Current strategies for COPD treatement
Jaideep A. Gogtay MD
Cipla Ltd,
Mumbai, India
New 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
Proportion of 1965 Rate
3.0
3.0
2.5
2.5
Coronary
Heart
Disease
Stroke
Other CVD
COPD
All Other
Causes
–59%
–64%
–35%
+163%
–7%
2.0
2.0
1.5
1.5
1.0
1.0
0.5
0.5
0.0 0
1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998
BURDEN OF DISEASE: COPD vs ASTHMA
MORTALITY
ASTHMA
Annual deaths
(UK 1992)
1,791
26,033
410
680
In-patient bed days
1,800
9,600
GP consultations
11,900
14,200
COPD
MORBIDITY
Workload in UK Health
District of 250,000
Hospital admissions
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
ANNUAL DECLINE IN LUNG FUNCTION
100
Non smoker
Non-susceptible
smoker
75
Susceptible
smoker
(10-20%)
50
Stopped smoking
aged 50 yr
Disability
25
Death
Stopped smoking
aged 60 yr
0
25
50
Age (years)
Fletcher C, Peto R: BMJ 1977
75
COPD and asthma
The Overlap
COPD
Asthma
Neutrophils
No airway
hyperresponsiveness
Less bronchodilator
response
Limited steroid
response
Eosinophils
Wheezy
bronchitis
10%
Airway
hyperresponsiveness
Bronchodilator
response
Steroid
response
Airway mucosa under light microscopy
Atopic asthmatic
Heavy smoker with COPD
FEV1< 40% predicted
COPD
Asthma
Reversibility
Sputum
production
Alveolar
Damage
Chronic
Bronchitis
Emphysema
INFLAMMATORY CELLS IN INDUCED SPUTUM
Induced sputum: inflammatory cell counts
Total cell count (x106/ml)
2.5
***
Macrophages
Neutrophils
2
1.5
Eosinophils
**
**
1
0.5
*
L
**
0
Normal
COPD
Keatings et al: Am J Respir Crit Care Med 1997
Asthma
SPUTUM CYTOKINES IN COPD
COPD patients: 62.5 ±3.2y; FEV1 = 34.6±4 % predicted
TNF-
IL-8
4
**
8
3
6
2
[IL-8 (nmol/l)]
[ TNF- (nmol/l)]
*
**
0
0
2
4
*
*
1
Controls Smokers COPD
(n=16) (n=12) (n=14)
Asthma
(n=22)
Controls Smokers COPD
(n=16)
(n=12) (n=14)
Keatings et al: Am J Respir Crit Care Med 1996
Asthma
(n=22)
AMPLIFICATION OF INFLAMMATION IN COPD
++++
Inflammation
Neutrophils
Macrophages
Cytokines
Mediators
Proteases
+
0
Non-smokers Normal smokers COPD
Amplification
Genetic?
Viral?
Oxidative
stress?
Other
New Drugs for COPD
What are we aiming to achieve with
drug therapy?
• 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
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 b2-agonist Salmeterol, Formoterol,
Bambuterol
Short-acting b2-agonist –
Salbutamol

Long-acting anticholinergics Tiotropium

Short acting anticholinergics –
Ipratropium

Methylxanthines Theophylline
Corticosteroids

Oral – Prednisolone

Inhaled - Fluticasone,
Budesonide
ANTICHOLINERGICS IN COPD
NORMAL
COPD
Vagus nerve
ACh
Vagal “tone”
ACh
Resistance 1/r4
ANTICHOLINERGIC
“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
ANTICHOLINERGICS IN COPD vs ASTHMA
I=ipratropium bromide, ß=fenoterol, P=placebo
0.8
Asthma
COPD
I+ß
0.6
ß
0.4
0.4
0.2
I+ß
I
ß
0.2
I
0
P
1
2
3h
P
Lefcoe NM et al: Chest 1982
0
1
2
Time (h)
3
Hyperinflation and Dyspnea
Effect of Ipratropium
n = 29
2.8
2.6
5
*
4
3
2
P
1
IB
0
*
* * *
2.4
IC (L)
Dyspnea ( Borg Scale)
6
2.2
2
1.8
1.6
1.4
1.2
0
2
4
6
8
10
Endurance Exercise Time
(min)
0
2
4
6
8
10
Endurance Exercise Time
(min)
O’Donnell AJRCCM 98;158:1557
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 to
provide relief
COPD: Therapeutic Options
MV
Surgery
Oxygen
ICS
ACH LABA
Theophylline
Beta agonists. P.R.
Smoking cessation. Exercise. Vaccination
Risk
Symptoms
FEV1
Celli’s schema
Long acting beta agonists in COPD
Salmeterol, 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 bronchodilators
Salbutamol/Levosalbutamol

Quick-acting

Rescue medication for acute bronchospasm
when patients are taking maintenance therapy

Can be given 3-4 times a day
Anticholinergic pharmacology
The discovery of muscarinic receptor subtypes
Cholinergic receptors
Muscarinic receptors
M1 M2
M3
M4 M5
Nicotinic receptors
Muscarinic
Receptors
in the
airways
Effect of a single dose of tiotropium
1.3
FEV1 L
1.2
+ 16%
+ 18%
Day 1 T
1 Year T
Day 1 P
1 Year P
1.1
1
0.9
0.8
-1
0
0.5
1
Post Dosing Hours
2
3
Casaburi ERJ 2002;19:217-224
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