Chronic Obstructive

Pulmonary Disease

Hanif Nasiatul Baroroh, M.Sc., Apt

Why do we care?

Fourth leading

cause of death
in the US

Half of cases
undiagnosed

 A systematic review and meta-analysis of studies

performed in 28 countries between 1990 and 2004 and
an additional study from Japan provide evidence that
the prevalence of COPD (stage I, mild COPD and
higher) is appreciably higher :
in smokers and ex-smokers compared with nonsmokers,
in those older than 40 years compared with those younger
than 40 years, and
in men compared with women

COPD Definition
Chronic obstructive pulmonary disease (COPD) is
a preventable and treatable disease state
characterized by airflow limitation that is not
fully reversible.
The airflow limitation is usually progressive and
is associated with an abnormal inflammatory
response of the lungs to noxious particles or
gases, primarily caused by cigarette smoking.
Although COPD affects the lungs, it also
produces significant systemic consequences.

COPD Definitions/Terms

Simple chronic

bronchitis
Asthmatic
bronchitis/Chronic
asthmatic bronchitis
Chronic obstructive
bronchitis small
airways disease
Pulmonary
emphysema

Risk Factor

Background - Lung function over time

Cigarette smoking
Airway responsiveness and Allergy
Air Pollution
Occupational exposure to
environmental dust and organic
antigens
Infection
Antioxidant deficiency
Molecular/Genetic risk factors

Cigarette Smoking
Responsible for 80% of risk of Chronic

Bronchitis
Doubles or triples rate of FEV1 decline
Responsible for 2-20 fold increase in death
from COPD
Never smokers account for 23% of COPD
Only 15% of white and 5% Asian smokers
develop COPD

Cigarette Smoking
Impairs ciliary movement
Inhibits alveolar macrophages
Leads to hypertrophy and hyperplasia of
mucus-secreting glands
Probably inhibits antiprotease
Acutely increases vagally mediated
smooth-muscle constriction

Model of annual decline in FEV1 with accelerated decline in

susceptible smokers

Airway Responsiveness
Increased airways responsiveness and allergy

are clinical phenotypes that predict increased

susceptibility to cigarette smoke.
Methacholine and histamine responsiveness
precedes and predicts accelerated decline in
lung function, thus a risk factor for COPD.*
*Silva, GE et al. Asthma as a risk factor for COPD in a longitudinal
study. Chest 2004; 126:59.

Air Pollution
Increased incidence and higher mortality
rates of COPD in industrialized urban
areas.
Exacerbations of CB clearly related to
periods of heavy sulfur dioxide pollution
and particulates.

Occupational Exposures
Environmental dusts gold and coal miners
Organic antigens COPD is most common

respiratory syndrome in agricultural workers,

and there is a 10% prevalence of COPD among
farm workers
Accelerated decline in lung function among
plastics workers exposed to toluene
diisocyanate and in carding room workers in
cotton mills

Infection
Severe viral pneumonia in childhood may lead to

small airways obstruction (SAO).

Mortality, morbidity, and frequency of ARI are
higher in patients with chronic bronchitis.
The Rhinovirus is found more often during COPD
exacerbationspathogenic bacteria, other viruses, &
mycoplasmas found as often between as during
exacerbations. However there is increased chance
of detecting bacteria if sputum purulent*, and
isolating new strain of bacteria may be associated
with exacerbations.@
*Stockley RA et al. Relationship of sputum color to
nature and outpatient management of acute
exacerbation of COPD. Chest 2000; 117: 1638.
@Sethi S et al. New strains of bacteria and
exacerbations of COPD. N Engl J Med 2002; 347:
465.

Antioxidant Deficiency
Oxidizing radicals derive from cigarette

smoke or may be released by phagocytes in

the lung. Deficiencies of antioxidants
vitamins may impair host defenses against
oxidative radicals and permit tissue
destruction leading to COPD.
Sanguinetti, CM. Oxidant/antioxidant imbalance:
role in the pathogenesis of COPD. Respiration
1992; 59 Suppl 1:20.

