
at the end of this period. All other electrolytes are within the larly if her blood eosinophil levels are elevated. This would mean
normal range. The theophylline level comes back as 30 mg/L switching Anoro to a different inhaler. If her inhaler technique is
(range 10–20 mg/L). The plan is to continue to monitor Ms M good with the Ellipta device, then a suitable ICS/LABA would be
on the cardiac monitor for 24 hours, repeat electrolytes and Relvar 92 micrograms/22 micrograms one puff daily plus Incruse
blood glucose every 6 hours and give i.v. potassium as and 55 micrograms one puff daily. Ms M would need to understand
when required. that the Anoro has been discontinued. Ms M should be provided
4. What pharmaceutical care planning should be made prior to Ms with a self-management plan together with reserve steroids and
M’s discharge?  antibiotics. Her vaccinations should also be checked to ensure
they are up to date. 
Answers
Case 26.3
1. 5, breathless whilst getting washed/dressed
2. Temperature, blood pressure, respiratory rate, pulse and arterial Mrs K is a well-known COPD patient who has had very frequent 471
admissions to hospital due to the symptoms related to end-stage
blood gases should be monitored to indicate if Ms M is clinically COPD. She has no family support at home and is severely dis-
improving or deteriorating. WCC should be measured to monitor abled by breathlessness. She is on LTOT and complies with the
improvement in infection in conjunction with the basic observa- 15 h/day prescription. She is an ex-smoker. Mrs K is cachectic
tions outlined previously. The pulse rate and potassium level are and extremely anxious, especially when she is acutely unwell and
important because the patient is receiving salbutamol, prednis- more breathless than usual. She finds it hard to sleep at night. She
olone and theophylline, all of which can lower potassium levels is adherent to her medications and knows precisely what each
significantly. In addition, potassium is likely to drop further with item is for and how often to take them. She is very reluctant for
her profuse and protracted vomiting. Platelets and creatinine need these medicines to be changed or altered. In the last few admis-
to be monitored because dalteparin can cause heparin-induced sions, Mrs K has required non-invasive ventilation and prolonged
thrombocytopenia, and the dose is affected by renal function. courses of antibiotics. Mrs K has recognised herself that recently
Theophylline levels should be monitored on admission to hospital, she has been more symptomatic and has been struggling to cope
particularly because Ms M is prescribed salbutamol nebules con- at home. She has decided that she does not want any more antibi-
currently, which predisposes the patient to theophylline toxicity. otics or respiratory support should her condition acutely deterio-
3. The most likely cause of Ms M’s vomiting is theophylline toxicity. A rate once more. It has been recognised by the medical team that
theophylline level (even if one was taken on admission) should now Ms K is entering into the last few weeks of her life, and a Do Not
be requested. Administration of theophylline should be stopped until Attempt Cardiopulmonary Resuscitation form has been discussed
the result is known. The most likely cause of theophylline toxicity is with Mrs K and has been signed to be valid to the end of life.
that Ms M has been unable to smoke whilst an in-patient. Stopping
smoking reduces the metabolism of theophylline, so the patient Her regular medications are as follows:
requires a lower dose when smoking has stopped. This had not been • alendronic acid 70 mg weekly,
identified as a risk factor when Ms M was admitted to hospital. • betahistine 16 mg three times daily,
Potassium, magnesium, calcium, blood glucose and phosphate • carbocysteine 750 mg three times daily,
levels need to be measured because profound and rapid hypoka- • domperidone 10 mg three times daily,
laemia can develop with theophylline toxicity, particularly if salbu- • furosemide 40 mg daily,
tamol is being administered concurrently; i.v. replacement may be • gabapentin 800 mg three times daily,
required. In the immediate situation, Ms M needs fluid resuscitation • lansoprazole 30 mg daily,
because her blood pressure is currently low; an arterial blood gas • prochlorperazine 5 mg three times daily,
needs to be analysed to exclude metabolic acidosis or respiratory • quinine sulfate 300 mg at night,
alkalosis. Salbutamol nebules need to be discontinued due to the • salbutamol 2.5 mg nebules four times daily,
tachycardia and likely hypokalaemia. Ms M needs to be placed on • senna 15 mg at night,
a cardiac monitor and a 12-lead ECG performed. Monitor for rest- • Seretide 500 Accuhaler one puff twice daily.
lessness, agitation and convulsions. Ensure 4 mg i.v. lorazepam is
prescribed as required in the event of convulsions. Beta blockers

