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. PERIPHERAL ADRENERGIC ACTIONS Bronchoconstriction Urinary Retention Tachycardia Arrhythmias Bronchodilation Uterine Relaxation Tremor DilatationHypertension Smooth Muscle Heart Skeletal Muscle Vascular AlphaBeta 1 Beta 2

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

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

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

9. Drawing by Dennis E. Doherty, MD

10. MECHANISMS OF BRONCHODILATION ANTICHOLINERGIC AGENTS Increased Cyclic GMP Calcium Calcium CHOLINERGIC RECEPTOR Acetyl- Choline (ACh) X CHOLINERGIC M Drawing by Dennis E. Doherty, MD Decreased Smooth Muscle Constriction and Mucus Gland Secretion Ipratropium Bromide Atropine M3M3

11. Parasympathetic Sympathetic DISTRIBUTION OF CHOLINERGIC AND ADRENERGIC RECEPTORS

12. CHRONIC BRONCHITIS EMPHYSEMA ASTHMA AIRFLOW OBSTRUCTION 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) Diagnose ReduceRisk Smoking cessation Immunize Reduce other exposures ReduceSymptoms ReduceComplications Bronchodilators Consider inhaled steroids Pulmonary rehabilitation Consider oxygen Treat exacerbations Spirometry Education

15. STEPWISE TREATMENT OF COPD BASED ON SEVERITY (GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276) Stage 0: At Risk Normal spirometry Avoid Risks Vaccinate Stage I: Mild COPD FEV 1 /FVC < 70% FEV 1 > 80% predicted Add a short-acting bronchodilator prn – Anticholinergic or – Beta 2 -agonist Stage IIA: Moderate COPD FEV 1 /FVC < 70% IIA: 50% < FEV 1 < 80% Add one or more short-acting bronchodilators on a scheduled basis (Anticholinergic + Beta 2 -agonist) Stage IIB: Moderate COPD FEV 1 /FVC < 70% IIB: 30% < FEV 1 < 50% Consider trial of inhaled steroids Add Pulmonary Rehabilitation Stage III: Severe COPD FEV 1 /FVC < 70% FEV 1 < 30% Evaluate for adding oxygen Consider surgical options

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

17. OFFICE SPIROMETERS

18. CHRONIC BRONCHITIS EMPHYSEMA ASTHMA AIRFLOW OBSTRUCTION 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 Bronchodilation is first-line pharmacologic therapy in COPD (GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276)

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. ANTICHOLINERGICS AND SHORT-ACTING BETA-AGONISTS ENHANCE FEV 1 IN COPD. 0 5 10 15 20 25 30 012345678 Hours After Test Dose Test Day 85 Ipratroprium (N=176) Albuterol (N=165) Chest 105:1411, 1994 % Change in mean FEV 1

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. SALMETEROL IN COPD (Mahler et al, Chest 115:957, 1999) Change from Baseline FEV 1 Placebo Salmeterol Ipratopium

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. 0.95 1.00 1.05 1.10 1.15 1.20 1.25 1.30 1.35 0123456789101112 Time after administration (h) Tiotropium (n = 202) Placebo (n = 179) Long-Acting Anticholinergic - Tiotropium Change in FEV 1 : Six Month Study P < 0.001 for tiotropium vs placebo FEV 1 (L) (DonohueJF, Chest 2002;122:47-55 ) Day 169

30. 0.95 1.00 1.05 1.10 1.15 1.20 1.25 1.30 1.35 0123456789101112 Time after administration (h) Tiotropium (n = 202) Salmeterol (n = 203) Placebo (n = 179) Day 169 Change in FEV 1 : Tiotropium vs Salmeterol vs Placebo P < 0.001 for tiotropium vs placebo P < 0.05 for tiotropium vs salmeterol FEV 1 (L) (DonohueJF, Chest 2002;122:47-55 )

31. 0.95 1.00 1.05 1.10 1.15 1.20 1.25 1.30 1.35 0123456789101112 Time after administration (h) Tiotropium (n = 202) Salmeterol (n = 203) Placebo (n = 179) Day 169 Day 1 Change in FEV 1 : Tiotropium vs Salmeterol vs Placebo 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 FEV 1 (L) (DonohueJF, Chest 2002;122:47-55 )

32. Binding and Dissociation Disse B et al. Life Sci 1993 Apparent K D (nM) Ipratropium 0.430.540.69 Tiotropium 0.270.120.33 Dissociation Half-Life (hours) [ 3 H]-Ipratropium 0.110.0350.26 [ 3 H]-Tiotropium 14.6 3.6 34.7 Human Muscarinic Receptors in CHO Cells M1 M2 M3M1 M2 M3 K D = dissociation constant

33. CHRONIC BRONCHITIS EMPHYSEMA ASTHMA AIRFLOW OBSTRUCTION Combination Therapy in COPD 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 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. Ikeda A, et al. Chest. 1996;109:294. 0 10 20 30 40 50 80 mcg ipratropium + 400 mcg salbutamol 40 mcg ipratropium + 200 mcg salbutamol 80 mcg ipratropium 40 mcg ipratropium Placebo FEV 1 (% change) 0 1 2 3 4 5 6 7 8 Time After Test Dose (h) IPRATROPIUM BROMIDE AND SALBUTAMOL

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

44. 050100150200250300350400450500 Acquisition cost of primary pulmonary drug Acquisition cost of drugs added during exacerbations Hospitalization cost Albuterol Ipratropium + Albuterol Friedman M, et al. Chest. 1999;115:635-641. COST OF HOSPITALIZATION FOR EXACERBATION

