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Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 1
Understanding COPD Pathophysiology and the
Rationale for Use of Different Therapeutic AgentsSeptember 10, 2013 • 2:00 PM–3:00 PM EDT
Dennis Williams, PharmDAssociate Professor
University of North Carolina at Chapel Hill
Eshelman School of Pharmacy
Chapel Hill, North Carolina
Development and Support
Developed by the American Pharmacists Association
Supported by an independent educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.
CPE Information Target Audience: Pharmacists
ACPE#: 0202-0000-13-198-L01-P
Activity Type: Knowledge-based
The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This session is approved for 1 hour of continuing pharmacy education or .01 CEUs.
To obtain continuing pharmacy education (CPE) credit for this activity, you are required to actively participate in this session. The attendance code, provided at the end of the session, is required to claim credit. To receive CPE credit, you must complete the online assessment and evaluation by September 20, 2013.
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 2
DisclosuresDennis Williams, PharmD, declares that his spouse/partner is an employee and stock/shareholder of GlaxoSmithKline.
APhA’s educational and editorial staff declare no conflicts of interest or financial interests in any product or service mentioned in this activity, including grants, employment, gifts, stock holdings, and honoraria. For complete staff disclosures, please see the Education and Accreditation Information section at www.pharmacist.com/education.
Objectives
At the end of this session, the participant will be able to:
Explain chronic obstructive pulmonary disease (COPD) pathophysiology, including the cholinergic, sympathomimetic, and inflammatory components
Identify medications used to treat COPD and describe the rationale for the use of therapeutic agents with different mechanisms of action
Explain how the pharmacist can work with prescribers to ensure optimal COPD therapy
Question 1
The increase in vagal tone that is observed in patients with COPD results in:
a. Increased airway diameterb. Decreased airway diameterc. Increased mucus productiond. Decreased mucus production
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 3
Question 2The effectiveness of tiotropium as a bronchodilator is based on the:
a. Selective binding and inhibition at the M3 receptor in the airway
b. Binding and inhibition of all muscarinic receptors in the airways
c. Selective binding and activation of the M2 receptor in the airway
d. Activation of adrenergic receptors in the airways
Question 3
The most important determinant of the effectiveness of medications for COPD delivered via inhalation is the:
a. Bioavailability from the lungb. pH of the inhaled moleculec. Technique of inhalationd. Patient age
Chronic Obstructive Pulmonary Disease
“Chronic Obstructive Pulmonary Disease (COPD), a common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients.”
2013 GOLD COPD Guidelines available at: www.goldcopd.org
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 4
Prevalence of Chronic Obstructive Pulmonary Diseases Chronic respiratory diseases (primarily COPD) are the
3rd leading cause of death in the United States
Affects 15 million Americans (6.3% of population), with women (6.7%) reporting higher prevalence than men (5.2%)
Prevalence is 11.6% for ages 65 years and older
Prevalence in smokers is higher (13.3%) compared with former smokers (6.8%) or never smokers (2.8%)
CDC. MMWR Morb Mortal Wkly Rep. 2012;61:938‒43.
