Current strategies for COPD treatementCurrent strategies for COPD treatement

Jaideep A. Gogtay MD Cipla Ltd, Mumbai, India

Jaideep A. Gogtay MD Cipla Ltd, Mumbai, India

New definition of COPDNew definition of COPD

Preventable and treatable disease characterized by airflow limitation partially reversible.

Abnormal inflammatory response to toxic inhaled particles.

COPD has important systemic consequences that also respond to therapy.

ATS/ERS ERJ 2004

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

Annual deathsAnnual deaths 1,7911,791 26,03326,033 (UK 1992)(UK 1992)

ASTHMAASTHMA COPDCOPDMORTALITY

Workload in UK HealthWorkload in UK HealthDistrict of 250,000District of 250,000

Hospital admissionsHospital admissions 410410 680680

In-patient bed daysIn-patient bed days 1,8001,800 9,6009,600

GP consultationsGP consultations 11,90011,900 14,20014,200

MORBIDITY

BURDEN OF DISEASE: COPD BURDEN OF DISEASE: COPD vsvs ASTHMA ASTHMA

Who gets COPD?

20-25% of chronic smokers

Prevalence of smoking in adults in Colombia is 22.3% (M:23.9% and F:21%) and in 15-16 year olds:up to 30%1

Pollution

– Occupation– Indoor air pollution – exposure to biomass fuels

Poor diet

Repeated infections in childhood

Untreated asthma??

1 www.who.com/tobacco

Chulla smoke

Chulla smoke increases the activity of MMP-12 (matrix metalloproteinase)

These enzymes degrade the collagen in the basement membrane of the airways

FE

V1

(% p

red

icte

d a

t ag

e 25

y)

100

75

50

25

025 50 75

Age (years)

Stopped smokingaged 60 yr

Stopped smokingaged 50 yr

Susceptiblesmoker

(10-20%)

Death

Disability

Fletcher C, Peto R: BMJ 1977

ANNUAL DECLINE IN LUNG FUNCTION ANNUAL DECLINE IN LUNG FUNCTION

Non smoker

Non-susceptible smoker

COPD and asthmaThe Overlap

COPD

Neutrophils

No airway hyperresponsiveness

Less bronchodilator response

Limited steroid response

Wheezy bronchitis

10%

Asthma

Eosinophils

Airway hyperresponsiveness

Bronchodilator response

Steroid response

Atopic asthmatic Heavy smoker with COPD FEV1< 40% predicted

Airway mucosa under light microscopy

Reversibility

Sputum production

Alveolar Damage

Asthma Chronic Bronchitis

Emphysema

COPD

INFLAMMATORY CELLS IN INDUCED SPUTUM

0

0.5

1

1.5

2

2.5

L To

tal

cell

co

un

t (x

106/m

l)

Macrophages

Neutrophils

Eosinophils

Keatings et al: Am J Respir Crit Care Med 1997

Normal COPD

***

**

*

**

Asthma

**

Induced sputum: inflammatory cell counts

SPUTUM CYTOKINES IN COPDSPUTUM CYTOKINES IN COPD

COPD patients: 62.5 ±3.2y; FEV1 = 34.6±4 % predicted

0

2

4

6

8

[ T

NF

- (

nm

ol/l

)]

Controls(n=16)

Smokers(n=12)

COPD(n=14)

Asthma(n=22)

*

*

**

TNF-

0

1

2

3

4

[IL

-8 (

nm

ol/l

)]

Controls(n=16)

Smokers(n=12)

COPD(n=14)

Asthma(n=22)

*

**

IL-8

Keatings et al: Am J Respir Crit Care Med 1996

Infl

amm

atio

n

Neutrophils Macrophages Cytokines Mediators Proteases

Non-smokers Normal smokers

AMPLIFICATION OF INFLAMMATION IN COPD

AmplificationGenetic?Viral?Oxidative stress?Other

COPD

0

+

++++

New Drugs for COPDNew Drugs for COPD

• Relieve symptoms: dyspnoea, shortness of breath and cough with expectoration

• Improve lung function

• Improve exercise tolerance

• Prevent and treat exacerbations

• Improve health status

• Prevent disease progression

• Reduce mortality

What are we aiming to achieve with drug therapy?

