Management of COPD

(Recent advances and Future prospects)

Dr. Dishank Patel

Introduction
COPD-

A disease state characterized by

airflow limitation that is not fully
reversible.
Emphysema- destruction and
enlargement of the lung alveoli;
Chronic bronchitis- chronic cough and
phlegm; and
Small airways disease- small bronchioles
are narrowed.
COPD is present only if chronic airflow
obstruction occurs.

RISK FACTORS
Cigarette

Smoking

Respiratory

Infections: Exacerbations

Occupational

Exposures: coal mining,

gold mining, and cotton textile dust

-1

Antitrypsin Deficiency

SNP

of MMP12

PATHOPHYSIOLOGY
Airflow

Obstruction: Reduced
FEV1, FVC and FEV1/FVC ratio.

Hyperinflation:

A. air trapping
-increased residual volume and
increased RV/TLC
B. progressive
hyperinflation- increased TLC

Gas

Exchange: Nonuniform
ventilation and ventilation-

PATHOLOGY
Large

Airway: Mucous gland enlargement

and goblet cell hyperplasia
cough
and mucus production.
- Neutrophil elastase: most potent
secretagogue.
Small

Airways: Airways 2 mm diameter.

luminal narrowing by fibrosis, excess mucus,
edema, and cellular infiltration.

Lung

Parenchyma: Destruction of gasexchanging air spaces- Emphysema.

CLINICAL FEATURES
Cough
Sputum

production

Exertional

dyspnea

LABORATORY FINDINGS
Airflow

obstruction (FEV1 and

FEV1/FVC)-prognostic factor

Recent

guidelines have suggested

testing for 1AT deficiency in all

subjects with COPD.

GOLD (Global Initiative for Lung Disease)

Classification for COPD
GOLD
Stage

Severity

Symptoms

Spirometry

At Risk

Chronic cough, sputum

production

Normal

Mild

With or without chronic

cough or sputum production

FEV1/FVC <0.7 and FEV1 80%

predicted

II

Moderate

With or without chronic

cough or sputum production

FEV1/FVC <0.7 and 50% FEV1

<80% predicted

III

Severe

With or without chronic

cough or sputum production

FEV1/FVC <0.7 and 30% FEV1

<50% predicted

IV

Very Severe

With or without chronic

FEV1/FVC <0.7 and FEV1 <30%
cough or sputum production
predicted or
FEV1 <50% predicted with
respiratory failure or signs of
right heart failure

TREATMENT
Stable

Phase COPD

1. Smoking cessation
2. Bronchodilators- Anticholinergic and long acting -agonist
Reduce

symptoms and exacerbations but not rate of

decline in FEV1.

3. Glucocorticoids- Reduces exacerbation freq by 25%

- Reduces rate of decline in lung function (controversial).
Indication- patients with frequent exacerbations (2/ year)
4. Theophylline- Requires monitoring of blood levels.

5. Oxygen- Only pharmacologic therapy demonstrated to

decrease mortality rates.
Indication: Resting O2 saturation 88% or <90% with signs of
pulmonary hypertension/right heart failure.
- Mortality benefit is proportional to the number of hours/day
oxygen is used.
6. Other agents- a] N-acetyl cysteine- mucolytic and antioxidant
b] 1 AT augmentation therapy- serum 1AT level <50 mg/dL
Nonpharmacologic
H

Therapies:

influenza and polyvalent pneumococcal vaccine

Lung

volume reduction surgery: mortality and symptomatic

benefit

Lung

transplantation

Rx of COPD exacerbations

Episodes

of increased dyspnea, cough and

change in the amount and character of sputum
with or without fever, myalgias, and sore
throat.

The

frequency of exacerbations increases as

airflow obstruction increases.

Precipitating

causes: Bacterial and viral

infections.
Chronic

suppressive or "rotating" antibiotics are

not beneficial in patients with COPD.

1. Bronchodilators: Inhaled -agonist +

anticholinergic agent methylxanthines
2. Antibiotics
3. Gucocorticoids: Hasten recovery and reduce
the chance of subsequent exacerbation or
relapse for a period of up to 6 months.

The GOLD guidelines recommend 3040 mg

of oral prednisolone for a period of 1014
days.

