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The following common respiratory disorders are discussed within this module:

• Asthma
  Chronic obstructive pulmonary disease
  Pulmonary hypertension

ASTHMA

Overview

Pulmonary disorders, including asthma, chronic obstructive pulmonary disease (COPD), and pulmonary arterial hypertension (PAH), are major public health concerns and affect a large number of patients in the U.S.^1-4 These disorders may have a considerable negative impact on patients' quality of life and carry a substantial burden on healthcare resources. Because of their chronic nature, pulmonary disorders often require life-long treatment with respiratory pharmacotherapy.

Asthma is one of the most common chronic diseases in the U.S.¹ Asthma prevalence increased from 20.3 to 25.7 million people between 2001 and 2010.² In 2014, 7.7% of the U.S. population had asthma. ⁵ Children, especially boys, are particularly susceptible, comprising approximately 26% of all U.S. patients with asthma. ^2-5 Asthma accounted for 1.8 million emergency department (ED) visits and 440,000 hospitalizations in 2010. The estimated national medical cost of asthma in 2007 was $14.7 billion. A disproportionate share of ethnic minorities is affected by asthma.³ The likelihood of hospitalization or death from asthma is approximately 3 times greater in African Americans compared with whites, and minorities living in urban areas have 4 times the risk of ED admission as whites.

The etiology of asthma is multifactorial, including genetic and environmental risk factors.⁶ These may include endogenous factors such as gender, ethnicity, and genetic predisposition as well as environmental factors such as allergens, occupational exposures, family size, urbanization, and exercise (e.g., exercise-induced bronchospasm [EIB]).

Pathophysiologic changes in asthma are rooted in inflammation, which leads to airflow obstruction and bronchial hyperreactivity to allergens and other stimuli.^3,6,7 The early phase of acute inflammation includes activation of local inflammatory mediators, including mast cells and eosinophils. Release of leukotrienes, histamine, and prostaglandins promotes contraction of smooth muscle, mucus secretion, and vasodilation, leading to airway narrowing that is characteristic of asthma. There is a continuous process of ongoing inflammation and repair in asthma.³ This leads to airway remodeling, which may be irreversible or may respond to early use of inhaled corticosteroids (ICS).⁶ 

Clinical presentation of asthma is comprised of characteristic intermittent symptoms of dyspnea, wheezing, coughing (particularly at night), and chest tightness.³ Clinical signs include wheezing on auscultation, tachypnea, other signs of atopy (e.g., allergic rhinitis), and compromised measures of spirometry.^4,7

The diagnosis of asthma is described by the National Asthma Education and Prevention Program (NAEPP) Expert Panel Report (EPR). ⁷ Diagnosis is confirmed by airflow limitation as demonstrated by spirometric testing, at least partly reversible airflow obstruction, and exclusion of other causes.^3,7 Physical examination should identify symptoms of asthma and spirometric testing should indicate reduced values for forced expiratory volume in 1 second (FEV₁) and FEV₁/forced vital capacity (FVC) relative to predicted values. Other pulmonary disorders should be ruled out, including allergic rhinitis and chronic obstructive pulmonary disease (COPD). ^3,7

A crucial step in appropriate asthma management is classification of disease severity. ^3,7  The NAEPP EPR provides a classification scheme for asthma severity based on domains of impairment and risk (Table 1). Classification differs for patients in distinct age groups, including those aged 0 to 4, 5 to 11, and ≥12 years.

Table 1. Classification of Asthma Severity7
Components of severity		Age group (yrs)	Classification of Asthma severity
			Intermittent	Persistent
				Mild	Moderate	Severe
Impairment Normal FEV1/FVC by age groups: 8-19 years: 85% 20-39 years: 80% 40-59 years: 75% 60-80 years: 70%	Symptoms	All ages	≤2 days weekly	>2 days weekly but not daily	Daily	Throughout the day
	Nighttime awakenings	0-4	0	1-2 times monthly	3-4 times monthly	>1 time weekly
		≥5	≤2 times monthly	3-4 times monthly	>1 time weekly but not nightly	Often nightly
	Frequency of SABA use (not including EIB prevention)	All ages	≤2 days weekly	>2 days weekly but not daily	Daily	Throughout the day
	Interference with normal activity	All ages	None	Minor limitation	Some limitation	Extremely limited
	Lung function	5-11	Normal FEV1 between exacerbations FEV1 >80% predicted FEV1/FVC >85%	FEV1 >80% predicted FEV1/FVC >80%	FEV1=60-80% predicted FEV1/FVC 75-80%	FEV1 <60% predicted FEV1/FVC <75%
		≥12	Normal FEV1 between exacerbations FEV1 >80% predicted FEV1/FVC normal	FEV1 ≥80% predicted FEV1/FVC >80%	FEV1=60-80% predicted FEV1/FVC normal	FEV1 <60% predicted FEV1/FVC reduced >5%
Risk	Exacerbations requiring oral systemic corticosteroids	0-4	0-1 times yearly	≥2 exacerbations in 6 months, or ≥4 wheezing episodes yearly lasting >1 day AND risk factors for persistent asthma
		≥5	0-1 times yearly	≥2 yearly
EIB = exercise-induced bronchospasm; FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; SABA = short-acting beta-agonist.

