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Chronic Obstructive Pulmonary Disease (COPD) Spring 2014

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Chronic Obstructive Pulmonary Disease(COPD)Spring 2014

1ReferencesPharmacotherapy: A Pathophysiologic Approach Pharmacotherapy: Principles and Practice Applied Therapeutics: The Clinical Use of Drugs The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (Feb 2014) http://www.goldcopd.com

3Case StudyChief complaint:

A 67 year old man presents to the chest clinic with a three month history of increasing shortness of breath and decreased exercise tolerance. 3Dyspnea, the sensation of breathlessness or inadequate breathing, 4History:He was in his usual state of health until three months ago when he began to experience dyspnea while climbing stairs.

He denies any acute changes in his breathing, but he does have a chronic cough that produces one to two tablespoons of clear sputum daily.

The cough and sputum production have not recently changed. He smokes one pack of cigarettes a day for 20 years. GOLD 2013 DEFINITION OF COPDChronic Obstructive Pulmonary Disease (COPD), a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients.

COPD Introduction and DefinitionsChronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction. The airflow obstruction is usually: progressive, not fully reversibledoes not change markedly over several months.associated with an abnormal inflammatory response of the lung to noxious particles or gases. The disease is predominantly caused by smoking.COPD is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients.The most common conditions comprising COPD are chronic bronchitis and emphysema. COPD is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterized 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.

The most common conditions comprising COPD are chronic bronchitis and emphysema.

6EpidemiologyCOPD prevalence, morbidity, and mortality vary across countries and across different groups within countries.

COPD is projected to be the Fourth leading cause of death and the fifth leading cause of morbidity worldwide by 2030.

COPD includes chronic bronchitis, emphysema, or a combination of these conditions but does not include conditions in which airflow limitation is the differential diagnosis (e.g., asthma, bronchiectasis, and cystic fibrosis).7Prevalence of asthma and COPD in the United States 2006

Etiology and Risk FactorsMultiple pathogenetic mechanisms likely contribute to the development of COPD. The most important risk factor is cigarette smoking, which can affect the lungs by a variety of mechanisms. Age of starting, total pack-years, and current smoking status are predictive of COPD mortality.Children and spouses of smokers are also at increased risk of developing significant pulmonary dysfunction by passive smoking,Other exposures also contribute, probably through similar pathways. Both genetic and acquired conditions, also play a role and likely account for much of the variable susceptibility of individuals to the effects of cigarette smoke and other exposures.Other risk factors for COPD include; lung growth, airway hyperresponsiveness, asthma, environmental and occupational exposures [e.g., grain, coal, asbestos], indoor and outdoors air pollution, and respiratory infections. 9Risk Factors for Development of COPDTobacco smoking is the major risk factor for the development of COPD. Cigarette smoke activates Macrophages and airway epithelial cells in the respiratory tract, which release Neutrophil chemotactic factors including Interluekin-8 [IL-8] and IL-B4.Neutrophils and Macrophages then release proteases that break down connective tissue in the lung parenchyma. Smoke also stimulates mucus hyper-secretion through increasing the number and activity of level of secretary cells in the airways contributing to airway obstruction. Proteases are normally counteracted by protease inhibitors [including 1-antitrypsin], but in COPD the balance is tipped in favor of proteolysis. Atmospheric pollution, plays a minor role compared to smoking. Inherited deficiency of 1-antitrypsin, is considered a rare cause of early onset Emphysema. A polymorphism in the gene coding for antiproteases can be associated with producing less protein or protein with lower activity.

10Pathophysiology

emphasis is currently placed on the pathophysiologic features of small airways disease and parenchymal destruction as contributors to chronic airflow limitation. Most patients with COPD demonstrate features of both problems.The underlying problem is persistent exposure to noxious particles or gases that sustain the inflammatory response.The airways of the lung and the parenchyma are both susceptible to inflammation and the result is chronic airflow limitation that characterizes COPD Other processes that have been proposed to play a major role in the pathogenesis of COPD include oxidative stress and an imbalance between aggressive and protective defense systems in the lungs (proteases and antiproteases). These processes may be the result of ongoing inflammation or occur as a result of environmental pressures and exposure

An altered interaction between oxidants and antioxidants present in the airways is responsible for the increased oxidative stress present in COPD. Increases in markers (e.g., hydrogen peroxide and nitric oxide) of oxidants are seen in the epithelial lining fluid.1 The increased oxidants generated by cigarette smoke react with and damage various proteins and lipids, leading to cell and tissue damage. Oxidants also promote inflammation directly and exacerbate the protease-antiprotease imbalance by inhibiting antiprotease activity.

