1. Current strategies for COPD treatement Jaideep A. Gogtay MD Cipla Ltd, Mumbai, India

2. New definition of COPD Preventable and treatable disease characterized by airflow limitation partially reversible. Abnormal inflammatory response to toxic inhaled particles. COPD has important systemic consequences that also respond to therapy. ATS/ERS ERJ 2004

3. Outline of presentation Why is COPD assuming importance? What happens in COPD? How do we assess COPD? What are the treatments available? What can we expect form treatment?

4. Percent Change in Age-Adjusted Death Rates, U.S., 1965-1998 0 0 0.5 1.0 1.5 2.0 2.5 3.0 Proportion of 1965 Rate 1965 - 1998 –59% –64% –35% +163% –7% Coronary Heart Disease Coronary Heart Disease Stroke Other CVD COPD All Other Causes All Other Causes

5. Annual deaths1,791 26,033 (UK 1992) ASTHMA COPD MORTALITY Workload in UK Health District of 250,000 Hospital admissions 410 680 In-patient bed days 1,800 9,600 GP consultations11,90014,200 MORBIDITY BURDEN OF DISEASE: COPD vs ASTHMA

6. Who gets COPD? 20-25% of chronic smokers Prevalence of smoking in adults in Colombia is 22.3% (M:23.9% and F:21%) and in 15-16 year olds:up to 30% 1 Pollution –Occupation –Indoor air pollution – exposure to biomass fuels Poor diet Repeated infections in childhood Untreated asthma?? 1 www.who.com/tobacco

7. Chulla smoke Chulla smoke increases the activity of MMP-12 (matrix metalloproteinase) These enzymes degrade the collagen in the basement membrane of the airways

8. FEV 1 (% predicted at age 25y) 100 75 50 25 0 5075 Age (years) Stopped smoking aged 60 yr Stopped smoking aged 50 yr Susceptible smoker (10-20%) Death Disability Fletcher C, Peto R: BMJ 1977 ANNUAL DECLINE IN LUNG FUNCTION Non smoker Non-susceptible smoker

9. COPD and asthma The Overlap COPD Neutrophils No airway hyperresponsiveness Less bronchodilator response Limited steroid response Wheezy bronchitis 10% Asthma Eosinophils Airway hyperresponsiveness Bronchodilator response Steroid response

10. Atopic asthmatic Heavy smoker with COPD FEV1< 40% predicted Airway mucosa under light microscopy

11. Reversibility Sputum production Alveolar Damage AsthmaChronic Bronchitis Emphysema COPD

12. INFLAMMATORY CELLS IN INDUCED SPUTUM 0 0.5 1 1.5 2 2.5 L Total cell count (x10 6 /ml) Macrophages Neutrophils Eosinophils Keatings et al: Am J Respir Crit Care Med 1997 Normal COPD *** ** * Asthma ** Induced sputum: inflammatory cell counts

13. SPUTUM CYTOKINES IN COPD COPD patients: 62.5 ±3.2y; FEV 1 = 34.6±4 % predicted 0 2 4 6 8 [ TNF-  (nmol/l)] Controls (n=16) Smokers (n=12) COPD (n=14) Asthma (n=22) * * ** TNF-  0 1 2 3 4 [IL-8 (nmol/l)] Controls (n=16) Smokers (n=12) COPD (n=14) Asthma (n=22) * ** IL-8 Keatings et al: Am J Respir Crit Care Med 1996

14. PROTEASE-ANTIPROTEASE IMBALANCE IN COPD Neutrophil elastase Neutrophil elastase Cathepsins Cathepsins MMP-1, MMP-9, MMP12 MMP-1, MMP-9, MMP12 Granzymes Granzymes Others…….. Others……..  1 -Antitrypsin  1 -Antitrypsin SLPI SLPI Elafin Elafin TIMPs TIMPs Neutrophil elastase Neutrophil elastase Cathepsins Cathepsins MMP-2, MMP-9, MMP12 MMP-2, MMP-9, MMP12 Granzymes Granzymes Others…….. Others……..

15. Inflammation Neutrophils Macrophages Cytokines Mediators Proteases Non-smokers Normal smokers AMPLIFICATION OF INFLAMMATION IN COPD Amplification Genetic? Viral? Oxidative stress? Other COPD 0 + ++++

16. COPD: Underdiagnosis NHANES III (1988-1994)

17. Assessment of COPD FEV1 – diagnosis and severity Dyspnea Exercise tolerance – Inspiratory capacity Quality of life

18. New Drugs for COPD

19. Relieve symptoms: dyspnoea, shortness of breath and cough with expectoration Improve lung function Improve exercise tolerance Prevent and treat exacerbations Improve health status Prevent disease progression Reduce mortality What are we aiming to achieve with drug therapy?