Molecular/Genetic Risk Factors

Protease/antiprotease
TNF-a gene polymorphisms
Microsomal epoxide hydrolase*
Glutathione S-transferase P1
Transforming growth factor beta 1*
Metalloproteinase dysregulation
Hersh, CP et al. Genetic association analysis of functional
impairment in chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 2006; 173: 977-984.

Protease/Antiprotease
Alpha 1- antitrypsin/elastase imbalance.
Alveolar macrophages from COPD patients

express more matrix metalloproteinase (MMP)-9

than normals. Elevated MMP-9 is associated
with an increase in degradation of elastin.
Russell RE et al. Release and activity of matrix
metalloproteinase-9 and tissue inhibitor of
metalloproteinase-1 by alveolar macrophages from
patients with chronic obstructive pulmonary disease.
Am J Respir Cell Mol Biol. 2002;283:L867-L873.

TNF alpha gene

polymorphisms
May influence host immune responses,

increase inflammatory tissue damage, and

favor the development of chronic
bronchitis- a specific TNF-a polymorphism
found in 19% CB vs. 5% schoolchildren
vs. 2% of controls
Huang SL et al. Tumor necrosis factor-alpha
gene polymorphism in chronic bronchitis. Am
J Respir Crit Care Med 1997; 156:1436

Microsomal epoxide hydrolase

Microsomal epoxide hydrolase (MEH) reduces

highly reactive epoxide intermediates generated

by smoking. The genotypes associated with
decreased activity of MEH were found in 19 and
22 per cent of COPD patients vs. 6% controls
Smith CAD, Harrison DJ. Association between
polymorphism in gene for microsomal epoxide
hydrolase and susceptibility to emphysema. Lancet
1997; 350:630.

Glutathione S-transferase P1
Glutathione S-transferase P1 aids in the

detoxification of substances in cigarette smoke,

and COPD may occur more frequently among
persons with decreased activity of this
enzyme by virtue of genetic polymorphisms.
Ishii, T et al. Glutathione S-transferase P1
polymorphism in patients with chronic obstructive
pulmonary disease. Thorax 1999; 54:693.

Noxious particles
and gases
Host factors

Lung inflammation
Anti-oxidants

Oxidative stress

Anti-proteinases

Proteinases

Repair mechanisms

COPD pathology

Spirometry Classification for COPD

Stage

FEV1:FVC FEV1

1: Mild

80% of predicted value,

With/without chronic
symptoms

2: Moderate

50% to 79% of predicted value,

With/without chronic
symptoms

3: Severe

4: Very
severe

<0.70

30% to 49% of predicted value

<30% of predicted value
OR
<50% of predicted value with
Adapted from GOLD, 2009
chronic respiratory failure,
Clinical signs of right heart
failure

Chronic Bronchitis
Pathophysiology
Chronic inflammation
Hypertrophy &

hyperplasia of
bronchial glands that
secrete mucus
Increase number of
goblet cells
Cilia are destroyed

Chronic Bronchitis
Pathophysiology
Narrowing of airway

Starting w/ bronchi
smaller airways
airflow resistance
work of breathing
Hypoventilation & CO2
retention hypoxemia
& hypercapnea

Chronic Bronchitis:
Clinical Manifestations
In early stages
Clients may not recognize early symptoms
Symptoms progress slowly
May not be diagnosed until severe episode with a
cold or flu
Productive cough
Especially in the morning
Typically referred to as cigarette cough
Bronchospasm
Frequent respiratory infections

Chronic Bronchitis:
Clinical Manifestations
Advanced stages
Dyspnea on exertion Dyspnea at rest
Hypoxemia & hypercapnea
Polycythemia
Cyanosis
Bluish-red skin color
Pulmonary hypertension Cor pulmonale

Chronic Bronchitis:
Diagnostic Tests

FVC: Forced vital capacity

FEV1: Forcible exhale in 1 second
FEV1/FVC = <70%
PaCO2
PaO2
Hct

Pulmonary Emphysema
Permanent, abnormal distension
of the air spaces distal to the
terminal bronchiole with
destruction of alveolar septae,
with or without fibrosis. Reduces
lung elastic recoil causing airway
collapse and irreversible airway
obstruction.