The consequences of an imbalance between proteases and antiproteases in the lungs was described over 40 years ago when the hereditary deficiency of the protective antiprotease AAT was discovered to result in an increased risk of developing emphysema prematurely. This enzyme (AAT) is responsible for inhibiting several protease enzymes, including neutrophil elastase. In the presence of unopposed activity, elastase attacks elastin, a major component of alveolar walls.

12YYYMast cellCD4+ cell(Th2)EosinophilAllergensEp cellsASTHMABronchoconstrictionBHRAlv macrophageEp cellsCD8+ cell(Tc1)NeutrophilCigarette smokeSmall airway narrowingAlveolar destructionCOPDReversibleIrreversibleAirflow Limitation13

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15The irreversible component of airflow limitation is primarilydue to remodeling42,43,87,88,96,97 fibrosis and narrowing of the small airways that produces fixed airways obstructionand a consequent increase in airways resistance.

Clinical PresentationThe characteristic symptoms of COPD are chronic and progressive dyspnea, cough, and sputum production that can be variable from day-to-day. Dyspnea: Progressive, persistent and characteristically worse with exercise.Chronic cough: May be intermittent and may be unproductive.Chronic sputum production: COPD patients commonly cough up sputum. Global Strategy for Diagnosis, Management and Prevention of COPDSymptoms of COPD 2013 Global Initiative for Chronic Obstructive Lung Disease17Chronic BronchitisChronic bronchitis presents clinically as: chronic excessive mucus production and secretion resulting in airflow obstruction secondary to inflammation and edema. Persistent productive cough is present on most days for three months or more during the year over at least two consecutive years.

The increased mucus is an excellent media for recurrent bronchial infections resulting in further damage. Repeated infections result because of inability to clear the mucus and mucous plugs.Chronic bronchitis is associated with chronic or recurrent excessive mucus secretion into the bronchial tree with cough that is present on most days for at least 3 months of the year for at least 2 consecutive years in a patient in whom other causes of chronic cough have been excluded.2

chronic bronchitis is defined in clinical terms18

Chronic bronchitis (blue bloaters)Typical patient is 45 to 65 years oldSmokerChronic productive coughRecurrent respiratory infectionsUsually overweight or obeseHypoxia and cyanosis [because of carbon dioxide retention] Dyspnea on exertionEnd-stage disease is complicated by polycythemia and cor pulmonale [right sided heart failure secondary to lung disease and pulmonary hypertension]The characteristic patient with chronic bronchitis is 45 to 65 years old with a chronic productive cough, moderate dyspnea, and recurrent respiratory infection.The patient with chronic bronchitis often is obese and suffers form significant hypoxemia, cyanosis with carbon dioxide retention. Classically, this patient has been called a blue-bloater. End-stage chronic bronchitis is complicated by polycythemia, and cor pulmonale.

20Chronic hypoxiaPulmonary vasoconstrictionMuscularizationIntimal hyperplasiaFibrosisObliterationPulmonary hypertensionCor pulmonaleDeathEdemacor pulmonale21EmphysemaEmphysema results from anatomical defects of the lung characterized by abnormal permanent enlargement of the air spaces distal to the terminal bronchiole, accompanied by destruction of alveolar walls, but without obvious fibrosis.

Destruction of alveolar tissue results in loss of elastic recoil and structural support; thus, obstruction and airway collapse occurs during expiration. Commonly, associated with a history of cigarette smoking and typically occurs after age 60. Rarely, associated with 1-antitrypsin enzyme deficiency caused by a genetic defect in the production of the 1-antitrypsin enzyme, which normally is protective to the alveolar lining of the lung. 1-antitrypsin functions as an antiprotease in the lung to inhibit neutrophil elastase.emphysema is defined in terms of anatomic pathology. Emphysema historically was defined on histologic examination at autopsy. Because this histologic definition is of limited clinical value, emphysema also has been defined as abnormal permanent enlargement of the airspaces distal to the terminal bronchioles accompanied by destruction of their walls yet without obvious fibrosis.

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Chronic obstructive pulmonary diseaseInterrelationship of chronic bronchitis and emphysemaNormalChronicbronchitisMixed(in variabledegree)Emphysema

Novartis24Chronic obstructive pulmonary disease, interrelationship of chronic bronchitis and emphysemaChronic obstructive pulmonary disease (COPD) is in most cases a combination of chronic bronchitis and emphysema. However, chronic bronchitis and emphysema are two distinct processes. Chronic bronchitis is characterized by cough and sputum production. In emphysema, the lungs lose their elasticity and the walls between the alveoli break down so that the alveoli are replaced by large air sacs. The physiological dead space is increased and because of inadequate and uneven alveolar ventilation and perfusion of underventilated alveoli, severe hypoxia develops. Hypercapnia also develops. Inspiration and expiration are laboured and the work of breathing is greatly increased.