Treatment

The goals of asthma therapy are to reduce symptom-related impairment and risk for disease progression. ⁷ Uncontrolled asthma leads to impaired quality of life, increased disease burden, and greater use of healthcare resources. The NAEPP EPR defines reduced impairment as the prevention of bothersome symptoms, infrequent use of short-acting beta-agonists (SABAs) on ≤2 days weekly, maintenance of normal pulmonary function and activity, and the fulfillment of patients' or caregivers' goals for disease management. Reduction of risk includes preventing recurrent exacerbations and ED visits, minimizing deterioration in lung function, and providing pharmacotherapy that balances therapeutic effects and adverse events.

Patients should be counseled to recognize and avoid environmental triggers and airway irritants to which they are susceptible.³ Triggers may include tobacco smoke, pollution, and allergens. Household allergens may be avoided by using dust-proof linens or removing carpet; evidence is limited for the benefits of air filtration systems.

The NAEPP EPR presents an individualized, step-wise treatment approach modeled around therapy intensification until asthma is controlled and, when possible, therapy de-escalation to minimize adverse drug events. ^7,8 Table 2 presents recommendations for initial therapy based on asthma severity and Table 3 presents recommendations for therapy adjustment based on asthma control. ⁷  Adherence to the pharmacotherapeutic regimen may improve outcomes and should be encouraged. This can be done through open patient communication that addresses their concerns, goals, perception of disease, social support, levels of stress, and specific barriers to adherence. ⁷

Table 2. Recommendations for Initial Management of Chronic Asthma7
Age (yrs)	Step 1	Step 2	Step 3	Step 4	Step 5	Step 6
	Intermittent asthma	Daily medication for persistent asthmaa
0-4	SABA as needed	Preferred: Low-dose ICS Alternative: cromolyn, montelukast	Medium-dose ICS	Medium-dose ICS + One of: LABA, montelukast	High-dose ICS + One of: LABA, montelukast	High-dose ICS + One of: LABA, montelukast + Oral corticosteroids
5-11	SABA as needed	Preferred: Low-dose ICS Alternative: cromolyn, LTRA, montelukast, theophylline	Medium-dose ICS or Low-dose ICS + One of: LABA, LTRA, theophylline	Medium-dose ICS + LABA Alternative: medium-dose ICS + One of: LTRA, theophylline	High-dose ICS + LABA Alternative: High-dose ICS + One of: LTRA, theophylline	High-dose ICS + LABA + Oral corticosteroids Alternative: High-dose ICS + One of: LTRA, theophylline + Oral corticosteroids
≥12	SABA as needed	Low-dose ICS Alternative: cromolyn, LTRA,  theophylline	Low-dose ICS + One of: LABA or Medium-dose ICS Alternative: Low-dose ICS + LTRA, theophylline, zileuton	Medium-dose ICS + LABA Alternative: Medium-dose ICS + One of: LTRA, theophylline, zileuton	High-dose ICS + LABAa	High-dose ICS + LABA + Oral corticosteroidsa
aConsider omalizumab for patients sensitive to perennial allergens. ICS = inhaled corticosteroid; LABA = long-acting beta agonist; LTRA = leukotriene receptor antagonist; SABA = short-acting beta agonist.

Table 3. Assessing Asthma Control and Adjusting Therapy7
Components of control		Age group (years)	Classification of asthma control
			Well controlled	Not well controlled	Very poorly controlled
Impairment	Symptoms	0-4	≤2 days weekly	>2 days weekly	Throughout the day
		5-11	≤2 days weekly	>2 days weekly or multiple times on ≥2 days weekly	Throughout the day
		≥12	≤2 days weekly	>2 days weekly	Throughout the day
	Nighttime awakenings	0-4	≤1 time monthly	>1 time monthly	>1 time weekly
		5-11	≤1 time monthly	≥2 times monthly	≥2 times weekly
		≥12	≤2 times monthly	1 to 3 times weekly	≥4 times weekly
	Interference with normal activity	All ages	None	Some limitation	Extremely limited
	Frequency of SABA use (not including EIB prevention)	All ages	≤2 days weekly	>2 days weekly	Several times daily
	Lung function	5-11	FEV1 >80% predicted/personal best or FEV1/FVC >80%	FEV1 60-80% predicted/personal best or FEV1/FVC 75-80%	FEV1 <60% predicted/personal best or FEV1/FVC <75%
		≥12	FEV1 or PF >80% predicted/personal best	FEV1 60-80% predicted/personal best	FEV1 or PF <60% predicted/personal best
	Questionnaire scores	≥12	ATAQ 0 ACQ ≤0.75 ACT ≥20	ATAQ 1-2 ACQ ≥1.5 ACT 16-19	ATAQ 3-4 ACQ N/A ACT ≤15
Risk	Exacerbations requiring oral systemic corticosteroids	0-4	0-1 yearly	2-3 yearly	>3 yearly
		≥5	0-1 yearly	≥2 yearly
Recommended action		≥5	Maintain current therapy, consider step down after 3 months	Step up 1 step, reevaluate in 2 to 6 weeks	Consider oral corticosteroids, step up 1 to 2 steps, reevaluate in 2 weeks
ACQ = asthma control questionnaire; ACT = asthma control test; ATAQ = asthma therapy assessment questionnaire; EIB = exercise-induced bronchoconstriction; FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; PF = peak flow; SABA = short-acting beta-agonist.