26 THERAPEUTICS

Questions be started on small doses of morphine sulfate solution (e.g. 2.5 mg
every 4–6 hours). Often patients are initiated with morphine sul-
1. How would you rationalise Mrs K’s current medication, and how fate modified-release (MR) tablets/capsules 10 mg twice daily
would you persuade her to stop unnecessary medications? with 2.5 mg as a breakthrough dose to be taken if breathless-
Upon talking to Mrs K, it becomes apparent that she is ness occurs during the day. This is calculated by dividing the
extremely low in mood. You suggest to her that an antidepres- total daily dose of morphine by six. Laxatives and anti-emetics
sant may help her feel better, although it will not change her should also be prescribed as required. The ‘as-required usage’
physical situation. She agrees that she feels ‘down in the dumps’, of the breakthrough morphine should be monitored and the
and she says she is willing to try a new tablet if it makes her feel maintenance dose increased as appropriate dependent on clini-
better about herself. cal effect and side effects. This is calculated by adding up how
much breakthrough morphine the patient has taken in the last
2. Which antidepressants would you consider suitable? 24 hours and adding this to the current maintenance dose. For
3. Mrs K is breathless and anxious at rest. What suggestions could example, if Mrs K had taken an additional 10 mg of morphine in
the last 24 hours, then the total daily dose of morphine is added
you make to help control these symptoms? to the 10 mg twice-daily maintenance prescription. This makes the
Next time Mrs K is admitted, she is extremely unwell. Her total daily dose of morphine 30 mg, which is then divided by 2 for
the MR preparations (i.e. 15 mg twice daily). The use of benzodi-
opioid usage is equivalent to 60 mg morphine sulfate per day. azepines is also an alternative option to morphine, with lorazepam
She is confused and in type 2 respiratory failure. Her wish was being the drug of choice. Mrs K could be started on 0.5 mg as
not for further intervention, and reversible causes for the confu- required (max 4 mg/day). This can be used regularly if a good
sion are ruled out. There is no evidence of opioid toxicity (e.g. effect is seen. It is also appropriate to combine benzodiazepines
pinpoint pupils/myoclonic jerks). Mrs K is breathless, scared with opioids for symptom control. Information should be provided
and agitated. She is now unable to take oral medication. Her on the hospital discharge letter to inform the primary care doctor
doctor decides that she is progressing to the last few hours/ of the newly started medications and their indications.
days of life. 4. Ms K should be started on a continuous subcutaneous syringe
4. What would you suggest to manage her symptoms?  driver containing both diamorphine (or morphine) and midazolam.
Administration of midazolam and opioids via the subcutaneous
Answers route is off-license, and mixing of these products is also unli-
censed. It is standard practice within palliative care to administer
1. Alendronic acid, betahistine, prochlorperazine, domperidone and these medications in this manner. To calculate the equivalent dose
quinine should be stopped because these are now nonessen- of subcutaneous diamorphine, divide the total daily dose of oral
tial medications that will not significantly contribute to symptom morphine by 3. In Mrs K’s case, she is taking a total daily dose of
management at this stage of her condition. A trusting relation- 60 mg oral morphine. To calculate the dose of diamorphine to
ship needs to be established with Mrs K and the risks and benefits add into the syringe driver, this total daily dose should be divided
of stopping all the medications discussed with her. Mrs K needs by 3. So, for Mrs K, the equivalent dose of diamorphine is 20 mg
gentle support to understand that the medicines will not cause over 24 hours. If subcutaneous morphine is to be added to
her symptoms to become worse and indeed may contribute to the syringe driver, then the total daily dose of oral morphine is
unnecessary side effects. It may be that one medicine at a time divided by 2, so Mrs K would need 30 mg of subcutaneous mor-
is stopped, with perhaps either the betahistine or the prochlor- phine in the syringe driver over 24 hours. A small dose of mid-
perazine being a suitable starting point. Betahistine and prochlor- azolam should be added to the syringe driver (e.g. 5–10 mg over
perazine are both used for vertigo, and therapeutic duplication is 24 hours). Appropriate breakthrough doses of both opioid and
unnecessary, so a pragmatic starting point would be to stop one of midazolam should be prescribed. In Mrs K’s case, this would be
these in the first instance. She should not take regular salbutamol 20 mg of diamorphine divided by 6, which is 3 mg or 30 mg of
in the nebuliser on top of Seretide, and instead this should be morphine divided by 6, which is 5 mg. Midazolam 2.5 mg should
changed to as required. also be prescribed as required. Hyoscine butylbromide 20 mg
subcutaneously every hour as required should be added to the
2. Selective serotonin reuptake inhibitors such as citalopram would prescription to reduce respiratory secretions. An anti-emetic (e.g.
be suitable for Mrs K; mirtazapine or duloxetine would be other subcutaneous haloperidol 1.5–2.5 mg every 4 hours as required)
appropriate choices. Choosing which option is better will depend should also be prescribed. During the dying phase, the usage of
on side effects, interactions with her current medications and ‘as-required medications’ should be monitored daily as a mini-
cost. Citalopram is licensed for panic disorder, whereas dulox- mum. Any medication that has been administered twice in the
etine is licensed for depression and generalised anxiety disorder. preceding 24 hours should be added to the syringe driver to
Mirtazapine is licensed for depression. Mrs K is cachectic and finds maintain adequate symptom control. Compatibilities should be
it hard to sleep at night because of her anxiety, so a suitable choice checked prior to mixing. At the end of life, it is not appropriate
for Mrs K would be mirtazapine because this is an appetite stimu- to continue with routine monitoring, such as blood pressure and
lant and causes some drowsiness. It should be started at 15 mg at temperature or blood glucose testing, because this does not add
night and then titrated if tolerated. to the clinical management of the patient and can be distressing
and uncomfortable.
3. A hand-held fan could be tried to relieve the breathlessness.
Mrs K should be referred to physiotherapy to be taught coping tech-
niques and to ensure there is no element of dysfunctional breath-
ing. Opioids are an option to control breathlessness. Mrs K could

472

CHRONIC OBSTRUCTIVE PULMONARY DISEASE 26

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473
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Kew, K.M., Seniukovich, A., 2014. Inhaled steroids and risk of pneumonia
for chronic obstructive pulmonary disease. Cochrane Database Syst.
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inhaled glucocorticoids and exacerbations of COPD. N. Engl. J. Med. 371
(14), 1285–1294.

26 THERAPEUTICS

Further reading McCarthy, B., Casey, D., Devane, D., et al., 2015. Pulmonary rehabilitation for
chronic obstructive pulmonary disease. Cochrane Database Syst. Rev. 2015
Bafadhel, M., McKenna, S., Terry, S., et al., 2012. Blood eosinophils (2), Art. No. CD003793. https://doi.org/10.1002/14651858.CD003793.pub3.
to direct corticosteroid treatment of exacerbations of chronic
obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. Suissa, S., Patenaude, V., Lapi, F., et al., 2013. Inhaled corticosteroids in
186 (1), 48–55. COPD and the risk of serious pneumonia. Thorax 68, 1029–1036.

Karner, C., Cates, C.J., 2011. The effect of adding inhaled corticosteroids Vollenweider, D.J., Jarrett, H., Steurer-Stey, C.A., et al., 2012. Antibiotics
to tiotropium and long-acting beta2-agonists for chronic obstructive for exacerbations of chronic obstructive pulmonary disease. Cochrane
pulmonary disease. Cochrane Database Syst. Rev. 2011 (9), Art. No. Database Syst. Rev. 2012 (12), Art. No. CD010257. https://doi.
CD009039. https://doi.org/10.1002/14651858.CD009039.pub2. org/10.1002/14651858.CD010257.

Useful websites British Lung Foundation: https://www.blf.org.uk/
British Thoracic Society: https://www.brit-thoracic.org.uk/
COPD Assessment Test: http://www.catestonline.org/images/pdfs/
CATest.pdf

474

THERAPEUTICS

27 Insomnia

Deborah Baidoo and Michele Sie

Key points interrelated, and their activity determines the degree and type of
alertness during wakefulness and the depth and quality of sleep.
• Hypnotic medicines do not cure insomnia but can provide use-
ful short-term symptomatic treatment. Sleep systems 475