Netter FH. The Netter Collection of Medical Illustrations. Vol.7, Respiratory System. 1995 Novartis Pharmaceutical Corporation US.Emphysema (pink puffers)Typical patient is 55-75 years oldSmokerMinimal cough, sputum produced is scanty and mucoidPatient is often thin, barrel-chested and breath through pursed lipsPatient maintain adequate oxygenation through an increased work of breathing [Flushed appearance] Earlier onset Emphysema is apparent in patients with 1-antitrysin deficiency.Typical emphysema patients are 55 to 75 years old with severe dyspnea as the primary complaint. Patients often are thin, barrel-chested, and breathe through pursed lips. Classically emphysema patients are termed pink-puffers because they maintain adequate oxygenation through an increased work of breathing.

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COPD diagnosis

Diagnosis and Patients AssessmentPrimary laboratory data useful in the diagnosis and assessment includespirometry

arterial blood gases (ABG) determinations. The pH will be normal, hypoxemia will be present in varying degrees, and hypercapnia will be a feature in some patients.

An 1-antitrypsin concentration determination is indicated For patients developing COPD at less than 50 years of age When emphysema occurs without a significant cigarette historyWhen there is a family history of the genetic deficiency.

A diagnosis of COPD should be considered in any patient who has cough, sputum production, or dyspnea and/or a history of exposure to risk factors. The diagnosis is confirmed by spirometry. To help identify individuals earlier in the course of disease, spirometry should be performed for patients who have chronic cough and sputum production even if they do not have dyspnea. Spirometry is the best way to diagnose COPD and to monitor its progression and health care workers to care for COPD patients should have assess to spirometry. Spirometry should be performed after the administration of an adequate dose of a short-acting inhaled bronchodilator to minimize variability.A post-bronchodilator FEV1/FVC < 0.70 confirms the presence of airflow limitation that is not fully reversible.Where possible, values should be compared to age-related normal values to avoid overdiagnosis of COPD in the elderly

28Spirometry: Normal and Patients with COPD

Spirometry should be performed after the administration of an adequate dose of a short-acting inhaled bronchodilator to minimize variability.A post-bronchodilator FEV1/FVC < 0.70 confirms the presence of airflow limitation that is not fully reversible.Where possible, values should be compared to age-related normal values to avoid overdiagnosis of COPD in the elderly

Spirometry is the most reproducible and objectivemeasurement of airflow limitation available. Peakexpiratory flow measurement alone cannot be reliably usedas the only diagnostic test, despite its good sensitivity,because of its weak specificity30GOLD UpdatesAssessment of COPD is based on the patients level of symptoms, future risk of exacerbations, the severity of the spirometric abnormality, and the identification of comorbidities. Whereas spirometry was previously used to support a diagnosis of COPD, spirometry is now required to make a confident diagnosis of COPD.

The spirometric classification of airflow limitation is divided into four Grades (GOLD 1, Mild; GOLD 2, Moderate; GOLD 3, Severe; and GOLD 4, Very Severe) using the fixed ratio, postbronchodilator FEV1/FVC < 0.70, to define airflow limitation. It is recognized that use of the fixed ratio (FEV1/FVC) may lead to more frequent diagnoses of COPD in older adults with mild COPD as the normal process of aging affects lung volumes and flows, and may lead to underdiagnosis in adults younger than 45 years.

The concept of staging has been abandoned as a staging system based on FEV1 alone was inadequate and the evidence for an alternative staging system does not exist. The most severe spirometric Grade, GOLD 4, does not include reference to respiratory failure as this seemed to be an arbitrary inclusion.Differential Diagnosis

Imaging. A chest X-ray is not useful to establish a diagnosis in COPD, but it is valuable in excluding alternative diagnoses and establishing the presence of significant comorbidities such as concomitant respiratory (pulmonary fibrosis, bronchiectasis, pleural diseases), skeletal (e.g., kyphoscoliosis), and cardiac diseases (e.g., cardiomegaly).Management of COPDGoals of TherapyPrevent disease progressionRelieve symptomsImprove exercise toleranceImprove overall health statusPrevent and treat exacerbationPrevent and treat complicationsReduce morbidity and mortality

37Four Components of COPD ManagementAssess and monitor disease Reduce risk factors Manage stable COPDEducationPharmacologicNon-pharmacologicManage exacerbations

Assess and Monitor COPD: Key PointsA clinical diagnosis of COPD should be considered in any patient who has: dyspnea, chronic cough or sputum production, and/or a history of exposure to risk factors for the disease.The diagnosis should be confirmed by spirometry. A post-bronchodilator FEV1/FVC < 0.70 confirms the presence of airflow limitation that is not fully reversible.Where possible, values should be compared to age-related normal values to avoid overdiagnosis of COPD in the elderly.Comorbidities are common in COPD and should be actively identified. COPD has significant extrapulmonary (systemic) effects including: Weight lossNutritional abnormalitiesSkeletal muscle dysfunction

Global Strategy for Diagnosis, Management and Prevention of COPDAssessment of COPDAssess degree of airflow limitation using spirometryAssess symptomsAssess risk of exacerbationsAssess comorbidities 2013 Global Initiative for Chronic Obstructive Lung Disease40Classification of COPD Severity by SpirometryThe hallmark of obstructive disease is a decrease in the forced expiratory volume in one second (FEV1), and the ratio of FEV1 to the forced vital capacity (FVC) is 80% predicted (GOLD 1). However, for all Group A patients a short-acting bronchodilator is recommended as first choice based on its effect on lung function and breathlessness.