Asthma pharmacotherapy includes short-acting bronchodilators for rapid reversal of acute airflow obstruction and long-acting bronchodilators that maintain disease control (Table 4). ⁷ All patients should receive a SABA (e.g., albuterol, levalbuterol, or pirbuterol) as rescue therapy for severe symptoms. These may also be used episodically to prevent exercise-induced bronchospasm (EIB).^9-11

Table 4. Inhaled Drug Products Used in Management of Asthma and Stable COPD3,10-18
Class	Drug product (brand)	FDA-approved disease states	Administration frequency
Short-acting bronchodilators
SABAs	Albuterol (ProAir HFA, ProAir Respiclick, Proventil HFA, Ventolin HFA)	Asthma, COPD	4x daily or as needed
	Levalbuterol (Xopenex HFA)	Asthma, COPD	4x daily or as needed
	Pirbuterol (Maxair Autohaler)	Asthma, COPD	4x daily or as needed
Anticholinergic	Ipratropium (Atrovent HFA)	COPD	4x daily or as needed
Combination SABA/anticholinergic	Albuterol/ipratropium (Combivent, Combivent Respimat)	COPD	4x daily or as needed
Long-acting bronchodilators
LABAs	Formoterol (Foradil Aerolizer)	Asthma, COPD	2x daily
	Indacaterol (Arcapta Neohaler)	COPD	1x daily
	Salmeterol (Serevent Diskus)	Asthma, COPD	2x daily
	Olodaterol (Striverdi Respimat)	COPD	1x daily
LAMAs	Aclidinium (Tudorza Pressair)	COPD	2x daily
	Tiotropium (Spiriva, Spiriva Respimat)	COPD	1x daily
	Umeclidinium (Incruse Ellipta)	COPD	1x daily
Combination LABA/LAMA	Vilanterol/Umeclidinium (Anoro Ellipta)	COPD	1x daily
	Olodaterol/Tiotropium (Stiolto Respimat)	COPD	1x daily
Inhaled corticosteroids
ICSs	Beclomethasone (QVAR)	Asthma	2x daily
	Budesonide (Pulmicort)	Asthma	2x daily
	Ciclesonide (Alvesco)	Asthma	2x daily
	Flunisolide  (Aerospan)	Asthma	2x daily
	Fluticasone propionate (Flovent)	Asthma	2x daily
	Mometasone furoate (Asmanex)	Asthma	1 to 2x daily
Combination LABA/ICS	Formoterol/budesonide  (Symbicort)	Asthma, COPD	2x daily
	Salmeterol/fluticasone propionate  (Advair Diskus, Advair HFA)	Asthma, COPD	2x daily
	Vilanterol/fluticasone furoate  (Breo Ellipta)	COPD	1x daily
COPD = chronic obstructive pulmonary disease; FDA = Food and Drug Administration; HFA = hydrofluoroalkane; ICS = inhaled corticosteroid; LABA = long-acting beta agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting beta agonist.

As asthma severity increases, patients may step up to a higher intensity of therapy and introduce long-term controller medications (Table 4). ⁷ Inhaled corticosteroids (ICS) are the principal therapy in patients who step up to treatment of persistent asthma. This drug class has the largest effect in the maintenance of asthma control by suppressing pathologic airway inflammation. A variety of ICSs are now available (Tables 4 and 5).

Table 5. Inhaled Corticosteroid Daily Dosage Levels3
Inhaled corticosteroid drug and administration device	Age groupa	Low daily dose (mcg)	Medium daily dose (mcg)	High daily dose (mcg)
Beclomethasone dipropionate HFA MDI	Children	80-160	160-320	>320
	Adults	80-240	240-480	>480
Budesonide DPI	Children	180-360	360-720	>720
	Adults	180-540	540-1080	>1080
Budesonide nebules	Children	500	1000	2000
Ciclesonide MDI	Children	80-160	160-320	>320
	Adults	160-320	320-640	>640
Flunisolide HFA MDI	Children	160	160-320	>320
	Adults	320	320-640	>640
Fluticasone propionate HFA MDI	Children	88-176	176-352	>352
	Adults	88-264	264-440	>440
Fluticasone propionate DPI	Children	100-200	200-400	>400
	Adults	100-300	300-500	>500
Mometasone furoate DPI	Children	110	220-440	>440
	Adults	220	440	>440
aIndicated ages for children vary based on product; consult individual package inserts. CFC = chlorofluorocarbon; DPI = dry powder inhaler; HFA = hydrofluoroalkane; MDI = metered dose inhaler.

Patients uncontrolled with ICS monotherapy may benefit from addition of a long-acting beta-agonist (LABA), which is the preferred therapy among adjunctive agents added to ICSs. ⁷ The use of LABA-ICS dual therapy has shown greater efficacy compared with increased ICS dose; dual therapy may also avoid increased ICS exposure and risk for related adverse events.^19,20 Importantly, use of LABAs without an ICS is contraindicated, as this results in unsuppressed airway inflammation, high rates of asthma exacerbations, and a potentially increased risk of asthma-related death.²¹ Alternative agents may be utilized in patients with asthma of varying severity (Table 2). ⁷ The leukotriene receptor antagonists (LTRAs) montelukast and zafirlukast prevent asthma induced by environmental exposures.^8,9 Cromolyn sodium is another alternative, though it has not shown consistent benefit versus placebo in clinical trials. Its main advantage is a favorable safety profile; however, clinical response may take up to 4 to 6 weeks. ⁷  Theophylline use has waned due to its narrow therapeutic index, drug interactions, and monitoring requirements.³ Any use of theophylline should utilize the sustained-release product and target serum concentrations of 5 to 15 mcg/mL. ⁷ Omalizumab, a biologic immunomodulator, is indicated for patients aged 12 years and older with moderate to severe persistent asthma who have inadequate response or contraindications to ICSs; similarly, mepolizumab and reslizumab are indicated as add-on therapy in patients with severe asthma of an eosinophilic phenotype. ^7,22-24 However, high costs and injectable administration are barriers to use of these biologic agents. Alternative agents that are approved by the U.S. Food and Drug Administration for EIB prevention include montelukast and cromolyn sodium. ⁷