COPD
A reported 20% of patients with a COPD diagnosis have not undergone spirometry
Another 24 million people have evidence of impaired lung function but not a COPD diagnosis
CDC. MMWR Morb Mortal Wkly Rep. 2012;61:938‒43. American Lung Association available at: www.lung.org/finding-cures/our-research/trend-reports/copd-trend-report.pdf
Causes of COPD
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 5
Inflammation in COPD
Generates
Burning Hydrocarbons
Respiratory Tract Macrophages
Activates
Neutrophils
Release
Release
Proteases
Airway and Parenchymal Damage
Resulting in
Protease-Antiprotease Imbalance in COPD
Proteases• Neutrophil elastase• Cathepsins• Matrix metalloproteinases
Antiproteases• α1‐Antitrypsin• Elafin• Secretory leukoprotease inhibitor• Tissue inhibitors of matrix
metalloproteinases
Consequences of Chronic Inflammation in COPD
Small Airway Disease• Inflammatory response • Airway remodeling
Parenchymal Destruction• Loss of alveolar attachments• Decreased elastic recoil
Chronic Airflow Limitation
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 6
Summary of COPD Pathophysiology
Airflow limitation (obstruction) in COPD is chronic and progressive based on continued exposure to the inciting factor
Airflow limitation is related to reduced airway diameter, inflammation, increased mucus production, structural destruction, and fibrosis
Hyperresponsiveness of the airways is not a factor for many patients with COPD
Diagnosis of COPD
COPD should be considered in any patient with: History of exposure to risk factors (especially
cigarette smoke)
Cough (sputum)
Dyspnea
Cough and sputum production may precede development of airflow limitation
Obtain spirometry testing
Spirometry in COPD Diagnosis
Spirometry is essential as the gold standard for diagnosis
Spirometry is standardized, reproducible, and objective
Peak flow meter use has limited value
Other components in the medical history also are important for diagnosis
Spirometry greatly underutilized
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 7
FEV1/FVC <0.70
FEV1 <30% predicted OR
FEV1 <50% predicted PLUS chronic respiratory failure
FEV1/FVC <0.70
FEV1 ≥80% predicted
Spirometry Testing Is Important for the Diagnosis, Grading, and
Monitoring of COPD
I: Mild II: Moderate III: Severe IV: Very Severe
FEV1/FVC <0.70
50% ≤ FEV1 <80% predicted
FEV1/FVC <0.70
30% ≤ FEV1 <50% predicted
GOLD Guidelines 2013. http://www.goldcopd.org/Guidelines/guidelines-resources.html
Possible Progression of COPD in Smokers
Well At-risk COPD diagnosis
No symptoms Symptoms but normal
spirometry
MILDstage
MODERATEstage
SEVEREstage
Reduced FEV1 to FVC Ratio
= Evidence of physiological damage
VERY SEVEREstage
Thorn J, Tilling B, Lisspers K, Jorgensen L, Stenling A, Stratelis G. Improved prediction of COPD in at-risk patients using lung function pre-screening in primary care: a real-life study and cost-effectiveness analysis. Prim Care Respir J 2012; 21 (2):159-66
Doherty DE. Identification and Assessment of Chronic Obstructive Pulmonary Disease in the Elderly. JAMDA 2003;s116-s120.
COPD: Severity of Chronic Disease
Three components determine severity
Spirometry to assess degree of airflow limitation
Symptoms assessment (various tools)
Risk for exacerbations
2013 GOLD COPD Guidelines available at: www.goldcopd.org/Guidelines/guidelines-resources.html
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 8
COPD Classification Criteria
CHigh risk
Less symptoms
DHigh risk
More symptoms
ALow risk
Less symptoms
BLow risk
More symptoms
MMRC <2 MMRC ≥2CAT <10 CAT ≥10
Symptoms
Spi
rom
etric
Gra
de
1
2
3
4
0
1
≥
2
Exa
cerb
atio
ns p
er Y
ear
Risk Risk
MMRC = Modified Medical Research Council Dyspnea ScaleCAT = COPD Assessment Test
GOLD Guidelines 2013. http://www.goldcopd.org/Guidelines/guidelines-resources.html
MMRC Questionnaire: Breathlessness Self-Assessment
Severity Score Level of Breathlessness
None 0 Only breathlessness with strenuous exercise
Mild 1 Short of breath hurrying or walking up a slight hill
Moderate 2 Walks slower than age group or has to stop for breath when walking on the level at own pace
