of COPD Wayne Kradjan, Pharm. D. Dean and Professor Oregon State University College of Pharmacy

Transcription

1 Pathophysiology and Treatment of COPD Wayne Kradjan, Pharm. D. y j, Dean and Professor Oregon State University College of Pharmacy

2 COPD Consensus Statementst t Global Initiative for Chronic Obstructive Lung Disease (GOLD) WHO and NHLBI institute. 2001, 2003, American Thoracic Society (ATS) and European Respiratory Society (ERS) joint guidelines Expanded information on smoking cessation. Annals Internal Medicine Nov 6, 2007 for American College of Physicians clinical practice guidelines.

3 COPD Chronic Obstructive Pulmonary Disease Any lung condition causing longstanding airflow limitation with impaired expiratory outflow airflow obstruction due to chronic bronchiolitis (and/or) emphysema. Excludes asthma. Generally progressive, may be accompanied by airway hyperreactivity, and may (or may not) be partially reversible (not fully reversible) caused dby abnormal linflammatory reaction to chronic inhalation of particles (primarily cigarette) 2-10% of US population over age 55; 4 th leading cause of death after CAD, cancer, stroke

4 Percent Change in Age-Adjusted Death Rates, U.S., Proportion of 1965 Rate Coronary Heart Disease Stroke Other CVD COPD All Other Causes % 64% 35% +163% 7% Source: Global Initiative for Chronic Lung Disease 2003.

5 Spectrum of Disease Chronic Bronchiolitis Emphysema ( ~75%) COPD ( ~17%) Mixed Disease ( ~8%) Asthma

6 Chronic Bronchiolitis (aka chronic bronchitis) Bronchiolitis: Inflammation of the bronchioles Clinical i l definition iti of chronic bronchiolitis: Presence of chronic productive cough for three months in each of two consecutive years in a patient in whom other causes of chronic cough (e.g., heart failure) have been excluded.

7 Large, central airways Small, peripheral Airways Only site of Only site of gas exchange

8 Small Airway Narrowing Small airways narrow, resulting in partially reversible airflow ifl limitation itti Normal Small Airway Mucus Hypersecretion Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. April 2001 (Updated 2003).

9 Bronchiolitis/ Chronic bronchitis blue bloater Progression over many years Early smokers cough mucous production minimal exercise intolerance, SOB or change in PFTs Seek help when shortness of breath and exercise intolerance interfere with normal living Progressive PFT decline. End stage <50% of normal, CO 2 retention, rales, rhonchi, SOB with few steps Recurrent infections impaired ciliary function, reduced mucous clearance, trapping and adherence of bacteria Strep. pneumoniae, H flu, Moraxella, Mycoplasma

10 Emphysema Defined anatomically Destruction of alveolar walls, but without obvious fibrosis Abnormal permanent enlargement of the terminal airspaces (below the terminal bronchioles) Impaired gas exchange Air trapping (more dead space) Loss of elastic recoil and structural support Obstruction and airway collapse during expiration Balloon shaped bullae on CXR

11 Large, central airways Small, peripheral Airways Only site of Only site of gas exchange

12 Alveolar Destruction 1 Normal COPD

13 Emphysema Pink Puffer Progression over many years Smokers or other inhaled irritants and pollutants. E.g.,coal dust Shortness of breath and decreased exercise capacity Prolonged expiratory phase Pursed lip breathing Barrel chest Less CO 2 retention and hypoxia by breathing harder Mucus production absent Bullae rupture; pneumothorax

14 COPD Smoking is the number one risk factor % of cases linked to smoking 50% of smokers s have symptoms s 15-20% of smokers develop COPD of degree that leads to MD visit 45 ml/yr decline in FEV1 in smokers compared to normal of 25 ml/yr. Rate of fdecline converts to that of non-smoker when smoking is discontinued. 1 pack year = one pack per day for one year.

15 If exposure to noxious agents stops, disease may still progress value at age 25) Never smoked or not susceptible to smoke Smoked regularly and susceptible to its effects Stopped smoking at 45 FEV 1 (% of 25 0 Disability Death Stopped smoking at Age (y) Source: Fletcher C. The natural history of chronic airflow obstruction. BMJ Source: Used with permission from BMJ Publishing Group.

