New Era of COPD TreatmentNew Era of COPD Treatment- Focusing on Treatment-- Focusing on Treatment-

Shih Wei Lee, MDShih Wei Lee, MD

Department of Chest Medicine Department of Chest Medicine

Tao-Yuan General Hospital Department of HealthTao-Yuan General Hospital Department of Health

BackgroundBackground

Percent Change in Age-Adjusted Death Rates, U.S., 1965-1998

Percent Change in Age-Adjusted Death Rates, U.S., 1965-1998

00

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0

Proportion of 1965 Rate Proportion of 1965 Rate

1965 - 19981965 - 1998 1965 - 19981965 - 1998 1965 - 19981965 - 1998 1965 - 19981965 - 1998 1965 - 19981965 - 1998

–59%–59% –64%–64% –35%–35% +163%+163% –7%–7%

CoronaryHeart

Disease

CoronaryHeart

Disease

StrokeStroke Other CVDOther CVD COPDCOPD All OtherCauses

All OtherCauses

Source: NHLBI/NIH/DHHSSource: NHLBI/NIH/DHHS

Adapt from 2005 GOLD teaching slide

Ischemic heart diseaseCerebrovascular diseaseLower resp infectionDiarrheal diseasePerinatal disordersCOPDTuberculosisMeaslesRoad traffic accidentsLung cancer

Ischemic heart diseaseCerebrovascular diseaseLower resp infectionDiarrheal diseasePerinatal disordersCOPDTuberculosisMeaslesRoad traffic accidentsLung cancer

Stomach CancerHIVSuicide

Stomach CancerHIVSuicide

6th6th

3rd3rd

Murray & Lopez. Lancet 1997

Future Mortality WorldwideFuture Mortality Worldwide1990 2020

Adapt from 2005 GOLD teaching slide

Definition

ERS-ATS COPD Guidelines

Definition of COPD Chronic Obstructive Pulmonary Disease (COPD)

is a preventable and treatable disease state characterised by airflow limitation that is not fully reversible.

The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking.

Pathogenesis

Noxious particles

and gases

Lung inflammation

Host factors

COPD pathology

ProteinasesOxidative stress

Anti-proteinasesAnti-oxidants

Repair mechanisms

Adapt from 2005 GOLD teaching slide

Pathology

Inflammation

Inflammatory Mechanisms of COPD

Cigarette smoke

Alveolar macrophage

Neutrophil

PROTEASES

Alveolar wall destruction(Emphysema)

Mucus hypersecretion(Chronic bronchitis)

Neutrophil chemotactic factors

Neutrophil elastaseCathepsins

Matrix metalloproteinases

Cytokines (IL-8)Mediators (LTB4)

?CD8+

lymphocyteMCP-1

PerforinGranzyme B

TNF-

Protease-Antiprotease Imbalance

Pulmonary/bronchial vessel

Neutrophil

Mac-1SLx

AdhesionICAM-1E-selectin

ChemotaxisIL-8, LTB4CXC chemokines

SurvivalGM-CSF

Macrophage

Activation

CXCR1CXCR2 Neutrophil elastase

CathepsinsProteinase 3

ELASTOLYSIS ELASTOLYSIS MUCUS HYPERSECRETIONMUCUS HYPERSECRETION

Mucus secretion

NF-B

IL-8

Neutrophil

recruitment

TNF-

REACTIVE OXYGEN SPECIES IN COPD

Plasma leak BronchoconstrictionIsoprostanes

ANTIOXIDANTSVitamins C and EN-acetyl cysteineGlutathione analoguesNitrones (spin trap)

O2-, H2O2

OH., ONOO-

Anti-proteases

SLPI 1-AT

Proteolysis

Blue Blue bloaterbloater

Pink Pink pufferpuffer

Diagnosis

Normal Alveolar EmptyingNormal Alveolar Emptying

Alveolar Emptying in COPDAlveolar Emptying in COPD

In COPD, airflow is limited because alveoli lose their elasticity, supportive structures are lost, and small airways are narrowed

Breathing in COPDBreathing in COPD

Volume- Time-CurveVolume- Time-Curve

Time

Volume

t3 t4t1 t2

V1

: It takes longer to expire the same volume V1

: At the same time (t3) more air is still in the lung, because of flow limitation (due to obstruction and / or loss of elasticity

: more time is needed (t3 to t4) to expire completely

HealthyCOPD

ERS-ATS COPD Guidelines

Diagnosis of COPD (2)Spirometry

Spirometric classification of COPD: Post-bronchodilator FEV1/forced vital capacity <0.7 confirms the

presence of airflow limitation that is not fully reversible.

