Ebook ABC of COPD (2/E): Part 2

Part 2 book “ABC of COPD” has contents: Pharmacological management – Inhaled treatment, pharmacological management - oral treatment, oxygen, exacerbations, non-invasive ventilation, primary care, future treatments.

CHAPTER Pharmacological Management (I) – Inhaled Treatment Graeme P Currie1 and Brian J Lipworth2 Aberdeen Royal Infirmary, Aberdeen, UK Asthma and Allergy Research Group, Ninewells Hospital and Medical School, Dundee, UK OVERVIEW • All patients with chronic obstructive pulmonary disease (COPD) should use a short-acting bronchodilator (short-acting β2 -agonist or short-acting anticholinergic) for as required relief of symptoms • A long-acting bronchodilator (long-acting anticholinergic or long-acting β2 -agonist) should be started in those with persistent symptoms and exacerbations if the FEV1 is ≥50% of predicted • Inhaled corticosteroids play no role as monotherapy in COPD • A long acting β2 -agonist plus inhaled corticosteroid or long acting anticholinergic should be considered in patients with persistent symptoms and exacerbations who have an FEV1 < 50% of predicted • A long-acting anticholinergic, long-acting β2 -agnoist and inhaled corticosteroid should be used in patients with advanced disease who have persistent symptoms and exacerbations Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition and all patients should be regarded as individuals This is apparent not only in terms of presentation, natural history, symptoms, disability and frequency of exacerbations but also in response to treatment The stepwise titration of pharmacological therapy in COPD is usually based around • • • • extent of airflow obstruction; severity of symptoms (usually breathlessness); functional limitation; presence and frequency of exacerbations Physiological effects of inhaled bronchodilators It is increasingly apparent that inhaled bronchodilators confer important clinical benefits over and above changes in forced expiratory volume in second (FEV1 ) Relying upon measures of lung function alone to monitor the effects of bronchodilators may be a rather simplistic approach, and has the potential to miss important physiological and clinical benefits Air trapping, which Total lung capacity Tidal ventilation Healthy lung At rest During During exercise with no exercise with bronchodilator bronchodilator Patients with COPD Figure 7.1 Patients with chronic obstructive pulmonary disease (COPD) have pulmonary hyperinflation with an increased functional residual capacity (purple) and a decreased inspiratory capacity (white) This increases the volume at which tidal breathing (oscillating line) occurs and places the muscles of respiration at mechanical disadvantage Hyperinflation worsens with exercise and therefore reduces exercise tolerance (dynamic hyperinflation) Inhaled bronchodilators improve dynamic hyperinflation, in addition to hyperinflation at rest, thereby reducing the work of breathing and increasing exercise tolerance is manifested clinically as hyperinflation, is frequently found in patients with advanced COPD; this places the respiratory muscles at a mechanical disadvantage During exercise, air trapping increases even further, which in turn perpetuates the mechanical disadvantage experienced at rest (Figure 7.1) Inhaled bronchodilators reduce measures of air trapping at rest and on exercise (static and dynamic hyperinflation), which may well occur without significant changes in FEV1 Moreover, as COPD is largely an irreversible condition, relying solely on outcome measures such as lung function may result in potentially important beneficial effects being missed upon parameters such as static lung volumes, quality of life and exacerbation frequency Short-acting bronchodilators ABC of COPD, 2nd edition Edited by Graeme P Currie  2011 Blackwell Publishing Ltd 32 Short-acting β2 -agonists such as salbutamol and terbutaline act directly upon bronchial smooth muscle to dilate the airway Pharmacological Management (I) – Inhaled Treatment Table 7.1 Pharmacological properties of the main inhaled bronchodilators used in COPD Class Drug Short-acting β2 -agonist Salbutamol Terbutaline Formoterol Long-acting β2 -agonist Salmeterol Short-acting anticholinergic Ipratropium Long-acting anticholinergic Tiotropium Onset Peak effect Duration (minutes) (minutes) (hours) 5 45–60 5–15 15 60–90 60–90 60–90 120–240 60–120 60–240 4–6 4–6 12 12 4–6 36 (Table 7.1) This class of drug reduces breathlessness, improve lung function and are effective when used on an ‘as required basis’ Short-acting anticholinergics such as ipratropium offset high-resting bronchomotor vagally induced tone and also dilate the airways These drugs have been shown in some studies to reduce breathlessness, improve lung function, improve health-related quality of life and reduce the need for rescue mediation All patients with COPD should therefore be prescribed a short-acting inhaled bronchodilator (β2 -agonist or anticholinergic) for as required relief of symptoms Patients using the long-acting anticholinergic tiotropium should not be prescribed a short-acting anticholinergic, but rather a short-acting β2 -agonist for as required use Long-acting bronchodilators In COPD, the two classes of inhaled long-acting bronchodilator available are long-acting anticholinergics (tiotropium) and long-acting β2 -agonists (formoterol and salmeterol) Numerous studies have evaluated their effects in COPD, and guidelines indicate that a long-acting bronchodilator as monotherapy should be given to symptomatic patients with an FEV1 ≥ 50% of predicted If symptoms persist thereafter, both classes of long-acting bronchodilator