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

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