Severity Postbrochodilator FEV1/FVC

FEV1 % pred

At risk Patients who:

smoke or have exposure to pollutants have cough, sputum or dyspnoeahave family history of respiratory disease

>0.7 80

Mild COPD 0.7 80

Moderate COPD 0.7 50–80

Severe COPD 0.7 30–50

Very severe COPD 0.7 <30

Evaluation

ERS-ATS COPD Guidelines

Definition, evaluation and treatment (3) The Operational Classification of Severity is as follows: ambulatory (Level I), requiring

hospitalisation (Level II) and acute respiratory failure (Level III).

Level I Level II Level III

Clinical historyCo-morbid conditions

History of frequent exacerbations

Severity of COPD

+

+

Mild/moderate

+++

+++

Moderate/severe

+++

+++

Severe

Physical findingsHaemodynamic evaluation

Use accessory respiratory muscles, tachypnoea

Persistent symptoms after initial therapy

Stable

Not present

No

Stable

++

++

Stable/unstable

+++

+++

Diagnostic proceduresOxygen saturation

Arterial blood gases

Chest radiograph

Blood tests

Serum drug concentrations

Sputum gram stain and culture

Electrocardiogram

Yes

No

No

No

If applicable

No

No

Yes

Yes

Yes

Yes

If applicable

Yes

Yes

Yes

Yes

Yes

Yes

If applicable

Yes

Yes

+: unlikely to be present; ++: likely to be present; +++: very likely to be present

ERS-ATS COPD Guidelines

Definition, evaluation and treatment (4) Level I: outpatient treatmentPatient education

Check inhalation technique

Consider use of spacer devices

BronchodilatorsShort-acting β2-agonist and/or ipratropium MDI with spacer or hand-held nebuliser as needed

Consider adding long-acting bronchodilator if patient is not using it

Corticosteroids (the actual dose may vary)Prednisone 30–40 mg per os q day for 10 days

Consider using an inhaled corticosteroid

Antibiotics May be initiated in patients with altered sputum characteristics

Choice should be based on local bacteria resistance patterns

Amoxicillin/ampicillin, cephalosporins

Doxycycline

Macrolides

     If the patient has failed prior antibiotic therapy consider:

Amoxicillin/clavulanate

Respiratory fluoroquinolones

ERS-ATS COPD Guidelines

Definition, evaluation and treatment (5) Level II: treatment for hospitalised patient

BronchodilatorsShort acting β2-agonist (albuterol, salbutamol) and/or

Ipratropium MDI with spacer or hand-held nebuliser as needed

Supplemental oxygen (if saturation <90% )

CorticosteroidsIf patient tolerates, prednisone 30–40 mg per os q day for 10 days

If patient can not tolerate oral intake, equivalent dose i.v. for up to 14 days

Consider use inhaled corticosteroids by MDI or hand-held nebuliser

Antibiotics (based on local bacteria resistance patterns) May be initiated in patients that have a change in their sputum characteristics (purulence and/or volume)

Choice should be based on local bacteria resistance patterns

Amoxicillin/clavulanate

Respiratory fluoroquinolones (gatifloxacin, levofloxacin, moxifloxacin)

If Pseudomonas spp. and/or other Enterobactereaces spp. are suspected, consider combination therapy

ERS-ATS COPD Guidelines

Definition, evaluation and treatment (6) Level III: treatment in patients requiring special or intensive care unit

Supplemental oxygen

Ventilatory support

Bronchodilators   Short-acting β2-agonist (albuterol, salbutamol) and ipratropium MDI with spacer, two puffs every 2–4 h

If the patient is on the ventilator, consider MDI administration, consider long-acting β-agonist

CorticosteroidsIf patient tolerates oral medications, prednisone 30–40 mg per os q day for 10 days

If patient can not tolerate, give the equivalent dose i.v. for up 14 days

Consider use inhaled corticosteroids by MDI or hand-held nebuliser

Antibiotics (based on local bacteria resistance patterns)Choice should be based on local bacteria resistance patterns

Amoxicillin/clavulanate

Respiratory fluoroquinolones (gatifloxacin, levofloxacin, moxifloxacin)

If Pseudomonas spp. and or other Enterobactereaces spp. are suspected consider combination therapy