• Before starting medication, the primary cause of insomnia The phenomenon of sleep is actively induced and maintained by
should be investigated and treated appropriately where neural mechanisms in several brain areas, including the lower
possible. brainstem, pons and parts of the limbic system. These mecha-
nisms have reciprocal inhibitory connections with arousal sys-
• Non-pharmacological approaches should be considered first line. tems so that the activation of sleep systems inhibits waking and
• Hypnotic medicines should only be used short-term (2–4 vice versa. Normal sleep includes two distinct levels of con-
sciousness, nonrapid eye movement (NREM) sleep and rapid
weeks); long-term regular use leads to tolerance, dependence eye movement (REM) sleep, which are promoted from separate
and other adverse effects. neural centres.
• Sleep hygiene, relaxation techniques and psychological
methods are more appropriate than hypnotics as long-term NREM sleep normally takes up about 80% of sleeping time.
treatment for patients with insomnia. It is divided into three stages (N1–N3), which merge into each
• Nonbenzodiazepine hypnotics, such as zopiclone, zolpidem other, forming a continuum of decreasing cortical and behav-
and zaleplon, have similar pharmacological and adverse effects ioural arousal (Fig. 27.1). Stage N3 represents the deepest phase
to benzodiazepines. of sleep and is also termed delta sleep (DS) due to the produc-
• Promethazine, an antihistamine, can be used for the short- tion of delta waves in the brain during this stage. Historically
term management of insomnia in adults, but tolerance to its NREM sleep was deined as four stages (1–4) until 2007 when
hypnotic effects can occur. the American Academy of Sleep Medicine reclassiied the sleep–
• A melatonin preparation is available for primary insomnia wake cycle and changed the stages by amalgamating NREM
licensed in those older than 55 years. It is a naturally occurring stages 3 and 4 into stage N3 (Schulz, 2008).
hormone that stimulates sleep initiation but does not cause
tolerance or dependence. REM sleep normally takes up about 20% of sleeping time and
has characteristics quite different from NREM sleep. The electro-
Definitions and epidemiology encephalogram (EEG) shows desynchronised fast activity similar
to that found in the alert conscious state, and the eyes show rapid,
Insomnia refers to dificulty in either falling asleep, remain- jerky movements. Peripheral autonomic activity is increased dur-
ing asleep or feeling refreshed from sleep. It is the most com- ing REM sleep, which may result in changes in blood pressure,
mon sleep disorder and in the UK adult population; an annual heart rate and respiration as well as sexual arousal. Atonia occurs,
prevalence of around 35% has been reported (Ellis et al., 2012). causing a temporary paralysis. Heightened cognition, resulting
Insomnia has been signiicantly associated with increasing age, in vivid dreams and nightmares, most often occurs during REM
female gender, comorbid anxiety, depression and pain. By age sleep, although brief frightening dreams (hypnagogic halluci-
50, a quarter of the population is dissatisied with their experi- nations) can occur in NREM sleep, especially at the transition
ence of sleep, rising to 30–40% (two-thirds of them women) between sleeping and waking. Normally stage N3 sleep occurs
among individuals older than 65 years (Sateia and Nowell, 2004).  primarily in the irst few hours of the night, whereas REM sleep
is most prominent towards the morning. Brief awakenings dur-
Pathophysiology ing the night are normal. Both DS and REM sleep are thought to
be essential for brain function, and both show a rebound after a
The pathophysiology of insomnia is related to the overactivity of period of deprivation, usually at the expense of lighter (stage N1
the arousal, emotional regulatory and cognitive sleep systems in and N2) sleep, which appears to be expendable. Many medicines
the brain (Riemann et al., 2015). These systems are functionally can affect the different stages of sleep. Benzodiazepines suppress
stage N3 of sleep but cause only a slight decrease in REM sleep.

27 THERAPEUTICS

R 21.00 22.00 23.00 00.00 01.00 02.00 03.00 04.00 05.00
W
N1
N2
N3

Time

Fig. 27.1 The stages of sleep across a single night in adults.
N1, N2, N3, nonrapid eye movement sleep stages 1, 2 and 3; R, rapid eye movement sleep; W, wake.
(Keenan and Hirshkowitz, 2011, Principles and Practice of Sleep Medicine. Reprinted with permission
from Elsevier.)

Z-hypnotics shorten stage N1 of sleep and prolong stage N2 of Dificulty in falling asleep may result directly from the action
sleep but have little effect on stage N3 and REM sleep. Sedating of stimulants, including caffeine, nicotine, theophylline, sym-
antihistamines cause a reduction in the duration of REM sleep.  pathomimetic amines, some antidepressants, levothyroxine and
antimuscarinics. Some illicit substances, cocaine, amphetamines
Aetiology and clinical and anabolic steroids can also cause insomnia. Withdrawal after
manifestations chronic use of central nervous system depressants, including
hypnotics, anxiolytics and alcohol, commonly causes rebound
Insomnia may be caused by any factor that increases activity in insomnia with delayed or interrupted sleep, increased REM sleep
arousal systems, which leads to decreased activity in sleep sys- and nightmares. With rapidly metabolised drugs, such as alco-
tems. Increased sensory stimulation (e.g. electronic media use) hol or short-acting benzodiazepines, duration of action is limited,
activates arousal systems, resulting in dificulty in falling asleep. which may result in early waking. Certain medicines, including
Common physical health causes include chronic pain, gastric antipsychotics, tricyclic antidepressants and propranolol, occa-
relux, uncontrolled asthma and external stimuli such as noise, sionally cause nightmares, which may result in insomnia. 
bright lights and extremes of temperature.
Investigations and differential
Mental health conditions often affect sleep. Anxiety may delay diagnosis
sleep onset as a result of increased emotional arousal. Dificulty
in staying asleep is characteristic of depression. Patients typi- Many patients complaining of insomnia overestimate their sleep
cally complain of early waking, but sleep records show frequent requirements. Although most people sleep for 7–8 hours daily,
awakenings, early onset of REM sleep and reduced NREM sleep. some healthy subjects require as little as 3 hours of sleep, and
Alteration of sleep stages, increased dreaming and nightmares sleep requirements decline with age. Such ‘physiological insom-
may also occur in schizophrenia, and recurring nightmares are nia’ does not usually cause daytime fatigue, although the elderly
a feature of posttraumatic stress disorder (PTSD). Interference may take daytime naps. If insomnia is causing distress, primary
with circadian rhythms, as in shift work or rapid travel across causes such as pain, medicines that disturb sleep, psychiatric dis-
time zones, can cause dificulty in falling asleep or early waking. turbance including anxiety and depression and organic causes
such as sleep apnoea should be identiied and treated before hyp-
Frequent arousals from sleep are associated with myoclonus, notic therapy is prescribed. 
‘restless legs syndrome’, muscle cramps, bruxism (tooth grind-
ing), head banging and sleep apnoea syndromes. Reversal of Treatment
the sleep pattern, with a tendency for poor nocturnal sleep but
a need for daytime naps, is common in the elderly, in whom it Non-pharmacological therapies
may be associated with cerebrovascular disease or dementia. In
general, decreased duration of sleep has been shown to increase Explanation of sleep requirements, attention to sleep hygiene
the future risk of musculoskeletal pain conditions and myocar- (Box 27.1), reduction in caffeine or alcohol intake and the use
dial infarction. Associations have also previously been identi- of analgesics where indicated may obviate the need for hypnot-
ied with an increased risk of obesity and diabetes, but in larger ics. Medications that cause insomnia should also be avoided if
studies, these have been shown not to be signiicant (Sivertsen possible. Sleep restriction, stimulus control and psychological
et al., 2014). Sleep disturbances in the elderly are also associ- techniques such as relaxation therapy and cognitive behavioural
ated with increased falls, cognitive decline and a higher rate of therapy (CBT) are also beneicial (Siebern et al., 2012). However,
mortality (Cochen et al., 2009). There is growing concern that studies comparing psychological approaches to hypnotics are
daytime sleepiness resulting from insomnia increases the risk of scarce (Riemann and Perlis, 2009). 
industrial, trafic and other accidents, medical errors and a gen-
476 eral decrease in performance and functioning.