may be used concurrently through separate inhaler devices Long-acting anticholinergics and long-acting β2 -agonists are usually well tolerated, although adverse effects occur in some patients (Box 7.1) 33 Long-acting anticholinergics Airflow obstruction in COPD is multifactorial in origin and is in part due to potentially reversible high cholinergic tone Moreover, mechanisms mediated by the vagus nerve are implicated in enhanced submucosal gland secretion in patients with COPD This knowledge has led to the development of a long-acting once-daily administered anticholinergic drug (tiotropium) Three main subtypes (M1 , M2 and M3 ) of muscarinic receptors exist The activation of both M1 and M3 receptors results in bronchoconstriction whereas the M2 receptor is protective against such an effect In contrast to ipratropium, tiotropium dissociates rapidly from the M2 receptor (therefore minimising the loss of any putative benefit) and dissociates only slowly from the M3 receptor This in turn causes a reduction in resting bronchomotor tone, smooth muscle relaxation and airways dilation for a greater length of time In the United Kingdom, it is the only licensed long-acting anticholinergic and can be delivered via a breath-activated dry powder inhaler (Handihaler) or soft mist inhaler (Respimat) Numerous studies of patients with COPD have shown tiotropium to be more effective than both placebo and ipratropium This is in terms of lung function, symptoms, quality of life and exacerbations In a meta-analysis of nine studies, tiotropium was associated with a reduction in exacerbations and hospital admissions compared to placebo and ipratropium In the same study, tiotropium was significantly better at improving lung function than long-acting β2 -agonists In the study by Tashkin et al (2008), the effects of add-on tiotropium to all other medication were evaluated over a 4-year period in nearly 6000 patients with an FEV1 of 13,000 individuals, long-term inhaled corticosteroids failed to reduce the decline in FEV1 and no beneficial effects upon mortality were observed Treatment was, however, associated with reductions in the mean rate of exacerbations per year and rate of decline in quality of life The dose of inhaled corticosteroid required to achieve maximal beneficial effect with minimal adverse effect (optimum therapeutic ratio) is uncertain Current evidence Mean change from baseline FEV1 (L) Pharmacological Management (I) – Inhaled Treatment 35 –0.05 –0.10 –0.15 –0.20 Budesonide Placebo –0.25 12 15 19 21 24 27 30 33 36 Time (months) Figure 7.3 Inhaled corticosteroids have not been shown to influence the rate in decline in lung function in chronic obstructive pulmonary disease (COPD) In this study of patients with mild COPD, no difference in mean change in baseline forced expiratory volume in second (FEV1 ) between placebo and budesonide was observed over 36 months Reproduced with permission from Vestbo et al Lancet 1999; 353: 1819–1823 Figure 7.4 Oropharyngeal candidiasis in a patient with chronic obstructive pulmonary disease (COPD) using high-dose inhaled corticosteroids suggests that inhaled corticosteroids should be prescribed in patients with an FEV1 < 50% predicted and who experience frequent (>2 per year) exacerbations Adverse effects of inhaled corticosteroids Inhaled corticosteroids cause both local and systemic adverse effects Common local adverse sequelae include oropharyngeal candidiasis (Figure 7.4) and dysphonia Previous studies have shown that skin bruising (Figure 7.5) occurs more commonly in patients using inhaled corticosteroids and variable effects have been observed in reduction of bone mineral density and suppression of the hypothalamic–pituitary–adrenal axis Moreover, the TORCH trial by Calverley et al (2007) demonstrated an increased risk of pneumonia in patients receiving inhaled corticosteroids alone and when used in conjunction with a long-acting β2 -agonist Figure 7.5 Extensive skin bruising in a patient using inhaled corticosteroids Combined inhaled corticosteroid plus long-acting β2 -agonist inhalers Most studies evaluating long-acting β2 -agonists and inhaled corticosteroids have shown superiority with the combination product over the single agent alone For example, in the largest study evaluating this combination of drugs (TORCH), fluticasone plus salmeterol in combination was better than either drug as monotherapy in terms of survival, FEV1 , exacerbation frequency and quality of life over a 3-year period In studies evaluating the combination of budesonide with formoterol, the proportion of reductions in exacerbations (25%) were similar to the TORCH study with the combination product versus placebo In most studies evaluating long-acting β2 -agonists and inhaled corticosteroids in combination, the mean FEV1 was 2 exacerbations annually Triple therapy In advanced symptomatic COPD, many patients are prescribed a combination of a long-acting anticholinergic, a long-acting β2 -agonist and an inhaled corticosteroid This approach has not been fully evaluated and only few studies have involved patients using such triple therapy In two studies by Tashkin et al (2008) and Welte et al (2009), the addition of tiotropium to fluticasone plus salmeterol resulted in a reduction in exacerbations in one study, but not the other However, in another study, the addition of tiotropium to formoterol plus budesonide compared to tiotropium alone did result in greater improvements in lung function, health status, symptoms and reduction in severe exacerbations (Figure 7.6) Exacerbations/patient 36 ABC of COPD 0.4 exists and the effects of the individual components are less than additive P