Current Treatment

Therapy at Each Stage of COPD

Old 0: At Risk I: Mild II: Moderate

IIA IIB

III: Severe

New 0: At Risk I: Mild II: Moderate III: Severe IV: Very Severe

Characteristics • Chronic symptoms

• Exposure to risk

factors

• Normal spirametry

• FEV1/FVC < 70%

• FEV1 ≥ 80%

• With or without

symptoms

• FEV1/FVC < 70%

• 50% ≤ FEV1 < 80%

• With or without

symptoms

• FEV1/FVC < 70%

• 30% ≤ FEV1 < 50%

• With or without

symptoms

• FEV1/FVC < 70%

• FEV1 < 30% or presence

of chronic respiratory failure

or right heart failure

Avoidance of risk factor(s); influenza vaccinationAvoidance of risk factor(s); influenza vaccination

Add Add short-acting bronchodilator when neededshort-acting bronchodilator when needed

Add Add regular treatment with one or moreregular treatment with one or more

long-acting long-acting bronchodilatorsbronchodilators

Add Add rehabilitationrehabilitation

Add Add inhaled glucocorticosteroidsinhaled glucocorticosteroids

AddAdd

Long-term Long-term oxygen if oxygen if chronic chronic respiratoryrespiratory

failurefailure

ConsiderConsider

Surgical Surgical treatmentstreatments

(GOLD EXECUTIVE SUMMARY2005)

Contraction Relaxation cAMP

AMP

SMOOTH MUSCLE CELL

M1

M2M3

Anticholinergic

-agonisttheophylline

BronchodilatorsBronchodilators

Cell membrane

α ｓ

γβAC

ATP

c-AMP

PKAPKG

GS GS

β ２ Stimulant↓

β ２ Receptor

Ca2+activationK+ channel activation

Na+/K+ ATPaseactivation Hyper-

polarization

Pl decomposition Ca2 +release

inhibition inhibition

Na+/Ca2+ exchange Ca2 +excretion

MLCK inhibition

K+

CHARYBDOTOXINExtracellular

Smooth muscle cell

α ｓ

γβ

AMP

Teophylline

PDESTO

P

K+ Release

STOP

Relaxation ofRelaxation ofmyofibermyofiber

Ca2 + decrease

Ⅱ- 13

PI ： phosphatidylinositol AC ： adenylate cyclasePKA ： protein kinase AMLCK ： myosin light chain kinaseGs ： Gs protein CHARYBDOTOXIN ： Calcium-dependent potassium

channel

Mechanism of relaxation of bronchial smooth muscle

acceleration

2

3

11

Onset And Duration - LIPOPHILICITY

Salbutamol (Albuterol)

hydrophilic short duration rapid onset

Formoterol

Intermediate lipophilicity

long duration

rapid onset

Salmeterol

lipophilic

long duration

slow onset

Anderson GP Life Sci 1993, 52:2145

Aqueous compartment

B2-receptor

Lipophilic bilayer

Pre-ganglionicPre-ganglionicnervenerve

ParasympatheticParasympatheticganglionganglion

Post-ganglionicPost-ganglionicnervenerve

AChACh

Airway smoothAirway smoothmusclemuscle

Nicotinic receptors (+)Nicotinic receptors (+)

MM11 receptors (+) receptors (+)

MM22 receptors (–) receptors (–)

MM33 receptors (+) receptors (+)

BarnesBarnes.. Eur Respir RevEur Respir Rev (1996) (1996)

Tiotropium Provides Specific, Tiotropium Provides Specific, Long-lasting MLong-lasting M33 Receptor Blockade Receptor Blockade

Anticholinergics and Airway Dynamics Anticholinergics and Airway Dynamics in the Normal State in the Normal State

Anticholinergics and Airway Dynamics Anticholinergics and Airway Dynamics in COPDin COPD

In COPD, hypertrophy of the airway wall exacerbates the effects of cholinergic constriction

ERS-ATS COPD Guidelines

Pharmacological Therapy (6)

Medication FEV1Lung volume Dyspnoea HRQoL

Short-acting β-agonist Yes (A) Yes (B) Yes (A) NAIpratropium bromide Yes (A) Yes (B) Yes (A) No (B)Long acting β-agonists Yes (A) Yes (A) Yes (A) Yes (A)Tiotropium Yes (A) Yes (A) Yes (A) Yes (A)Inhaled corticosteroids Yes (A) NA Yes (B) Yes (A)Theophylline Yes (A) Yes (B) Yes (A) Yes (B)

Medication AEExercise endurance

Disease modifier by FEV1 Mortality Side-effects

Short-acting β-agonist NA Yes (B) NA Na SomeIpratropium bromide Yes (B) Yes (B) No NA SomeLong acting β-agonists Yes (A) Yes (B) No NA MinimalTiotropium Yes (A) Yes (B) NA NA MinimalInhaled corticosteroids Yes (A) NA No NA SomeTheophylline NA Yes (B) NA NA Important

