DEFINITION

COPD
COPD
AIRFLOW
AIRFLOW
LIMITATION
LIMITATION
IN
IN SMALL
SMALL AIRWAYS
AIRWAYS

CHRONIC
CHRONIC
INFLAMMATIO
INFLAMMATIO
N
N

PROGRESSIVE
PROGRESSIVE

IRREVERSIBLE
IRREVERSIBLE

PARTIAL
PARTIAL
REVERSIBLE
REVERSIBLE

ALVEOLER
ALVEOLERSTRUCTURE
STRUCTUREDAMAGED
DAMAGED
DECREASED
DECREASEDELASTIC
ELASTICRECOIL
RECOIL

1 CHRONIC
CHRONIC BRONCHITIS
BRONCHITIS
2 EMPHYSEMATOUS
EMPHYSEMATOUS LUNG
LUNG

MIXED
MIXED

GOLD
GOLD [[ NHLBI
NHLBI WHO
WHO ]]
GUIDELINES
GUIDELINES MANAGEMENT
MANAGEMENT STRATEGY
STRATEGY
OF
OF COPD
COPD
WHO
WHO 2020
2020
MORTALITY
MORTALITY
33 million/year
million/year

MORBIDITY
MORBIDITY
&
&
MORTALITY
MORTALITY
IV
IV in
in USA
USA
HOSPITAL
HOSPITAL
MORTALITY
MORTALITY
10
10 %
%

INCREASING
INCREASING
PROBLEMS
PROBLEMS
OF
OF COPD
COPD

WORSEN
WORSEN
HEALTH
HEALTH
STATUS
STATUS

INCREASE
INCREASE OF
OF 51
51 %
% ACUTE
ACUTE EXACERBATION
EXACERBATION
IN
IN HOSPITAL
HOSPITAL ADMISSION
ADMISSION BETWEEN
BETWEEN 1991
1991 -- 2000
2000
PREMATURE
PREMATURE DEATH
DEATH

PATHOGENESIS OF COPD

PARTICLE
GASES

NOXIOUS

HOST FACTORS
ANTI OXIDANTS
[ environmental ]

LUNG INFLAMMATION
ANTI OXIDANTS

OXIDATIVE STRESS

ANTI PROTEINASES
[ genetic ]

PROTEINASE IMBALANCE

REPAIR
MECHANISM

REPAIR
MECHANISM

COPD
COPD

ANTI PROTEASE ENZYME

1-Antitrypsin

CELLS & INFLAMMATORY MEDIATORS IN COPD PATHOGENESIS

MEDIATORS
MEDIATORS
CELLS
CELLS

Macrophages
Neutrophils
CD8+ Lymphocytes
Eosinophils
Epithelial cells
Fibroblasts

IL-8, GRO-1
MCP-1, MIP-1
GM-CSF
Endothelin
Substance P

PROTEINASES
PROTEINASES
Neutrophil elastase
Cathepsin
Proteinase-3
MMPs

EFFECTS
EFFECTS

MUCUS HYPERSECRETION
FIBROSIS
ALVEOLAR WALL
DESTRUCTION

1
2

IL-8
IL-8

Inflammator
Inflammator
yy
marker
marker

LTB4
LTB4

Neutrophil
Neutrophil
chemoatracta
chemoatracta
nt
nt
4

GM-CSF
GM-CSF

Acute
Acute
exacerbation
exacerbation

TNF-
TNF-

Neutrophil
Neutrophil
chemoatractan
chemoatractan
tt

INFLAMMATORY
INFLAMMATORY
MEDIATOR
MEDIATOR
IN
IN COPD
COPD
6

MCP-1
MCP-1

Alveolar
Alveolar
macrophage
macrophage
recruitment
recruitment

TGF-
TGF-

Airway
Airway
remodelling
remodelling

Substance
Substance PP
Mukus
Mukus
hypersecretion
hypersecretion

REACTIVE OXYGEN SPECIES IN COPD

Antiproteinases
SLPI 1-AT

ANTIOXIDANTS
Glutathione Analogs
Vitamins C, E
N-acetylsisteine
Nitrones [spin-trap]

NF-KB
IL-8

Proteolysis
O2, H2O2
OH, ONOO

TNF

Neutrophil
recruitment

ISOPROSTANES
Mucus secretion

Plasma leak

Bronchoconstriction

DIAGNOSIS
DIAGNOSIS
OF
OF COPD
COPD
1

2
EXPOSURE TO
RISK FACTORS
Tobacco Smoke
Occupation
Indoor / outdoor
pollution

SYMPTOMS
COUGH
SPUTUM
DYSPNEA

SPIROMETRY

COPD
COPD

Complications
Complications
CARDIO
CARDIO
VASCULAR
VASCULAR
DISORDER
DISORDER

NUTRITIONA
NUTRITIONA
LL
DISORDER
DISORDER

SYSTEMIC
SYSTEMIC
INFLAMMATO
INFLAMMATO
RY
RY
RESPONS
RESPONS

SYSTEMIC
SYSTEMIC
EFFECT
EFFECT
OF
OF COPD
COPD
PSYCHOLOGICAL
PSYCHOLOGICAL
FACTOR
FACTOR
ANXIETY
ANXIETY-DEPRESSION
DEPRESSION

