|Year : 2013 | Volume
| Issue : 2 | Page : 75-80
Chronic obstructive pulmonary disease: An evidence-based update
Department of Intensive Care, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia
|Date of Web Publication||10-Sep-2013|
Department of Intensive Care Medicine, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh
Kingdom of Saudi Arabia
The use of bronchodilators represents the cornerstone drug management of chronic obstructive pulmonary disease (COPD), and the employed bronchodilating agents include β2 -adrenergic agonists, anticholinergic agents, and the methylxanthines. Combination therapy combining bronchodilating agents with differing durations of action and from different classes provides greater symptomatic improvement and reduced risk of adverse drug effects. As a result of the observed tendency to precipitate steroid myopathy, oral glucocorticosteroids are not recommended for long-term use in COPD management, but the adjunctive use of inhaled forms in cases of COPD stages III and IV reduces the frequency of exacerbations and improves the patient's quality of life. The absence of medications modifying the lung function decline, a major hallmark describing the course of COPD, necessarily implies that drug management involves an amelioration of COPD symptoms. Preventive approach to COPD management involves measures aimed at reducing individuals' exposure to tobacco smoke and other airborne pollutants; measures geared towards smoking cessation is the most efficacious way of halting the progression of COPD.
Keywords: Chronic bronchitis, chronic obstructive pulmonary disease, emphysema
|How to cite this article:|
Alshimemeri A. Chronic obstructive pulmonary disease: An evidence-based update. Saudi J Health Sci 2013;2:75-80
| Introduction|| |
Chronic obstructive pulmonary disease is a respiratory condition characterized by airflow impairment usually resulting from an underlying inflammatory response to persistent exposure of the lung to particulate matters. , Chronic exposure to inhaled insult is associated with chronic inflammatory response alongside mucous overproduction, which ultimately impairs ciliary clearance function and renders the airway environment vulnerable to microbial infections.  The resulting tissue damage, scarification, and the accompanying collagen deposition later lead to a compromise of its structural integrity and, as a consequence, a narrowing of the airway lumen. The ensuing airway obstruction sets the stage for a range of events including decreased inspiratory capacity, expiratory flow (the clinical hallmark of the disease), and loss of elastic recoil.  The condition is further worsened by emphysema and chronic bronchitis, both of which are considered as common associative conditions in COPD. Although COPD is effectively managed at any phase of the illness, the most important intervention measure is preventive, involving avoidance of exposure to smoking (cigarette smoke and other organic smoke), recognized as the single most important factor in the development of COPD. 
COPD is characterized by breathlessness (particularly during physical exertion), most frequently as a result of a severe expiratory airflow impairment causing a progressive pulmonary hyperinflation. The airflow limitation characterizing COPD results from the loss of the elastic recoil in the lung parenchyma, from airway hyperplasia, from fibrotic tissues, or from "peribronchial inflammation."  Other reported causes of breathlessness are impairment of cardiovascular, metabolic, and respiratory processes. Administration of bronchodilators reduces dynamic hyperinflation and breathlessness by reducing the absolute pulmonary volume at which expiratory airflow impairment takes place. The use of bronchodilators in the management of symptomatic stable COPD is currently recognized as the mainstay of treatment typically associated with improvement in hyperinflation, dyspnoea, and expiratory flow resulting from smooth muscle relaxation and amelioration of the airway obstruction.
There has been an increase in the number of trials conducted for COPD in the past decade involving various aspects of disease management,  many of which involves the use of bronchodilators either as monotherapy or in combination with similar mechanisms of action or with inhaled corticosteroids. Some of these trials have generated unusual, if not contradictory, results such that their interpretation should be pursued with utmost caution. Changes in baseline demographics, protocols followed in recent trials, the inclusion criteria, and the availability of newer bronchodilator agents are some of the factors that should be taken into cognizance before drawing conclusions from the generated data. Added to these are the issues of trials involving concomitant or prior treatment with other agents where carried-over effects not completely removed in the wash-out interval are likely to influence clinical outcomes. For these reasons, trial results may be better discussed within the particular context of relevance and only extended to other studies when there is a valid basis for such a comparison.