INSOMNIA 27

Box 27.1 Principles of typical advice for good sleep hygiene Oxidation of benzodiazepines is decreased in the elderly, in patients
with hepatic impairment and in the presence of some medication,
• Have a good bedtime routine; go to bed and get up at the for example, oral contraception, disulfram and propranolol.
same time every day, and avoid daytime naps.
Pharmacokinetic characteristics are important in selecting
• Avoid stimulants such as caffeine, nicotine, chocolate and a hypnotic medicine. A rapid onset of action combined with a
alcohol 6 h before bedtime. medium duration of action (elimination half-life about 6–8 hours)
is usually desirable. Too short a duration of action may lead to,
• Take regular exercise during the day, but avoid strenuous or fail to control, early morning waking, whereas a long duration
exercise within 4 h of bedtime. of action (e.g. nitrazepam) may produce residual effects the next
day and may lead to accumulation if the medication is used regu-
• Avoid large meals close to bedtime. larly. However, frequency of use and dosage are also important.
• Associate bed with sleep. Do not watch TV or listen to music For example, diazepam (5–10 mg) produces few residual effects
when used occasionally, despite its slow elimination, although
when retiring to bed. chronic use impairs daytime performance. Large doses of short-
• The bedroom should be a quiet, relaxing place to sleep; make acting medicines may produce hangover effects, whereas small
doses of longer-acting medicines may cause little or no hangover. 
sure the room is not too hot or too cold.
• If after 30 min you cannot get off to sleep, then get up. Leave Mechanism of action. Most of the effects of benzodiazepines
result from their interaction with speciic binding sites associated
the bedroom and try to do something else; return to bed with postsynaptic GABAA receptors in the brain. All benzodiaz-
when sleepy. This can be repeated as often as necessary until epines bind to these sites, although with varying degrees of afin-
you are asleep. ity, and potentiate the inhibitory actions of GABA at these sites.

Hypnotic medicines GABAA receptors are the major inhibitory transmitter recep-
tor in the brain. They are multi-molecular complexes (Figs. 27.2
Hypnotic medicines provide only symptomatic treatment for and 27.3) that control a chloride ion channel and contain speciic
insomnia. Although often eficacious in the short-term they do binding sites for gamma aminobutyric acid (GABA), benzodiaz-
little to alter the underlying cause, which should be sought and epines and several other medicines, including many nonbenzodi-
treated where possible. About 9 million prescriptions for hypnot- azepine hypnotics and some anticonvulsant medicines (Richter
ics are issued each year in primary care in England, and there is a et al., 2012). The various effects of benzodiazepines (hypnotic,
trend that prescribing of these medicines is reducing year on year. anxiolytic, anticonvulsant, amnesic, muscle relaxant) result from
These medicines can improve the quality of life if used rationally. GABA potentiation in speciic brain sites and at different types of
GABAA receptor. There are multiple subtypes of GABAA recep-
The ideal hypnotic would: tor, which may contain different combinations of at least 19 sub-
• gently suppress brain arousal systems while activating sys- units (including α1–6, β1–3, γ1–3 and others), and the subtypes are
differentially distributed in the brain.
tems that promote deep and satisfying sleep,
• have a rapid onset of action with no residual effects, Benzodiazepines predominantly bind to receptors containing
• have no ataxic or memory effects, α, β, and γ subunits, and it appears that their combination with
• not induce tolerance or dependence if used long-term α1-containing subtypes mediates their sedative, amnesic and anti-
• not cause withdrawal effects when stopped, convulsant effects whilst α2-containing subtypes mediate their
• not depress respiration, anxiolytic effects (Möhler, 2006). 
• be safe for use in the elderly patient.
Zopiclone 477
Unfortunately, most available hypnotics are general central
nervous system depressants which inhibit both arousal and sleep Zopiclone, a cyclopyrrolone, was the irst nonbenzodiazepine to
mechanisms. Thus, they do not induce normal sleep and often be approved for the treatment of insomnia in the European mar-
have adverse effects, including daytime sedation (‘hangover’) and ket. Although classed as a nonbenzodiazepine, it still binds to ben-
rebound insomnia on withdrawal. They are unsuitable for long- zodiazepine receptors and is more selective for the α1 subtype. It
term use because of the development of tolerance and dependence. has been shown to be effective in promoting sleep initiation and
sleep maintenance and is licensed in the UK for up to 4 weeks of
Benzodiazepines use. It has an elimination half-life of approximately 5 hours. This
medicine appears to have no particular advantages over benzodiaz-
By far the most commonly prescribed hypnotics are the benzo- epines, although it may cause less alteration of sleep stages.
diazepines. Various benzodiazepines are available (Table 27.1).
These medicines differ considerably in potency (equivalent dos- It has hypnotic effects similar to benzodiazepines and car-
age) and in rate of elimination but only slightly in clinical effects. ries a similar potential for adverse effects including tolerance,
All benzodiazepines have sedative/hypnotic, anxiolytic, amnesic, dependence and abstinence effects on withdrawal. Psychiatric
muscular relaxant and anticonvulsant actions, with minor differ- reactions, including hallucinations, behavioural disturbances and
ences in the relative potency of these effects. nightmares, have been reported to occur shortly after the irst
dose. Other common adverse reactions include a bitter taste, a
Pharmacokinetics. Most benzodiazepines marketed as hypnot- dry mouth and dificulty arising in the morning (Zammit, 2009). 
ics are well absorbed and rapidly penetrate the brain, producing
hypnotic effects within half an hour after oral administration. Rates
of elimination vary, however, with elimination half-lives from 6
to 100 hours (see Table 27.1). These medicines undergo hepatic
metabolism via oxidation or conjugation and some form pharmaco-
logically active metabolites with even longer elimination half-lives.

