BMJ  2006;332:1439-1441 (17 June), doi:10.1136/bmj.332.7555.1439

Practice

ABC of chronic obstructive pulmonary disease

Pharmacological management—inhaled treatment

¹ Respiratory Unit, Aberdeen Royal Infirmary, Aberdeen., ² Asthma and Allergy Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee.

Chronic obstructive airways disease (COPD) is a heterogeneous condition, and all patients should be viewed as individuals—not only in terms of presentation, history, symptoms, and disability, but also in response to treatment. Acceptability to the patient, possible adverse effects, and efficacy of treatment are important factors to consider when prescribing inhaled drugs. The titration of drug treatment in COPD is usually based on the degree of airflow obstruction, severity of symptoms, exercise tolerance, and frequency of exacerbations.

All patients with established COPD should be prescribed a short acting inhaled bronchodilator for use as required

 

Short acting bronchodilators

For all patients with established COPD, prescribe a short acting inhaled bronchodilator (₂ agonist or anticholinergic, or both in combination).

View larger version (26K): [in this window] [in a new window]   Patients with COPD have pulmonary hyperinflation, with increased functional residual capacity (red) and decreased inspiratory capacity (white). This increases the volume at which tidal breathing (oscillating line) occurs and places the respiratory muscles at mechanical disadvantage. Hyperinflation worsens with exercise and reduces exercise tolerance (dynamic hyperinflation). Inhaled bronchodilators improve dynamic hyperinflation and hyperinflation at rest, reducing the work of breathing and increasing exercise tolerance

 

Short acting ₂ agonists such as salbutamol reduce breathlessness and improve lung function, and are effective when used "as required." They act directly on bronchial smooth muscle and cause the airways to dilate for up to six hours.

Short acting anticholinergics such as ipratropium reduce breathlessness, improve lung function, improve health related quality of life, and reduce the need for rescue medication. They offset high resting bronchomotor tone and improve airway calibre for up to six hours.

Both drugs in combination (salbutamol plus ipratropium delivered via a metered dose inhaler) have been shown to confer greater improvement in lung function than either drug given alone.

Long acting bronchodilators

For patients with persistent symptoms and exacerbations, prescribe a long acting bronchodilator. Current guidelines recommend monotherapy with a long acting ₂ agonist or anticholinergic for symptomatic patients with mild airflow obstruction (forced expiratory volume in 1 second (FEV₁) 50-80% of predicted value).

Inhaled long acting bronchodilators confer important clinical benefits beyond changes in FEV₁. Therefore, relying on measures of lung function alone to monitor the effects of bronchodilators may miss important physiological and clinical benefits. Air trapping, which is manifest clinically as hyperinflation, often occurs in advanced COPD and places the respiratory muscles at mechanical disadvantage. During exercise, air trapping increases even further, perpetuating the mechanical disadvantage experienced at rest. Long acting bronchodilators often reduce measures of air trapping at rest and on exercise (static and dynamic hyperinflation), and these may well occur without significant changes in FEV₁.

This is the sixth in a series of 12 articles

Long acting ₂ agonists
₂ agonists act directly on ₂ adrenoceptors, causing smooth muscle to relax and airways to dilate. The two most widely used long acting drugs—formoterol and salmeterol—have a duration of action of at least 12 hours and therefore are indicated for twice daily use. In contrast to the short acting ₂ agonists, these drugs are relatively lipophilic (fat soluble) and have prolonged receptor occupancy. Factors such as these may in part explain their prolonged duration of action. In vitro data have shown that formoterol relaxes smooth muscle more potently than does salmeterol, and it has a much quicker onset of action, similar to that of the short acting ₂ agonist salbutamol.

View larger version (129K): [in this window] [in a new window]   Breath activated inhaler device used to deliver tiotropium to the endobronchial tree

 

Regular use of a long acting ₂ agonist by patients with COPD generally leads to improved lung function, symptoms, and quality of life. A Cochrane systematic review of eight trials evaluating the effects of these drugs on COPD found inconsistent effects on exacerbations.

View larger version (25K): [in this window] [in a new window]   Effect of inhaled corticosteroid (budesonide) on rate of decline in lung function of patients with mild COPD: compared with placebo, corticosteroid made no difference in mean change in baseline FEV over 36 months

 

Long acting anticholinergics
The characteristic airflow obstruction in COPD is multifactorial in origin and is partially due to potentially reversible high cholinergic tone. Furthermore, mechanisms mediated by the vagus nerve are implicated in the enhanced secretion by submucosal glands seen in patients with COPD. This knowledge has led to the development of a long acting anticholinergic taken once daily (tiotropium), which is likely to supersede short acting drugs (ipratropium and oxitropium).

View this table: [in this window] [in a new window]   Adverse effects of long acting bronchodilators Although long acting 2 agonists and anticholinergics are generally well tolerated, adverse effects do occur in a minority of patients.

 

Three main subtypes of muscarinic receptor exist (M₁, M₂, and M₃). Activation of the 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 prolongs the reduction in resting bronchomotor tone, smooth muscle relaxation, and airway dilation. Tiotropium's onset of peak bronchodilation is between one and three hours. It is the only long acting anticholinergic currently licensed in the United Kingdom and is delivered to the airways via a breath activated, dry powder inhaler at a dose of 18 µg/day. With this device, tiotropium can be successfully deposited in the airways of patients with very low inspiratory flow rates.