COPD should be suspected in subjects presenting with persistent cough, breathlessness upon exercise (dyspnoea), and sputum production.  Although the suspicion is further reinforced in patients possessing history of tobacco use,  a definitive diagnosis of COPD is only established by performing pulmonary function tests with spirometry, which also forms the cornerstone of disease staging and assessment of management efforts. According to the GOLD guideline, a COPD diagnosis is established when the forced expiratory volume in 1 second (FEV1) related to the forced vital capacity (FVC)-that is, the FEV1/FVC ratio-is <0.7. (See [Table 1] below for the GOLD guideline for diagnosis and staging of COPD). ,
|Table 1: Categorization of COPD stages in accordance with GOLD's specification|
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The extensive overlap between the COPD presented symptoms and certain other respiratory disorders has necessitated the need for a chest X-ray scan in order to rule out co-morbidities (e.g., airway infections and lesions, malignant growths, heart problems, and foreign particles). However, the presentation of abnormal X-ray spectra should not be taken as indicative of COPD: But the spectral patterns indicative of COPD include, among others, the presence of vascular marks that rapidly taper, lung hyperlucency, and hyperinflation.  Unresolved diagnosis may benefit from high resolution computed tomography scan (HRCT), a technique which is of special importance when lung resection is contemplated.  In addition, a corticosteroid test may be required to rule out asthma, and asthmatic patients are expected to show an improvement in the FEV1 of about ≥12%, following the administration of short-acting β2 -agonists. 
The management of COPD is generally aimed at halting disease progression, improving respiratory symptoms, preventing and handling exacerbations and complications, improving exercise tolerance and patient's quality of life (QoL), and ultimately reducing mortality.  These steps make the management of COPD a multicomponent theme including both pharmacological and non-drug management strategies. It is recommended that physicians adopt treatment plans that, while pursuing these generic treatment goals, tailor management first to handle the specific challenges presented in each case.
Physicians are uniquely placed to identify tobacco users: physicians are recommended to actively promote tobacco use cessation as a cardinal COPD management effort.
A large randomized Lung Health Study published in 2002  reported significant lung tissue preservation in patients who achieved between 85% to total cessation of tobacco use as compared to that in other patients.
A comprehensive management plan is recommended to integrate disease monitoring and assessment, risk factors evaluation and reduction, and an efficient case-specific management of both stable COPD and cases of exacerbation.
Although physical examination does not accurately represent a pathological state in COPD, the degree of presented symptoms should be employed in conjunction with results from spirometric measurement and existence of COPD complications (arterial hypoxemia, right heart failure, weight loss, and respiratory failure) while assessing disease severity. Such assessment has a direct relevance in drawing up a management plan with the early stages of the disease (I and II)-requiring both measures for risk factor avoidance and drug treatment- and the late stages (III and IV), as well as calling for a multicomponent management strategy.  Measures to identify and reduce likely risk factors in each case of COPD must also be taken.
Although the past few years have witnessed an increasing use of bronchodilators in the management of COPD, exposure to tobacco smoke remains the single most important risk factor in COPD and measures aimed at reducing it have gradually become an important aspect of COPD management. These include the use of behavior-modifying approaches such as health education and the use of nicotine replacement therapy, which have been shown to be effective at aiding tobacco abstinence. ,
Pharmacological management of COPD
The management of COPD is a nontrivial matter. It involves both the facilitation of a smoking cessation program as well as controlling symptomatic stable COPD. Owing to the disease progression pattern characterizing stable COPD, its management often requires increasing drug treatment.  This is a fundamental aspect of COPD therapeutic management.
Presently, there are no drugs capable of altering the disease progression or halting pulmonary function decline, and it is recommended that physicians increase dosage as needed in accordance with the growing severity of the disease.
The use of bronchodilators, whether pro re nata or in strict regimen, remains the core component of COPD pharmacotherapy, and their use affords symptomatic benefits in stable COPD, thus improving the patients QoL and exercise tolerance, but without any demonstrable improvement of the progressive lung function decline associated with the disease. ,
The β2 -adrenoceptor agonists, anticholinergic agents, and methylxanthines are the most prescribed, and phosphodiesterase enzyme inhibitors have also been administered in COPD.
The β2 -agonists potentiate their effect by activating the G-protein coupled β2 -receptors in the wall of the pulmonary system's smooth muscles. Activation of β2 -adrenoceptors leads to a cascade of events involving activation of adenyl cyclase, formation of cAMP from intracellular ATP, and the subsequent activation of protein kinase A, which inhibits the Na + /Ca ++ pump.  The resulting fall in intracellular Ca ++ causes relaxation of the bronchial smooth muscles and the pharmacological effect observed following administration of β2 -agonists.
Short-acting agents are available on an as-needed basis to provide initial symptom control.  The long-acting β2 -agonists, salmeterol and formoterol, however, are more effective than the short-acting fenoterol, albuterol and terbutaline, typically allowing twice daily administration (as opposed to four times daily application of the short-acting β-agonists).
Formoterol and salmeterol are respectively formulated as 4.5-12 μg and 20-50 μg inhaler forms [both metered dose inhaler (MDI) and dry powder inhaler (DPI)] providing 12 hour-bronchodilatory coverage and, hence, a twice daily dosing.