16 Enzymatic activity Natural enzymes enhance lung tissue destruction. Elastases, proteases, trypsin Protection via elastase inhibitors, antiproteases α 1 -antitrypsin (α 1 protease inhibitor) - Serum glycoprotein. Enhances metabolism of neutrophil elastase, trypsin, chymotrypsin, plasmin, thrombin. Smoking attracts neutrophils and macrophages. Promote elastase release, inactivate inhibitors

17 α 1 - Antitrypsin deficiency Serum levels mg/dl Gene phenotypes (Pi types) PiM = normal enzyme activity PiS = dysfunctional enzyme, but normal serum levels l PiZ = active enzyme, low secretion Pi null = undetectable serum levels Individual phenotyping by paired parenteral genes (Alleles ) PiMM allele = normal enzyme activity PiMZ, PiSZ, PiSS all 35% normal activity, but little disease PiZZ. Serum levels <80 mg/dl and 15-30% of normal enzyme action. Rapid progressive emphysema in young adults. 2% of all emphysema.

18 COPD Patients Not tnecessarily the Stereotype t Stereotypical pictures of COPD patients 31 Pink Puffer Blue Bloater

19 Similarities to Asthma Obstruction to airways that can become progressive/chronic Presence of acute and chronic inflammation Cellular proliferation Overproduction and over activity it of mucus producing glands and cells (chronic bronchitis only) Smooth muscle hypertrophy Bronchial hyperactivity it and reversibility ersibilit (limited)

20 Differences from Asthma Lower airway disease in COPD Greater role of neutrophils; lesser role for eosinophils Predominance of IL-8 and type- I helper (CD8) T lymphocytes; relative absence of IL-5 Oxidative i stress Chronic mucous production (bronchitis) vs transient during acute episodes Fixed airway obstruction with minimal reversibility Tissue destruction (emphysema)

21 Differential Diagnosis Onset Usual letiology Course Airflow Limitation Clinical Features Inflammatory Mediator Asthma Early in life (often childhood) Immunologic stimuli, family history of asthma Intermittent Largely reversible Episodic wheeze, chest tightness, dyspnea, cough Eosinophils COPD Later in life (midlife) Cigarette smoking, exposure to other risk factors Chronic, progressive Partially reversible Chronic cough/ sputum, persistent or worsening dyspnea Neutrophils Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. April 2001 (Updated 2003). Source: Barnes PJ. Chronic Obstructive Pulmonary Disease. N Engl J Med

22 Presumptive Diagnosis COPD should be considered in any patient who has: A smoking history of at least pk/yrs and/or a history of exposure to other risk factors Chronic cough with or without sputum production ( smoker s cough ) Dyspnea (perception of shortness of breath) Onset of respiratory symptoms in 40s Respiratory infection that persists or recurs Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. April 2001 (Updated 2003).

23 Medical Research Council Dyspnea Scale 0. Breathlessness only with strenuous exercise 1. Shortness of breath when hurrying or walking up slight hill 2. Walks slower than people of same age due to breathlessness; stops for breath when walking at own pace on level lground 3. Stops for breath after walking <300feet or a few minutes on level ground 4. Too breathless to leave the house or when dressing/ undressing

24 GOLD Staging At risk (Previously stage 0) Chronic sputum production and cough, but normal PFTs. No good predictors for progression. Stage 1: Mild COPD FEV 1 >80%, but FEV 1 /FVC ratio <70%. Chronic symptoms, but patient not aware of limitations or that disease is present Stage 2: Moderate COPD FEV %, ratio <70%. Reduced QOL; productive cough; reduced physical activity with or without exertional dyspnea; acute exacerbation uncommon

25 GOLD staging (Continued) Stage 3: Severe COPD FEV %, ratio <70%. Reduced QOL; productive cough; dyspnea with moderate exertion; occasional exacerbations Stage 4: Very Severe COPD FEV 1 <30% Severe limitations on QOL and frequent exacerbations. Dyspnea with mild exertion or at rest. Presence of respiratory failure or right sided heart failure (cor pulmonale) PaO 2 < 60 mm Hg (room air) PaCO 2 > 50 mm Hg

26 COPD Goals of Therapy Goals of Therapy Slow disease progression Minimize symptoms Maximize pulmonary function Note: green, yellow, red zones from asthma do not apply. Best possible may be <50% normal Maximize functional ability Patient and caregiver must be realistic Prevent acute exacerbations Prolong survival Educate patient to understand cause and realistic expectations