Second choice is a combination of short acting bronchodilators or the introduction of a long-acting bronchodilator. The evidence for this step-up is weak; few studies of the combination exist, and most trials of therapy with long-acting bronchodilators have been performed in patients with more severe airflow limitation.Group B patients have more significant symptoms but still a low risk of exacerbations.

Long-acting bronchodilators are superior to short-acting bronchodilators (taken as needed, or prn) and are therefore recommended. There is no evidence to recommend one class of long acting bronchodilators over another for initial treatment. In the individual patient, the choice should depend on the patients perception of symptom relief.

For patients with severe breathlessness, the second choice is a combinationof long-acting bronchodilators. Only short-term studies of this treatment option have been reported and patients on a combination of long-acting bronchodilators should be carefully followed and their treatment effect evaluated.

Alternative choices include short-acting bronchodilators and theophylline, the latter of which can be used if inhaled bronchodilators are unavailable or unaffordable.Group C patients have few symptoms but a high risk of exacerbations.

As first choice a fixed combination of inhaled corticosteroid/long-acting beta2-agonist or a long acting anticholinergic is recommended. Unfortunately, there is only one study directly comparing these treatments, which makes differentiation difficult.

As second choice, a combination of two long-acting bronchodilators or the combination of inhaled corticosteroid/ long-acting anticholinergic can be used. Both long-acting anticholinergic and long-acting beta2-agonist reduce the risk of exacerbations, and although good long-term studies are lacking, this principle of combination treatment seems sound (although in many countries expensive). The recommendation for a combination of inhaled corticosteroid/ long-acting anticholinergic is not evidence-based, but this lack of evidence seems to be the result of lack of interest from the pharmaceutical industry rather than doubts about the rationale.

Alternative choices include short acting bronchodilators and theophylline if long-acting inhaled bronchodilators are unavailable or unaffordable. A phosphodiesterase-4 inhibitor could be considered if the patient has chronic bronchitis.Group D patients have many symptoms and a high risk of exacerbations.

The rationale for the first choice of therapy is the same as that for patients in Group C, as reduction of exacerbation risk seems most important.

As second choice a combination of all three classes of drugs (inhaled corticosteroid/long-acting beta2-agonist/long-acting anticholinergic) is recommended, although there are conflicting findings concerning this treatment; support for it mainly comes from short-term studies. It is also possible to add a phosphodiesterase-4 inhibitor to the treatment chosen as first choice, provided the patient has chronic bronchitis.

A phosphodiesterase-4 inhibitor is effective when added to a long-acting bronchodilator, whereas evidence of its benefit when added to inhaled corticosteroid comes from less valid secondary analyses.

Alternative choices include short-acting bronchodilators, and theophylline or carbocysteine can be used if long-acting inhaled bronchodilators are unavailable or unaffordable.

Short-Acting BronchodilatorsThe initial therapy for COPD patients who experience symptoms intermittently are short-acting bronchodilators. Among these agents, the choices are a short acting 2-agonist or an anticholinergic. Either class of agents has a relatively rapid onset on action, relieves symptoms, and improves exercise tolerance and lung function.

In general, both classes are equally effective.Clinicians differ about preference in choosing the initial short acting bronchodilator therapy for the patient with COPD. Both a short-acting 2-agonist and ipratropium represent reasonable choices for initial therapy.71Long-Acting Bronchodilators For patients with moderate to severe COPD who experience symptoms on a regular and consistent basis, or in whom short-acting therapies do not provide adequate relief, long-acting bronchodilator therapies are the recommended treatment. Long-acting, inhaled bronchodilator therapy can be administered as: 2-agonist /or anticholinergic.

Long-acting bronchodilators: provide similar benefits to short-acting agents. reduce exacerbation frequency improve quality of life.

72AnticholinergicsTiotropium reduces exacerbations and related hospitalizations, improves symptoms and health status (Evidence A), and improves the effectiveness of pulmonary rehabilitation (Evidence B). In a large, long-term clinical trial on patients with COPD, there was no effect of tiotropium added to other standard therapies on the rate of lung function decline and no evidence of cardiovascular risk. In another large trial, tiotropium was superior to salmeterol in reducing exacerbations although the difference was small.