27 THERAPEUTICS

Table 27.1 Overview of the medication used for insomnia

Usual dose at night Half-life in

Drug (adult) (mg) adults (h) Licensed indication Tolerance Dependence
Benzodiazepines
Yes
Diazepam 5–15 24–36 Insomnia (short-term use) Yes Yes
Yes
Loprazolam 1 11 Insomnia (short-term use) Yes Yes
Yes
Lorazepam 1–2 12–16 Insomnia (short-term use) Yes Yes

Lormetazepam 0.5–1.5 10 Insomnia (short-term use) Yes Yes
Yes
Nitrazepam 5–10 18–36 Insomnia (short-term use) Yes Yes

Temazepam 10–20 5–11 Insomnia (short-term use) Yes Yes
Z-Hypnotics
Yes
Zaleplon 5–10 2 Insomnia (short-term use up to 2 weeks) Yes
Yes
Zolpidem 5–10 2–3 Insomnia (short-term use up to 4 weeks) Yes
No
Zopiclone 3.75–7.5 3.5–6 Insomnia (short-term use up to 4 weeks) Yes No

Orexin receptor antagonist No

Suvorexant 10 10–22 Insomnia up to 3 months Yes

Chloral and derivatives (rarely used)

Cloral betainea 707–1414 Unclear Insomnia (short-term use) Yes
Clomethiazole

Clomethiazole 192–384 4–5 Severe insomnia in elderly (short-term Yes
Antihistamines use)

Promethazine 25–50 10–19 Insomnia (short-term use) Yes

Diphenhydramine 50 2.5–9 Relief of temporary sleep disturbance Yes
Melatonin (short-term use up to 2 weeks)

Melatonin (Circadin) 2 3.5–4 Insomnia in adults older than 55 years No
Unlicensed products (up to 13 weeks)
also available

aChloral betaine 707 mg is equivalent to 414 mg chloral hydrate tablets.

Eszopiclone Zolpidem

The S(+) enantiomer of zopiclone is available in the USA, but Zolpidem is an imidazopyridine that binds preferentially to the
there are no current plans for it to be launched in the UK. The α1 benzodiazepine receptor subunit thought to mediate hypnotic
advantage that the isomer incurs over zopiclone is unclear. effects. It is an effective hypnotic with only weak anticonvul-
Eszopiclone has been shown to promote sleep onset and sleep sant and muscle relaxant properties. It has a short elimination
maintenance. It has a mean elimination half-life of approxi- half-life (2–3.5 hours), reducing the risk of hangover effects, but
mately 7 hours. There is no evidence of tolerance, rebound rebound effects may occur in the later part of the night, causing
insomnia or serious withdrawal effects (Hair et al., 2008; early morning waking and daytime anxiety. Zolpidem can cause
478 Zammit, 2009).  tolerance and a pharmacodependence, leading to a withdrawal

INSOMNIA 27

β2 differently according to gender following evidence that women
α1 α1 were more susceptible to next-day impaired alertness due to
slower elimination (Farkas et al., 2013). A controlled-release ver-
Cl– sion of zolpidem (zolpidem-CR) is available in some countries. 

β2 γ2 Zaleplon

GABAA receptor Zaleplon is a pyrazolopyrimidine which, like zolpidem, binds
selectively to the α1 benzodiazepine receptor. It has been shown
6 different α subunits to effectively promote sleep initiation but is less effective in pro-
moting sleep maintenance. It has a very short elimination half-
4 different β subunits life of 1 hour and appears to cause minimal residual effects on
psychomotor or cognitive function after 5 hours.
3 different γ subunits
There is little evidence of tolerance or withdrawal effects in
Most common mammalian short-term use, and the medicine appears suitable for use in the
structure (α1)2(β2)2(γ1) elderly. 

Fig. 27.2 The GABAA receptor and subunits. The GABAA receptor is Suvorexant
a heteropentameric glycoprotein. A total of five distinct polypeptide
subunits have been cloned to date—α, β, γ, d, and r—and multiple Suvorexant, a novel hypnotic, is a dual orexin-1 receptor and
isoforms of these subunits are reported in the literature. Different orexin-2 receptor antagonist. Suvorexant is structurally unrelated
conformations of the GABAA receptor are found throughout the to benzodiazepines and other hypnotic agents. It has been shown
brain, and the most common mammalian arrangements of subunits to be effective in promoting sleep initiation and maintaining sleep
is (α1)2(β2)2(γ1). The specific subunits in the GABAA receptor confer and can be used for periods of up to 3 months. It has an elimina-
functional diversity on the receptor. For example, the γ subunit needs tion half-life of approximately 15 hours (range of 10–22 hours).
to be co-expressed with the α and β subunits to observe the potentia-
tion of the GABAA receptor by benzodiazepines. Clinical trial data showed no evidence of rebound insomnia on
discontinuation, no evidence of physical dependence with pro-
Benzodiazepine binding site γ subunit longed use and no reports of withdrawal symptoms. However,
GABA Cl– further clinical trials may be required to determine tolerance and
withdrawal effects in long-term use (Yang, 2014). 

Synaptic cleft Other hypnotic medicines

GABA binding site The risk of adverse effects, including dependence and dangerous
respiratory depression in overdose, generally outweighs the poten-
αα tial beneits of the older hypnotics – chloral derivatives, clomethia-
binding binding zole and barbiturates. Therefore, these treatments are best avoided.
Antidepressants with sedative properties, such as mirtazapine or
site site agomelatine, may be helpful if sleep disturbance is secondary to
depression. Sedative antipsychotics are not recommended for the
Post-synaptic membrane Cytoplasm management of insomnia due to their adverse effects. 

Fig. 27.3 Schematic representation of the GABAA receptor. GABA Antihistamines
is the major inhibitory neurotransmitter in the central nervous system.
Diphenhydramine and promethazine
The GABAA receptor is composed of five subunits—two α, two β and
one γ subunit. Two molecules of GABA activate the receptor by bind- Diphenhydramine and promethazine are H-1 receptor antago-
nists. Activating H-1 receptors promotes wakefulness, and there-
ing to the α subunits. Once activated the receptor allows the passage fore H-1 receptor antagonists promote sedation. The evidence for
of negatively charged ions (Cl–) into the cytoplasm, which results in the eficacy in the management of acute or chronic insomnia is
sparse. Diphenhydramine and promethazine have an elimination
hyperpolarisation and the inhibition of neurotransmission. (Source: half-life of approximately 2–9 hours and 5–14 hours, respectively.

www.CNSforum.com.) The long duration of action may lead to hangover effects, and
antihistamines are associated with a potential for tolerance and
syndrome and causing irritability, agitation, nervousness and, in abuse. Abrupt discontinuation can be associated with activa- 479
severe cases, seizures. Anecdotal case reports have also associ- tion, insomnia and mild antimuscarinic withdrawal symptoms
ated zolpidem with complex sleep-related behaviours. These have such as nausea, sweating and headache. Many antihistamines
included sleep-walking, ‘sleep-driving’, ‘sleep self-intoxication’, have potent anticholinergic activity, leading to adverse effects of
amnesia, making phone calls, preparing food and eating while
asleep. Long-term use of zolpidem has been shown to increase
the risk of major injury (head trauma or fracture). In the USA
in 2013 zolpidem became the irst medication to be prescribed

27 THERAPEUTICS

sedation, dizziness, dry mouth, constipation, urinary retention, of certain GABA/benzodiazepine receptors and sensitisation of
blurred vision and weight gain.  receptors for excitatory neurotransmitters (Allison and Pratt,
2003). These changes encourage continued hypnotic usage and
Melatonin contribute to the development of dependence. 