Oropharyngeal candidiasis is a common adverse effect of using high dose inhaled corticosteroids

 

Many studies of patients with COPD have shown tiotropium to be more effective than ipratropium (and placebo) in terms of lung function, symptoms, quality of life and exacerbations. Few studies have directly compared tiotropium with long acting ₂ agonists, but in one study tiotropium was better than salmeterol at improving lung function. Further investigations are needed to clarify the place of tiotropium in treating patients with COPD of varying severity and how it compares with other inhaled treatments.

Inhaled corticosteroids

Commonly prescribed inhaled corticosteroids include beclometasone dipropionate, budesonide, and fluticasone propionate. Many patients with COPD, even those with minimal symptoms and mild airflow obstruction, have been traditionally treated with inhaled corticosteroids as monotherapy. This is despite corticosteroids' relative ineffectiveness on the neutrophilic inflammation found in COPD and lack of evidence of significant short or long term benefits. Historically, this was due to clinicians incorrectly extending the beneficial role of anti-inflammatory treatment in asthma to COPD, plus a lack of alternative drug treatments.

The exact role of inhaled corticosteroids in the management of COPD is uncertain. It is fairly well established that, as monotherapy, they do not have any appreciable impact on the rate of decline in FEV₁ or in improving survival. In one large study (ISOLDE), 1000 µg/day of fluticasone did confer a 25% reduction in exacerbations, with most benefit being observed in patients with mean FEV₁ < 50% of predicted. Other studies have shown inconsistent effects on secondary end points, with no or only small improvements in symptoms and quality of life.

The dose of inhaled corticosteroid required to achieve maximal beneficial effect with minimal adverse effect (optimum therapeutic ratio) is uncertain, and more data are needed. As a consequence, consider prescribing regular, high dose, inhaled corticosteroids in patients with an FEV₁ < 50% of predicted and who experience frequent exacerbations (> 2 a year).

Extensive skin bruising in a patient using high dose inhaled corticosteroids

 

Combined corticosteroid plus long acting ₂ agonist inhalers
Using a long acting ₂ agonist combined with a corticosteroid in a single inhaler device—such as Symbicort (budesonide plus formoterol) and Seretide (fluticasone plus salmeterol)—is more convenient than taking the drugs separately. This facilitates compliance by patients with more severe airflow obstruction and frequent exacerbations, who require both drugs. Studies have shown that the combination product is often more effective than the individual component as monotherapy, although in all of these studies the mean FEV₁ was < 50% of predicted. Trials of combination inhalers for patients with less severe airflow obstruction are required to establish their role fully. The role of "triple therapy" (corticosteroid and long acting ₂ agonist combination inhaler plus long acting anticholinergic) in more severe disease also needs to be defined.

View larger version (32K): [in this window] [in a new window]   Algorithm for inhaled drug treatment in patients with COPD

 

Summary of inhaled treatment

Since airflow obstruction is the universal feature of clinically significant COPD, bronchodilators play an integral role in all stages of disease. All patients with symptomatic COPD need a short acting inhaled bronchodilator for use "as required," while those with mild airflow obstruction (FEV₁ 50-80% of predicted) should regularly use a long acting bronchodilator. In other words, patients with persistent symptoms despite intermittent use of a short acting bronchodilator should use a long acting ₂ agonist twice daily or a long acting anticholinergic once daily as first line treatment. Guidelines do not suggest which class of long acting bronchodilator should be used in the first instance.

View this table: [in this window] [in a new window]   Adverse effects of inhaled corticosteroids

 

If symptoms persist despite use of a long acting bronchodilator, prescribe both classes of long acting bronchodilator concomitantly to maximally dilate the airways. Inhaled corticosteroids play less of a role in COPD management and should be reserved for patients with more advanced airflow obstruction (FEV₁ < 50% of predicted) and frequent exacerbations. Consider prescribing "triple therapy" with all three classes of inhaled drug in those with persistent symptoms, exacerbations, and severe airflow obstruction.

Further reading • National clinical guideline on management of chronic obstructive pulmonary disease in adults in primary and secondary care. Thorax 2004;59(suppl 1): 1-232[Free Full Text] • Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) workshop summary. Am J Respir Crit Care Med 2001;163: 1256-76[Free Full Text] • Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23: 932-46[Free Full Text] • Appleton S, Poole P, Smith B, Veale A, Bara A. Long-acting -agonists for chronic obstructive pulmonary disease patients with poorly reversible airflow limitation. Cochrane Database Syst Rev 2002;(3): CD001104 • Currie GP, Rossiter C, Miles SA, Lee DKC, Dempsey OJ. Effects of tiotropium and other long acting bronchodilators in chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2006;19: 112-9[Medline] • Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320: 1297-303[Abstract/Free Full Text] • Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000;343: 1902-9[Abstract/Free Full Text]

 

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The ABC of chronic obstructive pulmonary disease is edited by Graeme P Currie. The series will be published as a book by Blackwell Publishing in autumn 2006.

Competing interests: GPC has received funding for attending international conferences and honoraria for giving talks from pharmaceutical companies GlaxoSmithKline, Pfizer, and AstraZeneca. BJL has received funding for attending conferences, payment for speaking and consulting activity, and research funding from pharmaceutical companies AstraZeneca, Atlanta, Aerocrine, Sepracor, MSD, Neolab, Cipla, Innovata, UCB-Celltech, and Schering-Plough.

The picture of an elderly patient using an inhaler was supplied by Mark Clarke and Science Photo Library. The diagram of the effects of bronchodilators on hyperinflation was adapted from Sutherland et al. N Engl J Med 2004;350: 2689-97.[Free Full Text] The graph of the effect of budesonide on rate of lung function decline was adapted from Vestbo et al. Lancet 1999;353: 1819-23.[CrossRef][ISI][Medline]

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