COPD: MANAGEMENT OF STABLE DISEASE AND EXACERBATIONS

1. COPD: MANAGEMENT OF STABLE DISEASE AND EXACERBATIONS Dennis E. Doherty, M.D. Professor of Medicine Chief, Division of Pulmonary and Critical Care Medicine Co-chairman, National Lung Health Education Program University of Kentucky Medical Center Lexington Veterans Administration Medical Center

2. OBJECTIVES • Historical Perspective • Mechanisms of Airflow Obstruction • Treatment Modalities

4. MECHANISMS OF AIRFLOW OBSTRUCTION IN COPD

5. Alpha Beta1 Beta2 Smooth Muscle Bronchoconstriction Urinary Retention Bronchodilation Uterine Relaxation Tachycardia Arrhythmias Heart Skeletal Muscle Tremor Hypertension Dilatation Vascular PERIPHERAL ADRENERGIC ACTIONS

6. Beta -selective 2 Adrenergic Agents Adenylyl Cyclase MECHANISMS OF BRONCHODILATION BETA2-ADRENERGIC AGENTS ATP cAMP cAMP BRONCHODILATION BRONCHODILATION Drawing by Dennis E. Doherty, MD

7. Drawing by Dennis E. Doherty, MD MECHANISMS OF AIRWAY OBSTRUCTION

8. CNS Vagal Parasympathetic (X) Parasympathetic Nerves M 2 RECEPTORS Inhibit Ach Release Acetylcholine Acetylcholine M 3 RECEPTORS AIRWAY SMOOTH MUSCLE CELLS MUCUS GLANDS Drawing by Dennis E. Doherty, MD Muscarinic Receptor Subtypes in Airways

9. Drawing by Dennis E. Doherty, MD

10. Increased Cyclic GMP MECHANISMS OF BRONCHODILATIONANTICHOLINERGIC AGENTS C H O L I N E R G I C M Ipratropium Bromide Atropine M3 X A c e t y l - C h o l i n e ( A C h ) C a l c i u m C H O L I N E R G I C R E C E P T O R C a l c i u m Decreased Smooth Muscle Constriction and Mucus Gland Secretion Drawing by Dennis E. Doherty, MD

11. DISTRIBUTION OF CHOLINERGIC AND ADRENERGIC RECEPTORS Parasympathetic Sympathetic

12. CHRONIC BRONCHITIS EMPHYSEMA AIRFLOW OBSTRUCTION ASTHMA Treatment of COPD American Thoracic Society. Am J Respir Crit Care Med. 1995.

13. PREVENT EMPHYSEMA

14. CHRONIC MANAGEMENT OF COPD (GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276) Education • Spirometry Diagnose • Smoking cessation • Immunize • Reduce other exposures Reduce Risk Education • Bronchodilators • Consider inhaled steroids • Pulmonary rehabilitation Reduce Symptoms Education Reduce Complications • Consider oxygen • Treat exacerbations Education

15. STEPWISE TREATMENT OF COPD BASED ON SEVERITY (GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276)

16. NATIONAL LUNG HEALTH EDUCATION PROGRAM (NLHEP) A new national healthcare initiative aimed at the diagnosis of early stages of COPD and related disorders. • TEST YOUR LUNGS • KNOW YOUR NUMBERS www.nlhep.org

17. OFFICE SPIROMETERS

18. CHRONIC BRONCHITIS EMPHYSEMA AIRFLOW OBSTRUCTION ASTHMA Treatment of COPD American Thoracic Society. Am J Respir Crit Care Med. 1995.

19. OBJECTIVES FOR INTERVENTIONS IN THE CHRONIC MANAGEMENT OF COPD • Improvement in Lung Function • Improve Quality of Life (Healthcare Status) • Relieve Symptoms • Decrease Exacerbations • Decrease Hospitalizations • Decelerate Decline in Lung Function • Increase Life Expectancy • Achieve Objectives in a Cost-Effective Manner

20. First Line Therapy in COPD is • Preventative • AVOID TOBACCO

21. GOLD Guidelines (GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276) Bronchodilation is first-line pharmacologic therapy in COPD

22. PHARMACOLOGIC ARMAMENTARIUM • Anticholinergics (Parasympatholytic) • Short-acting inhaled (Ipratropium) • Long-acting (Tiotropium) • Beta Agonists (Sympathomimetic) • Short-acting inhaled (numerous available) • Long-acting inhaled (Salmeterol, Formoterol) • Methylxanthines (Sympathomimetic) • Anti-Inflammatory • Oral Steroids • Inhaled Steroids • Other anti-inflammatory agents (data pending)

