Management of COPD- An update

Management of COPD- An update

Dr. Biswas Akhtar Hossain

Assistant Prof.
NIDCH

INTRODUCTION

No present treatment reverses COPD

Underlying cellular and molecular mechanisms
Chronic inflammation
-Neutrophils, macrophages, CD 8 lymphocytes
Fibrosis
-Destruction (neutrophil elastase, MMP)
Asthma is different

Definition
GOLD
Airflow limitation
not fully reversible
progressive
abnormal inflammatory response to
noxious particles or gases

4 components of COPD management

Assess and monitor disease
Reduce risk factors
Manage stable COPD
Manage exacerbations

Diagnosis of COPD
SYMPTOMS
cough
sputum
shortness of breath

EXPOSURE TO RISK
FACTORS
tobacco
occupation
indoor/outdoor pollution

SPIROMETRY

Pt. with Plethoric

appearance

Pt. with Exertional

Dyspnoea

Pt. with COPD

Treatment Options
Conventional Therapy
Pharmacologic therapy
Bronchodilators
Glucocorticosteroids
Vaccines
Alpha-1 antitrypsin augmentation therapy
Antibiotics
Mucolytics
Antitussives
Respiratory Stimulants
Narcotics

Conventional Therapy (Cont.)

Non-pharmacologic
Pulmonary rehabilitation
Oxygen
Ventilatory support
Surgery

Bullectomy
Lung Volume Reduction Surgery (LVRS)
Lung Transplantation

Therapy at Each Stage of COPD

I: Mild

II: Moderate

III: Severe

IV: Very Severe

FEV1/FVC < 70%

FEV1 > 80%

predicted

FEV1/FVC < 70%

30% < FEV1 < 50%

predicted

FEV1/FVC < 70%

50% < FEV1 < 80%
predicted

FEV1/FVC < 70%

FEV1 < 30%

predicted
or FEV1 < 50%
predicted plus
chronic respiratory
failure

Active reduction of risk factor(s); influenza vaccination

Add short-acting bronchodilator (when needed)
Add regular treatment with one or more long-acting
bronchodilators (when needed); Add rehabilitation
Add inhaled glucocorticosteroids if
repeated exacerbations
Add long term
oxygen if chronic
respiratory failure.
Consider surgical
treatments

Emerging Therapies for COPD

Smoking cessation
New drugs
Bronchodilators
Mediator antagonists
Anti-inflammatory agents
Protease inhibitors
Remodeling agents
Bronchoscopic LVRS

Smoking Cessation
Major cause for COPD
Nicotine addiction
Quit rates
Placebo 6%
NRT and behavioural therapy 9%
Bupropion (6-9 wks) 18% at 1 yr

Well tolerated, sleeplessness, epilepsy

Better drugs may emerge

New Bronchodilators
Indacaterol
Ultra-long-acting 2-agonist (LABA)
Once-daily (od) dosing
Inhaled

Indacaterol is a highly effective bronchodilator

that is superior to other available long-acting
bronchodilators for COPD.
*US-FDA approval- 05 July 2011

MEDIATOR ANTAGONISTS
On going inflammation; even in ex-smokers
Neutrophillic inflammation
Reactive oxygen species
Inhibition of Leukotriene B4,chemokines,
TNF, iNOS, anti-oxidants.

Leukotriene B4
Potent chemoattractant of neutrophils

Increased in sputum of COPD pts

Synergy with IL-8

BLT1(granulocyte monocyte)

BLT2 (T lymphocytes)
Antagonists (BLT1)
-LY29311, SB 201146, B11L284 etc
5 lipoxygenase inhibitors
- zileuton (synthesis)

Chemokine inhibitors
IL-8 marked increase, disease severity
Monoclonal Ab to IL-8 in clinical trials
Block common receptor for CXC family
- CXCR1, CXCR2 (Antagonists)
- Monocyte chemotactic protein 1:CCR2 (Antagonist)

TNF alpha inhibitors

TNF increased, increases IL-8 via NF-
Severe wasting
Infliximab (monoclonal Ab), etanerecept (soluble
recep) may act.
- Blocking Ab if long term
- Repeated injections inconvenient

TNF converting enzyme (TACE) better target for

inhibition with small molecules.

