Management of chronic obstructive pulmonary disease

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Toby GD Capstick, MRPharmS
Pharmacy department, St James’s University Hospital, Leeds Teaching Hospitals NHS Trust, West Yorkshire, UK

Robyn Sanderson, MRPharmS
Pharmacy department, St James’s University Hospital, Leeds Teaching Hospitals NHS Trust, West Yorkshire, UK

Chronic obstructive pulmonary disease (COPD) is defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as ‘a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases.’1

COPD is now the preferred term used to describe conditions with airflow limitation such as those that were previously labelled emphysema or chronic bronchitis.

The worldwide prevalence of COPD was estimated by the World Health Organization (WHO) to be approximately 63.5 million in 2004, comprising approximately 11.3 million in Europe.2 It is estimated that three million people in the UK have COPD, although only 900,000 have been diagnosed.3

COPD is the fourth leading cause of death worldwide,3 although due to an increasing burden, it is anticipated to become the third leading cause of death by the year 2020.4 There were three million deaths attributed to COPD worldwide in 2005,3 while in the UK there are 30,000 deaths annually.3 The most common risk factor for COPD is cigarette smoking, although other causes include genetic predisposition (alpha1-antitrypisin deficiency), occupational dusts and chemicals, and pollution.

Pathological changes observed in COPD comprise of chronic inflammation mediated by increased numbers of neutrophils, macrophages and CD8+ lymphocytes in the airways, as well as increased oxidative stress and protease-antiprotease imbalance.

Airflow obstruction
Airflow obstruction is caused by a combination of small airway disease (obstructive bronchiolitis), loss of elastic recoil of the small airways and parenchymal destruction (emphysema). The airway obstruction results in air-trapping during expiration, causing hyperinflation. This means that the lung volume of COPD patients is higher at the end of expiration than that of their normal adults and so subsequently reduces inspiratory capacity, increasing dyspnoea and reducing exercise capacity.

Gas-exchange abnormalities such as hypoxaemia and hypercapnia result from worsening gas transfer as the disease progresses. Mild to moderate pulmonary hypertension resulting from hypoxic vasoconstriction of pulmonary arteries may develop in late-stage COPD.

Mucous hypersecretion, predominantly in the large airways, produces a chronic productive cough and is characteristic of chronic bronchitis. Systemic features of COPD include cachexia, skeletal muscle wasting, osteoporosis, depression and cardiovascular disease.

Common symptoms that suggest COPD include exertional breathlessness, chronic cough, regular sputum production, frequent winter ‘bronchitis’ and wheeze, although other symptoms may be present such as weight loss, ankle swelling and fatigue. However, in early stages of COPD, patients may have minimal or no symptoms.

A clinical diagnosis of COPD should be considered in patients with relevant symptoms and a history of exposure to one or more risk factors, particularly if aged over 40 years.1 Spirometry can be used to identify airflow obstruction, which is defined as a reduced post-bronchodilator FEV1/FVC ratio less than 0.7 (where FEV1 is forced expiratory volume in 1 second and FVC is forced vital capacity),1,3 while severity of the condition can be defined by the reduction in FEV1 (see Table 1). The impact of a patient’s breathlessness on their health status, measured using the British Medical Research Council dyspnoea scale, can be used to predict mortality (see Table 2).1,3

Current treatments
COPD management aims to prevent and control symptoms, prevent progression, reduce the frequency and severity of exacerbations, improve health status and exercise tolerance, and reduce mortality.1

Non-pharmacological therapies
Smoking cessation is the single most effective way to reduce disease progression and subsequent mortality. All patients who are still smoking should be advised to quit and offered nicotine replacement therapy, varenicline or bupropion combined with an appropriate behavioural support programme to optimise smoking quit rates.1,3

Pulmonary rehabilitation programmes should be offered to all patients functionally disabled by COPD and those who have recently experienced an exacerbation requiring hospitalisation. These programmes are multidisciplinary and comprise a mixture of exercise training, disease education, nutrition counselling and psychological and behavioural interventions. Pulmonary rehabilitation has been shown to increase exercise tolerance, reduce symptoms of breathlessness, improve quality of life and reduce the number of hospitalisations and length of stay in hospital.1