The inhalational formulations of the short-acting β2 -agonists are available as albuterol, 100 and 200 μg (MDI and DPI); fenoterol, 100-200 μg (MDI), and terbutaline, 400-500 μg (DPI). The oral forms (albuterol, 0.024% syrup and 5 mg tablet; fenoterol, 0.05% syrup; terbutaline, 2.5 mg and 5 mg tablet), the parenteral administration form (vials for injection: Albuterol, 0.1 and 0.5 mg; terbutaline, 0.2 and 0.5 mg) and solutions for nebulizer (available as 1 mg/ml for albuterol and 5 mg/ml for terbutaline) are also available for the short-acting agents and typically provide between 4 and 6 hours of symptomatic relief.
The anticholinergic bronchodilators dilate the lung smooth muscles by blocking the muscarinic receptors, producing symptomatic relief in COPD. The long-acting tiotropium [formulated as 18 μg inhaler (DPI)] possesses a much higher receptor affinity alongside slower dissociation kinetics (approximately 100 times slower) than the short-acting agents. Tiotropium is dosed once daily. The short-acting ipratropium (inhaler, 20 and 40 μg MDI; solution for nebulizer, 0.25-0.5 mg/ml) and oxitropium (inhaler, 100 μg MDI; solution for nebulizer, 1.5 mg/ml) are usually administered thrice daily. Methylxanthines, available as theophylline (200-600 mg tablet, 240 mg injectable), and theophylline (100-200 mg tablet), provide up to 24 hour coverage.
The methylxanthines potentiate bronchodilatory activity by reducing the intracellular level of cAMP, which reduces the intracellular calcium levels and brings about bronchodilation.
Glucocorticosteroids are also used in managing different stages of COPD although oral glucocorticosteroids are presently not recommended for use in COPD due to an association of the long-term use with steroid myopathy and the absence of data on their demonstrated efficacy. 
Nevertheless, both prednisolone and methyl-prednisolone are respectively available as 5-60 mg tablets and as 4, 8, and 16 mg tablets for use in COPD.
The regular use of inhaled glucocorticosteroids has been demonstrated to improve patients' QoL, reduce the frequency of exacerbation,  and has been associated with a reduction in mortality. 
Budesonide (100 μs, 200 μs, 400 μs DPI), beclomethasone (50-400 μs MDI and DPI), triamcinolone (100 μs MDI), and fluticasone (50-100 μs MDI and DPI) are recommended for use in severe COPD (stages III and IV, and FEV1 < 50%) and COPD exacerbations. The solutions for nebulizer are also available (budesonide, 0.20 mg/ml, 0.25 mg/ml, 0.40 mg/ml; beclomethasone, 0.2-0.40 mg/ml; and triamcinolone, 40 mg/ml) and, in the case of triamcinolone, the 40 mg tablet.
Combined administration of bronchodilators in the management of COPD are associated with superior therapeutic benefit and fewer side-effects and is generally preferred to increasing the dosage of a single therapy.
Formulations combining short-acting β2 -agonists with anticholinergic agents are available and these include fenoterol/ipratropium combination dosed three times daily and presented as a 200/80 μg inhaler (MDI) or 1.25/0.5 mg/ml solution for nebulizer and combined albuterol/ipratropium given three times daily and available as 75/15 μg (MDI) inhaler or 0.75/4.5 mg/ml solution for nebulizer.  This combination was indicated to significantly improve the FEV 1 as compared to either of the bronchodilators administered singly.
Long-acting β2 -agonists are also available combined with glucocorticosteroids with the available formulations including formoterol/budesonide [4.5/160 μg, 9/320 μg (DPI)] and salmoterol/fluticasone (50/100, 250, 400 μg (DPI) and 25/50, 125, 250 μg (MDI)). 
Mild cases of COPD (stage I) are often managed sufficiently with short-acting bronchodilators (inhalational route) pro re nata. Symptom severity is associated with more severe stages of COPD (stages II to IV), and the short-acting agents become less optimal for controlling symptoms. In this case, a long-acting agent is recommended alone or in combination with theophylline, depending on the level of symptom control achieved. Very severe cases of COPD (FEV 1 < 50%) may necessitate inhaled glucocorticosteroids, which lower exacerbation rates and improve the QoL.
Adverse drug effects
Because oral formulations are generally associated with a higher incidence of adverse drug effects, the use of the inhalational forms are generally preferred for COPD treatment.