Severe 3 Stops for breath after walking 100 meters or a few minutes on the level
Very Severe 4 Breathless when dressing/undressing or too breathless to leave the house
MMRC patient questionnaire available at http://copd.about.com
COPD Assessment Test Eight questions; 5-point scale (0 = least severe; 5 = most severe)
Cough Phlegm (mucus) Chest tightness Breathless walking up a hill or one flight of stairs Activity limitations Confident to leave home Sleep Energy
Assessment Minimum score: 0 Maximum score: 40
COPD Assessment Test available at: http://www.catestonline.org
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 9
COPD Classification Criteria
CHigh risk
Less symptoms
DHigh risk
More symptoms
ALow risk
Less symptoms
BLow risk
More symptoms
MMRC <2 MMRC ≥2CAT <10 CAT ≥10
Symptoms
Spi
rom
etric
Gra
de
1
2
3
4
0
1
≥
2
Exa
cerb
atio
ns p
er Y
ear
Risk Risk
MMRC = Modified Medical Research Council Dyspnea ScaleCAT = COPD Assessment Test
GOLD Guidelines 2013. http://www.goldcopd.org/Guidelines/guidelines-resources.html
Treatment Goals for Stable COPD
Reduce Symptoms
Relieve symptoms
Improve exercise tolerance
Improve overall health status
Reduce Risks
Prevent disease progression
Prevent and treat exacerbations
Reduce mortality
Prevent and treat complications
Minimize adverse effects
2013 GOLD COPD Guidelines available at: www.goldcopd.org
Pharmacotherapy Recommendations for COPDPatient Group (Classification)
Recommended 1st Choices Alternative Choices Other Options
A • Short-acting anticholinergic PRN• Short-acting β2-agonist PRN
• Long-acting anticholinergic• Long-acting β2-agonist • Short-acting β2-agonist and short-
acting anticholinergic in combo
• Theophylline
B • Long-acting anticholinergic• Long-acting β2-agonist
• Long-acting anticholinergicplus
Long-acting β2-agonist
• Short-acting anticholinergic PRN• Short-acting β2-agonist PRN• Combo of two above• Theophylline
C • Inhaled corticosteroid plus long-acting β2-agonist
• Long-acting anticholinergic
• Long-acting anticholinergicplus
Long-acting β2-agonist
• Either of the above agents with phosphodiesterase-4 inhibitor
• Short-acting anticholinergic PRN• Short-acting β2-agonist PRN• Combo of two above• Theophylline
D • Inhaled corticosteroid plus long-acting β2-agonist
• Long-acting anticholinergic• Combo of both above
• Inhaled corticosteroid plus long-acting β2-agonist and long-acting anticholinergic
• Inhaled corticosteroid plus long-acting β2-agonist and phosphodiesterase-4 inhibitor
• Long-acting anticholinergic and long-acting β2-agonist
• Long-acting anticholinergic plus phosphodiesterase-4 inhibitor
• Short-acting β2-agonist• Short-acting anticholinergic• Combo of two above• Carbocysteine• Theophylline
GOLD Guidelines 2013. http://www.goldcopd.org/Guidelines/guidelines-resources.html
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 10
Pharmacotherapy for COPD
Primary medications for chronic COPD treatment work as: Bronchodilators By relaxing bronchial smooth muscle that
surrounds the airways
Anti-inflammatories By suppressing inflammatory cells and
mediators
Autonomic Physiology of the Airways
Cholinergic innervation of bronchial smooth muscle is a major determinant of bronchomotor tone Muscarinic (M3) receptors are present on bronchial smooth
muscle in large and, to a lesser extent, small airways
There is minimal direct adrenergic innervation of bronchial smooth muscle Beta2 (β2) adrenergic receptors are present on bronchial
smooth muscle in large and small airways as well as on selected target cells (e.g., mast cells)
Barnes PJ. Proc Am Thorac Soc. 2004;1:345‒51. Barnes PJ. Postgrad Med J. 1989;65:532‒42.
Bronchomotor Tone Is Increased in COPD
ACh
ACh
Normal Bronchiole
Bronchiole in COPD
Anticholinergic Agent
Anticholinergic Agent
Vagal Nerve
Vagal Nerve
Brusasco V. Reducing cholinergic constriction: the major reversible mechanism in COPD. Eur Respir Rev 2006;15 (99): 32-36.
Restrepo RD. Use of Inhaled Anticholinergic Agents in Obstructive Airway Disease Respir Care 2007;52(7):833–851.