The long-acting anticholinergics aclidinium and glycopyrronium seem to have similar action on lung function and breathlessness as tiotropium, whereas far less data are available for other outcomes.

Long-Acting, Inhaled 2-AgonistsThey offer the convenience and benefit of a long duration of action for patients with persistent symptoms. Both salmeterol and formoterol are dosed every 12 hours and provide sustained bronchodilation.Formoterol has an onset of action similar to albuterol (less than 5 minutes), whereas salmeterol has a slower onset (15 to 20 minutes); however, neither agent is recommended for acute relief of symptoms. The clinical benefits of long-acting inhaled 2-agonists compared to short-acting therapies include similar or superior improvements in lung function and symptoms, as well as reduced exacerbation rates.Their use should be considered for patients with frequent and persistent symptoms.When patients require short-acting 2-agonists on a scheduled basis, long-acting agents, such as formoterol and salmeterol, are more convenient based on dosing frequency, but are also more expensive.

74Long-acting -agonists compared to other bronchodilatorsThey are also useful to reduce nocturnal symptoms and improve quality of life.

When compared to short-acting bronchodilators or theophylline, both salmeterol and formoterol:improve lung function, symptoms, exacerbation frequency and quality of life.These benefits are apparent even in patients with poorly reversible lung function and are related to improvements in inspiratory capacity.

Both salmeterol and formoterol have been compared to ipratropium. In separate studies, each agent improved FEV1 compared to ipratropium and, in addition, the long-acting bronchodilator was more effective for other selected outcomes (e.g., prolonged time to exacerbation for salmeterol while formoterol reduced symptoms and rescue inhaler use)

75Long-Acting AnticholinergicsTiotropium bromide, a longactingquaternary anticholinergic agenttiotropium bromide inhalation powder (Spiriva HandiHaler, Boehringer Ingelheim) received marketing approval from the Food and Drug Administration (FDA) for the long-term treatment of bronchospasm associated with COPD.Like other drugs administered by inhalation, only a limited amount of tiotropium reaches the lungs.Improvements in FEV1 are maintained over 24 hours. Tiotropium appears to be at least as effective as currently available alternatives in the treatment of patients with COPD who require bronchodilator treatment.

Tiotropium simplified dosing and tolerable adverse-effect profile can potentially lead to enhance patient compliance.Combination Anticholinergics and -AgonistsCombination regimens of bronchodilators are used often in the treatment of COPD, especially as the disease progresses and symptoms worsen over time. Combining bronchodilators with different mechanisms of action allows the lowest possible effective doses to be used and reduces potential adverse effects from individual agents.Combinations of both short- and long-acting 2-agonists with ipratropium have been shown to provide added symptomatic relief and improvements in pulmonary function.combination of albuterol and ipratropium (Combivent) offers the obvious convenience of two classes of bronchodilators in a single inhaler.TheopyllineThe role of theophylline in COPD is controversial. Theophylline provides no additional bronchodilator effect beyond that of beta agonists or anticholinergics. On the other hand, long-acting preparations may reduce overnight declines in pulmonary function and improve morning symptoms. This beneficial response to theopylline to prevent diaphragmatic fatigue, stimulate mucociliary clearance, increase the central response to breath, and reduce airway inflammation.Sustained-release preparations are most appropriate for the long-term management of COPD, they have the advantages of improving patient compliance and achieving more consistent serum concentrations over rapid-release theophylline and aminophylline preparations. Do not switch brands.78GOLD 2014 - AnticholinergicsThe most important effect in COPD patients of anticholinergic medications, such as ipratropium, oxitropium and tiotropium bromide, appears to be blockage of acetylcholines effect on muscarinic receptors. Current short-acting drugs block M2 and M3 receptors and modify transmission at the pre-ganglionic junction, although these effects appear less important in COPD. The long-acting anticholinergic tiotropium has a pharmacokinetic selectivity for the M3 and M1 receptors. The bronchodilating effect of short-acting inhaled anticholinergics lasts longer than that of shortacting beta2-agonists, with some bronchodilator effect generally apparent up to 8 hours after administration. Among long-acting anticholinergics, acclidinium has a duration of at least 12 hours whereas tiotropium and glycopyrronium have a duration of action of more than 24 hours. CorticosteroidsThere is little evidence that inhaled steroids have any effects on the inflammatory cells present in COPD: neutrophils, unlike eosinophils are relatively insensitive to the effects of steroids. Even high doses of inhaled steroids do not reduce the number of inflammatory cells or the levels of cytokines.

Currently up to 70% of patients with COPD are prescribed an inhaled steroid and approximately 5% are prescribed oral steroids.