Pharmacological therapies
Beta2-agonists… stimulate beta2-adrenergic receptors on airway smooth muscle, causing bronchodilation. Short-acting beta2-agonists (SABAs) such as salbutamol and terbutaline are used on a ‘when required’ basis to provide relief of breathlessness and exercise limitation, and should be used for all disease stages. SABAs have a rapid onset, making them useful for emergency use, and last four to six hours. Long-acting beta2-agonists (LABAs) such as formoterol and salmeterol produce bronchodilation over a 12-hour period. Indacaterol, a novel once-daily LABA with a rapid onset of action, is associated with clinically important improvements in lung function, health-related quality of life and dyspnoea compared with formoterol and tiotropium.5 It may be a useful option for patients requiring a LABA inhaler, where adherence to twice-daily dosing is poor.

However, there is currently a lack of data on the effect on exacerbation rate and rate of health status decline, and so it should not be used in preference to twice-daily LABAs. Adverse effects with beta2-agonists are more common when used in large doses or administered orally or intravenously. These include resting tremor (particularly in elderly patients), sinus tachycardia and hypokalaemia.

Muscarinic antagonists… block the action of acetylcholine, most importantly on M3 receptors, to produce bronchodilation. The long-acting muscarinic antagonist (LAMA), tiotropium, is an antagonist at M1 and M3 receptors, while short-acting muscarinic antagonists also block M2 receptors to modify transmission at the pre-ganglionic junction, although these effects are thought to be unimportant in COPD.

Ipratropium has a duration of action of six to eight hours and is useful for symptom control, while tiotropium has a duration of at least 24 hours.

Patients requiring regular treatment with muscarinic antagonist drugs should be prescribed the more cost-effective tiotropium in preference to four-times-daily short-acting muscarinic antagonists.3 Systemic adverse effects are uncommon and the main side effect is dry mouth, although ipratropium has a bitter metallic taste.

There have been concerns raised recently about the cardiovascular safety of anticholinergic drugs.6,7 However, the safety of tiotropium, when administered via a HandiHaler, device was shown to significantly reduce the rate of congestive heart failure and myocardial infarction compared to placebo over four years in the UPLIFT study.8

Confusingly, the Medicines and Healthcare products Regulatory Agency (MHRA), recently issued a drug safety alert stating that tiotropium, when administered by the Respimat device, has been found to be associated with a non-significant increase in mortality compared to placebo.9

Methylxanthines… such as theophylline and aminophylline produce bronchodilation and improve FEV1 in patients with COPD and may be used in patients who remain symptomatic despite using inhaled bronchodilators.1,3 However, their use is limited by their narrow therapeutic range, frequent adverse effects (for example indigestion, headache, nausea, tremor, arrhythmias and convulsions) and potential to interact with may other commonly prescribed drugs.

Inhaled corticosteroids… have been shown to reduce exacerbation rates in severe COPD;10 however, in the UK, these are only licensed for use in COPD in the combination inhaled corticosteroid/LABA inhalers Seretide® 500 Accuhaler (fluticasone/salmeterol) and Symbicort® Turbohaler (budesonide/formoterol). The long-term safety of inhaled corticosteroids is not known, but common adverse effects include oral candidiasis, dysphonia and skin bruising. Recent data has also demonstrated an increase risk of pneumonia in COPD patients treated with inhaled corticosteroids.11

Combination inhaled corticosteroid/long-acting beta2-agonist… inhalers are more effective than either component alone on reducing exacerbation rate, 
and improving health status and lung function. However, combination therapy failed to demonstrate a significant effect on mortality in a large prospective clinical trial.11

Selective phosphodiesterase-4 inhibitors… such as roflumilast, which is a novel oral once-daily drug licensed for the maintenance treatment of severe COPD associated with chronic bronchitis and a history of frequent exacerbations. Roflumilast produces a small improvement in lung function in patients with moderate to very severe COPD when used in addition to beta2-agonists,12 or tiotropium.13 Additionally, roflumilast was demonstrated to reduce the number of moderate to severe exacerbations compared to placebo in patients treated with beta2-agonists.12

The place in therapy of roflumilast is uncertain, as there is a lack of data to inform of any benefit in patients currently treated with maximal inhaled therapy (inhaled corticosteroid, LABA, LAMA and SABA). Common adverse effects include diarrhoea, weight loss and nausea.