27 General Treatment Principles Be realistic!! Help patient understand disease process and realistic i expectations. Smoking cessation Flu shots Pneumococcal vaccine Begin inhaled bronchodilators if symptomatic and FEV 1 < 60% predicted

28 Treatment Guidelines by GOLD stages Stage 0 Stage 1 Educate re avoidance of risk factors (smoking, flu vaccine) Add PRN short acting bronchodilator Albuterol or ipratropium (Atrovent) Combivent Stage 2 Add one or more scheduled long acting bronchodilators Formoterol (Foradil, Perforomist nebulizer soln 20 mcg BID), Arformoterol (Brovana nebulizer soln -15 mcg BID; R enantiomer of formoterol), or salmeterol (Serevent) Tiatropium (Spiriva) Theophylline SR

29 Treatment Guidelines by GOLD stages (continued) Stage 3 Add inhaled steroid, especially if multiple acute exacerbations Stage 4 Beclomethasone (Qvar, Vanceril) Budesonide (Pulmicort) (Symbicort approved for COPD) Fluticasone (Flovent or Advair) (Advair approved for COPD) Triamcinolone (Azmacort) Oxygen if indicated (PO 2 < 50) Surgery (emphysema)

30 Step-up Therapy Stage 0: At risk Stage I: Mild Stage II: Moderate Stage III: Severe Smoking cessation and avoid risk factors; influenza vaccination Add short-acting bronchodilator as needed for intermittent symptoms Add regular treatment with one or more long-acting bronchodilators Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations Stage IV: Very Severe Add long-term O 2 if chronic respiratory failure Consider surgical treatments Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. April 2001 (Updated 2003).

31 General Pharmacologic Principles Medications may reduce or eliminate symptoms, increase exercise capacity, reduce exacerbations and improve quality of life. Applies to long acting anticholinergics, i long acting beta agonists, and inhaled steroids. Current medications have not been shown to stop or slow the long term decline in lung function or prolong survival.

32 Further treatment principles Make take 4-8 weeks to assess response to a given drug or dose Greater role for anticholinergics, but no evidence of superiority compared to long acting β-agonist Response to bronchodilators may be greater during acute exacerbations than during chronic treatment. Consider Advair, Symbicort if require inhaled steroids Once a particular medication is started, it is often difficult to discontinue Pharmacologic response vs psychological dependence Exacerbations following inhaled steroid withdrawal

33 Pulmonary function bronchodilation Bronchodilation: aim for 15-20% improvement Consider: easier to get higher percent change with low baseline Look at absolute change (> 0.2 L FEV 1 ) (> 20 L/min PEFR)

34 Other considerations Does the patient feel better? Does the patient have side effects? Single dose response vs cumulative response after 1-4 weeks Single dose response poor predictor Albuterol vs ipratropium single dose Response (>20% increase FEV 1 ) to one only 27% albuterol, 11% ipratropium Response to both 35% Response to neither 27%

35 Case example 1 75 year old male; 5 10 tall (70 inches) Predicted normal FEV 1: 3.8 L Observed FEV 1 : 1.8 L 1.8/ 3.8 = 47 % of predicted normal 10 minutes after 2 puffs albuterol: 2.1 L (55% of predicted normal); no symptom improvement % Change = ( ) / 1.8 = 16 % improvement. Clinical significance?

36 Case example 2 75 year old male; 5 10 tall (70 inches) Predicted normal FEV 1: 3.6 L Observed FEV 1 : 0.7 L 0.7/ 3.6 = 19 % of predicted normal 10 minutes after 2 puffs albuterol: 0.9 L (25% of predicted normal); no symptom improvement % Change = ( ) / 0.7 = 29 % improvement. Clinical significance?

37 Inhaled Anticholinergics in the Management of Chronic Obstructive Pulmonary Disease (COPD)

38 Cholinergic Tone in the Airways acetylcholine Airway Normal resting tone Vagal Tone - Higher in COPD Normal Vagus nerve Vagus nerve COPD acetylcholine Airway Exaggerated effect Source: Barnes PJ. Managing Chronic Obstructive Pulmonary Disease, 2nd ed. London: Science Press Ltd; Used with permission.

39 Muscarinic Receptor Subtypes in Airways CNS Cranial Nerve X Parasympathetic nerve ganglia M 1 receptors enhance cholinergic (Ach) neurotransmission M 2 receptors provide inhibit feedback to reduce Ach release from cholinergic nerve endings Acetylcholine M 3 RECEPTORS Acetylcholine M 1 RECEPTORS M 2 RECEPTORS AIRWAY SMOOTH MUSCLE CELLS MUCUS GLANDS M 3 RECEPTORS Source: Drawing by Dennis E. Doherty, MD, University of Kentucky Medical Center. Used with permission.