The rationale for this is unclear and at least some of this prescribing may have been based on an extrapolation from the effects of these drugs in asthma and their effects at the time of an exacerbation CorticosteroidsAs with theophylline, the benefit of corticosteroids therapy for patients with stable COPD is controversial, Many clinicians use oral corticosteroids when patients fail to respond to other therapies. For chronic management in stable COPD, the benefits of systemic corticosteroids therapy are minimal. Patients more likely to benefit include those with a larger degree of reversibility, potentially those who have asthma. Steroids are useful in management inflammation associated with acute exacerbations and in ameliorating respiratory failure. Dosing of corticosteroids in acute exacerbations of COPD is similar to that for acute asthma attacks. 81Other Pharmacologic TherapiesAntioxidant agents. Antioxidants, in particular N-acetylcysteine, have been reported in small studies to reduce the frequency of exacerbations, leading to speculation that these medications could have a role in the treatment of patients with recurrent exacerbations (Evidence B). However, a large randomized controlled trial found no effect of N-acetylcysteine on the frequency of exacerbations, except in patients not treated with inhaled glucocorticosteroids.Mucolytic (mucokinetic, mucoregulator) and Antioxidant Agents (ambroxol, erdosteine, carbocysteine, iodinated glycerol). The regular use of mucolytics in COPD has been evaluated in a number of long-term studies with controversial results. Although a few patients with viscous sputum may benefit from mucolytics, the overall benefits seem to be very small; the widespread use of these agents cannot be recommended at present.Nedocromil and leukotriene modifiers. These have not been adequately tested in COPD patients and cannot be recommended. There was no evidence of benefit -and some evidence of harm (malignancy and pneumonia)- from an anti-TNF-alpha antibody (infliximab) tested in moderate to severe COPD. Use of endothelin-receptor antagonist bosentan fails to improve exercise capacity and may increase hypoxemia; it should not be used to treat patients with severe COPDThe phosphodiesterase-4 inhibitor roflumilast has been approved for use only in some countries (FDA approved in 2011, brand names Daliresp, Daxas). It is a once daily oral medication with no direct bronchodilator activity, although it has been shown to improve FEV1 in patients treated with salmeterol or tiotropium. Roflumilast reduces moderate and severe exacerbations treated with corticosteroids by 15-20% in patients with chronic bronchitis, severe to very severe COPD, and a history of exacerbations(Evidence A).

The effects on lung function are also seen when roflumilast is added to long-acting bronchodilators (Evidence A), whereas the effects on patient-related outcomes and particularly exacerbations remain controversial. There are no comparison or add-on studies of roflumilast and inhaled corticosteroids.

The most frequent adverse effects are nausea, reduced appetite, abdominal pain, diarrhea, sleep disturbances, and headache.Indacaterol (brand names Arcapta, Onbrez ) is a once-daily LABA that is approved for the treatment of COPD. It has both a rapid onset and a long duration of action. It was FDA approved in 2011.

The dose of indacaterol approved for use in the United States (75 mcg once daily) is lower than the dose approved for Europe (150 and 300 mcg). The impact of the different dosages of this medication on long-term outcomes remains unknown.

It is delivered as an aerosol formulation through a dry powder inhaler (DPI).Clenbuterol is a 2 agonist with some structural and pharmacological similarities to epinephrine and salbutamol, but its effects are more potent and longer-lasting as a stimulant and thermogenic drug. It causes an increase in aerobic capacity, central nervous system stimulation, and an increase in blood pressure and oxygen transportation.

Clenbuterol is usually used in dosages anywhere from 20-60 micrograms (mcg) a day when prescribed. A dose of about 120 mcg (women) or 140 mcg (men) should never be exceeded in a day.

Clenbuterol is approved for use in some countries, via prescription only, as a bronchodilator for asthma patients. Recently though, the drug has been publicized for its off-label use as a weight loss drug, similar to usage of other sympathomimetic amines such as ephedrine. It is commonly used as a slimming aid despite lack of sufficient clinical testing either supporting or negating such use.Not FDA approved87Investigational drugsAclidinium bromide, a new experimental drug, was effective on 6 indexes of symptoms as a treatment for chronic obstructive pulmonary disease (COPD) in a phase III clinical trial, researchers reported here at CHEST 2011: American College of Chest Physicians Annual Meeting.