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 11
Bronchodilators for COPD
Bronchodilators are the primary therapies used in the management of COPD
Act by relaxing bronchial smooth muscle and increasing the diameter of the airway lumen
Effect can be achieved by activating β2-adrenergic receptors or inhibiting M3 receptors on bronchial smooth muscle
β2-Adrenergic AgonistsMechanism of Action
AdenylCyclase
cAMP
Beta2 AgonistBeta2
Receptor
G Protein (Alpha S)
Increases
Bronchial Smooth Muscle Relaxation and Bronchodilation
Barisione G, Baroffio M, Crimi E, Brusasco V. Beta-adrenergic agents. Pharmaceuticals 2010, 3, 1016-1044.
Ohar JA, Donohue JF. Mono- and Combination Therapy of Long-acting Bronchodilators and Inhaled Corticosteroids in Advanced COPD. Semin RespirCrit Care Med. 2010;31(3):321-333.
β2-Adrenergic Agonists
Short-acting agents Albuterol Levalbuterol Pirbuterol
Long-acting agents (based on longer residence time at the β2-adrenergic receptor) Arformoterol Formoterol Indacaterol Salmeterol
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 12
Anticholinergics Mechanism of Action
Vagal Nerve Terminal
Acetylcholine
M2 Receptor (Inhibitory)
M3 Receptor (Stimulatory)
Bronchial Smooth Muscle
Results in
Bronchoconstriction
Blocked by Anticholinergics
Belmonte KE. Cholinergic Pathways in the Lungs and Anticholinergic Therapy for Chronic Obstructive Pulmonary Disease. Proc Am Thorac Soc 2005; 2: 297–304.Briggs DD Jr, Doherty DE. Long-term pharmacologic management of patients with chronic obstructive pulmonary disease. Clin Cornerstone 2004; Suppl 2: S17–28.
Anticholinergic Agents
Short-acting agent Ipratropium
Long-acting agents (based on longer residence time at muscarinic receptor and improved selectivity for M3 receptor) Aclidinium
Tiotropium
Anticholinergic Agents
Side effects are also related to muscarinic-blocking actions Dry mouth
Blurred vision (not common but possible)
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 13
FRC
TV
IRV
RV
Normal
Rest
Mechanism for Bronchodilators Relieving Dyspnea in COPD
Rest
COPD
Exercise
Exercise
O’Donnell DE. Chest. 2000;117(2 suppl):42S‒7S.
Long-Acting Bronchodilators:β2-Agonists and Anticholinergics
For patients with chronic symptoms and/or frequent use of short-acting bronchodilators, these agents: Are more effective at relieving symptoms and
improving lung function
Are more convenient to use
Reduce exacerbation frequency
Choosing a Long-Acting Bronchodilator
Expert guidelines do not favor one class over the other
Long-acting β2-agonists Salmeterol, formoterol, arformoterol, indacaterol
Long-acting anticholinergic agents Tiotropium, aclidinium
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 14
Corticosteroids Mechanism of Action
Corticosteroid Molecule Cell Wall
Cytoplasm
Chaperone
Nucleus
+GRETransactivation
- GRETransrepression
Increased anti-inflammatory mediators
Reduced inflammatory mediators
Newton R, Holden NS. Separating transrepression and transactivation: A distressing divorce for the glucocorticoid receptor? Molecular Pharmacol 2007;72(4): 799-809.
Corticosteroid Agents
Beclomethasone
Budesonide
Ciclesonide
Fluticasone (various salts)
Mometasone
Corticosteroid Agents
Inhaled agents indicated for chronic use in COPD
Best evidence for Grades 3 and 4 as well as for patients with frequent exacerbations
Increased risk of respiratory infections in patients with COPD
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 15
Phosphodiesterase-4 InhibitorsMechanism of Action
PDE4 Inhibitors
Mast Cell
T cell
Macrophage
Neutrophil
Eosinophil
Inflammatory Cells
Airway Smooth Muscle
Structural Changes
Epithelial Cell
NerveWang D, Cui X. Evaluation of PDE4 inhibition for COPD. Int J Chron Obstruct Pulmon Dis 2006 (Dec); 1(4): 373-379.Price D, Chisholm A, Ryan D, Crockett A, Jones R. The use of roflumilast in COPD: a primary care perspective. Primary Care Respiratory Journal 2010;19 (4): 342-351.