Patients with intermittent asthma may need only a SABA.⁷ Prior to stepping up therapy, the influence of medication adherence, inhaler technique, and environmental factors on symptom control should be considered. Patients with asthma controlled for at least 3 months should be considered for therapy step-down; however, this should be done carefully because recent data have not fully defined the benefit of therapy step-down. ²⁵ Patients uncontrolled on step 5 therapy may require chronic oral corticosteroids to achieve asthma control. ⁷ These patients should receive the lowest possible dose and be monitored frequently for adverse events and potential dose reduction or corticosteroid discontinuation. Consultation with an asthma specialist is generally recommended for patients with serious exacerbations or hospitalization, those who require long-term oral corticosteroid treatment, or patients aged 0 to 4 and ≥5 years who step up to level 3 or 4, respectively.

An additional consideration in chronic asthma management includes vaccination. ⁷ The NAEPP EPR recommends that clinicians consider inactivated influenza vaccination for patients with asthma due to their increased susceptibility to influenza complications. The vaccine is safe for children 6 months and older and adults. Other vaccinations, such as pneumococcal vaccine, may be warranted based on the patient's age and type of asthma controller therapy.⁸

Acute Exacerbations of Asthma

Acute asthma exacerbations should be immediately treated with a SABA and, depending on the severity of the episode, systemic corticosteroids, ipratropium, and inhaled oxygen. ^3,7 Two treatments of 2 to 6 puffs of a SABA may be administered 20 minutes apart, with an assessment of response after 30 minutes. Patients whose wheezing and dyspnea persist or worsen should seek urgent care. The use of LABAs in acute exacerbations is not recommended. Strategies to prevent acute asthma exacerbations include asthma action plans that patients may initiate as dictated by symptoms or peak expiratory flow rate (PEFR) monitoring.

Monitoring Parameters

Monitoring of outcomes in asthma is related to the severity of disease, extent of symptom control, and responsiveness of symptoms to therapy. ⁷ Severity and control can be evaluated using questionnaires developed to standardize the assessment and grading of therapeutic outcomes. These include the Asthma Control Questionnaire (ACQ), Asthma Therapy Assessment Questionnaire (ATAQ), and the Asthma Control Test (ACT), which gauge the severity of symptoms, rescue medication use, and loss of daily activity.^26-31 While all are validated and quantify asthma control, pharmacists and APRNs may prefer certain tests based on their target population and available information. For example, pulmonary function test results, which may not be available at all clinics, are incorporated into ACQ scores, whereas a version of the ACT is available for children.^26-32

Patient questionnaires may not be reliable in adult patients who poorly perceive or report symptoms; this may occur in patients who are elderly, obese, or who have adapted to asthma symptoms.^7,32 These patients should be monitored using objective spirometric assessments Measures of FEV₁ and FEV₁/FVC are compared to values predicted for patients of various ages and heights. Increases in FEV₁ of 12% or greater are generally considered indicative of treatment effectiveness. ⁷

The NAEPP EPR generally recommends follow-up every 3 months for patients with intermittent or mild persistent asthma that has been controlled for at least 3 months, while those with uncontrolled or severe asthma should be monitored more often. ⁷ Spirometry should be performed at the time of diagnosis, after treatment initiation and lung function stabilization, and during periods of worsening control.

The NAEPP EPR recommends the development of written asthma action plans for all patients, particularly those with moderate to severe persistent asthma. ⁷ Action plans instruct patients on how to recognize asthma symptoms and adjust medications accordingly.  Action plans should incorporate peak expiratory flow rate measurements to determine if response to treatment is adequate and if there is a need to seek immediate care. Action plans for patients with moderate or severe persistent asthma or who have a history of exacerbations may incorporate patient-initiated corticosteroids for home treatment of exacerbations to avoid ED visits or hospitalization.

Adverse events related to SABAs and LABAs are predominantly sympathomimetic in nature, including chest pain, palpitations, and tremor.³³ Adverse events related to LABAs include asthma-related death, as described above; these agents should be used for the shortest duration possible and discontinued when asthma is controlled.^3,34 Systemic effects of ICSs at normal doses are rare, as approximately 20% of the inhaled dose is delivered to the lungs, and swallowed drug is inactivated by first-pass hepatic metabolism.⁸ The long-term risk of meaningful adverse outcomes with low- to medium-dose ICS is minimal. High ICS doses may cause bruising, elevated intraocular pressure, or loss of bone mass. Growth retardation is a theoretical, though mostly inconsequential, ICS-related adverse outcome; growth decreases by 1 cm during the first year of treatment but nearly all children ultimately reach normal height.^35,36 Other ICS-related adverse events include cough, sore throat, and hoarseness; incidence may vary with individual ICSs.⁸ Candidiasis may occur, the risk of which may be mitigated by rinsing the mouth after ICS administration or using a valved holding chamber (VHC) for ICSs administered via MDI. Cromolyn sodium and LTRAs are considered extremely safe, with low potential for adverse events.