Stopping smoking

Only smoking cessation has been shown to decline the progression of the disease

The most important part of treatment plan

Sustained quitters – 25%

Pharmacotherapy for Stable COPD

Bronchodilators Long-acting 2-agonist -

Salmeterol, Formoterol, Bambuterol

Short-acting 2-agonist – Salbutamol

Long-acting anticholinergics - Tiotropium

Short acting anticholinergics – Ipratropium

Methylxanthines - Theophylline

Corticosteroids

Oral – Prednisolone

Inhaled - Fluticasone, Budesonide

Vagal “tone”

Vagus nerve

ACh

NORMALNORMAL

ANTICHOLINERGIC

Resistance 1/r4

ACh

COPDCOPD

ANTICHOLINERGICS IN COPDANTICHOLINERGICS IN COPD

“Bronchodilator medications are central to the symptomatic management of COPD”

“Patients with moderate to severe symptoms of COPD require combination of bronchodilators”

GOLD Report 2003

Lefcoe NM et al: Chest 1982

I=ipratropium bromide, ß=fenoterol, P=placebo

ANTICHOLINERGICSANTICHOLINERGICS IN COPD IN COPD vsvs ASTHMA ASTHMA

I+ß

ß

I

P

Incr

ease

in

FE

V1

(L)

Asthma

1 2 3 h

0.8

0.6

0.4

0.2

0

COPD

0 1 2 3

I+ß

ß

I

P

Time (h)

0.4

0.2

Hyperinflation and DyspneaEffect of Ipratropium

0

1

2

3

4

5

6

0 2 4 6 8 10

Endurance Exercise Time (min)

Dys

pnea

( B

org

Scal

e)

P

IB

1.2

1.4

1.6

1.8

2

2.2

2.4

2.6

2.8

0 2 4 6 8 10

Endurance Exercise Time (min)

IC (

L)*

* ** *

O’Donnell AJRCCM 98;158:1557O’Donnell AJRCCM 98;158:1557

n = 29n = 29

Complementary Actions of Beta agonists + Anticholinergics

Possible additive/synergistic activity

Fast, greater and prolonged action on bronchodilation

Different sites of action

Non-bronchodilator effects

Improvement in exercise tolerance

Effects on mucus hypersecretion

Curr Opin Pharmacol 2003; 3: 270 – 276

Chest 1995; 5: 1715 - 1755

Rationale for combining in a single inhaler device

Complementary mechanisms of action as per recommendations eg. scientific evidence

COPD patients are generally elderly, many are from lower socioeconomic class,and illiterate

Polypharmacy is the rule in advanced COPD cases

Not easy when multiple inhalers are prescribed – affects compliance; patients tend to stop taking the inhaler which does not seem toprovide relief

FEV1Symptoms

Smoking cessation. Exercise. VaccinationSmoking cessation. Exercise. Vaccination

Beta agonists. P.R.Beta agonists. P.R.

ACH LABA TheophyllineACH LABA Theophylline

Risk

OxygenOxygenSurgerySurgery

MVMVCOPD: Therapeutic OptionsCOPD: Therapeutic Options

Celli’s schemaCelli’s schema

ICSICS

Long acting beta agonists in COPDSalmeterol, Formoterol

Widely used

Stimulation of beta receptors and increase in cyclic AMP

May have some effects on inhibiting neutrophil recruitment

Improve mucociliary transport

Role of inhaled steroids in COPD

Benefits

– Improve quality of life– Decrease exacerbations– Do not affect disease progression– May act synergistically when given with LABA

Watch for side effects

Currently indicated in

– Severe COPD– Frequent (>2) exacerbations

Short acting bronchodilatorsSalbutamol/Levosalbutamol

Quick-acting

Rescue medication for acute bronchospasm when patients are taking maintenance therapy

Can be given 3-4 times a day

Anticholinergic pharmacologyThe discovery of muscarinic receptor

subtypes

Cholinergic receptors

Muscarinic receptors Nicotinic receptors

M1 M2 M3 M4 M5

Muscarinic

Receptors in the

airways

Effect of a single dose of tiotropiumEffect of a single dose of tiotropium

0.8

0.9

1

1.1

1.2

1.3

-1 0 0.5 1 2 3

Post Dosing Hours

FEV1

L

Day 1 T

1 Year T

Day 1 P

1 Year P

Casaburi ERJ 2002;19:217-224Casaburi ERJ 2002;19:217-224

+ 16%+ 18%

Summary Treatment for COPD is improving

Diagnosis needs to be made early in order to take preventive action

Combination bronchodilators seem to be the best option

Role of inhaled steroids is getting defined

New long acting drugs will soon be available