Phosphodiesterase-4 Inhibitors
Roflumilast Oral therapy indicated for patients with chronic
bronchitis who experience frequent exacerbations
Most common side effect is nausea/vomiting
May be associated with excessive weight loss or personality changes
Combination Inhalers for COPD
Albuterol and ipratropium
Budesonide and formoterol
Fluticasone propionate and salmeterol
Fluticasone furoate and vilanterol
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 16
COPD Classification Criteria
CHigh risk
Less symptoms
DHigh risk
More symptoms
ALow risk
Less symptoms
BLow risk
More symptoms
MMRC <2 MMRC ≥2CAT <10 CAT ≥10
Symptoms
Spi
rom
etric
Gra
de
1
2
3
4
0
1
≥
2
Exa
cerb
atio
ns p
er Y
ear
Risk Risk
MMRC = Modified Medical Research Council Dyspnea ScaleCAT = COPD Assessment Test
GOLD Guidelines 2013. http://www.goldcopd.org/Guidelines/guidelines-resources.html
Pharmacotherapy Recommendations for COPDPatient Group (Classification)
Recommended 1st Choices Alternative Choices Other Options
A • Short-acting anticholinergic PRN• Short-acting β2-agonist PRN
• Long-acting anticholinergic• Long-acting β2-agonist • Short-acting β2-agonist and short-
acting anticholinergic in combo
• Theophylline
B • Long-acting anticholinergic• Long-acting β2-agonist
• Long-acting anticholinergicplus
Long-acting β2-agonist
• Short-acting anticholinergic PRN• Short-acting β2-agonist PRN• Combo of two above• Theophylline
C • Inhaled corticosteroid plus long-acting β2-agonist
• Long-acting anticholinergic
• Long-acting anticholinergicplus
Long-acting β2-agonist
• Either of the above agents with phosphodiesterase-4 inhibitor
• Short-acting anticholinergic PRN• Short-acting β2-agonist PRN• Combo of two above• Theophylline
D • Inhaled corticosteroid plus long-acting β2-agonist
• Long-acting anticholinergic• Combo of both above
• Inhaled corticosteroid plus long-acting β2-agonist and long-acting anticholinergic
• Inhaled corticosteroid plus long-acting β2-agonist and phosphodiesterase-4 inhibitor
• Long-acting anticholinergic and long-acting β2-agonist
• Long-acting anticholinergic plus phosphodiesterase-4 inhibitor
• Short-acting β2-agonist• Short-acting anticholinergic• Combo of two above• Carbocysteine• Theophylline
GOLD Guidelines 2013. http://www.goldcopd.org/Guidelines/guidelines-resources.html
Pharmacists’ Role in Optimizing Outcomes for Patients With COPD
Identify patients with risk factors
Encourage (and consider performing) spirometry testing
Assist patients with smoking cessation
Provided vaccines to protect against influenza and pneumococcal disease
Collaborate with other clinicians to determine optimal pharmacotherapy regimens
Explain the rationale for various medications
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 17
Assisting Patients With COPD Medication Use
Educate patient regarding the role and proper use of each therapy
Assess safety and effectiveness of medication regimen
Monitor for drug interactions
Periodically assess patient understanding, adherence, and ability to use inhalation therapies
Provide care and services for all stages of COPD
Question 1
The increase in vagal tone that is observed in patients with COPD results in:
a. Increased airway diameterb. Decreased airway diameterc. Increased mucus productiond. Decreased mucus production
Question 2
The effectiveness of tiotropium as a bronchodilator is based on the:
a. Selective binding and inhibition at the M3 receptor in the airway
b. Binding and inhibition of all muscarinic receptors in the airways
c. Selective binding and activation of the M2 receptor in the airway
d. Activation of adrenergic receptors in the airways
Understanding COPD Pathophysiology and the Rationale for Use of Different Therapeutic Agents© 2013 American Pharmacists Association 18
Question 3
The most important determinant of the effectiveness of medications for COPD delivered via inhalation is the:
a. Bioavailability from the lungb. pH of the inhaled moleculec. Technique of inhalationd. Patient age
How to Obtain CPE Credit Record Attendance Code: QRTB
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