Pharmacological therapy by 
disease severity
The current international GOLD guidelines1 recommended that treatment of COPD should be determined by severity of COPD based on post-bronchodilator spirometry. In these guidelines, mild COPD should be treated with SABA inhalers to treat dyspnoea, moderate COPD should be treated with long-acting bronchodilators, and inhaled corticosteroids should be reserved for patients with severe to very severe COPD.

However, the latest UK guidelines3 recommend an emphasis that is based more on assessment of clinical features and the persistence of symptoms including exacerbations and shortness 
of breath rather than an over-reliance 
on spirometry – since this is an arbitrary value not related to a patient’s functional status (see Figure 1).3

Exacerbations
Exacerbations of COPD may be defined 
as ‘a sustained worsening of the patient’s symptoms from his or her usual stable state that is beyond normal day-to-day variations, and is acute in onset. Commonly reported symptoms are worsening breathlessness, cough, increased sputum production and change in sputum colour. The change in these symptoms often necessitates a change in medication’.3

Causes of exacerbations include bacteria (commonly Haemophilus influenza, Moraxella catarrhalis and Streptococcus pneumoniae), viruses 
(for example influenza, parainfluenza, respiratory syncytial virus, coronavirus and rhinovirus) and pollution.1,3 Exacerbations of COPD are associated with worse prognosis, with frequent exacerbations linked to higher mortality, poorer quality of life, increased airway inflammation and a faster decline in 
lung function.14

The treatment of exacerbations at home or in hospital comprises increased dose and/or frequency of short-acting bronchodilators (via nebuliser or metered dose inhaler plus spacer) and systemic corticosteroids (for example prednisolone 30–40mg for seven to 14 days).1,3 Antibiotics should be reserved for patients presenting with a history of dyspnoea and either increased sputum volume or increased sputum volume. Initial empirical therapy should 
be with an aminopenicillin, tetracycline or macrolide.1,3

Patients presenting with severe exacerbations require hospital admission for more intensive treatment and monitoring. Hypoxaemia should be treated with controlled oxygen to achieve a target oxygen saturation of 88–92% in order to prevent hypercapnia resulting from carbon dioxide retention, and subsequent worsening respiratory acidosis.15 Therefore, arterial blood gases should be checked 30–60 minutes after commencing oxygen therapy to ensure 
an improvement in oxygenation without worsening of hypercapnia and acidosis.

Patients with persistent moderate to severe respiratory acidosis (pH ≤7.35) and hypercapnia (pCO2 >6kPa) despite optimal medical therapy should be treated with non-invasive ventilation.1,3 Additionally, intravenous aminophylline may be used if there is an insufficient response to inhaled bronchodilators, with close monitoring of serum theophylline levels.1,3

Additional therapies that should 
be prescribed for patients admitted to hospital include nutritional supplements, when needed, and low molecular weight heparin for prophylaxis against venous thromboembolism.1 There is no evidence to support the use of mucolytics such as carbocisteine or inhaled acetylcysteine 
to aid mucous expectoration during 
an exacerbation.

Future treatments in COPD
In the near future, alternative ultra long-acting β2-agonists such as carmoterol (Cheisi, Italy), long-acting antimuscarnincs such as aclidinium (Almirall/Forest Laboratories) and other combination inhalers are likely to be launched.

However, these and currently available treatments in COPD have only been shown to be effective in improving symptoms of breathlessness, quality 
of life and lung function, but none have 
so far been proven to prevent disease progression or reverse damage. Also many of the current therapies have side effects that can be detrimental, such as corticosteroid-induced diabetes and osteoporosis, or the cardiac-stimulatory effects of beta-agonists. As more is learnt about the mechanisms involved in the development of COPD, it is hoped that future therapies may become more specific to its pathology and target the multi-component model of inflammation and tissue remodelling in COPD.

Consequently, targets could include oxidants, cytokines and pro-inflammatory markers, proteases and inflammatory mediators. Treatments that may be of benefit in COPD patients in the future:

• Antioxidants: N-aceytlcystine is an oral antioxidant used for the treatment of idiopathic-pulmonary fibrosis. Small trials suggest that it may have 
a role in protecting lung tissue from macrophage damage caused by inflammation. However, more potent anti-oxidants are in development16
• Novel anti-inflammatory targets: a number of biologic and pharmacologic therapies are currently in the early stages of clinical development for COPD, such as TNFα-antagonists, neutrophil elastase inhibitors, elastase inhibitors, p38 mitogen-activated protein kinase (MAPK) inhibitors and chemokine receptor CXCR1/CXCR2 antagonists.16-18

Role of the pharmacist
Inhaler technique and device selection
It is important that patients are prescribed inhaler devices inhalers only after they have received training and education on how to use their device and have demonstrated satisfactory technique.1,3 
If a patient is unable to effectively use an inhaler, then they may be unlikely use the device or obtain benefit from it and may also be more likely to experience side effects such as oral candidiasis with inhaled corticosteroids.

