MU C OA CTIVE AGENTS IN COPD TREATMENT

1. MUCOACTIVE AGENTS IN COPD TREATMENT Doç.Dr. Elif Şen Ankara University School of Medicine Pulmonary Diseases Department

2. Conflict of interestCongress participation • Novartis • Glaxo-Smith Kline

3. Mucoactive Agents • Mechanisms of action in COPD • Use in the treatment • Evidence Based Data- Guideline recommendations

4. Mucoactive Agents • Expectorants • Mucoregulators • Mucolytics • Mucokinetics Hypertonic saline, Guaifenesin Carbocysteine, Anticholinergics, Glucocorticoids, Macrolids N-Acetylcysteine, N-Acysteline, Erdosteine, Dornase-α, Gelsolin, Tymosin-ß4, Dextran, Heparine Broncodilators, Ambroxol, Surfactant

5. Mechanisms of action EXPECTORANTS Increase in expulsion of mucus from the respiratory tract. Aerosol hypertonic saline – increases secretion volume and/or hydration Guaifenesin- stimulate the cholinergic system and increase mucus secretion

6. MUCOREGULATORS Agents regulating mucus secretion or interfere with theDNA/F-actin network Carbocysteine - regulates mucus viscoelasticity -antioxidant, antiinflammatory Anticholinergics- inhibits colinergic system which increases mucus secretion (M3 res). Glucocorticoids – decrease airway inflammation and mucus secretion. Macrolids – decrease airway inflammation and mucus secretion.

7. MUCOLYTİCS Decrease mucus viscosity, depolymerize DNA / F-actin network N-Acetylcysteine– breaks disulphide bonds linking mucinpolymers. -antioxidant, antiinflammatory Erdosteine– regulates mucus production. - increases mucociliary transport.

8. MUCOKINETICS Agents increasingmucociliary transport Bronchodilators - Improves cough by increasing expiratory flow and increase in secretion expulsion -antioxidant, antiinflammatory Ambroxol-increases in surfactant production, inhibits chloride channels -decrease in viscosity of secretions Surfactant –decreases surface adhesion between mucus and airway.

9. Mucus Hypersecretion in COPD • “Major symptom in chronic bronchitic phenotype” • Frequent lower airway infection • Frequent hospitalization • Increased FEV1 decline • Relationship between mucus impacted small ariways in patients performed lung volume reduction surgery and early death

10. COPD • “Oxidative Stress” Mucoactive Antioxidant • In stable COPD Treatment • In prevention of acute exacerbations

11. Mechanisms of action in COPD • Decrease of viscosity • Increase of mucociliary transport • Effects on small airways? • Other effects Antioxidant

12. Mechanisms of action in COPD • N-Acetylcysteine, carbocysteine • Other effects • Antioxidant • Decrease in neutrophil, monocyte chemotaxis • Decrease of neutrophil, monocyte count and activation in smokers • Decrease of bacterial adhesion to ciliated epithel cells.

13. Acute Exacerbations • Decrease of inflammatory marker levels • Efficient in bacterial eradication

14. Cochrane 2010 Analyze • In chronic bronchitis and COPD patients • Oral mucolytics / Placebo • Randomized studies • 28 studies • 7042 patients • At least 2 months therapy

15. Aylık Alevlenme Sıklığı Yıllık atak sayısında %20 azalma

16. Exacerbation free patients during study Exacerbation free patients during study odds ration1.93 , p<0.001

17. NNT : 6 Number Needed to Treat To prevent 1 patient from exacerbation it is needed to treat 6 patients

18. If studies of 8 months of treatment in winter months are considered, odds ratio for exacerbation free patients number is 2 .23.