Effects on commonly used medications on important clinical outcomes in COPD

Combination Therapy

Chest 1999;115:966–971

Combination Therapy

Chest 1997;112:1514–21

Combination Therapy

James F. Donohue

James F. Donohue

Manage Stable COPD Key PointsManage Stable COPD Key Points

Regular treatment with inhaled glucocorticosteroids is appropriate for symptomatic COPD patients with an FEV1 < 50% predicted (Stage III: Severe COPD and Stage IV: Very Severe COPD) and repeated exacerbations e.g. 3 in the last three years (Evidence A).

Inhaled glucocorticosteroid combined with a long-acting B2-agonist is more effective than the individual components (Evidence A).

Regular treatment with inhaled glucocorticosteroids is appropriate for symptomatic COPD patients with an FEV1 < 50% predicted (Stage III: Severe COPD and Stage IV: Very Severe COPD) and repeated exacerbations e.g. 3 in the last three years (Evidence A).

Inhaled glucocorticosteroid combined with a long-acting B2-agonist is more effective than the individual components (Evidence A).

Adapt from 2005 GOLD teaching slide

ICS and LABAs improve symptoms and lung function via different mechanisms in COPD

Inflammation

Increased neutrophils andCD8+ lymphocytes

Elevated IL–8, TNF

Protease/anti-proteaseimbalance

Structural changes

Alveolar destruction

Collagen deposition

Glandular hypertrophy

Airway fibrosis

Symptoms

FEV1

Exacerbations

Inhaled corticosteroidsreduce

LABAs inhibit

Smooth muscle contraction

Increased cholinergic tone

Loss of elastic recoil

Sensory nerve activation

Airway constriction

Corticosteroid

Corticosteroidreceptors

HSP 90

Long-acting 2-agonists

2- adrenoceptor synthesis

Increased anti-inflammatory effectIncreased anti-inflammatory effect Decreased acquired toleranceDecreased acquired tolerance

Synergistic Interaction of 2-Agonists with Corticosteroid

cyclic AMP

PKA

MAPK

Budesonide/Formoterol Reduces Severe Exacerbations/Patient/Year

Budesonide/Formoterol Reduces Severe Exacerbations/Patient/Year

*†

Red

uct

ion

vs

pla

ceb

o (

%)

*p<0.05 vs placebo†p<0.05 Symbicort vs formoterol

–30

–25

–20

–15

–10

–5

0

Symbicort Budesonide Formoterol

–24%

–15%

–2%

Budesonide/Formoterol Reduces Mild Exacerbations/Patient/Year

Budesonide/Formoterol Reduces Mild Exacerbations/Patient/Year

***p<0.001 vs placebo; p<0.05 Symbicort vs budesonide

–70

–60

–50

–40

–30

–20

–10

0

Symbicort Budesonide Formoterol

–62%

–41%

–55%

***

***

***Red

uct

ion

in m

ild e

xace

rbat

ion

s vs

pla

ceb

o (

%)

(Adapted from Szafranski et al. ERS 2002)(Adapted from Szafranski et al. ERS 2002)

Budesonide/Formoterol Reduces the Use of Oral Corticosteroids in COPD

–35

–30

–25

–20

–15

–10

–5

0

–31%–29%

–3%

**

*p<0.05 vs placebo; p<0.05 Symbicort vs formoterol

Symbicort Budesonide Formoterol

Red

uct

ion

in

ora

l st

ero

id u

se

vs

pla

ceb

o (

%)

Budesonide/Formoterol Reduces the Symptoms of COPD within 1 Week

Budesonide/Formoterol Reduces the Symptoms of COPD within 1 Week

–1.4

–1.2

–1

–0.8

–0.6

–0.4

–0.2

0Symbicort Budesonide Formoterol

p<0.001

p=0.024p=0.004

Mea

n c

han

ge

in t

ota

l sym

pto

m

sco

re v

sp

lace

bo

p<0.001 Symbicort vs budesonide; p<0.001 Symbicort vs formoterol

Budesonide/ Formoterol Reduces 2-agonist Reliever Medication

Budesonide/ Formoterol Reduces 2-agonist Reliever Medication

–1.6

–1.4

–1.2

–1

–0.8

–0.6

–0.4

–0.2

0Symbicort Budesonide Formoterol Placebo

******

p=0.001

Ad

jus

ted

mea

n c

ha

ng

e in

no

. re

liev

er i

nh

ala

tio

ns

/24

h

***p<0.001 vs placebo; p<0.001 Symbicort vs budesonide

Budesonide/ Formoterol Improves Health-related Quality of Life (SGRQ Total Score)