23. 30 25 20 15 10 5 0 ANTICHOLINERGICS AND SHORT-ACTING BETA-AGONISTS ENHANCE FEV1 IN COPD . Test Day 85 Albuterol (N=165) 1 Ipratroprium (N=176) % Change in mean FEV 0 1 2 3 4 5 6 7 8 Hours After Test Dose Chest 105:1411, 1994

24. LONG-ACTING INHALED BETA AGONISTS • Duration: Bronchodilation lasts for up to 12 hours • Peak action: Fomoterol (30 min), onset within 5 min Salmeterol (1-2hr), not indicated for exacerbations • Most helpful: • Non-compliant patients (less frequent dosing) • Nocturnal component of COPD • ? Of cost-benefit compared to short-acting beta-agonists

25. Placebo Salmeterol Ipratopium Change from Baseline FEV1 SALMETEROL IN COPD(Mahler et al, Chest 115:957, 1999)

26. SALMETEROL IN COPD(Mahler et al, Chest 115:957, 1999) • For patients ‘non-responsive’ to albuterol, (n=145, 35% ), ipratropium lead to greater bronchodilation compared to other treatments • The mean transitional dyspnea index was significantly improved vs placebo and not significantly different for salmeterol vs ipratropium • Ipratropium lead to a significantly improved 6 min walk vs placebo whereas salmeterol did not • Night time dyspnea was improved with salmeterol treatment • Overall, ipratropium lead to a greater reduction in dyspnea related to activities of daily living vs placebo or salmeterol • The incidence of total lower respiratory tract adverse events (exacerbations) was different for salmeterol vs ipratropium, but both lead to fewer exacerbations vs placebo

29. Long-Acting Anticholinergic - Tiotropium Change in FEV1: Six Month Study Tiotropium (n = 202) Day 169 Placebo (n = 179) 1.35 1.30 1.25 1.20 1.15 FEV1 (L) 1.10 1.05 1.00 0.95 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 Time after administration (h) P < 0.001 for tiotropium vs placebo (DonohueJF, Chest 2002;122:47-55 )

30. Change in FEV1: Tiotropium vs Salmeterol vs Placebo Tiotropium (n = 202) Salmeterol (n = 203) Day 169 Placebo (n = 179) 1.35 1.30 1.25 1.20 1.15 FEV1 (L) 1.10 1.05 1.00 0.95 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 Time after administration (h) P < 0.001 for tiotropium vs placebo P < 0.05 for tiotropium vs salmeterol (DonohueJF, Chest 2002;122:47-55 )

31. Change in FEV1: Tiotropium vs Salmeterol vs Placebo Day 1 Tiotropium (n = 202) Salmeterol (n = 203) Day 169 Placebo (n = 179) 1.35 1.30 1.25 1.20 1.15 FEV1 (L) 1.10 1.05 1.00 0.95 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 Time after administration (h) P < 0.001 for tiotropium vs placebo on all test days post-treatment P < 0.05 for tiotropium vs salmeterol on all test days except day 1 (DonohueJF, Chest 2002;122:47-55 )

32. Binding and Dissociation Human Muscarinic Receptors in CHO Cells M1 M2 M3 Apparent KD (nM) Ipratropium 0.43 0.54 0.69 Tiotropium 0.27 0.12 0.33 Dissociation Half-Life (hours) [3H]-Ipratropium 0.11 0.035 0.26 [3H]-Tiotropium 14.6 3.6 34.7 Disse B et al. Life Sci 1993 KD = dissociation constant

33. Combination Therapy in COPD CHRONIC BRONCHITIS EMPHYSEMA AIRFLOW OBSTRUCTION ASTHMA American Thoracic Society. Am J Respir Crit Care Med. 1995.

34. Bronchodilating Effects of Combined Therapy With Clinical Dosages of Ipratropium Bromide and Salbutamol for Stable COPD: Comparison With Ipratropium Bromide Alone Akihiko Ikeda, MD, Koicht Nishimura

35. 50 80 mcg ipratropium + 400 mcg salbutamol 40 mcg ipratropium + 200 mcg salbutamol 40 80 mcg ipratropium 40 mcg ipratropium 30 Placebo FEV1 (% change) 20 10 0 0 1 2 3 4 5 6 7 8 Time After Test Dose (h) IPRATROPIUM BROMIDE AND SALBUTAMOL Ikeda A, et al. Chest. 1996;109:294.

37. Ipratropium and Albuterol per MDIis More Effective than Either Agent Alone

38. COMBINATION METERED DOSE INHALER(Ipratropium Bromide plus Albuterol Sulfate) Effective bronchodilation via two distinct mechanisms. Useful in the subset of patients who require both classes of agents to achieve maximal bronchodilation without potentiation of side effects over either single component alone. Useful in noncompliant (non-adherent) patients- can improve adherence and patient satisfaction- by decreasing their time, effort, and the number of puffs required to administer two efficacious drugs. Cost effective if restricted to these subsets of patients, and if the combination inhaler is properly priced.

