COPD

Monday, July 09, 2012

10:05 AM
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Obstructive Lung Disease: COPD
Anthony J. Busti, PharmD, FNLA, FAHA
Editor-in-Chief
Pharmacology Weekly Inc.
Background of COPD
COPD is also a major contributor to other co-
morbidities:
- Pneumonia
- Stroke
- lung cancer
- Heart Disease
Right sided heart failure (indicates severe COPD)
Pulmonary hypertension
Cor pulmonale
Arch Intern Med 2003,163 797802
Ctrculat.on 2003;107 1514-1519
Arln Intern Med 1987,106 512-518
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Background of COPD
A chronic disease characterized as:
- An irreversible obstruction of airflow typically
from inflammation and emphysematous changes
in lung tissue.
- Airway hyperresponsiveness also occurs in about
60- 80% of patients.
- Broken down into chronic bronchitis and
emphysema (centriacinar and panacinar)
Am J Resp11Cnt Care Med 2001.163 1256-1276
ArnRev Resplf Ots 1992.145301310
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Types of Emphysema
Centriacinar (Centrilobular):
- Most common type in smokers
- Destruction of the distal terminal and respiratory bronchioles
in mainly UPPER airway
Panacinar:
- Most common type in patients with alpha-1 antitrypsin (AAT)
deficiency; patients with MM phenotype make normal
amounts vs. ZZ phenotype release very little from liver
Smokmg 1nh1b1ts AAT abtlity to breakdown elastase released from the
neutrophtls thereby causmg proteolytiC degradation of elastm m lung
- Presents early in life if genetic type
- Destruction of the distal respiratory unit ( respiratory
bronchioles) in mainly LOWER airway
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Types of Emphysema
Paraseptal Emphysema:
- Localized disease in a subpleural location
- Primarily targets the alveolar ducts and alveoli
- Does not produce obstructive airway disease
- Increased spontaneous pneumothorax due to
rupture of subpleural blebs
Irregular Emphysema:
- Localized disease associated with scar tissue
-Also does not produce obstructive airway disease
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Comparison of Obstructive Lung Diseases
Asthma:
- Eosinophiles
- Airway hyperreactivity
- Bronchodilator response
- Inhaled corticosteroid
response
COPD:
- Neutrophils
- No airway hyperreactivity
- limited bronchodilator
response
- limited inhaled
corticosteroid response
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Obstructive Airway Diseases
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Risk Factors
Tobacco smoking is leading ri sk factor
Smoking
- 80-90% of all risk factors
- Only 12-15% of smokers have COPD
- Smoking cessation is the most important therapy for
improving health outcomes
Occupational effects (chronic exposure to vapors,
etc.)
Childhood illnesses especially associated with
low-birth weight, respiratory infections, &
symptomatic childhood asthma
JAN.A 1994 27214971505
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COPD: Pathophysiology
Chronic Bronchitis:
- Airway inflammation and hypersecretion of
mucous
Peri bronchiolar fibrosis results in narrowing of
peripheral airways, loss of elastic recoil
Intraluminal mucous may contribut e to airflow
obstruction
Reflected by a Reid index >0.4 (ratio of the thickness
of mucous gland layer to t hickness of the wall
between epithelium & cartilage)
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COPD: Pathophysiology
Emphysema:
- Influx of neutrophils that release IL-8, LTB4, elastase, cathepsin
and proteinase-3-A creating an imbalance towards destruction
- Macrophages are activated by cigarette smoking and release of
TNFo, LTB4, ll-8, ROA, & proteinases
- T-lymphocytes infiltrate small airways, lung parenchyma and
adventitial layer of pulmonary arteries & shift balance of
CD4+/CD8+ T cell ratio towards CDS+ which correlates to the
degree of airflow obstruction
- Loss of elastic recoil (patency in the smaller airways depends on
elastic recoil and as intraluminal pressure is reduced the airways
collapse)
- Presence of parenchymal destruction & airflow obstruction
- Airway obstruction
Is progressive
May be partially due to hyperreactivity
May be partially reversible
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Cl inical Presentation
Chronic Bronchitis:
- Chronic, productive cough >
3 months in 2
consecutive years
- Moderate dyspnea
- Recurrent respiratory
infections
-Obese
- Greater risk of cor
pulmonale due to hypoxia
- " Blue Bloater" because of
mucous plugs in terminal
bronchioles
Emphysema:
- Little to no cough
- Diminished breath
sounds due to
hyperinflation
- Severe dyspnea
- Thin extremities
- Barrel-chested
- Pursed lipped breathing
- "Pink Puffer"
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Pertinent History
Smoking history
- Pack per day
- Cessation history
- Willingness to quit: use clinical markers as an incentive to
quit.
Ext ent and severity of symptoms
Occupational and environmental exposure
Use of oxygen
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Differential Diagnosis
Bronchial asthma
Bronchiectasis
Cystic fibrosis
Bronchiolitis (obliterative, follicular, diffuse)
Alpha-1 antitrypsin deficiency
Coal workers pneumoconiosis
Upper airway obstruction: vocal cord paralysis
or dysfunction, tracheal tumors, tracheal
stenosis, traf:heomalacia
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Diagnosis of COPD
Patient history and clinical presentation
Presence of nonreversible airway restriction
Confirmed by spirometry
- FEV
1
< 80% of predicted value
- FEV dFVC < 70%
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Normal Lung Volumes