HANDICAP
HANDICAP // DISABILITY
DISABILITY

RESPIRATORY
RESPIRATORY
MUSCLE
MUSCLE
DISFUNCTION
DISFUNCTION

GOALS OF
COPD TREATMENT
1
SMOKING
CESSATION

2
SHORT
TERM
GOALS

GLOBAL GOLD
3
LONG TERM
GOALS

IMMEDIATE BENEFITS
RELIEF OF SYMPTOMS
[ BREATHLESSNESS ]

PREVENT DISEASE PROGRESSIVE

REDUCE EXACERBATIONS
IMPROVE QUALITY OF LIFE
IMPROVE EXERCISE TOLERANCE
REDUCE MORTALITY

COPD MANAGEMENT
1
ESTABLISH DIAGNOSIS
ASSESS SYMPTOMS

STOP SMOKING
HEALTHY
LIFESTYLE
IMMUNISATION

2
TREAT OBSTRUCTION

BRONCHODILATO
RS

3
ASSESS FOR HYPOXIA

4
PULMONARY REHABILITATION
PROGRAMME

LONG TERM
OXYGEN THERAPY

1
STOP SMOKING

TRIAL OF BUPROPION
NICOTINE REPLACEMENT

LONG TERM
OXYGEN THERAPY
[ SELECTED PATIENT ]

5
NEW ANTI
INFLAMMATORY
TREATMENT
NEEDED

COPD
PHARMACOTHERAPY
2
4
INHALED CORTICOSTEROIDS
ONLY FOR CONCOMITANT
ASTHMA

BRONCHODILATOR
S

ANTICHOLINERGICS
[ TIOTROPIUM SOON AVAILABLE ]
LABA
THEOPHYLLINE
[ ANTI INFLAMMATORY EFFECT ]

MUCOLYTIC
S
1

ANTIOXIDANT
S
2

CARBOCYSTINE
BROMHEXOL
AMBROXOL

N-ACETYLCYSTEINE

OTHER TREATMENT
IN COPD
ANTI
LEUCOTRIEN
TS

ANTI INFLAMMATORY
DUGS
INHALED CORTICOSTEROID ?

PROPHYLACT
IC
ANTIBIOTICS
NO EVIDENCE

1
AVOIDANCE OF POLLUTANT

2
EXERCISE

8
SURGERY
7

NON
PHARMACOLOGICAL
MANAGEMENT

OBESITY
&
NUTRITIONAL
INTERVENTION

6
PHYSIOTHERA
PY

EDUCATION

VACCINATIO
N

PULMONARY REHABILITATION

1
INHALED
ANTICHOLINERGI
CS

IPRATROPIUM BROMIDE
OXITROPIUM BROMIDE
TIOTROPIUM BROMIDE

BRONCHODILATORS
FOR COPD
3

2
COMBINATIO
N
INHALER

BETA 2
AGONIST

SHORT ACTING INHALED

BETA 2 AGONIST

4
THEOPHYLLI
NE

IPRATOPRIUM BROMIDE
&
SHORT ACTING INHALED
BETA 2 AGONIST

1
RELAX
AIRWAY SMOOTH
MUSCLE

2
DECREASED
PLASMA
EXUDATION ?

3
DECREASED
INFLAMMATO
RY
MEDIATOR
RELEASE ?

BRONCHODILATORS
IN COPD
5
IMPROVE
RESPIRATORY
MUSCLE
FATIGUE ?

4
DECREASED
NEUROTRANSMITT
ER
RELEASE ?

CONTROL OF THE AIRWAYS

PARASYMPATHETIC NERVE SYSTEM

ANTICHOLINERGIC

CHOLINERGIC RECEPTOR

GUANILCYCLASE

GTP

ATP

Cyclic GMP
BRONCHOCONSTRICTION

BRONCHODILATATION
ADENYLCYCLASE

Cyclic AMP

5GMP

5AMP
FOSFODIESTERASE

BETA ADRENERGIC RECEPTOR

METHYLXANTIN
BETA 2 AGONIST
SYMPATHETIC NERVE SYSTEM

INCREASED
FEV1, FVC,PEF
[ < 10 % ]

BRONCHODILATORS
EFFECT IN COPD
2
DECREASED
HYPERINFLATIO
N
DECREASED
DYSPNOEA

3
IMPROVED
EXERCISE
TOLERANCE

IMPROVED RESPIRATORY MUSCLE STRENGTH ?