Anti oxidants
Oxidative stress increases in COPD
Reactive Oxygen sp. aid pathology
Anti-oxidants may help
Oral NAC (small decrease in AE)
Glutathione compounds (Resveratrol)
Superoxide desmutase
Selenium based drugs

iNOS inhibitors
Increased NO release
Peroxynitrite- potent radical: may nitrate
proteins and alter fn.
3-nitrotyrosine (indicator) inc in COPD
Selective inhibitors in development : L-N6 (1imminoethyl) Lysine

New Anti-inflammatory Treatments

Chronic inflammation
Macrophages,neutrophils,CD8+ cells
Airways and parenchyma
Steroid resistance
Inhibitory effect of smoking (histone
deacetylation)
New agents/unlocking steroid resistance

PDE4 inhibitors
PDE4 predominant form expressed
Selective inhibitors
- Cilomilast
- Roflumilast

Roflumilast

The selective PDE4-inhibitor anti-inflammatory drug

Prevents the breakdown of cyclic AMP
Plays an important role in regulating inflammatory
cell activity.
Offers sustained and significant improvement in lung
function in patients with a FEV1 less than 50%
predicted and a reduction in exacerbations
Limited by side effects (GIT)
Isoenzyme subtype selective inhibitors may have
less side effects

Nuclear Factor-B inhibitors

Regulates IL-8, TNF,MMP
Several approaches
- Gene transfer of inhibitor
- Inhibition of NIK, IKK
- Hypoestoxide in African remedy for inflm.
- Possibility of sepsis as a result

Adhesion molecule inhibitors

Recruitment depends on adhesion mol.
E-selectin (endothelial cells)
Sialyl-Lewis (neutrophils)
InhibitorsAnti CD-11/CD-18
Anti ICAM-1
E-Selectin Inhibitors

IL-10
Anti-inflammatory cytokine
Inhibits TNF and IL-8
Favours antiproteases (lowers MMP)
Levels are low in COPD
Tried in RA, psoriasis, IBD
Daily injections over weeks
Selective activator of IL-10 receptors

Phosphoinositide-3 kinase inhibitors

PI-3K enzymes promote lipid 2nd messengers
PI-3K neutrophil recruitment, activation
Selective inhibitors may help COPD

PROTEASE INHIBITORS
Protease- Antiprotease imbalance.
Proteases digest elastin.
Anti-proteases protect
Inhibiting proteases/Increasing antiproteases.
Progress in identification of these.

Endogenous antiproteases
Supply endogenous antiproteases
Recombinant form/Viral vector gene delivery
Poor efficacy/ Not cost effective
Gene delivery inadequate protein

Protease inhibitors
More promising
Small molecule inhibitors of proteinases
- ONO-5046, FR901277
Inhibit elastase induced injury
Neutrophil elastase, MMP-9,cathepsins

REMODELLING AGENTS
Retinoic acid reverses histo/physiochanges
in rats (Increases alveoli)
Activates receptors
Growth/diffrentiation genes
Trial of ATRA in emphysema underway

Genetic factors
10-20% of smokers have COPD.
Identification of genes predisposing to
COPD may identify new approaches to
therapy.

Bronchoscopic LVRS
Established palliative therapy in emphysema
Improves lung function, ex.capacity, QOL.
Significant mortality and morbidity
Attempts at technique modification.
Plication, stapling without removal
Faster, less post-op air leak.

Conclusion

COPD has systemic consequences.

Smoking cessation can decrease the prevalence of
COPD.
Long term oxygen therapy for hypoxic COPD pt.
increase survival.
Pharmacological therapy, Pulmonary rehabilitation,
Non-invasive ventilation & surgery for selective
COPD pt can effectively improve lung function,
quality of life, exercise capacity, dyspnoea and even
survival.

Conclusion

With a better understanding of the

inflammatory and destructive process,
several targets have been identified, and new
treatments are now in clinical development.
With all these options a nihilistic attitude
towards a pt. with COPD is not justified. The
evidence supports a positive and aggressive
attitude .