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

47. Theophylline Metabolism Age Smoking Formulation Liver Disease Heart Disease Infection 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. The inflammation of asthma is responsive to steroids –Mast cells, eosinophils, T H 2-like lymphocytes (CD4) –IL-4, IL-5, IL-13, ECP, LTC 4 The chronic inflammation in COPD is not responsive to steroids –Macrophages, Neutrophils, T-Lymphocytes (CD8) –LTB 4, TNF, IL-8, Chemokines LUNG INFLAMMATION IN ASTHMA IS DIFFERENT THAN THE LUNG INFLAMMATION IN COPD

50. GOLD Guidelines 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. (GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276)

51. INHALED CORTICOSTEROIDS IN COPD Copenhagen City Heart Study (Lancet 1999;353:1819-23) Mild-Moderate COPD (n=290) Budesonide 1200-800 micrograms/day No difference vs placebo in rate of decline in FEV 1 over 3 years EUROSCOP Trial (N Engl J Med 1999;340:1948-53) Mild COPD (n=1277) Budesonide 800 micrograms/day No difference vs placebo in rate of decline in FEV 1 over 3 years Increase of 30-40ml FEV 1 in treatment group early on which was sustained throughout the study

52. INHALED CORTICOSTEROIDS IN COPD Lung Health Study (N Engl J Med 2000;343:1902-1909) Moderate COPD, FEV 1 of 2L (n=1116) Triamcinolone 1200 micrograms/day No difference vs placebo in rate of decline in FEV 1 over 3.5 years Modest improvement in dyspnea and onset of severe symptoms Increased risk of osteoporosis ISOLDE Trial (BMJ 2000;320:1297-303) Moderate to severe COPD, FEV 1 of 1.5L (n=751) Fluticasone 1000 micrograms/day No difference vs placebo in rate of decline in FEV 1 over 3 years Increase of 100ml FEV 1 in treatment group early on which was sustained throughout the study Exacerbations decreased by 25% in treatment group

53. SYSTEMIC CORTICOSTEROIDS SHOULD BE USED DURING ACUTE EXACERBATIONS OF COPD Two studies have shown efficacy for the use of systemic steroids during acute COPD exacerbations Niewoehner DE et al, NEJM 340:1941, 1999 Davies L et al, Lancet 354:456, 1999 Once daily Solumedrol (60 mg iv) or Once daily Prednisone (30 - 40mg po) Taper off in 5-7 days

54. CORTICOSTEROIDS DURING ACUTE EXACERBATIONS OF COPD Niewoehner et al NEJM 1999;340:1941

55. 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

56. MONTHLY ACQUISITION COSTS FOR COPD DRUGS (AWP) (REDBOOK, 2002 Edition) Albuterol AWP/month (Dollars) No. MDIs/Month Ipratropium Albuterol + Ipratropium Albuterol + Ipratropium (single MDI) Formoterol Salmeterol Salmeterol + Albuterol 1.2 1.2 + 1.2 1.2 1.0 1.0 + 1.2

57. MONTHLY ACQUISITION COSTS FOR COPD DRUGS (AWP) (REDBOOK, 2002 Edition) AWP/month (Dollars) No. MDIs/Month Albuterol Ipratropium Albuterol +Ipratropium (Single MDI) Salmeterol + Albuterol Formoterol + Albuterol Beclomethasone Fluticasone 110 Fluticasone 220 Flunisolide Budesonide Fluticasone 500 + Salmeterol 50 Combination 1.2 1.0 + 1.2 1.2 1.0 1.2 0.6 1.0

58. 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

59. MODALITIES IMPROVING SURVIVAL IN COPD Successful Smoke Cessation (Behavioral Modification Required) Oxygen Therapy (Minimum of 15-18 hr qd)

60. NON-PHARMACOLOGIC ARMAMENTARIUM Successful Smoke Cessation Pulmonary Rehabilitation (formal/informal) Overall Education Exercise Program (home program) Nutrition Vaccination Pulmonary Hygiene (?mucolytic agents) Antibiotics Transplantation (Single Lung) Oxygen, Noninvasive Ventilation Experimental (LVRS, Anti-oxidants/Vitamins)

61. Carol Boland (Nurse Practitioner) Dick D. Briggs (Pulmonary) Dennis E. Doherty (Pulmonary) Harold Hedges III (Family Medicine) Louis Kuritzky (Family Medicine) Ron Levine (Internal Medicine) Kenneth Pellegrino (Family Medicine) Alan Radin (Internal Medicine) Steven A. Sahn (Pulmonary) THE NATIONAL COPD AWARENESS PANEL (NCAP) Journal of Respiratory Diseases 21:S1-21, Sept 2000 Journal of Respiratory Diseases 23:S1-52, Sept 2002

62. COPD Management in Primary Care NCAP- Journal of Respiratory Diseases 23:S1-52, Sept 2002 GOLD Guidelines Am J Respir Crit Care Med 2001;163:1256-1276 Sustained Smoking Cessation First-line Therapy is to Maximize Bronchodilation Anticholinergics (short- or long-acting) Beta-2 Agonists (short- or long-acting) Methylxanthines After Maximal Bronchodilation with multiple agents in patients with severe COPD and frequent exacerbations A trial of Inhaled Corticosteroids can be considered – 6 week to 3 month trial – Monitor Spirometry and Symptoms – Discontinue if no improvement in that time period

63. VACCINNATION IN COPD Pneumococcal In all COPD Patients Patients > 65 vaccinated more than 5 years previously should be revaccinated, if unsure - revaccinate Evidence for efficacy is inconclusive (some studies show a 65- 85% efficacy amongst high-risk populations) Influenza Administer annually unless there is a history of severe anaphylaxis to egg protein 30-80% effective in preventing illness, complications, and death in high-risk populations Can be administered concurrently with pneumococcal vaccine if administered at different sites

64. For more information on COPD National Lung Health Education Program www.nlhep.org U.S. COPD Coalition www.uscopd.com