The selection of an appropriate inhaler device can be assisted by using an In-Check DIAL inspiratory flow meter (Clement Clarke Ltd, Harlow, UK), which mimics the internal resistance of a range of inhaler devices allowing the measurement of inspiratory flow rate to ensure that each patient can inhale through a device at its optimal inspiratory flow rate.

This is an important consideration, because patients with severe COPD may have a poor inspiratory flow, which means that some dry powder inhaler devices may be unsuitable, since they require a strong and fast inspiration to achieve optimal drug delivery. Many COPD patients may also experience problems using metered dose inhaler devices due to problems 
with co-ordination, and so may require additional education.

Education and counselling
COPD patients often have complex management plans and more severely affected patients may require nebulisers at home. Patients at high risk of having an exacerbation of COPD should be provided with a self-management plan and given a course of oral corticosteroids and antibiotics to keep at home.

This, combined with instructions on when to start taking rescue treatment as well as increasing their bronchodilator therapy, allows patients to promptly respond to symptoms of an exacerbation.3 To ensure these are used appropriately and not dangerously, clear advice and education is needed.

Adherence to medications
A typical patient may be prescribed three different inhalers and a number of oral treatments for their COPD, and this is often just a small part of their treatment, as many patients have other co-morbidities such as cardiovascular disease and osteoporosis. Medication can therefore be difficult and daunting for the patient, and the pharmacist can play a huge role in patient education and in helping the patient to remember to take their various medications. Interventions to improve adherence include the use of medicines reminder charts and compliance aids, simplifying the dosing regimen, addressing beliefs and concerns that the patient has about their treatment, and managing potential or actual 
side effects.19

Prescribing role
Prescribing pharmacists could have role in prescribing and monitoring for COPD patients in GP practices, hospital clinics or in community pharmacies, ensuring that treatment is optimised and fits in with each patient’s lifestyle.

References

1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2009. 
Available at: www.goldcopd.com/Guidelineitem.asp?l1=2&l2=1&intId=2003. Accessed: 
17 January 2010.
2. World Health Organisation. The global burden 
of disease: 2004 update. Available at: 
www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_full.pdf. Accessed 7 November 2010.
3. National Clinical Guideline Centre. Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care. London: National Clinical Guideline Centre. 2010. Available from: http://guidance.nice.org.uk/CG101/Guidance/pdf/English. Accessed 11 July 2010.
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7. Lee TA et al. Ann Intern Med 2008;149:380-90.
8. Tashkin DP et al. N Engl J Med. 2008;359:1543-554.
9. Medicines and Healthcare products Regulatory Agency. Drug Safety Update 2010;4:H2. 
Available at: www.mhra.gov.uk/home/groups/dsu/documents/publication/con099854.pdf. Accessed: 12 November 2010.
10. Burge PS et al. The ISOLDE trial. BMJ. 2000;320:1297-303.
11. Calverley PM et al. N Engl J Med 2007;356:775-89.
12. Calverley PMA et al. Lancet 2009;374:685-94.
13. Fabbri LM et al. Lancet 2009;374:695-703.
14. Wedzicha JA & Seemungal TA. Lancet 2007;370:786-96.
15. O’Driscoll BR et al. Thorax 2008;63:vi1-vi68.
16. Augusti AGN. Resp Med 2005;99:670-82.
17. Barnes PJ. Future treatments for chronic obstructive pulmonary disease and its comorbidities. Proc Am Thorac Soc 2008;5:857-64.
18. Morjaria JB et al. Drug Discovery Today 2010;15:396-405.
19. Nunes V et al. Medicines Adherence: involving patients in decisions about prescribed medicines and supporting adherence. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners. 2009. Available at: www.nice.org.uk/nicemedia/live/11766/42971/42971.pdf. Accessed 14 November 2010.