39. COMBINATION THERAPY IN COPD Combination of ipratropium and long-acting beta-agonists have been shown to lead to significantly greater bronchodilation than that observed in response to either agent alone Ipratropium + Salmeterol (Van Noord, Eur Resp J 2000;15:878-885) Ipratropium + Formoterol (D’Urzo, Chest 2001;119:1347-1356) A new generation anticholinergic agent, tiotropium bromide, which is more selective, more potent, and has a longer duration of action compared to ipratropium bromide is currently in development (Litner, Am J Respir Crit Care Med 2000;161:1136-1142)

40. Salmeterol 50 µg + ipratropium 40 µg Salmeterol 50 µg Placebo 12.5 10 7.5 5  FEV1 (% Pred.) 2.5 0 -2.5 -5 0 0.5 1 2 3 4 5 6 7 8 9 10 11 12 Time (hours) Combination Therapy with an Anticholinergic and a Long-Acting Beta-2 Agonist van Noord JA et al. Eur Respir J 2000;15:878-885

41. OBJECTIVES FOR INTERVENTIONS IN THE CHRONIC MANAGEMENT OF COPD • Improvement in Lung Function • Relieve Symptoms • Decrease Exacerbations • Decrease Hospitalizations • Improve Quality of Life (Healthcare Status) • Decelerate Decline in Lung Function • Increase Life Expectancy • Achieve Objectives in a Cost-Effective Manner

42. COPD EXACERBATION - DEFINITION • Acute Worsening of Respiratory Symptoms (72hr) • Increased Dyspnea • Increased Quantity of Sputum • Increased Purulence of Sputum Anthonisen NR 1987 Ann Int Med 106:196-204

43. FREQUENCY OF EXACERBATIONS 20 % of Patients With Exacerbations 10 0 Albuterol Ipratropium Ipratropium + Albuterol Friedman M, et al. Chest. 1999;115:635-641.

44. COST OF HOSPITALIZATION FOR EXACERBATION Acquisition cost of primary Albuterol Ipratropium Ipratropium + Albuterol pulmonary drug Acquisition cost of drugs added during exacerbations Hospitalization cost 0 50 100 150 200 250 300 350 400 450 500 Friedman M, et al. Chest. 1999;115:635-641.

45. PHARMACOLOGIC ARMAMENTARIUM • Anticholinergics (Parasympatholytic) • Short-acting inhaled (Ipratropium) • Long-acting (Tiotropium) • Beta Agonists (Sympathomimetic) • Short-acting inhaled (numerous available) • Long-acting inhaled (Salmeterol, Fomoterol) • Methylxanthines (Sympathomimetic) • Anti-Inflammatory • Oral Steroids • Inhaled Steroids • Other anti-inflammatory agents (data pending)

46. 5 10 20 40 60 Relationship Between Plasma Theophylline Concentrations and Clinical Effects Concentration Toxicity Efficacy mg/liter } Minimal Gastrointestinal Upset Optimal Nervousness Arrhythmias Convulsions

47. Liver Disease Age Heart Disease Formulation Theophylline Metabolism Infection Smoking Severity of Illness

48. PHARMACOLOGIC ARMAMENTARIUM • Anticholinergics (Parasympatholytic) • Short-acting inhaled (Ipratropium) • Long-acting (Tiotropium) • Beta Agonists (Sympathomimetic) • Short-acting inhaled (numerous available) • Long-acting inhaled (Salmeterol, Fomoterol) • Methylxanthines (Sympathomimetic) • Anti-Inflammatory • Oral Steroids • Inhaled Steroids • Other anti-inflammatory agents (data pending)

49. LUNG INFLAMMATION IN ASTHMA IS DIFFERENT THAN THE LUNG INFLAMMATION IN COPD • The inflammation of asthma is responsive to steroids • Mast cells, eosinophils, TH2-like lymphocytes (CD4) • IL-4, IL-5, IL-13, ECP, LTC4 • The chronic inflammation in COPD is not responsive to steroids • Macrophages, Neutrophils, T-Lymphocytes (CD8) • LTB4, TNF, IL-8, Chemokines

50. GOLD Guidelines (GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276) • Trial of inhaled corticosteroids (6 wks – 3 mo) given only if patient with moderate to severe COPD (defined by spirometry) continues with significant symptoms and frequent exacerbations (3 - 4 per yr) despite maximal bronchodilation. • If symptoms or the frequency of exacerbations are not improved, steroids should be discontinued.