Numerous drug interactions exist between theophylline, a cytochrome P450 (CYP) 1A2 substrate, and drugs that alter function of CYP isoenzymes 1A2, 2E1, and 3A4.^3,8,9 As a class, drug interactions are few among ICSs, though levels of budesonide, fluticasone, and mometasone may be increased by strong 3A4 inhibitors.⁹ Concomitant use of LABAs with sympathomimetics may precipitate cardiovascular adverse events; similarly, coadministration of drugs that prolong the QT interval may increase risk for arrhythmia. Salmeterol levels may be increased by strong 3A4 inhibitors.  A theoretical concern exists that the effectiveness of SABAs may be decreased in patients receiving beta blockers, but coadministration is not contraindicated.⁸ No known interactions exist for cromolyn.⁹

Inhaler technique is of paramount importance in optimizing drug efficacy.^3,37 Dry powder inhalers are breath-actuated and require a minimum inspiratory flow to aerosolize the drug; these may not be optimal for patients with difficulty inhaling. Dry powder inhalers should be primed according to manufacturer's instructions prior to the patient exhaling completely, forming a tight seal around the mouthpiece, inhaling rapidly, holding breath for 10 seconds, and exhaling slowly. Pressurized MDIs eject aerosol; thus, coordination between actuation and inhalation is important. Generally, patients should shake the inhaler, exhale completely, form a tight seal around the mouthpiece, inhale upon actuation, hold their breath for 10 seconds, and then exhale slowly. Patients with difficulty coordinating these actions may benefit from using spacers or VHCs to decrease the velocity of the aerosol prior to inhalation. Spacers allow for slower inhalation, while VHCs allow for multiple inhalations due to a one-way valve. Clinicians should confirm initially and periodically that patients use appropriate technique. Both spacers and VHCs should be washed every 1 to 2 weeks with water and dilute detergent and air-dried; towel-drying may cause static and lead to drug deposition and decreased delivery. Both devices require prescriptions. Proper technique may be ensured by having patients demonstrate or describe their inhaler technique to the pharmacist.

Patient Case #1: JN is a 19-year-old female diagnosed 3 months ago with asthma of intermittent severity who enters your clinic today to establish care. She complains of recent nighttime awakenings at least 3 times monthly and reports the need to use her rescue inhaler several times weekly, not including use to prevent EIB prior to her daily exercise sessions. She experiences minor limitation in her activity on her high school volleyball team. Current medications: Albuterol HFA inhaler 1 puff every 4 to 6 hours as needed for asthma Ethinyl estradiol/drospirenone 0.02/3 mg 1 tablet daily for moderate acne vulgaris and contraception Ibuprofen 400 mg every 4 to 6 hours as needed for pain What is JN's current classification of asthma? JN's symptoms place her in the moderate persistent classification (Table 1). What step of therapy is JN currently receiving? The receipt of a SABA as needed constitutes Step 1 therapy (Table 2). What is the most appropriate change to JN's asthma regimen? JN's asthma is not well controlled (Table 3). Appropriate management would constitute stepping up to the next level of asthma therapy, including the addition of a low-dose ICS (Tables 4 and 5). What pertinent information should be collected to establish a baseline from which to assess JN's future asthma control? JN's baseline information on asthma control should include medication adherence, inhaler technique, precipitating factors of asthma symptoms, current symptom score on a validated asthma symptom scoring test, and spirometric or PEFR data, if available. What is an appropriate time interval until JN's next follow-up visit with you? After the recommended action of stepping up therapy for JN's uncontrolled asthma, she should be reevaluated in 2 to 6 weeks (Table 3).

CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

Overview

The prevalence of chronic obstructive pulmonary disease (COPD) has increased in recent decades, particularly among elderly patients, and currently affects over 10 million Americans.^15,38-40 Chronic obstructive pulmonary disease ranks as the sixth leading cause of death in the U.S., and predictions estimate that COPD will rise to the third most common cause of death worldwide by 2020. It is the second leading cause of disability in the U.S., accounting for 15 million physician office and 1.5 million ED visits annually.

The etiology of COPD includes host and environmental factors, though the latter confer the majority of risk.¹⁵ Cigarette smoking accounts for up to 90% of all COPD cases; secondhand smoke exposure also increases risk. While not all smokers develop COPD, age at starting and pack-year history predict mortality. Environmental or occupational exposure to chemicals is also a risk factor. Hereditary deficiency of α₁-antitrypsin (AAT), an enzyme that protects lungs from destruction by elastase and neutrophils, can cause a rare form of COPD that occurs in less than 1% of all cases.

Pathophysiologic changes in COPD contribute to chronic inflammation and airflow limitation which, in contrast to asthma, is not fully reversible.¹⁵ An imbalance between destructive and protective processes in the lung may lead to progressive loss of elasticity.^15,39 Environmental exposure to noxious agents leads to lung inflammation, oxidative stress, and neutrophilic infiltration. These inflammatory processes lead to proteolytic degradation of the extracellular lung matrix and eventually scarring and fibrosis. The inability to effectively repair this damage ultimately leads to decreased ciliary motility, increased mucus production, and thoracic hyperinflation.

Hallmark symptoms of COPD include cough, sputum production, and dyspnea on exertion.^15,39,40 Signs of COPD include the characteristic "barrel chest" caused by thoracic hyperinflation and decreased ability to contract the diaphragm. Patients may sit in a "tripod" position to facilitate recruitment of accessory muscles to improve inspiratory flow.³⁹ Cyanosis may occur in the lips and nail beds. Advanced disease may be accompanied by weight loss and muscle wasting.

Diagnosis of COPD should be considered in patients exhibiting any of the hallmark symptoms.^40,41 Spirometry is required, as the presence of a post-bronchodilator FEV₁/FVC <70% confirms a diagnosis of COPD.