Emphysema
Abnormal distension

of air spaces
Actual cause is
unknown

Emphysema: Pathophysiology
Structural changes
Hyperinflation of alveoli
Destruction of alveolar &
alveolar-capillary walls
Small airways narrow
Lung elasticity decreases

Emphysema: Pathophysiology
Mechanisms of structural
change
Obstruction of small
bronchioles
Proteolytic enzymes destroy
alveolar tissue
Elastin & collagen are
destroyed

PATOGENESIS EMPHYSEMA
Smoking
Air polution

Lung Inflammation
makrofag,
leukocytes
neutrofil

Proteolytic enzymes
elastase, collagenase

Other inflammatory
mediators

if alpha antitrypsin low

EMPHYSEMA
Gas exchange
Destruction of lung tissue
Weakened airways
Airways elasticity
Lung compliance

Alpha-antitrypsin
Normally inhibits proteolytic enzymes

35

FIG. 1. Inflammatory mechanisms in COPD. Cigarette smoke (and other irritants) activate
macrophages in the respiratory tract that release neutrophil chemotactic factors, including IL-8
and LTB4. These cells then release proteases that break down connective tissue in the lung
parenchyma, resulting in emphysema, and also stimulate mucus hypersecretion. These
enzymes are normally counteracted by protease inhibitors, including 1-antitrypsin, SLPI, and
TIMP. Cytotoxic T cells (CD8) may also be recruited and may be involved in alveolar wall
destruction. Fibroblasts may be activated by growth factors releases from macrophages and
epithelial cells. CTG, connective tissue growth factor; COB, chronic obstructive bronchiolitis.
36

37

Sign & symptoms of emphysema

Signs
Prolonged expiration
Thin
Use of accesory muscles to assist breathing
Pink puffers
Barrel chest
Decreased breath sounds
Decreased FEV1/FVC
Altered blood gas (advanced stages)

Symptoms

Dypsnea
Weight loss
Cough (nonproductive)

Emphysema:
Clinical Manifestations
Early stages

Dyspnea
Non productive cough
Diaphragm flattens
A-P diameter increases
Barrel chest
Hypoxemia may occur
Increased respiratory rate
Respiratory alkalosis
Prolonged expiratory phase

Emphysema:
Clinical Manifestations
Later stages
Hypercapnea
Purse-lip breathing
Use of accessory muscles to breathe
Underweight
No appetite & increase breathing workload
Lung sounds diminished

Emphysema: Clinical
Manifestations
Pulmonary function

residual volume, lung capacity, DECREASED FEV1,

vital capacity maybe normal

Arterial blood gases

Normal in moderate disease

May develop respiratory alkalosis
Later: hypercapnia and respiratory acidosis

Chest x-ray

Flattened diaphragm
hyperinflation

TERAPI PPOK

Panatalaksanaan terapi
Tujuan terapi
Terapi pemeliharaan PPOK stabil
Memperbaiki keadaan obstruksi saluran nafas
Mencegah dan mengatasi eksaserbasi/serangan akut
Menurunkan progresivitas penyakit
Meningkatkan keadaan fisik dan psikis
Menurunkan angka kematian
Terapi eksaserbasi akut
Memelihara fungsi pernafasan dan memperpanjang survival

TATA LAKSANA TERAPI

Non-farmakologi
Menghentikan kebiasaan merokok
Rehabilitasi paru-paru secara
komprehensif dengan OR dan latihan
pernafasan
Perbaikan nutrisi
(untuk menambah energi)
Tidak ada obat yang dapat
menunda memburuknya fungsi
paru jika pasien tetap merokok

45

Terapi PPOK
Terapi fase akut
Inhalasi beta agonis aksi

pendek (salbutamol)
Inhalasi antikolinergik
(ipratropium)
Kortikosteroid inhalasi atau
sistemik jangka pendek
Aminophylline i.v.
Antibiotik (jika ada tandatanda infeksi)
oksigenasi

Terapi pemeliharaan
Inhalasi antikolinergik aksi

panjang (tiotropium)
Inhalasi beta agonis aksi
panjang
Theophyline sustained-release
Inhalasi kortikosteroid pada
pasien dengan stage III atau IV
Vaksinasi influenza dan
pneumonia
Oksigen long term (>15
jam/hari) utk yg gagal respirasi
kronis