Melatonin is a naturally occurring hormone, produced by the pineal Oversedation and hangover effects
gland, which regulates the circadian rhythm of sleep. It begins to
be released once it becomes dark and continues to be released until Many benzodiazepines and z-hypnotics used to treat insomnia
the irst light of day. Melatonin release decreases with age, which can give rise to a subjective ‘hangover’ effect, and after most
may in part explain why older adults require less sleep. Melatonin of them, even those with short elimination half-lives, psychomo-
supplementation promotes sleep initiation and helps reset the cir- tor performance, including driving ability and memory, may be
cadian clock, allowing uninterrupted sleep. It has also been shown impaired on the following day. Oversedation is most likely with
to improve next-day functioning. Contrary to most other hypnot- slowly eliminated medicines, especially if used chronically, and
ics, melatonin shows no abuse or tolerance potential and appears is most marked in the elderly in whom drowsiness, incoordina-
to have no next-day sedation problems (Riemann et al., 2015). tion and ataxia, leading to falls and fractures, and acute confu-
Prolonged-release melatonin (Circadin) was launched in June sional states may result, even from small doses. Chronic use can
2008 and is available at a dose of 2 mg at night for up to 13 weeks. cause considerable cognitive impairment, sometimes suggesting
It is licensed as monotherapy in primary insomnia for adults older dementia. Paradoxical excitement may occasionally occur.
than 55 years old. Although the adverse-effect proile looks advan-
tageous, there are currently no trials comparing melatonin against These medicines may also decrease alveolar ventilation and
psychological or other hypnotic treatments. Circadin is also much depress the respiratory response to hypercapnia, increasing the
more expensive than other currently prescribed hypnotics  risk of cerebral hypoxia, especially in the elderly and in patients
with chronic respiratory disease. 

Potential adverse effects of Drug interactions
hypnotic use
Concomitant use of two or more medicines that cause central ner-
Tolerance and dependence vous system (CNS) depression result in additive effects that can
increase drowsiness, cause marked sedation and reduce alertness,
Tolerance to the hypnotic effects of benzodiazepines, z-hypnotics which may lead to accidents and severe respiratory depression.
and antihistamines develops rapidly and may lead to unprescribed Medicines that can cause CNS depression include antidepressants,
dose escalation by users. Nevertheless, poor sleepers may report antiepileptics, antihistamines, antipsychotics, anxiolytics, benzo-
continued eficacy. Physical and psychological dependence are diazepines, barbiturates, hypnotics, opioid analgesics and skeletal
common with benzodiazepines and z-hypnotics, and despite muscle relaxants as well as alcohol (all amounts). (Zammit, 2009).
safety recommendations for short-term use, these medicines
are often used long-term because of dificulties on withdrawal. Suvorexant is metabolised via cytochrome P450 isoenzyme
Prescribing hypnotics beyond limited short courses brings poten- CYP3A, and therefore use with potent inhibitors of these enzymes
tial hazards, of dependence, adverse effects and adverse events, (e.g. ketoconazole) is not recommended. Dose adjustment may be
for example, falls. Targeted deprescribing of hypnotic medicines required when used with moderate inhibitors (e.g. luconazole);
can lead to better health outcomes.  conversely, concomitant use with potent CYP3A inducers (e.g.
rifampicin) is likely to reduce eficacy of suvorexant (Yang, 2014). 

Rebound insomnia Rational pharmacological treatment of insomnia

Rebound insomnia, in which sleep is poorer than before phar- A hypnotic may be indicated for insomnia when it is severe,
macological treatment, is common on withdrawal of benzodi- disabling, unresponsive to other measures or likely to be tem-
azepines. Sleep latency (time to onset of sleep) is prolonged, porary. In choosing an appropriate agent, individual variables
intra-sleep wakenings become more frequent and REM sleep relating to the patient and to the medicine need to be considered
duration and intensity are increased, with vivid dreams or night- (see Table 27.1). 
mares which may add to frequent awakenings. These symptoms
are most marked when the medicines have been taken in high Patient care
doses or for long periods but can occur after only a week of low
dose administration. They are prominent with moderately rapidly Type of insomnia
eliminated benzodiazepines (temazepam, lorazepam) and may
last for many weeks. With slowly eliminated benzodiazepines The duration of insomnia is important in deciding on a hypnotic
(diazepam), DS and REM sleep may remain depressed for some regimen. Transient insomnia may be caused by changes of rou-
weeks and then slowly return to the baseline, sometimes without tine such as overnight travel, change in time zone, alteration of
a rebound effect. Tolerance and rebound effects are relections shift work or temporary admission to hospital. In these circum-
of a complex homeostatic response to regular use of medi- stances, a hypnotic with a rapid onset, medium duration of action
480 cines, involving desensitisation, uncoupling and internalisation and few residual effects could be used on one or two occasions.

INSOMNIA 27

Short-term insomnia may result from temporary environmen- Choice of pharmacological treatment
tal stress. In this case, a hypnotic may occasionally be indicated
but should be prescribed in low dosage for 1 or 2 weeks only, There is little difference in hypnotic eficacy between most of
preferably intermittently, on alternate nights or one night in three the available agents. The main factors to consider in the rational
to prevent tolerance and dependence. choice of a hypnotic regimen are duration of action and the risk
of adverse effects, especially oversedation and the development
Chronic insomnia presents a much greater therapeutic prob- of tolerance and dependence. There is no compelling evidence to
lem. It is usually secondary to other conditions (organic or psy- distinguish z-hypnotics from the shorter-acting benzodiazepine
chiatric) at which treatment should initially be aimed. In selected hypnotics (National Institute for Health and Care Excellence,
cases, a hypnotic may be helpful, but it is recommended that such 2004). Patients who do not respond to either a benzodiazepine or
medicines should be prescribed at the minimal effective dosage z-hypnotic should not be prescribed the other. Cost may also be a
and administered intermittently (one night in three) or temporar- factor when prescribing melatonin.
ily (not more than 2 or 3 weeks). Occasionally it is necessary to
repeat short, intermittent courses at intervals of a few months. Rate of elimination