20. Stopping smoking Only smoking cessation has been shown to decline the progression of the disease The most important part of treatment plan Sustained quitters – 25%

21. Pharmacotherapy for Stable COPD Bronchodilators Long-acting  2 -agonist - Salmeterol, Formoterol, Bambuterol Short-acting  2 -agonist – Salbutamol Long-acting anticholinergics - Tiotropium Short acting anticholinergics – Ipratropium Methylxanthines - Theophylline Corticosteroids Oral – Prednisolone Inhaled - Fluticasone, Budesonide

22. Vagal “tone” Vagus nerve ACh NORMAL ANTICHOLINERGIC Resistance  1/r 4 ACh COPD ANTICHOLINERGICS IN COPD

23. “ Bronchodilator medications are central to the symptomatic management of COPD” “Patients with moderate to severe symptoms of COPD require combination of bronchodilators” GOLD Report 2003

24. Lefcoe NM et al: Chest 1982 I=ipratropium bromide, ß=fenoterol, P=placebo ANTICHOLINERGICS IN COPD vs ASTHMA I+ß ß I P Increase in FEV 1 (L) Asthma 1 2 3 h 0.8 0.6 0.4 0.2 0 COPD 0 1 2 3 I+ß ß I P Time (h) 0.4 0.2

25. Hyperinflation and Dyspnea Effect of Ipratropium * * ** * O’Donnell AJRCCM 98;158:1557 n = 29

26. Complementary Actions of Beta agonists + Anticholinergics Possible additive/synergistic activity Fast, greater and prolonged action on bronchodilation Different sites of action Non-bronchodilator effects Improvement in exercise tolerance Effects on mucus hypersecretion Curr Opin Pharmacol 2003; 3: 270 – 276 Chest 1995; 5: 1715 - 1755

27. Rationale for combining in a single inhaler device Complementary mechanisms of action as per recommendations eg. scientific evidence COPD patients are generally elderly, many are from lower socioeconomic class,and illiterate Polypharmacy is the rule in advanced COPD cases Not easy when multiple inhalers are prescribed – affects compliance; patients tend to stop taking the inhaler which does not seem to provide relief

28. FEV1 Symptoms Smoking cessation. Exercise. Vaccination Beta agonists. P.R. ACH LABA Theophylline ACH LABA Theophylline Risk Oxygen Oxygen Surgery MV COPD: Therapeutic Options Celli’s schema ICS

29. Muscarinic Receptors in the airways M1M1 M2M2 M3M3

30. Mechanism of action of Tiotropium

31. Tiotropium vs Ipratropium (FEV 1 ) Eur Resp J 2002; 19: 209-16 160 -80 -40 0 40 80 120 0100200300400 Test day T r o u g h F E V m L 1 Difference Tiotropium Ipratropium

32. Change in lung volumes with Tiotropium Celli. Chest 2003; 124:1743-1748.

33. Tiotropium vs Ipratropium (Time to first exacerbations and hospitalization) Eur Resp J 2002; 19: 209-16 050100150200250300350 TiotropiumIpratropium

34. Tiotropium vs salmeterol (SGRQ) 47 40 41 42 43 44 45 46 057113169 Test day M e a n S G R Q t o t a l s c o r e Difference Tiotropium (n=186) Salmeterol (n=187) Placebo (n=159) * * Chest 2002; 122: 47-55

35. Effect of tiotropium on Oxygen Desaturation Design: Randomised, double-blind trial in 49 COPD patients Duration: 4 week trial Result: Oxygen desaturation during REM sleep was improved with tiotropium given in the morning (+ 2.31%) or in the evening (+ 2.13%), both p < 0.05 vs placebo Drugs 2002; 62(8): 1195-1203

36. Tiotropium pMDI Vs DPI in COPD:Single dose randomized crossover Data on file, Cipla Ltd 2004

37. Long acting beta agonists in COPD Salmeterol, Formoterol Widely used Stimulation of beta receptors and increase in cyclic AMP May have some effects on inhibiting neutrophil recruitment Improve mucociliary transport

38. Addition of formoterol to tiotropium further improves bronchodilation ATS, 2003 Poster 421 @# @p<0.05 Vs Form #p<0.05 Vs Tio

39. Role of inhaled steroids in COPD Benefits –Improve quality of life –Decrease exacerbations –Do not affect disease progression –May act synergistically when given with LABA Watch for side effects Currently indicated in –Severe COPD –Frequent (>2) exacerbations

40. Short acting bronchodilators Salbutamol/Levosalbutamol Quick-acting Rescue medication for acute bronchospasm when patients are taking maintenance therapy Can be given 3-4 times a day

41. Anticholinergic pharmacology The discovery of muscarinic receptor subtypes Cholinergic receptors Muscarinic receptors Nicotinic receptors M 1 M 2 M 3 M 4 M 5

42. Muscarinic Receptors in the airways

43. Effect of a single dose of tiotropium Casaburi ERJ 2002;19:217-224 + 16% + 18%

44. THEOPHYLLINE IN COPD Induced sputum COPD patients: mean age 62y (n=25) FEV 1 49% predicted Theophylline: 9.5 mg/L IL-8 (ng/mL ) 0 4 8 12 P<0.001 Placebo Theophylline Interleukin-8 0 0.5 1 1.5 2 2.5 Neutrophils x10 6 /ml) P<0.001 Placebo Theophylline Neutrophils Culpitt S et al: AJRCCM 2002

45. A new algorithm based on GOLD Short acting bronchodilator – as required Tiotropium Tiotropium+LABA Long acting beta agonist LABA + tiotropium Tiotropium + LABA + ICS + theophylline Mild Severe Chest, Jan 2004 Decreasing FEV 1 Increasing Symptoms FEV1<50%, exacerbations

46. Summary Treatment for COPD is improving Diagnosis needs to be made early in order to take preventive action Combination bronchodilators seem to be the best option Role of inhaled steroids is getting defined New long acting drugs will soon be available