IRV
I(

vc
Volume TV
TLC
2.2 L
ERV
1.2 L 1----+-
FRC
RV
RV
Ol
Figure 1. Normal lung volumes during various respiratory cycles.
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Lung Volumes: Restricted vs. Obstructive
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Normal Flow Volume Loop
Expiration
Inspiration
8L/s
4L/S
Volume (L)

4L/S
Peak Inspiratory flow Rate
8L/S
rigure 1. Nonnallung flow volume loop.
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Obstructive Lung Disease
Expiration
Inspiration
8L/s
4L/S
4L/S
8L/s
Normal: = > 0.70
Obstruction: FEV1/FVC = < 0.70
Figure 1. Obstructive lung disease flow volume loop.
Pharmacology Weekly Inc.
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Classification of COPD
Guidelines for Obstructive Lung Disease (GOLD)
Stage Severity FEV
1
FEV
1
/FVC Symptoms
I Mild 2!80% <70% With/without
II Moderate 50%-80% <70% With/without
Ill Severe 30%-50% <70/o With/without
Respiratory
IV
Very
<30%
<70% failure/right
Severe
<50%
heart failure
Arterial Blood Gases
Low to normal cq.mpensated pH (normal 7.35-
7.45)
High pC02 (chronic respiratory aci dosis; normal
is 35-45)
Low Pa02 (chronic hypoxemia; normal 80-100
mmHg)
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Chest X-Ray Findings
Hyperlucency
Increased anterior-post erior diamet er
Vert ically oriEfcnted heart
Depressed or "fl attened" di aphragms due to
hyperinflati on

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Progression of COPD
Nonsmokers: ! FEVl 25-30 ml/yr (after age 35)
..
Smokers: !>60 ml/yr
5 year mortality is about SO% in patients with an FEVl < 1
Liter
Only way to stop decline in FEVl is smoking cessation.
Prognosis: BODE Index
- j!ody mass index (BMI)
- Obstruction or Degree of airflow limitation (0)
- Dyspnea
- capacity (6 minutes walk test)
Value: 0-10; the higher the worse the prognosis/mortalit y
cern BR elal NEJM 2004.350(10) 1005-12
Protalb tood
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Goals of Treatment
Stop smoking
Improve symptoms and quality of life
- Attempt to reduce health care utilization
Prevent and treat complications
Reduce decline in lung function
Increase survival
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Monitoring
Disease of
- Expect condition to worsen over time
Monitor for changes in symptoms
- Patient diary
- Spouse and family
Spirometry if significant change in symptoms
Adverse Effects
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General Considerations to Current Therapy
No cure
- symptom control
- Prevent1on of exacerbations
- None of the short-acting bronchodilators decrease the rate of decline in
lung function or survival.
Regimen not decreased
Patient specific
Increase therapy based on patient progression
Pulmonary rehabilitation should be considered as part
of the treatment plan especially in moderate to severe
patients
Consider ::!: home 0
2
JAMA.1994 272 1497-1505
Am J Respw Cnt Cere Med 2002,166 333-339
Eur Resptt J 2002.19 393-404
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Current Therapy
Smoking cessation: tt
- Consider incentives as a motivation:
The FEV
1
1n smokers dechnes at a rate of 60 ml/yr vs. 30 ml/yr in ex-
smokers
Reductions in all-cause mortahty of about 27'"/o
Reductions in cardiOvascular related mortalit y- relat1ve nsk of 0.54
compared to contmued
- Approach to treatment:
Counseling, education, mcotme replacement and buprop1on can
resul t in abstinence rates of about 25%
JAJ.'.A.1994 2721497-1505
JAA'.A 1982 2481465-1477
Prev M_, 2002.35 314-319
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Current Pharmacotherapeutic Options
Bronchodilators:
-