Carmoterol, a once daily selective 2 agonist is now in clinical development. COPD Exacerbations

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Acute COPD ExacerbationsCommon symptoms include: increased shortness of breath an increase in the amount and purulence of sputum. Hypoxemia and hypercapnia may also be present. With an exacerbation, patients using rapid-acting bronchodilators may report an increase in the frequency of use. Exacerbations are commonly staged as mild, moderate, or severe according to the criteria summarized in the TableMild (type 1)One cardinal symptom plus at least one of the following: URTI within 5 days, fever without other explanation, increased wheezing, increased cough, increase in respiratory or heart rate >20% above baselineModerate (type 2)Two cardinal symptomsSevere (type 3)Three cardinal symptomsCardinal symptoms include worsening of dyspnea, increase in sputum volume, and increase in sputum purulence.An important complication of a severe exacerbation is acute respiratory failure. In the emergency department or hospital, an ABG usually is obtained to assess the severity of an exacerbation. The diagnosis of acute respiratory failure in COPD is made on the basis of an acute change in the ABGs. Defining acute respiratory failure as a PaO2 of less than 50 mm Hg or a PaCO2 of greater than 50 mm Hg often may be incorrect and inadequate because these values may not represent a significant change from a patient's baseline values. A more precise definition is an acute drop in PaO2 of 10 to 15 mm Hg or any acute increase in PaCO2 that decreases the serum pH to 7.3 or less. Additional acute clinical manifestations of respiratory failure include restlessness, confusion, tachycardia, diaphoresis, cyanosis, hypotension, irregular breathing, miosis, and unconsciousness.92An important complication of a severe exacerbation is acute respiratory failure. In the emergency department or hospital, an ABG usually is obtained to assess the severity of an exacerbation. The diagnosis of acute respiratory failure in COPD is made on the basis of an acute change in the ABGs. Defining acute respiratory failure as a PaO2 of less than 50 mm Hg or a PaCO2 of greater than 50 mm Hg often may be incorrect and inadequate because these values may not represent a significant change from a patient's baseline values. A more precise definition is an acute drop in PaO2 of 10 to 15 mm Hg or any acute increase in PaCO2 that decreases the serum pH to 7.3 or less. Additional acute clinical manifestations of respiratory failure include restlessness, confusion, tachycardia, diaphoresis, cyanosis, hypotension, irregular breathing, miosis, and unconsciousness.

Arterial blood gas measurements (in hospital): PaO2 < 8.0 kPa with or without PaCO2 > 6.7 kPa when breathing room air indicates respiratory failure.Chest radiographs: useful to exclude alternative diagnoses. ECG: may aid in the diagnosis of coexisting cardiac problems. Whole blood count: identify polycythemia, anemia or bleeding. Purulent sputum during an exacerbation: indication to begin empirical antibiotic treatment.Biochemical tests: detect electrolyte disturbances, diabetes, and poor nutrition.Spirometric tests: not recommended during an exacerbation.Global Strategy for Diagnosis, Management and Prevention of COPDManage Exacerbations: Assessments 2013 Global Initiative for Chronic Obstructive Lung Disease96Goals of TherapyThe goals of therapy for patients experiencing exacerbations of COPD:prevention of hospitalization or reduction in hospital stay, prevention of acute respiratory failure and death, resolution of exacerbation symptoms and a return to baseline clinical status and quality of life.

TherapyCommentsAntibioticsRecommended if two or more of the following are present:Increased dyspneaIncreased sputum productionIncreased sputum purulenceCorticosteroidsOral or intravenous therapy may be used.If intravenous is used, it should be changed to oral after improvement in pulmonary status.If continued longer than 14 days, then the dose should be tapered to avoid hypothalamicpituitaryadrenal axis suppression.BronchodilatorsMetered-dose inhalers and dry-powder inhalers equal in efficacy to nebulization.-Agonists also may increase mucociliary clearance.Long-acting -agonists should not be used for quick relief of symptoms or on an as-needed basis.Controlled oxygen therapyTitrate oxygen to desired oxygen saturation (>90%).Monitor arterial blood gas for development of hypercapnia.Noninvasive mechanical ventilationConsider for patients with acute respiratory failure.Not appropriate for patients with altered mental status, severe acidosis, respiratory arrest, or cardiovascular instability.Treatment of Acute COPD Exacerbations99Short-acting inhaled beta2-agonists with or without short-acting anticholinergics are usually the preferred bronchodilators for treatment of an exacerbation.Systemic corticosteroids and antibiotics can shorten recovery time, improve lung function (FEV1) and arterial hypoxemia (PaO2), and reduce the risk of early relapse, treatment failure, and length of hospital stay.COPD exacerbations can often be prevented. Global Strategy for Diagnosis, Management and Prevention of COPDManage Exacerbations: Key Points 2013 Global Initiative for Chronic Obstructive Lung Disease100Treatment of Acute COPD ExacerbationsIntensification of bronchodilator therapiesThe use of short-acting inhaled 2-agonist and anticholinergics improve airflow obstruction during acute exacerbations of COPD.

Although similar improvement in FEV1 is achieved with either drug class with no apparent benefit in improving FEV1 with a combination of these agents, frequently combinations of bronchodilators are used as submaximal doses of each agent.