11/4/2014

Zullies Ikawati's Lecture Notes

47

Short acting beta agonist

Bekerja pada reseptor adrenergik 2 di otot polos
saluran pernafasan bronkorelaksasi
Merupakan drug of choice pada serangan akut

Mengaktifkan adenilat
siklase
Meningkatkan kadar
cAMP mengaktifkan
Protein Kinase A (PKA)
relaksasi otot polos

Dosis

NAEPP Guideline, 2007

Lanjutan
dosis
lanjutan

NAEPP Guideline, 2007

Antikolinergik
Merupakan first line

terapy pada terapi

pemeliharaan lebih
disukai aksi panjang:
tiotropium
Bekerja memblok
reseptor muskarinik M3 di
saluran pernafasan
Tersedia dalam sediaan
tunggal atau kombinasi
dengan beta agonis

Belmonte, Proc Am Thorac Soc Vol 2.

pp 297304, 2005

Kortikosteroid
Kortikosteroid sistemik (oral atau i.v) direkomendasikan sebagai
tambahan terapi pada eksaserbasi akut, terutama pada pasien
yang FEV1-nya < 50% prediksi.

Contoh: prednisolon per oral dengan dosis 30-40 mg/hari selama

7-10 hari, atau metilprednisolon 0,5 1 mg/kg IV setiap 6 jam.
Jika gejala pasien telah membaik, dapat diganti dengan

prednisone 40 60 mg sehari

utk terapi pemeliharaan: penggunaan kortikosteroid inhalasi

dapat dipertimbangkan pada pasien PPOK dengan FEV1 < 50%,
(tingkat keparahan III atau IV dan yang mengalami eksaserbasi
berulang (misalnya 3 kali dalam 3 tahun).

 Penggunaan teratur inhalasi KS tidak dapat

memperbaiki penurunan jangka panjang pada FEV1

pasien PPOK, namun cukup tepat jika digunakan
pada PPOK pada stage III dan IV - PPOK berat dan
sangat berat
Terapi dengan KS dapat mengurangi frekuensi
kekambuhan sehingga meningkatkan status
kesehatan pasien dan penghentian tiba-tiba dapat
memicu kekambuhan pada sebagian pasien
Penggunaan KS oral jangka panjang tidak
direkomendasikan pada pasien PPOK
Kombinasi inhalasi KS dengan b agonis aksi panjang
lebih baik daripada jika dipakai secara tunggal

Vaksinasi
Vaksin influenza terbukti dapat
mengurangi gangguan serius dan
kematian akibat PPOK sampai 50%.
Vaksin influenza direkomendasikan
bagi pasien PPOK usia lanjut karena
cukup efektif.
Pasien PPOK sebaiknya menerima
satu atau dua kali vaksin
pneumococcal dan vaksinasi
influenza per tahun untuk
mengurangi insiden pneumonia.
Bila pasien terpapar pada influenza
sebelum divaksinasi, maka dapat
digunakan amantadin dan
rimantadin.

AAT replacement therapy

Digunakan pada pasien dengan defisiensi

AAT secara herediter

terdiri dari infus AAT secara rutin
(mingguan) untuk memelihara kadar AAT
plasma di atas 10 mikromolar.
dapat memperlambat progresivitas penyakit
(dengan parameter FEV1) dan mengurangi

mortalitas

Regimen dosis : 60 mg/kg i.v. sekali

seminggu, kecepatan 0.08 mL/kg per menit,

disesuaikan dengan toleransi pasien.
Masalah : harga yang mahal dan
ketersediaan produk yang memenuhi
syarat.
Contoh produk : Prolastin, Aralast, dan
Zemaira.

Antibiotika (Dipiro, 588)

Diberikan pada pasien jika :
Eksaserbasi akut dgn 3 gejala cardinal : dypsnea
meningkat, volume sputum meningkat, sputum
purulence meningkat
Eksaserbasi akut dg 2 gejala utama, sputum
purulence meningkat salah satunya
Eksaserbasi akut dg Ventilation mechanical

Therapeutics

You have the power

Time spent
talking with
patients
improves their
success in
quitting in a
dose dependent
manner.