40 Effects of Anticholinergic Drugs Vagus nerve acetylcholine Vagus nerve acetylcholine Anticholinergic Constricted airway with high h cholinergic tone COPD Airway with reduced cholinergic i tone/ greater bronchodilation Source: Barnes PJ. Managing Chronic Obstructive Pulmonary Disease, 2nd ed. London: Scientific Press Limited.; Used with permission.

41 The ideal anticholinergic drug Block M 1 receptor to inhibit acetylcholine release Block M 3 receptor to block smooth muscle contraction and mucous production Minimal effect on M 2 receptor to allow negative feedback to turn off acetylcholine release. Paradoxical increase in Ach release if block these receptors.

42 Ipratropium (Atrovent) Non-selective inhibition of all three muscurinic receptors Clinical i l significance ifi unclear Relatively rapid dissociation from receptors short acting; QID dosing Relatively low potency May need 4 or more 40mcg inhalations/ dose

43 Anticholinergics Ipratropium (Atrovent) Safety Profile Not readily absorbed into the systemic circulation either from the surface of the lung or from the gastrointestinal tract The most common adverse reactions reported: Dryness of the oropharynx (about 5 in 100) Exacerbation of symptoms and irritation from aerosol (about 3 in 100) Additional adverse reactions reported in less than 1% of patients, considered possibly due to ipratropium inhalation aerosol include urinary difficulty, fatigue, insomnia, and hoarseness

44 Tiotropium (Spiriva) Long acting anticholinergic Selectively binds and slow dissociation from M 1 and M 3 muscurinic (acetylcholine) receptors in lung. MayalsobindM also M 2 receptor, but more rapid dissociation than from other receptors. 18 mcg gqd vs 50 mcg BID salmeterol x 6 months Equally effective in symptom improvement, but greater improvement in FEV 1 with tiotropium. More dry mouth than ipratropium

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47 Tiotropium: Improvement in FEV 1 Over 1Y Year (vs. Placebo) Day 1 Day 8 Day 92 Day % increase over placebo (p<0.01) Clinical significance? Tiotropium (n=518) FEV 1 (L) Placebo (n=328) Time After Administration (minutes)

48 Tiotropium: Improvement From Baseline in Trough FEV 1 Over 1 Year (vs. Ipratropium) Tiotropium (n=329) Δ FE EV 1 (ml) baseline 150mL Ipratropium (n=161) Test Day P<0.0001

49 Incidence of Dry Mouth Placebo Ipratropium Tiotropium (Atrovent) (Spiriva) 2.7% (0.3% withdrawals) (N = 371) 16% (0.5% withdrawals) (N= 550) 6.1% 12.1% (N= 179) (N= 356)

50 Inhaled Long-Acting Beta Agonists in the Management of Chronic Obstructive Pulmonary Disease (COPD)

51 Peak FEV 1 Response Over Six Months (2 Combined Trials) 360 * * * * Δ FEV 1 (ml L) * * * * * * Tiotropium (n=386) 18 mcg QD Salmeterol (n=388) 50 mcg BID 60 Placebo (n=362) *P<0.05 VS.. placebo P<0.05 VS.. salmeterol Test day Donohue J, et. Al, Chest 2002; 122: Brusasco V, et. Al, Thorax 2003; 58:

52 FEV 1 Over Six Months (Primary Trial) 1.35 Day 1 Day 169 FEV 1 (L) Tiotropium (n=202) Salmeterol (n=203) Placebo (n=179) Time (hours) Donohue J. et. Al, Chest 2002; 122:47-55.