The elderly Slowly eliminated medicines should be avoided because of the
risk of oversedation and hangover effects. Very short-acting
The elderly are especially vulnerable both to insomnia and to drugs such as zaleplon carry the risk of late-night rebound
adverse effects from hypnotic medicines. They may have reduced insomnia and daytime anxiety. Medicines with a medium elimi-
metabolism of some medicines and may be at risk of cumula- nation half-life (6–8 hours) appear to have the most suitable pro-
tive effects. They are also more susceptible than younger people ile for hypnotic use. These include temazepam and zopiclone,
to CNS depression, including cognitive impairment and ataxia and as such, these are the medicines of irst choice in most situ-
(which may lead to falls and fractures). They are sensitive to ations where hypnotics are indicated in adults. Sedative antihis-
respiratory depression, prone to sleep apnoea and other sleep tamines are a reasonable second choice, followed by melatonin. 
disorders and are more likely to have ‘sociological’, psychiat-
ric and somatic illnesses which both disturb sleep and may be Duration and timing of administration
aggravated by hypnotics. For some of these elderly patients, hyp-
notics can improve the quality of life, but the dosage should be To prevent the development of tolerance and dependence, the
adjusted (usually half the recommended adult dose), and hypnot- maximum duration of treatment should be limited to between 2
ics with long elimination half-lives or active metabolites should and 4 weeks, and treatment should, where possible, be intermit-
be avoided. tent (one night in two or three). Dosage should be tapered slowly
if hypnotics have been taken regularly for more than a few weeks
A considerable number of elderly patients give a history of to prevent potential withdrawal effects such as rebound insom-
regular hypnotic use going back for 20 or 30 years. In many nia, anxiety, loss of appetite, tremor, perspiration and seizures
of these patients, gradual reduction of hypnotic dosage or even (Tapering advice is available in the British National Formulary.).
withdrawal may be indicated and can be carried out success- Doses should be taken 20 minutes before retiring in order to
fully, resulting in improved cognition and general health with no allow dissolution in the stomach and absorption to commence
impairment of sleep or escalation of other symptoms.  before the patient lies down in bed. 

The young Medicines and driving 481

Traditional benzodiazepine-like hypnotics are generally contra- In the UK the Department for Transport has introduced a new
indicated for children. Promethazine is the only licensed paedi- offence of driving with certain controlled drugs above speciied
atric sedative for use in those aged 5 years or older. The use of limits in the blood. The new law came into force on 2 March
promethazine in young children is usually unjustiied, and there 2015 and outlaws driving while under the inluence of drugs.
have been reports of a possible association between the use of As well as illegal drugs, the new legislation also includes some
phenothiazine antihistamines and sudden infant death syndrome prescription medicines. Medicines included in the new offence
(SIDS), although this has not been conirmed. The off-label use that might be used for insomnia include benzodiazepines (e.g.
of melatonin is common particularly in those with attention-dei- temazepam and diazepam). The legislation provides for a statu-
cit/hyperactivity disorder (ADHD).  tory ‘medical defence’, if patients are taking medicines in accor-
dance with instructions and their driving is not impaired. Patients
Disease states who are unsure about the effects of their medication or how the
new legislation may affect them are advised to seek the advice
Hypnotics are contraindicated in patients with acute pulmonary of their doctor or pharmacist. Drivers who are taking prescribed
insuficiency, signiicant respiratory depression, marked neuro- medication at high doses are advised to carry evidence with them,
muscular respiratory weakness, sleep apnoea syndrome or severe such as prescriptions slips, when driving in order to minimise any
hepatic impairment. In terminal conditions, the possibility of inconvenience should they be asked to take a test by the police
pharmacodependence becomes a less important issue, and regu- (Department for Transport, 2014). 
lar use of hypnotics with a medium duration of action should not
be denied if they provide symptomatic relief of insomnia. 

27 THERAPEUTICS

Case studies • Signs of drug-seeking behaviour, such as visiting more than one
doctor, fabricating stories and forging prescriptions, should be
Case 27.1 addressed. The series of primary care doctors who gave Mr PH
prescriptions should have been aware that he was likely to attempt
Mr PH, aged 24, was hospitalised for 3 months after a serious to obtain illicit supplies and should have referred him to a with-
motorcycle injury followed by painful complications. While in drawal clinic or substance misuse unit. Doses should be reduced
hospital he developed panic attacks and insomnia. He received steadily and/or weekly or even daily prescriptions issued for small
no psychological support but was prescribed temazepam, ini- amounts if dependence is suspected.
tially in 20 mg doses but later increased to 60 mg because of
continued insomnia. After discharge from hospital Mr PH contin- • Prescribers should closely monitor amounts prescribed for medi-
ued to receive temazepam from his primary care doctor, and the cines with abuse potential to prevent patients or their carers from
dosage was increased over a period of years until he was taking accumulating stocks. A minimal amount should be prescribed in
80 mg temazepam each night and 40–80 mg during the day. At the first instance, or when seeing a new patient for the first time.
the age of 30, Mr PH was removed from the practice list of his Patients seen by temporary care services should be given small
doctor after he altered a prescription. He later attended several amounts of medicines unless they present an unequivocal letter
different primary care doctors, obtaining multiple temazepam from their own primary care doctor. 
prescriptions. When he could no longer satisfy his need from
prescriptions, he took to obtaining temazepam on the street, Case 27.2
taking large and irregular doses by mouth. All this time, his anxi-
ety levels increased. His behaviour became chaotic, and he was Mrs RS, a recently widowed woman aged 75, had difficulty sleep-
twice imprisoned for credit card fraud, but he was able to obtain ing after her bereavement. She was initially prescribed temazepam
temazepam and other drugs from his co-prisoners. When last 10 mg at night, which was changed following reports of next-day
heard of, Mr PH, aged 35, was again buying temazepam illic- hangover effect to zopiclone in a bedtime dose of 7.5 mg. This
itly, as well as other addictive drugs, had started injecting intra- was very effective and was continued for over 4 weeks. Mrs RS
venously and was involved in a court case for obtaining money lived alone but was visited occasionally by her daughter. On a visit
under false pretences. 2 weeks after the zopiclone was started, Mrs RS seemed calm
and said that she was sleeping well, but the daughter noticed her
Question mother was unsteady on her feet. A few weeks later the daughter
visited again and found her mother lying on the bedroom floor, in
How could the risk of creating dependence and subsequent personal pain and unable to move. She said that she had lost her balance
tragedy have been avoided? on getting out of bed. An ambulance was called, and it was found
in hospital that Mrs RS had broken her hip.
Answer
Question
Mr PH’s problematic situation could have been averted by judicial
prescribing, supply and management of medicines likely to cause Should the doctor have prescribed temazepam or zopiclone for this
dependence or substance misuse. patient, and what other treatment options are available?
• The risk of creating dependence could be reduced by not intro-
Answer
ducing medicines with an abuse potential unless absolutely nec-
essary. Non-pharmacological approaches (e.g. sleep hygiene and/ • First-line treatment for insomnia should be non-pharmacologi-
or cognitive behavioural therapy) should have been considered in cal, such as sleep hygiene and relaxation techniques. The doctor
the first instance. should have completed a healthy sleep assessment to identify any
• Rapid and large dose escalation of temazepam should be contributory factors to Mrs RS’s insomnia, such as using stimulant
avoided, and the lowest effective therapeutic dose for hypnot- substances (e.g. caffeine) or taking other medicines that may have
ics should be used. The appropriate dose of hypnotic should be affected her sleep (e.g. diuretics in the evening).
reviewed at each opportunity because the signs of dependence,
its effects, and withdrawal from medicines with abuse potential • Benzodiazepines and z-hypnotics should be avoided in the elderly.
are not always obvious, so timely recognition and assessment If used, a medication with a short duration of action should be
may be difficult. selected, and the dose of hypnotic should be reduced to ¼–½ of the
• The treatment and management of the underlying cause for adult dose. Zopiclone starting dose in the elderly is 3.75 mg at night.
insomnia should be investigated because Mr PH may have been
experiencing PTSD or panic disorder. Along with psychological • Hypnotics should be used on alternate nights or one night in three
approaches, an antidepressant with sedative effects may have to prevent tolerance and dependence.
been a more appropriate prescription choice, instead of pro-
longed treatment with excessive doses of temazepam. • The elderly are particularly prone to ataxia and light-headedness
• A slow reducing-dose schedule for hypnotics should be imple- with benzodiazepines and z-hypnotics, and this can lead to falls
mented when the acute episode for insomnia has been managed. and fractures.
On discharge from hospital, Mr PH’s primary care doctor should
have been warned about his temazepam intake and a slow with- • Benzodiazepines and z-hypnotics are not recommended, except
drawal schedule communicated. acutely, for bereavement. Their amnesic effects may interfere with
subsequent psychological adjustment.