agonists (short & long acting)
- Anticholinergics (short & long acting)
- Methylxanthines
- Mucolytic:s (no longer recommended by GOLD)
'(
Corticosteroids:
-Oral vs.IV
-Inhaled
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Inhaled Anticholinergics
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Anticholinergic Agents
Short-Acti ng Agents:
- lpratropium bromide (Atrovent): MDI, Neb
- lpratropium/albuterol (Combivent, OuoNeb) : MDI, Neb
Long-Acti ng Agents:
- Tiotropium Bromide (Spiriva): DPI
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MOA: Anticholinergic Agents
Blocking of the muscarinic receptor

results in j cGMP levels
l
! Intracellular c a
1
Smooth muscle relaxation
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Anticholinergic Agents
Tiotropium bromide (Spiriva)
1 capsule per inhaler QD
Side Effects: minimat but can experience
dry eyes, increase risk of worsening narrow
angle glaucoma, and dry mouth.
Notes:
-May offer improvement compared to
ipratropium due to compliance
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Anticholinergic Agents
Tiotropium bromide:
- A recent meta-analysis of 5 clinical trials including 3,574
patients witt+moderate - severe COPD followed up for 6
months showed a 26% (RR, 0.74; 95%CI, 0.62- 0.89)
reduction in exacerbation rates when compared to
placebo.
- When compared to ipratropium there was still a reduction
in exacerbations (RR, 0.78; 95% Cl, 0.63- 0.95).
JAJ,'IA 2003 290 23012312
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Anticholinergic Agents
Tiotropium bromide:
-It is FDA approved to reduce exacerbation rates
when compared to long-acting P
2
-agonists. Can
delay time to first exacerbation by about 4
months.
-In addition, the effect of tiotropium on trough
FEV
1
is good:
an average of 121 ml per year compared to placebo or
ipratropium monotherapy.
An additional 37 ml compared to long-acting

agonists over 6 months

JAMA2003 290 2301-2312
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Corticosteroids
Inhaled corticosteroids:
- A recent meta-ar:}alysis of 6 placebo-controlled clinical
trials including 1,741 patients w1th follow up for 2 6
months showed a 24% (95%CI, 20- 28%) reduction in
exacerbation rates.
- The majority of this benefit was seen in patients with
mean FEV
1
< 2l; pooled RR, 0.75 (95% Cl, 0.71-0.80)
compared toRR of 0.96 (95% Cl, 0.77-1.20) in patients
whose mean FEV
1
was > 2l.
JAMA 2003 290 2301-2312
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Lung Health Study and EUROSCOP
Bone Mineral Data
972 patients with 3 to 4 years of follow up
A net reduction in BMD of 1.57% (95% Cl , 2.40%-
0.74%) in the femoral neck and 1.07/o (95/o Cl,
1.86%-0.28/o) in the lumbar spine.
No excess fractures seen (RR, 0.70; 95% Cl , 0.36-
1.37)
The lifetime risk remains unknown
N Engl J Med 2000 3.4319021909
EurRespvJ 2002.191058-1063
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Mucolytic Agents
L
Ambroxol, erdosteine, carbocysteine
May be of very small benefit in pts with viscous
sputum
Not enough evidence to support wide spread
use per GOLD guidelines
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Vaccinations
It
Pneumococcal (Pneumovax-23)
Influenza
Though their use has not been specifically
evaluated in COPD, in the elderly population
they have been shown to reduce all -cause
pneumonia and cardiac hospitalization and
deaths by 30- 40%.
JAMA 1994 272 16611665
N Engl J Med 2003.348 13221332
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Home Oxygen Therapy

Supplemental home 0
2
is effective a
prolonging survival whose resting Pa02 is <
60 mm Hg.
2 trials totaling 290 patients, revealed a RR,
0.61 (95% Cl, 0.46-0.82)
Only has small benefit on mean pulmonary
arterial pressure and CRQ scores.
Eur Respr J 2002 20 306-312
Ann Intern Med 1985,102 2936
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Home Oxygen Therapy
Indications for long-term oxygen therapy:
- Pa02 s; 55 fl\mHg or Sa02 < 88%
- Pa02 56-59 mmHg with:
EKG evidence of pulmonary HTN or cor pulmonale
Secondary erythrocytosis (Hct > 55%)
Clinical evidence of right sided heart failure and/or pedal
edema
- Oxygen delivery options:
Concentrator (converts room air to higher concentrations)
0-cylinder (carry on the patients back)
E-cylinder (type that you pull canister around with)