A recent meta-analysis suggests there is little evidence to support the use of Theophylline for acute exacerbations. Theophylline use may be warranted in patients experiencing severe exacerbations of COPD who are not responding to other aggressive measures. 101Systemic corticosteroidsSystemic corticosteroids can improve spirometry, arterial blood gas results and symptoms during acute exacerbations. The optimal regimen [dose and duration], is not clear because the regimens used in clinical studies were quite variable. Regimens demonstrating benefit have ranged from Methylprednisolone 125mg IV Q 6 hours for 3 days before tapering over 2 weeks with an oral drug to prednisolone 30mg orally daily for 2 weeks without prior intravenous corticosteroid. It is clear that regimen durations longer than 2 weeks offer no additional benefit.

Antimicrobial therapyThere is no clear consensus about the antibiotic of choice, but antibiotics are of great value in acute exacerbations.

102Clinical Controversy : AB in COPDShould Antibiotics be Used Early for Acute Exacerbations of COPD?

Rothberg MB, Pekow PS, Lahti M, et al. Antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease. JAMA 2010;303:20352042. [PMID: 20501925]

Current treatment guidelines recommend antibiotics to treat COPD exacerbations based on cough, sputum volume, and purulence.

Rothberg, et al. completed a retrospective cohort study of 84,621 patients hospitalized for acute exacerbations of COPD at 413 acute care facilities throughout the U.S.

The study objective was to compare outcomes of patients treated with antibiotics in the first 2 days of hospitalization with those treated later or not at all. The main outcome measure was a composite of treatment failure (defined as the initiation of mechanical ventilation after the second hospital day), inpatient mortality, or readmission for acute COPD exacerbations within 30 days of discharge as well as length of stay and hospital costs.

The authors conclude that early antibiotic administration was associated with improved outcomes among patients hospitalized for acute exacerbations of COPD regardless of the risk of treatment failure

104A systematic review of the very few available placebo-controlled studies has shown that antibiotics reduce the risk of short-term mortality by 77%, treatment failure by 53% and sputum purulence by 44%.The choice of the antibiotic should be based on the local bacterial resistance pattern. Usually initial empirical treatment is an aminopenicillin with or without clavulanic acid, macrolide, or tetracycline.In patients with frequent exacerbations, severe airflow limitation and/or exacerbations requiring mechanical ventilation, cultures from sputum or other materials from the lung should be performed, as gram-negative bacteria (e.g., Pseudomonas species) or resistant pathogens that are not sensitive to the above-mentioned antibiotics may be present. Antibiotics should be given to patients with:

Three cardinal symptoms: increased dyspnea, increased sputum volume, and increased sputum purulence. Sputum purulence an one other cardinal symptomWho require mechanical ventilation.Global Strategy for Diagnosis, Management and Prevention of COPDManage Exacerbations: Treatment Options 2013 Global Initiative for Chronic Obstructive Lung Disease106OxygenSupplemental oxygen or assisted ventilation is used in more severe exacerbations. Supplemental oxygen should be used if required to maintain oxygen saturation above 90% (PaO2 >60 mmHg). This must be done cautiously in patients with hypercapnia because of the risk of worsening hypoventilation.

Prophylactic immunizationThe benefits of immunization preventing acute infective exacerbations have not been demonstrated in all patient groups. A single dose of Pneumococcal vaccine should be received by all COPD patients.Influenza vaccine should be given annually to patients with COPD, and this has been shown to reduce clinical infection rates in the general elderly population by about 70%.

Patient EducationThe patient should be further instructed to seek medical help if he needs more than four doses of albuterol per day.

Proper inhalation technique is required to receive benefit from any inhaled therapy.

There is general agreement that when a bronchodilator is being used with a nonbronchodilator (anti-inflammatory agent), the bronchodilator should be administered first followed by the other medication.

111Evaluation of Therapeutic OutcomesIn acute exacerbations, pulmonary function tests, WBC count, vital signs, chest X-ray, and changes in frequency of dyspnea, sputum volume, and sputum purulence should be assessed at the onset and through out the exacerbation. ABGs and oxygen saturation should be followed. In chronic stable COPD, mechanical lung function parameters should be assessed on regular basis. FEV1 should be assessed with any change in therapy and periodically after that through the disease course. Patient adherence to and compliance with therapeutic regimens is essential for the overall success of management. Side effects, potential drug interactions, and subjective measures of quality of life must be evaluated. 112113

114Noninvasive mechanical ventilation in exacerbations improves respiratory acidosis, increases pH, decreases the need for endotracheal intubation, and reduces PaCO2, respiratory rate, severity of breathlessness, the length of hospital stay, and mortality (Evidence A).Medications and education to help prevent future exacerbations should be considered as part of follow-up, as exacerbations affect the quality of life and prognosis of patients with COPD115

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