• If a hypnotic was indicated, melatonin would have been a better
option for Mrs RS because it has less adverse effects, has no toler-
ance or dependence risks, does not exhibit the increased risk of falls
observed with other hypnotics and can be used for up to 13 weeks.

482

INSOMNIA 27

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Further reading Wilson, S.J., Nutt, D.J., Alford, C., et al., 2010. British Association for Psy-
chopharmacology consensus statement on evidence-based treatment of
Anon., 2009. Melatonin for primary insomnia. Drug Ther. Bull. 47, 74–77. insomnia, parasomnias and circadian rhythm disorders. J. Psychopharm.
Bloom, H.G., Ahmed, I., Alessi, C.A., et al., 2009. Evidence-based recom- 24, 1577–1600. Available at: https://www.bap.org.uk/pdfs/BAP_
Guidelines-Sleep.pdf
mendations for the assessment and management of sleep disorders in
older persons: supplement. J. Am. Geriatr. Soc. 57, 761–789. Winkelman, J.W., 2015. Insomnia disorder. N. Engl. J. Med. 373, 1437–
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Sleep. Med. 15 (4), 487–504.

Useful websites The Royal College of Psychiatrists’ website provides information for profes-
sionals, patients and the public, including a number of health advice
The National Sleep Foundation was founded in 1990 by the leaders in sleep lealets: http://www.rcpsych.ac.uk/
medicine. The website has a number of resources covering topics such
as sleep science, healthy sleep habits, and sleep disorders for medical pro- The NHS Choices website provides advice for patients and the public,
fessionals, patients and the public: https://sleepfoundation.org including advice on the management on insomnia. https//www.
nhs.uk
The Clinical Knowledge Summaries website from NICE is a concise sum-
mary of current evidence for primary care professionals: https://cks.nice.
org.uk/insomnia

483

THERAPEUTICS

28 Anxiety Disorders

Stephen Bleakley and David S. Baldwin

Key points Anxiety facilitates Anxiety debilitates

• Benzodiazepines should typically only be used short-term Very good
(2–4 weeks) because long-term regular use can lead to toler-
ance, dependence and other adverse effects in some patients. Performance Average

• If benzodiazepines are indicated, the smallest effective dose Very poor
should be used along with intermittent dosing where possible.
Start with small doses; increase if necessary. Use half the adult Calm Tense Panic
dose in elderly patients.
Anxiety level
• Psychological therapies (‘talking therapies’) are generally Fig. 28.1 The Yerkes–Dodson curve.
considered first-line treatments in all anxiety disorders because
they may provide lower relapse rates than pharmacotherapy. Sensitivity to noise Constriction in the chest
Difficulty inhaling
• Some antidepressants are appropriate as long-term treatment Dry mouth
for anxiety disorders. Difficulty in swallowing Feeling of breathlessness

• Selective serotonin reuptake inhibitors (SSRIs) are the recom- Palpitations Fearful anticipation
mended antidepressants in anxiety disorders but can worsen Discomfort in the chest Irritability
symptoms at the beginning of treatment, so patients should be Awareness of missed
monitored carefully in the first weeks. Poor concentration
beats Worrying thoughts
• When antidepressants are used, they often require higher
therapeutic doses in anxiety disorders than those used in Restlessness Headache
patients with depression. Tremor Dizziness
Insomnia
Definitions and epidemiology Aching muscles Avoiding the
situation/object
Anxiety is a normal, protective, psychological response to an
unpleasant or threatening situation. Mild to moderate anxiety GI discomfort
can improve performance and ensure appropriate action is taken. Excessive wind
However, excessive or prolonged anxiety can be disabling, lead to Frequent or loose motions
severe distress and cause much impairment in social functioning. Frequent or urgent micturition
Fig. 28.1 shows that as anxiety levels increase, performance and Failure of erection
actions initially increase; however, as the anxiety level increases Menstrual discomfort
beyond acceptable or tolerated levels, performance declines. Amenorrhoea

The term anxiety disorder encompasses a variety of conditions Fig. 28.2 The symptoms of anxiety.
that can either exist on their own or in conjunction with another
psychiatric or physical illness. Symptoms of anxiety vary, but
patients generally present with a combination of psychological,
physical and behavioural symptoms (Fig. 28.2). Some of these
symptoms are common to many anxiety disorders, whereas oth-
ers are distinctive to a particular disorder. Anxiety disorders are
broadly divided into generalised anxiety disorder (GAD), panic
disorder, social anxiety disorder, speciic phobias, separation
anxiety disorder and illness anxiety disorder. Posttraumatic stress
disorder (PTSD) and obsessive-compulsive disorder (OCD) were
484 previously classiied under the umbrella of anxiety disorders but