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Drugs to use with Caution in COPD
P-Biockers: (especial ily
- Recent data suggests carvedilol may be better tolerated
than selective B-Biocker
Respiratory Depressants:
- Opioids
- Benzodiazepines
- Only a concern initially & at specific doses
- Antitussives {regular use)
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Smoking Cessation
Pack per day
Cessation history
Willingness to quit
Method:
- Use of US Pu'blic Healt h Service 5-step program
- Use of bupropion (Wellbutrin; Zyban) or nortriptyline
- Nicotine patches, gum
- Counseling
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Global lnitiative for Chronic
Obstructive Lung Disease
(GOLD)
2008 Guidelines
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Significant Changes
Stage 0: At Risk
- no longer included as a stage of COPD
- insufficient evidence that patients with chronic cough and
sputum production and normal spirometry necessarily
progress to Stage 1: Mild COPD

Varenicline (Chantix)
- mentioned as being safe and efficacious for smoking
cessation
- no recommendation regarding its specific role
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Bronchodilators
Central to symptomatic management
No effect on disease progression Qr prognosis
Give PRN for relief of persist ent or worsening symptoms or
regularly to prevent or reduce symptoms
Regular use of LABA or anticholinergic improves health status
Inhaled route preferred
Long-acting agents
- more effective and convenient than short-acting agents

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Bronchodilators
Nebulizers not recommended
- more expensive, require maintenance
- not appropriate for stable patients unless shown to be better
than conventional therapy
- nebulized anticholinergics reported to precipitate glaucoma
Increasing dosage of bronchodi lator
- beneficial in acute episodes, but not in stable disease
- higher doses increase side effects

Combination bronchodilator therapy
- increased bronchodilation
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Corticosteroids
Effect s less dramatic in COPD t han in asthma
- Role limited to specific indications
Oral not r ec:ornrnended for routine
use
Inhaled corti cost eroids
- no effect on long-term decline of FEVl
- do reduce frequency of exacerbations and improve health
status
- appropriate for patients with Stage Ill (Severe) and Stage IV
(Very Severe) COPD and repeated exacerbations
- combination of inhaled glucocorticosteroid + LABA more
effective than individual components
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Stepwise Approach to Therapy
Stage 1: Mild COPO (few or intermittent symptoms)
- Short-acting i nhaled bronchodilator PRN
Stage II: Moderate to Stage IV: Very Severe COPD with dyspnea
during daily activities not c-ontrolled with PRN short-acting
bronchodilator
- Add long-acting bronchodilator (LABA or tiotropium)
- addition of theophylline may provide additional benefits

Stage Ill or IV with repeated exacerbations
- Add regular treatment with ICS to long-acti ng inhaled bronchodilator
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Exacerbations - Home Management
Increase dose and/or frequency of existing short-acting
bronchodilator therapy
- If not already used, anticholinergic can be added until symptoms
improve
- No difference in clinical response between MOl with a spacer
and nebulizer
Systemic glucocorticosteroids beneficial
- 30-40 mg/day for 7-10 days
Exacerbations - Home Management
Increase dose and/or frequency of existing short-acting
bronchodilator therapy
- If not already used, anticholinergic can be added until symptoms
improve
- No difference in clinical response between MOl with a spacer
and nebulizer
Systemic glucocorticosteroids beneficial
- Prednisolone 30-40 mg/day for 7-10 days
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Therapy at Each Stage of COPD
I: Mild II: Moderate
FEVdFVC < 70%
FEVtfFVC < 70%
III: Severe
FEV P.-./C < 7 ~ o
30% < FEV < soo'O
pred1cted
Conclusion
Differences in t reatment
IV: Very Severe
FEV FVC < 70o'o
FEV < 300.o pred>cted
o FEY < 50% prea cted
pas chron c ew;atory
fa ue
long term oxygen
if chronic respiratory
failure.
surgiCal treatments
Importance of t reatment vs. maintenance t herapy
Importance of education and inhaler technique
GINA and GOLD Guidelines
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