MUCOACTIVE AGENTS IN COPD TREATMENT

Doç.Dr. Elif Şen

Ankara University School of Medicine Pulmonary Diseases Department

Conflict of interest

Congress participation

Novartis Glaxo-Smith Kline

• Mucoactive Agents

• Mechanisms of action in COPD

• Use in the treatment

• Evidence Based Data- Guideline

recommendations

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

Mechanisms of action

EXPECTORANTSIncrease in expulsion of mucus fromthe respiratory tract.

Aerosol hypertonic saline – increases secretion volume and/or hydration

Guaifenesin- stimulate the cholinergic system and increase mucus secretion

Agents regulating mucus secretion or interfere with the DNA/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.

MUCOREGULATORS

MUCOLYTİCS

Decrease mucus viscosity, depolymerize DNA / F-actin network

N-Acetylcysteine – breaks disulphide bonds linking mucin

polymers.

- antioxidant, antiinflammatory

Erdosteine – regulates mucus production.

- increases mucociliary transport.

MUCOKINETICS

Agents increasing mucociliary 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.

“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

Mucus Hypersecretion in COPD

“Oxidative Stress”

Mucoactive Antioxidant

In stable COPD Treatment

In prevention of acute exacerbations

COPD

Mechanisms of action in COPD

Decrease of viscosity

Increase of mucociliary transport

Effects on small airways?

•Other effects Antioxidant

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.

Acute Exacerbations

Decrease of inflammatory marker levels

Efficient in bacterial eradication

Cochrane 2010 Analyze

In chronic bronchitis and COPD patients

Oral mucolytics / Placebo

Randomized studies

28 studies

7042 patients

At least 2 months therapy

Aylık Alevlenme Sıklığı

Yıllık atak sayısında %20 azalma

Exacerbation free patients during study

Exacerbation free patients during study odds ration 1.93 , p<0.001

NNT : 6 Number Needed to Treat

To prevent 1 patient from exacerbation it is needed to treat 6

patients

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

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

Cochrane Analyse

Chronic bronchitis and COPD studies

COPD – 5 studies

• 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

• 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).

• 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.

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”

BRONCUS Study

No effect on quality of life.

Significant decrease in FRC(374 ml, p < 0.001)

Study group of GOLD II patients

What are the effects on GOLD III-IV patients?

Dose >600 mg/day?

Inhaled steroid use of 70 %

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) .

•The decreasing effect on exacerbations in carbocysteine treated 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.

Increase in quality of life after 1 year treatment

No difference on FEV1

Oxygen saturation

Side effects – not different than placebo

Mucolytic treatment in acute exacerbations :

•Improvement of subjective complaints

•Decrease of inflammatory markers

•Bacterial eradication

•No difference on hospitalization lenght

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.

RESULTS

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.

NICE Guideline

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)

GOLD 2011

Mucolytic drugs have a small effect in decreasing acute exacerbations.

They are not effective on FEV1 decline.

They may have some effects on frequent exacerbators requiring hospitalization.

They can be effective in patients not using inhaled steroids.