The 2016 guidelines from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classify the severity of airflow limitation in COPD based on post-bronchodilator FEV₁ (Table 6).⁴⁰ This spirometric classification is combined with other characteristics of disease that reflect dyspnea (modified British Medical Research Council [mMRC] scale) and overall well-being (COPD Assessment Test [CAT]) as well as risk of exacerbations to stratify patients and determine appropriate therapy (Table 7).^15,40 Patients should be categorized in the stage with criteria corresponding to the most severe combined assessment criteria.

Table 6. Classification of Severity of Airflow Limitation in COPD 40
Severity	GOLD 1 (Mild)	GOLD 2 (Moderate)	GOLD 3 (Severe)	GOLD 4 (Very severe)
Post-bronchodilator FEV1	≥80% predicted	50% to <80% predicted	30% to <50% predicted	<30% predicted
FEV1=forced expiratory volume in 1 second; GOLD = Global Initiative for Chronic Obstructive Lung Disease.

Treatment

Treatment goals in stable COPD address symptoms and risk.⁴⁰ Symptom relief and improvements in exercise tolerance and health state should be targeted. Symptoms can be improved by targeting exercise tolerance and health status. Risk reduction is achieved through preventing disease progression and exacerbations and reducing the risk for mortality. Appropriate treatment selection should be based on the patient group (Table 7), COPD assessment criteria, medication availability, and patient response.

Table 7. Patient Groups, Assessment Criteria, and Pharmacotherapy of Stable COPD40
Patient group	Combined COPD assessment criteria	First choicea	Alternative choicea	Other optionsa,b
A Few symptoms, low risk of exacerbations	GOLD 1-2 airflow limitation and/or ≤1 exacerbation per year with no hospitalization and CAT score <10 or mMRC grade 0-1	Short-acting anticholinergic as needed or SABA as needed	LAMA or LABA or SABA + short-acting anticholinergic	Theophylline
B More symptoms, low risk of exacerbations	GOLD 1-2 airflow limitation and/or ≤1 exacerbation per year with no hospitalization and CAT score ≥10 or mMRC grade ≥2	LAMA or LABA	LAMA + LABA	SABA +/or short-acting anticholinergic or Theophylline
C Few symptoms, high risk of exacerbations	GOLD 3-4 airflow limitation and/or ≥2 exacerbations per year or ≥1 with hospitalization and CAT score <10 or mMRC grade 0-1	ICS + LABA or LAMA	LAMA + LABA or LAMA + roflumilast or LABA + roflumilast	SABA +/or short-acting anticholinergic or Theophylline
D Many symptoms, high risk of exacerbations	GOLD 3-4 airflow limitation and/or ≥2 exacerbations per year or ≥1 with hospitalization and CAT score ≥10 or mMRC grade ≥2	ICS + LABA +/or LAMA	ICS + LABA + LAMA or ICS + LABA + roflumilast or LAMA + LABA or LAMA + roflumilast	Carbocysteine or SABA +/or short-acting anticholinergic or Theophylline
aNot in order of preference. bAlone or in combination with first or second choice. CAT = COPD Assessment Test; COPD=chronic obstructive pulmonary disease; ICS = inhaled corticosteroids; LABA = long-acting beta agonist; LAMA = long-acting muscarinic antagonist; mMRC = modified British Medical Research Council; SABA = short-acting beta agonist.

The most important determinant in preventing the onset and progression of COPD is smoking cessation, which is an essential non-pharmacologic management strategy.⁴⁰ Physical activity is recommended in all patients.¹⁵ In patients with more symptoms or at higher risk, pulmonary rehabilitation and long-term oxygen therapy may also improve quality of life, exercise capacity, and improve survival.

All COPD patients should receive a SABA as rescue therapy.^9,40 The core component of maintenance pharmacotherapy includes bronchodilators, which relax smooth muscle, providing reduced hyperinflation and improved activity tolerance; these benefits may be evident without objective spirometric improvements.¹⁵ Bronchodilators include inhaled LABAs and anticholinergics and oral theophylline; of these, the inhaled medications are preferred. Appropriate initial treatment includes short-acting anticholinergics or SABAs, which are generally equally effective (Table 4). Patients with symptoms that are chronic or unresponsive to short-acting bronchodilators may benefit from long-acting agents, which offer greater convenience. Long-acting beta agonists have shown improvements in spirometry readings, symptoms, quality of life, and exacerbation frequency compared with short-acting therapy.^15,42,43 Long-acting muscarinic antagonists (LAMAs) are an alternative option, which have shown clinical benefits similar to LABAs but without tolerance that occurs with long-term LABA therapy.⁴⁴ Some evidence indicates that tiotropium may be more effective than LABAs in reducing COPD exacerbations, but not hospitalizations or mortality.⁴⁵ Another recently approved drug is olodaterol, a LABA available alone (Striverdi Respimat) and in combination with tiotropium (Stiolto Respimat) in a metered-dose inhaler for maintenance treatment of COPD.^11,18

Although COPD pathophysiology involves inflammation, chronic ICS therapy should be avoided due to its poor risk-to-benefit profile in this population.^15,40 Use should be limited to patients with severe COPD and frequent exacerbations. The phosphodiesterase 4 (PDE4) inhibitor roflumilast, available as an oral tablet, is not a bronchodilator and should only be used to reduce exacerbations in patients with chronic bronchitis, a history of exacerbations, and severe to very severe COPD; it should always be used in combination with a long-acting bronchodilator once bronchodilator therapy has been maximized.⁴⁰ Patients with inherited AAT deficiency are treated with weekly infusions of replacement AAT preparations.¹⁵