4. Oxygen: To keep arterial saturations >90%.

5. Mechanical ventilation:
Noninvasive

positive-pressure ventilation
(NIPPV) in patients with respiratory failure
(PaCO2 >45 mmHg) results in a significant
reduction in mortality rate.

Invasive

mechanical ventilation via an

endotracheal tube is indicated for patients
with severe respiratory distress despite
initial therapy, life-threatening hypoxemia,
severe hypercarbia and/or acidosis.

PATHOGENESIS and Newer

Targets

Cigarette smoke and pollutants

Oxidative stress
Inactivation of histone deacetylase
Activation of transcription factor B
Transcription of MMP, IL-8 and TNF-
Macrophage activation

Newer drug classes

Newer

concepts for the existing Rx

Anti-inflammatory
Antioxidant

drugs

therapy

Antiprotease
Regenerative

therapy
therapy

Mucoregulators
Newer

drug delivery systems

Newer concepts for

existing Rx

Smoking

cessation: Nicotine Ab and vaccine. NicotineAb complex cant cross BBB.

Bronchodilators:

Problem with short acting-frequent

dosing and compliance.

Ultra-LAMA-

Aclidinium, glycopyrronium, darotropium,

Dexpirronium
Ultra-LABA-

Carmoterol, indacaterol, milveterol,

vilanterol, olodaterol

Novel

Combinations: COPD patients respond variably

to LAMAs and LABAs.

- Furthermore, LAMAs and LABAs have been shown to

have synergistic effects [MABA- GSK-91081].

Anti-inflammatory drugs
PDE-4

inhibitors- Specifically expressed in many

proinflammatory cells. Oral/inhaled roflumilast-best add-on with
LAMA and LABA.

PDE7A

inhibitors-like PDE4, has a widespread distribution in

inflammatory cells. The PDE7-selective inhibitor BRL 50481 has
minimal inhibitory effects, but potentiates the anti-inflammatory
effects of a PDE4 inhibitor.

Cytokine

inhibitors- TNF-, (IL)-1, IL-6 and IL-7. Tocilizumab is

a potent inhibitor of IL-6.

Chemokine

antagonists- CXCR-2, 3 and 5 mediate chemotactic

effect on neutrophils and monocytes. [ADZ8309: CXCR1/2
antagonist]

Anti-inflammatory drugs
TGF-

inhibitors- Plays a key role in fibrosis of small airways,

which is a major cause of progressive FEV1 decline and
reduced exercise capacity in COPD patients. [SD-280]

Nuclear

factor B inhibitors- Gene transfer of the inhibitor

of NF-kB (IkB)

- Inhibitors of IkB kinases (IKK).

p38

MAP kinase inhibitors- Regulates the expression of IL-8,

TNF- and MMPs [SB 203580, SB 239063 and RWJ 67657].

PPAR

agonist- PPAR- and PPAR- have demonstrated

immunomodulatory properties. PPAR- agonists also inhibit
TGF-, inhibit release of cytokines from macrophages and
induce apoptosis of T-lymphocytes. Rosiglitazone is under Ix.

Anti-inflammatory drugs
LTB4

antagonist- Neutrophilic inflammation plays pivotal

role in COPD and LTB4 is a potent chemoattractant for
neutrophills. BLT1 receptors are mainly expressed on
granulocytes and monocytes, whereas BLT2 receptors are
expressed on T lymphocytes.
- Drugs: BLT1 antagonists such as LY29311, 5 LOX
inhibitors and FLAP inhibitors.

Chemokine

inhibitors- IL-8 levels are markedly increased

in the sputum of patients with COPD and are correlated
with disease severity. IL-8 activates two receptors:1) Low
affinity CXCR1-neutrophills and 2) High affinity CXCR2
neutrophills and monocytes.
- Blocking antibodies to IL-8

Anti-inflammatory drugs
TNF-

inhibitors- TNF- induces IL8 via activation of the transcription

factor nuclear factor-kB (NF-kB).
Causes severe wasting in advanced
COPD by skeletal muscle apoptosis.
Drugs: 1) Anti-TNF- antibodies
2) TNF- converting enzyme (TACE)
inhibitor- which is required for the
release of soluble TNF-

Anti-inflammatory drugs
Adhesion

molecule inhibitors- Mac-1 (CD11b/CD18)

expression is increased on neutrophils and
macrophages.

- ICAM-1, E-selectin inhibitors.

IL-10:

Anti-inflammatory actions.