19. They are not effective on the decrease of FEV1 decline rate. • The decrease on FRC was significant • Their effects on quality of life are variable

20. Cochrane Analyse • Chronic bronchitis and COPD studies • COPD – 5 studies

21. 313 patients • Mean FEV1 of 60 % • Double-blind, placebo controlled, NAC 600 mg/ day • Mean treatment duration of 8 months • Number of exacerbation per month 0.03 NAC/0.06 placebo • In NAC treated group the exacerbation free period is longer • Pela et al. • 169 patients • NAC 600 mg day/ placebo • Patients using inhaled bronchodilators • Inhaled steroids use of 40 % • 41% decrease in exacerbations in the treatment arm

22. Double blind, placebo controlled randomized • Erdosteine 300 mg bid • 8 month • 124 patients • Decrease in exacerbations • Shortened lenght of hospitalization • Improvement of SF-36 , SGRQ scores • 1 year • Ambroxol 75 mg bid /placebo • More symptomatic patients had a lower exacerbation free period during study (63 v 37%; P< 0.038).

23. Retrospective pharmacological data • 1219 patients • Hospitalied patients of COPD treated with NAC after discharge/not treated with NAC • 1 year follow-up • Risk of rehospitalization decreased by 30 % • This effect is dose related.

24. BRONCUS Study • Double blind, placebo controlled, randomized • 523 patient (mean FEV1 %57±9 pred) • 3 year N-acetylcystein 600 mg/day/Placebo • RESULTS: • FEV1 decline rate per year is not different. • (placebo 54 ml / year /NAC 47 /ml / year) • No decrease in exacerbations. • “Decrease in exacerbation rates in a subgroup of patients not using inhaled steroid”

25. No effect on quality of life. • Significant decrease in FRC(374 ml, p < 0.001)

26. Study group of GOLD II patients • What are the effects on GOLD III-IV patients? • Dose >600 mg/day? • Inhaled steroid use of 70 %

27. PEACE Study • Double blind, placebo controlled, randomized • 709 patients (mean FEV1 %45 pred) • 3 year treatment of carbocysteine 3 x 500 mg/day/Placebo • RESULTS: • Yearly FEV1 decline rate is not different. • Significant decrease in exacerbation rate per year (1.01/ 1.35, 25 % reduction) .

28. The decreasing effect on exacerbations in carbocysteinetreated group • Disease severity • Inhaled steroid use • Smoking status doesn’t affect • The exacerbation reduction is not significant at 3rd month of therapy. • Reduction of exacerbations at 6th month and 1 year.

29. Increase in quality of life after 1 year treatment • No difference on FEV1 • Oxygen saturation • Side effects – not different than placebo

30. Mucolytic treatment in acute exacerbations : • Improvement of subjective complaints • Decrease of inflammatory markers • Bacterial eradication • No difference on hospitalization lenght

31. RESULTS • Exacerbation frequency – may be reduced especially in patients not using inhaled steroids • Sick days– some studies show benefit. • Lung function decline- not influenced. • Quality of life – may be improved in patients not treated with standard therapy • Decrease in symptoms– no reliable data. • Side effects – not different than placebo in long-term use. Treatment in exacerbation • Decrease in symptoms, shortened exacerbation period– may influence.

32. Mucolytics (mucokinetics, mucoregulators) The studies of long term use in COPD had variable results. In systematic analysis of randomized controlled studies with mucolytics in chronic bronchitis and COPD, small decreases were found in exacerbation rates and severity. N-acetylcystein trials showed a decrease of exacerbations in moderate to severe patients not treated with inhaled steroids. Carbocysteine decreased exacerbations and improved quality of life. Routine use of mucolytics can not be recommended. Their mechanicms of actions are not clear.

33. NICE Guideline

35. GOLD 2011 Mucolytics and Antioxidant Agents • The regular use of mucolytics in long-term studies are controversial. • Patients with viscous sputum may benefit from mucolytics. The overall benefit seems to be very small The widespread use of these agents can not be recommended at present (Evidence D) • Drugs like N-acetylcysteine may have antioxidant effects leading to speculationthat these medications could have a role in treatment of patients with recurrent exacerbations (Evidence B) • In patients not treated with inhaled steroids, carbocysteine, N-acetylcysteine may reduce exacerbations (Evidence B)

36. Mucolytic drugs have a small effect in decreasing acute exacerbations. They are not effective on FEV1decline. They may have some effects on frequent exacerbators requiring hospitalization. They can be effective in patients not using inhaled steroids.