Treatment of COPD exacerbations includes intensification of the dose and/or frequency of bronchodilator therapy and initiation of short-term oral corticosteroids.¹⁵ Prednisone 40 mg (or equivalent) for 10 to 14 days appears effective for most patients; those treated longer than 14 days should receive a dose taper to avoid adrenal suppression.  Antibiotic courses of 7 to 10 days may be appropriate for patients with all 3 of the following: increased sputum production, increased sputum purulence, or increased dyspnea; antibiotics may also be appropriate if any 2 of these are present so long as sputum purulence is increased. The most common pathogens are treated with macrolides, second- or third-generation cephalosporins, or doxycycline. Some patients may receive chronic prophylaxis with macrolides due to their immunomodulatory effects; however, prophylaxis should be limited to patients with severe disease and frequent hospitalizations because of the risk of bacterial resistance.^40,46 Mucolytics and expectorants have shown no benefit. Influenza and pneumococcal immunization should be offered to all eligible COPD patients.⁴⁰

Monitoring Parameters

Patients with COPD should be monitored for changes in symptoms, exacerbations, and objective airflow measurements.⁴⁰ Symptoms can be scored by using the COPD Assessment Test every several months.^40,47 The use of as-needed bronchodilators or corticosteroids can gauge the severity of disease.  Pulmonary function testing should occur at least annually and with any change in dose or addition or deletion of medications.¹⁵ Measures such as FEV₁ are not perfectly reliable, as the difference between assessments in a single patient can vary by more than the amount considered clinically significant.⁴⁰

Adverse events due to inhaled LABAs, SABAs, and ICSs used in COPD are equivalent to those in asthma. Inhaled LAMAs may cause paradoxical bronchospasm, and exacerbation of glaucoma or urinary retention.^9,15 Once a concern, the risk of cardiovascular events associated with tiotropium was refuted by findings from the recent 4-year UPLIFT clinical trial.⁴⁸ Inhaled ICSs may increase the risk for pneumonia and fracture.^15,49 Long-term use of oral corticosteroids may cause osteoporosis, cataracts, and adrenal suppression or insufficiency; while the risks of this therapy generally outweigh the benefits, ICS-related risks can be minimized by administering the lowest effective dose.¹⁵

A theoretical concern exists regarding the concomitant use of systemic beta-blockers and inhaled beta-agonists in COPD.⁴⁰ However, some evidence indicates that beta-blocker use in COPD, due to the effect on coexisting heart disease, may improve survival and decrease exacerbations without affecting respiratory symptoms.^50,51 Therefore, COPD patients with indications for beta-blocker use should not be denied therapy; however, cardioselective beta-blockers are preferred.⁴⁰ Roflumilast concentrations may be increased by coadministration of CYP 3A4 and 1A2 inhibitors or oral contraceptives containing combination gestodene and ethinyl estradiol; concentrations may decrease with strong CYP 3A4 and 1A2 inducers. Roflumilast may also cause weight loss and neuropsychiatric effects. Vilanterol/umeclidinium should be administered with caution if coadministered with drugs that prolong the QT interval.

Inhaler technique is as important in COPD as in asthma, and poor technique is associated with worse COPD control.⁵² The same counseling points on inhalers for patients with asthma should be reinforced in patients with COPD. Specifically, COPD patients may have difficulty using dry powder inhalers (DPIs) if they cannot achieve inspiratory flow sufficient to activate the inhaler.⁵³ Elderly COPD patients with osteoarthritis who have problems connecting or activating inhalers may benefit from the use of breath-activated inhalers (e.g., Maxair Autohaler, Table 4).⁵⁴

Patient Case #2: AS is a 68-year-old male former smoker with COPD presenting to establish care at your clinic. He was previously classified as group C and controlled on his current regimen, but recently has experienced many symptoms of COPD and was hospitalized twice in the past year for COPD exacerbation. He has received no other medications for COPD besides his current regimen. He does not use any spacers or VHCs and demonstrates to you poor coordination between actuation and inhalation. He presents with a prescription from his primary care provider for roflumilast. Current medications: Budesonide/formoterol 160/4.5 mcg 2 inhalations twice daily Metformin 1000 mg twice daily for type 2 diabetes Lisinopril 20 mg daily for hypertension Fluvoxamine 100 mg daily for major depression In what COPD patient group would AS be classified? Because he is experiencing many symptoms and was hospitalized twice in the last year for COPD exacerbation, AS is in Group D. Which of AS's current medications are most concerning with initiation of roflumilast? Fluvoxamine is a CYP 3A4 inhibitor, which may increase levels of roflumilast, a CYP 3A4 substrate. Roflumilast also may cause neuropsychiatric side effects, which may interact pharmacodynamically with fluvoxamine. What is an appropriate alternative recommendation to AS's prescriber in place of roflumilast? AS is now in group D due to his increasing symptoms and rate of exacerbation. Therefore, preferred therapy would include an ICS/LABA combination (which he is already taking) with or without a LAMA, which he has never received. Addition of a LAMA may be warranted to attempt to maximize inhaler therapy prior to initiation of an alternative regimen that includes a drug with potential concerns for interactions (roflumilast). What counseling points should be emphasized to AS? AS should be counseled on the importance of coordinating inhalation with actuation. If this cannot be achieved, he may benefit from a spacer or VHC. He should be counseled to shake the inhaler, hold it upright, breathe out, form a tight seal around the mouthpiece, take a slow deep breath upon actuation, and hold breath for 10 seconds.