- It inhibits the secretion of TNF- and IL-8 from

macrophages.
- Decreases expression of matrix metalloproteinases
while increasing the expression of endogenous tissue
inhibitors of matrix metalloproteinases (TIMP).
- IL-10 concentrations are reduced in sputum from
patients with COPD.

Anti-inflammatory drugs
Phosphoinositide-3

kinase (PI-3K) inhibitorsPI-3Kgamma, is involved in neutrophil recruitment

and activation.

Macrolide

antibiotics- Inhibit chemotaxis,

cytokine expression and reactive oxygen species
generation.

- Also inhibit the activation of nuclear factor (NF)kB and reverses steroid resistance by increasing
HDAC2 activity.
- Clinical trials of non-antibiotic macrolides are
currently underway.

Antioxidant therapy
Antioxidants-

N-acetyl cysteine, N-acestelyn (NAL), Nisobutyrylcysteine (NIC), erdosteine, procysteine and

carbocysteine

- More effective antioxidants: Stable glutathione compounds,

analogues of superoxide dismutase (AEOL-10113) and
selenium based drugs are under development.
NRF-2

activators- Nuclear factor erythroid-2 related factor

2 (NRF2) is a transcription factor

- Induces antioxidant gene expression.

- Drugs: Sulforaphane isolated from broccoli and its synthetic
analog.
Statins-

Anti-oxidant and anti-inflammatory action

Antioxidant therapy
iNOS

inhibitors: 3-Nitrotyrosine which indicates

peroxynitrite formation is markedly increased in
sputum of patients with COPD [L-NIL].

Resveratrol-

Phenolic component of red wine

that has anti-inflammatory and antioxidant
properties.

- Inhibits cytokine release from alveolar

macrophages.
- Resveratrol has a very low oral bioavailability so
related drugs or a suitable inhaled formulation will
need to be developed.

Antiprotease therapy
Endogenous

antiproteases- 1- antitrypsin, secretory

leukoprotease inhibitor, elafin, tissue inhibitors of MMP (in
recombinant form)

Protease

inhibitors:

a) Serine protease (Neutrophil elastase -inhibited by 1-AT,

sivelestat and ONO-6818)
b) Cysteine proteases such as cathepsin K, S and L
(released from macrophages)
c) MMP: Released from macrophages and neutrophils.
- Non- selective MMP inhibitors [Marimastat, batimastat].
- MMP-9 and MMP-12 [AZ11557272: Dual MMP-9/MMP-12

Regenerative therapy
Stem

cells- Infusion with allogenic mesenchymal stem cells

Retinoic

acid- Increase alveolar septation during lung

development.

- All-trans-retinoic acid induce regeneration of the terminal

respiratory tract and reverse elastase induced emphysema.
- Acts on retinoic acid receptors to activate transcription factors
that switch on the genes involved in growth and differentiation.
Anti-ageing

therapy- Accelerated aging has been implicated in

the pathogenesis of COPD and is mediated by inactivation of Silent
Information Regulator Two (SIR2) or sirtuin1 (SIRT1).

- Resveratrol activates SIRT1.

- New SIRT1 activators under development are SRT1720, SRT501
and SRT2104.

Mucoregulators
Mucus

hypersecretion is associated with a more rapid decline in FEV1

and increase the frequency of exacerbations.

Mucus

hypersecretion is driven by the neutrophil inflammatory

response, so that effective anti-inflammatory treatments directed at
this cell or its products would be expected to reduce mucus
hypersecretion.

a. EGFR inhibitors: Mediates mucus secretory response to several

secretagogues, including oxidative stress, cigarette smoke and
inflammatory cytokines and causes mucous cell hyperplasia [Gefitinib
and erlotinib].
b. Ca2+ activated Cl- channel inhibitors: Niflumic acid and
talniflumate.
c. Other approaches: Tachykinin receptor antagonists, P2Y2 purinergic
receptor agonist (diquafosol) and potassium-channel openers.

Newer drug delivery systems

a. Packaging of drugs to be phagocytised by
alveolar macrophages.
b. Inactive prodrug that can be made to be
converted into active drug by elastase.

Reversal of steroid resistance

Oxidative

stress-mediated reduction in Histone

Deacetylase (HDAC).

Theophyline,

nortryptiline, macrolide, PI3 kinase inhibitors, antioxidants and iNOS.