CLINICALLY IRRELEVANT EFFECT

ON EXACERBATIONS

NO EFFECT
ON
PROGRESSION
OF DISEASE

INHALED
CORTICOSTEROIDS
IN COPD

NO SIGNIFICANT
EFFECT ON
INFLAMMATION

HIGH RISK
OF ADVERSE
SYSTEMIC
EFFECTS

EXPENSIVE
SHOULD NOT
BE
RECOMMENDED

TREAT ASSOCIATED ASTHMA

BRONCHODILATATION

DECREASED
PLASMA
EXUDATION

ACTION OF
BETA2-AGONISTS
IN COPD
INCREASED
MUCOCILIAR
Y
CLEARANCE

DECREASED
NEUTROPHIL
FUNCTION

DECREASED
CHOLINERGIC
NEURO
TRANSMISSIO
N

DECREASED
BACTERIAL
ADHERENCE

DECREASED
PLASMA
EXUDATION

DECREASE
D
T CELL
FUNCTION

BRONCHODILATATION
Incl. Small airways

ACTION OF
METHYLXANTHINE
IN COPD

INCREASED
MUCOCILIAR
Y
CLEARANCE

DECREASE
D
NEUTROPHI
L
FUNCTION

INCREASED
RESPIRATOR
Y
MUSCLE
STRENGTH

THEOPHYLLINE

DECREASED
MACROPHAG
E
FUNCTION

ANTICHOLINERGICS IN COPD
NORMAL
Vagus
nerve

ACh

COPD

VAGAL TONE

ACh

The main reversible

Component in COPD

Resistance
1/r

ANTICHOLINERGICS

BRONCHO
DILATATIO
N

ANTICHOLINERGICS BLOCKS
MUSCARINIC RECEPTORS
THEREBY REDUCTION
VAGAL TONE

CLEARANC
E
OF EXCESS
MUCUS

MUSCARINIC RECEPTOR SUBTYPES IN AIRWAYS

M1 + M2 + M3 +

PREGANGLIONIC NERVE

MUSCARINIC
RECEPTOR
PARASYMPATHETIC
GANGLION

N+

NICOTINIC RECEPTOR

M1 +

ANTICHOLINERGIC
POSTGANGLIONIC NERVE

M2 +
CHOLINERGIC
EFFECT

AIRWAY SMOOTH MUSCLE

ACh
M3 +

CONTROL OF THE AIRWAYS

ADRENERGIC & CHOLINERGIC ( MUSCARINIC ) RECEPTORS

ADRENERGIC
RECEPTORS

CHOLINERGIC
RECEPTORS

ADRENERGIC
RECEPTORS
RECEPTORS

ADRENERGIC

NEURO
TRANSMITTER

NOR
ADRENALINE

SUB-TYPES OF
RECEPTOR

ALPHA [a1&a2]
BETA [b1&b2]

RESULT OF
STIMULATION
IN THE LUNGS

Airways dilated &

Reduced airflow
Obstruction
[bronchodilatation]

CHOLINERGIC
RECEPTORS
RECEPTORS

CHOLINERGIC

NEURO
TRANSMITTER

ACETYL
CHOLINE

SUB-TYPES OF
RECEPTOR

MUSCARINIC
M1-M2-M3

RESULT OF
STIMULATION
IN THE LUNGS

Airways constricted
& increased airflow
Obstruction
[broncho
constriction]

CHOLINERGIC
RECEPTORS
M1-RECEPTORS ENHANCE
THE CHOLINERGIC REFLEX

M2-RECEPTORS INHIBIT
ACETYLCHOLINE RELEASE

M3-RECEPTORS MEDIATE
BRONCHOCONSTRICTION
AND MUCUS SECRETION

M4 & M5-RECEPTORS
NOT DETECTED IN
THE LUNG

1
NEW BRONCHODILATORS
2
MEDIATOR
ANTAGONIST
S

TRIOTROPIUM

3
PROTEASE
INHIBITORS

NEW DRUG
FOR COPD
4
NEW ANTI
INFLAMMATO
RY
DRUGS

5
ALVEOLAR
REPAIR
DRUGS

LONG ACTING ANTICHOLINERGIC

TIOTROPIUM
BROMIDE

SIGNIFICANT
IMPROVEMENT
IN LUNG FUNCTION
SUSTAINED
OVER 12 MONTHS

SIGNIFICANT
REDUCTION
IN
EXACERBATIONS

STATISTICALLY
SIGNIFICANT
IMPROVEMENT
IN
BREATHLESSNESS
SCORE

STATISTICALLY SIGNIFICANT
IMPROVEMENT IN HEALTH-RELATED
QUALITY OR LIFE SCORE

LONG ACTING ANTICHOLINERGIC

TIOTROPIUM
BROMIDE

SIGNIFICANTLY
REDUCES THE USE
OF SHORT ACTING
BETA AGONISTS

PROLONGED
BLOCKADE OF
M3 RECEPTOR
SUBTYPE

NO OTHER
ANTICHOLINERGIC
EFFENTS
GREATER THAN
IPRATOPRIUM

SAFETY
SAFE & WELL TOLERATED IN CLINICAL STUDY
ONLY SIGNIFICANT ADVERSE EVENT IS
DRY MOUTH