However, serious adverse effects are not very common with bronchodilators and can easily be anticipated from the knowledge of their pharmacological effects. Although rare, the use of β2 -receptor agonists may affect cardiac rhythm (vulnerable groups only), alter somatic tremor (high doses in elderly patients) and hypokalemia (concurrent use with thiazide diuretics). ,
Anticholinergics may cause dry mouth and a metallic taste (ipratropium), while the improper use of the nebulizer has been indicated to result in acute glaucoma. The nonspecific inhibitory activities of the PDE by the methylxanthines, together with the associated narrow therapeutic window, account for their many side effects. Reported side effects include epileptic seizures (grand mal), arrhythmias, insomnia, headache, heartburn, and nausea. There is a paucity of information about the side-effects of the glucocorticosteroids and there are conflicting reports on the causal relationship between the use of budesonide and triamcinolone and an increased risk of a reduced bone density and bone fracture. ,,
| Research Perspective and Conclusion|| |
Because of their greater effectiveness, long-acting bronchodilators are recommended for use as the first-line of treatment in managing COPD, usually combined with the short-acting agents. Clinical trials have associated higher clinical benefits with the use of long-acting agents either as a single therapy or combined with other agents. Tiotropium 18 μg dose, once daily, in a 12-week randomized double-blind trial by Johansson et al., reportedly resulted in significant symptomatic amelioration in patients with mild COPD.  Similar trials have also demonstrated improvement in hyperinflation, spirometry, and frequency of exacerbations requiring hospitalization.  Pre-operative administration of tiotropium bromide was demonstrated to grant superior benefits over oxitropium, another anticholinergic agent,  as it improved exercise tolerance and the dyspnoea index when combined with chest rehabilitation as against the use of physiotherapy alone.  There have also been a number of studies comparing the clinical profile of tiotropium and members of the β-agonists. A 2005 study by Matera et al., comparing the short-term effect between 18 μg tiotropium and 50 μg salmeterol, reported comparable effect in both agents.  However, in a recent 1-year randomized trial involving 7376 patients, treatment with the anticholinergic was reported to prolong the time to first exacerbation, 185 days as compared with 145 days in the group treated with salmeterol.  With higher reduction in the total number of mild to severe exacerbations recorded per year, tiotropium was demonstrated to possess better efficacy than the long-acting β-agonist in preventing exacerbations. In another review of comparative long-term benefits of β-agonists and antimuscarinic agents, the latter groups were indicated to be associated with a higher reduction both in hospitalization and "respiratory mortality" and also generally provided a better control of severe exacerbations. 
Reports on the use of β-agonists as a single therapy have also indicated improvement in symptoms compared with placebo effects, which are more associated with the long-acting agents like salmeterol, rac-formoterol, arformoterol, and the ultra-long acting indacaterol and carmoterol. ,,,,,,,,,, Using trough FEV1 as a clinical endpoint, indacaterol 150 μg and 300 μg treatments after 14 days were shown to possess comparable efficacy as tiotropium  and superior effect compared to placebo treatment in moderate to severe cases of COPD.  The pattern of improvement in lung function indices and COPD symptom control is, however, not limited to the long-acting β-agonists alone as there have been reports, admittedly fewer, demonstrating the efficacy of the short-acting agents compared to placebo. In 2009, Costa et al., reported improvement in the "resistive and reactive properties" in the lungs of COPD patients.  There, however, appears to be a higher impetus, possibly deriving from a much wider application to investigate the role of long-acting agents in the management of COPD patients than the shorter-acting agents.
Compared to the β-agonists and anticholinergic agents, the phosphodiesterase inhibitors have received much less attention, possibly as a result of an associated narrow therapeutic index and a higher incidence of adverse events reported for theophylline. Apart from a modest improvement in acid-base homeostasis, no further effect on the course of disease was recorded after treatment with theophyline.  There is evidence, however, that the newer PDE inhibitor, roflumilast, is associated with better clinical efficacy. This is likely due to the augmentation of efficacy resulting from by its anti-inflammatory activity. ,, Roflumilast selectively inhibits PDE4 enzyme and possesses demonstrable efficacy at reducing exacerbation rates.  It is presently licensed as 500 μg tablets in Europe and the US indicated for use in severe COPD to reduce the frequency of exacerbations. It is administered four times daily. The progressive course of COPD will likely cause an inadequate control of symptoms and attempts to optimize therapy include combining bronchodilating agents with mechanisms of action and dosage in accordance to disease severity.  There are several possibilities when considering a particular drug combination and the final selection is influenced by a need to individualize therapy.  Studies have demonstrated superior clinical benefits in combination treatment over monotherapy.  Different bronchodilator combination regimens involving tiotropium with long-acting β-agonists such as formoterol and salmeterol were reported to significantly improve lung function and symptom control compared to these agents administered alone.  In a 6-week double-blind trial with 605 patients randomized between tiotropium plus formoterol and salmeterol plus, the inhaled corticosteroid fluticasone, superior respiratory endpoints of peak FEV 1 in the tiotropium-formoterol group suggested better lung function improvement over that in the other treatment group.
There is currently a need for large randomized trials to assess the impact of bronchodilator therapy on long-term benefits derivable from treatment. Some of these agents are likely to witness increasing use in the management of stable COPD as newer drugs progress through clinical trials and become available in the clinics. With the superior benefit demonstrated in combination therapy, concerns about safety of co-administration is likely to influence future trials designed to gain insight into the toxicity patterns likely to be associated with different combination options.
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