Budesonide/ Formoterol Improves Health-related Quality of Life (SGRQ Total Score)

Adjusted mean change from run-in

–6

–5

–4

–3

–2

–1

0Symbicort Budesonide Formoterol Placebo

*

MCID

MCID = minimum clinically important difference*p<0.05 vs placebo

Budesonide/Formoterol Reduces Shortness of BreathBudesonide/Formoterol Reduces Shortness of Breath

Symbicort Budesonide Formoterol Placebo

–35

–30

–25

–20

–15

–10

–5

0

–32%

–18%

–24%

–10%

Red

uct

ion

in s

ho

rtn

ess

of

bre

ath

se

ver

ity

sc

ore

fro

m r

un

-in

(%)

p<0.001 Symbicort vs placebo and budesonide

Budesonide/Formoterol Reduces Night-time AwakeningsBudesonide/Formoterol Reduces Night-time AwakeningsA

dju

ste

d m

ean

ch

an

ge

(%)

in n

igh

t-ti

me

aw

ake

nin

gs

–0.4

–0.35

–0.3

–0.25

–0.2

–0.15

–0.1

–0.05

0

Symbicort Budesonide Formoterol Placebo

* p<0.05, ** p<0.01, ***p<0.001 vs placebo

p=0.003 Symbicort vs budesonide; p=0.019 Symbicort vs formoterol

***

***

(Adapted from Szafranski et al. ERS 2002)(Adapted from Szafranski et al. ERS 2002)

Combination Therapy

Treat Respir Med. 2004;3:173–181

ERS-ATS COPD Guidelines

Pharmacological therapy (4) Bronchodilators Short-acting bronchodilators can increase exercise tolerance acutely in

COPD.

Anticholinergics given q.i.d. can improve health status over a 3-month period.

Long-acting inhaled β-agonists improve health status, possibly more than regular ipratropium. Additionally, these drugs reduce symptoms, rescue medication use and increase the time between exacerbations.

Combining short-acting agents (salbutamol/ipratropium) produces a greater change in spirometry over 3 months than either agent alone.

Combining long-acting inhaled β-agonists and ipratropium leads to fewer exacerbations than either drug alone.

Combining long-acting β-agonists and theophylline produces a greater spirometric change than either drug alone.

Tiotropium improves health status and reduces exacerbations and hospitalisations compared with both placebo and regular ipratropium.

New Approaches to COPD

P. J. Barnes

EUROPEAN RESPIRATORY REVIEW, 2005;14: 2-11

New Targets for COPD treatment

Alveolar macrophage

Neutrophil

Alveolar wall destruction

(Emphysema)

Mucus hypersecretion

Neutrophil elastaseCathepsinsMatrix metalloproteinases

Cytokines (IL-8)

Mediators (LTB4)

?CD8+

lymphocyte

MCP-1

PROTEASES PROTEASES

Stop smokingbupropion

Mediator antagonistsLTB4 inhibitors

Chemokine inhibitorsAntioxidants

Mucoregulators

Immunosuppressants?

Neutrophil inhibitorsPDE4 inhibitors

p38 MAPK inhibitorsNF-B inhibitors

Protease inhibitorsNE, MMP inhibitors

1-AT, SLPI

Alveolarrepair

P J Barnes

P.J. BARNES AND R.A. STOCKLEY

P.J. BARNES AND R.A. STOCKLEY

Phosphodiesterase-4 inhibtors• PDE type 4 is expressed predominately in inflammatory

cells, such as neutrophils, CD8+ lymphocytes, and macrophages, makes this enzyme an attractive target for the development of new drugs to treat pulmonary inflammation that is characterisitic of COPD.

• Cilomilast, Roflumilast• Postive effect on lung function but also on the frequency

of exacerbations, may also slow disease preogression• Side effect: headache, sleep distubrance, and nausea,

vascular inflammatory( arteritis ) in the messentery and organ organs.

Roland Buhl and stephen G. Farmer 2005 ATS

Antileukotriene drugs

• LTB4: endogeneous chemoattaractants for peripheral blood neutrophils to bronchial tissues

• LTB-109: an oral LTB4 receptor antagonist, clinical trial results have been disappointing.

• BIIL-284:phase I

• Zafirlukask: bronchodilatation

Roland Buhl and stephen G. Farmer 2005 ATS

THANK FOR YOUR ATTENTION

新春愉快