53 Shortness of Breath Score Over Six Months (Combined Trials) Scale: 0=none 1=mild 2=moderate 3=severe Placebo (n=366) Salmeterol l (n=391) Tiotropium (n=388) Me ean scor re baseline 1.1 * Test day P<0.05 at all timepoints beyond Day 0 for active VS.. placebo *P<0.05 tiotropium VS.. salmeterol

54 Lung Function: Salmeterol vs. Salmeterol l Plus Ipratropium in COPD 1 Δ FEV 1 % Pre edicted Weeks Salmeterol/Ipratropium Salmeterol Placebo P<.01 VS.. salmeterol alone. P<.01 salmeterol plus ipotropium and salmeterol alone VS.. placebo. 1 van Noord JA, de Munck DR, Bantje TA, et al. Eur Resp J. 2000;15:

55 Formoterol vs Salmeterol Formoterol has more rapid onset of effect with each dose than either salmeterol or tiotropium Unclear if this imparts any clinical superiority i Consider also Symbicort vs Advair

56 Tiotropium plus Formoterol x 2 weeks (Not Symbicort) van Noord, J. A. et al. Chest 2006;129:

57 Safety considerations for beta-agonistsagonists Common side effects include cough, throat irritation Can produce clinically significant cardiovascular effects in some patients as measured by pulse rate, blood pressure, and/or symptoms Adverse events include tachycardia; palpitations; ti immediate hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm, headache; tremor; nervousness; and paradoxical bronchospasm

58 Clinical relief without bronchodilation If patient derives symptom relief from any drug, even in the absence of a change in pulmonary function, the drug should be continued Long acting beta agonist Long acting anticholinergic Theophylline can be added to a regimen of one or more long acting bronchodilators

59 Corticosteroids in COPD Seem to work best in patients with >20% response to beta agonists. Possible asthma component? Allow 3-6 months for full assessment of benefit fewer exacerbations? Combination of salmeterol or formoterol plus inhaled steroids have additive effect in COPD. May need relatively l large dose of both thdrugs. Advair, Symbicort both FDA approved for COPD Systemic corticosteroids t id required for acute exacerbations

60 TORCH Trial NEJM. Feb 22, 2007 >6100 COPD pts; FEV1 < 60% with <10 reversibility with albuterol Four groups x 3 years Placebo Salmeterol Diskus 50 mcg BID Fluticasone 500 mcg BID Advair 50/500 BID (note high dose) Anticholinergics and short acting beta agonists continued

61 TORCH Trial Results All cause mortality rates Placebo = 15.2% Salmeterol = 13.5% Fluticasone = 16.0% Combination = 12.6% (P = vs placebo) Annual exacerbation rates 1.13 with placebo vs 0.85 with combination Improved health status and FEV 1 with combo. Higher pneumonia rates in steroid arms 44% dropouts with placebo; 34-38% in active arms

62 Tiotropium in combination with placebo, salmeterol, or Advair Aaron, SD. Ann Intern Med. 2007; 146: subjects with moderate to severe COPD; at least one exacerbation in last year Incidence of exacerbations over 1 year Tiotropium QD + placebo BID = 62.8% Tiotropium op QD + Salmeterol e BID = 64.8% Tiotropium QD + Advair BID = 60.0% Premature discontinuation due to lack of benefit or side effects Tiotropium QD + placebo BID = 47% Tiotropium QD + Salmeterol BID = 43% Tiotropium QD + Advair BID = 26%

63 Tiotropium in combination with placebo, salmeterol, or Advair Median time to first exacerbation 130 days 120 days 217 days Aaron, SD. Ann Intern Med. 2007; 146: Figure 2

64 Change in Pulmonary Function

65 Salmeterol, Fluticasone, or Advair Morning FEV1 over 24 weeks Hanania, N. A. et al. Chest 2003;124:

66 Improvement in 2-h postdose FEV1 with FSC compared with the individual components (FP and salmeterol) and placebo Hanania, N. A. et al. Chest 2003;124:

67 Other treatments Oxygen PaO 2 < 55 mm Hg At least 16 hrs/day Mucolytics?

68 GOLD Stages of COPD Old New Characteristics 0: At Risk 0: At Risk Chronic symptoms Exposures to risk factors Normal spirometry I: Mild I. Mild FEV 1 /FVC<70% FEV 1 >80% With or without symptoms Source: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease. April 2001 (Updated 2003). II. Moderate II Moderate IIA IIB FEV 1 /FVC<70% 50%>FEV 1 <80% With or without symptoms III. Severe FEV 1 /FVC<70% 30%>FEV 1 <50% With or without symptoms Avoidance of risk kf factor(s); influenza vaccination i Add short-acting bronchodilator when needed III: Severe IV. Very severe FEV 1 /FVC<70% FEV 1 <30% or presence of chronic respiratory failure or right heart failure Add regular treatment with one or more long-acting bronchodilators Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations Add long-term oxygen if chronic respiratory failure Consider surgical treatments