PULMONARY HYPERTENSION

Overview

The estimated prevalence of pulmonary hypertension in the U.S. is between 50,000 and 100,000.⁵⁵ Pulmonary hypertension prevalence approximates 15 cases per million people, with more cases being idiopathic in nature rather than secondary to other causes.⁵⁶ The disease typically occurs in the third to fifth decades of life and occurs more often in women.

Genetic and environmental factors likely interact to lead to pulmonary hypertension. The World Health Organization (WHO) has classified pulmonary hypertension into 5 groups based on mechanism (Table 8).⁵⁶ Pulmonary arterial hypertension (PAH) is the focus of this module.

Table 8. World Health Organization Classification of Pulmonary Hypertension56
Classification of disease	Select examples of etiologic mechanism
Pulmonary arterial hypertension	Idiopathic, heritable, drug-induced, or associated with connective tissue disease, HIV infection, portal hypertension, CHD
Pulmonary hypertension owing to left heart disease	Systolic or diastolic dysfunction, valvular disease
Pulmonary hypertension owing to lung disease and/or hypoxia	COPD, interstitial lung disease, sleep-disordered breathing, chronic exposure to high altitude, developmental abnormalities
Chronic thromboembolic pulmonary hypertension	None
Pulmonary hypertension with unclear multifactorial mechanisms	Hematologic, systemic, metabolic disorders
CHD = coronary heart disease; COPD = chronic obstructive pulmonary disease; HIV = human immunodeficiency virus; PAH = pulmonary hypertension.

Pathophysiologic changes in PAH include endothelial cell dysfunction, platelet activation, vasoconstriction, hypertrophy, fibrosis, and inflammation.⁵⁵ Mediators in dysfunctional pathways include prostacyclins, endothelin-1, and nitric oxide. The resultant pulmonary vascular remodeling causes imbalances between vasoconstriction and vasodilation as well as regulators of platelet function.

The characteristic presentation of PAH includes fatigue, weakness, and dyspnea on exertion, although the extent of manifestations differs based on the stage of disease.⁵⁵ Patients with advanced disease may experience symptoms of right-sided heart failure, including chest pain or syncope. Signs of advanced PAH include jugular vein distension, peripheral edema, low blood pressure, cool extremities, wheezing, and prolonged exhalation.

Diagnosis of PAH is assured only with right heart catheterization.^55,57,58 Findings diagnostic of PAH include a mean pulmonary artery pressure (mPAP) ≥25 mmHg at rest with a pulmonary wedge pressure (also referred to as pulmonary artery occlusion pressure) or left ventricular end-diastolic pressure ≤15 mmHg.

The WHO classification of PAH categorizes patients based on the extent of activity limitation.⁵⁶ Patients in class I may have no limitation of normal activity, with progressive limitation present in New York Heart Association (NYHA) functional classes II, III, and IV (Table 9).

Table 9. Recommended and Alternative Initial Monotherapy by Functional Class of Pulmonary Arterial Hypertension 57,59,60
PAH Class	Recommended treatmenta	Alternative treatmenta
Class II Slight limitation of physical activity. Comfortable at rest, but limitations with ordinary physical activity.	Ambrisentanb-d Bosentanb-d Macitentanb-d Riociguatb-d Selexipagd Sildenafilb-d Tadalafilb-d	Vardenafild
Class III Marked limitation of physical activity. Comfortable at rest, but limitations with less than ordinary physical activity.	Ambrisentanb-d Bosentanb-d Epoprostenol IVb-d Iloprost inhaledb-d Macitentanb-d Riociguatb-d Selexipagd Sildenafilb-d Tadalafilb-d Treprostinil SCb-d Treprostinil IVc Treprostinil inhaledb,d	Iloprost IVb,d Treprostinil SCc Treprostinil IVb,d Treprostinil orald Vardenafild
Class IV Inability to perform physical activity without symptoms. Signs of right-sided heart failure may be present.	Epoprostenol IVb-d Treprostinil IVc Treprostinil SCc Treprostinil inhaledc Iloprost inhaledc	Ambrisentanb,d Bosentanb-d Iloprost inhaledb,d Iloprost IVb,d Macitentanb,d Riociguatb,d Sildenafilb-d Tadalafilb,d Vardenafild Treprostinil SC, IVb,d Treprostinil inhaledb,d
aNot in order of preference. Recommended therapies are those receiving Class 1 or consensus-based recommendations in guidelines. bAs recommended by 2013 Fifth World Symposium on Pulmonary Hypertension. cAs recommended by 2014 ACCP guidelines. dAs recommended by ESC/ERS 2015 guidelines IV = intravenous; SC = subcutaneous.

Treatment

The goals of PAH treatment are to slow the advancement of disease and improve symptoms to NYHA functional class I or II, quality of life, and survival.^55,61

Dietary modification includes restricting daily intake of fluid to <1.5 liters and sodium to <2,400 mg to avoid fluid retention.^55,56 Low-impact exercise as tolerated is also recommended.⁵⁶

Global and US treatment guidelines for pharmacologic therapy of PAH were updated in 2013 by the World Society for Pulmonary Hypertension and in 2014 by the American College of Chest Physicians, respectively. ^59,60 However, the most recently updated guideline is the 2015 European Society of Cardiology/European Respiratory Society (ESC/ERS) joint task force, which includes newly approved drugs.⁵⁷ Strongly recommended and alternative therapies are presented in Table 9, based on the grading systems employed in each guideline.

Primary therapy for PAH may include oral anticoagulation, diuretic therapy, oxygen, and digoxin.^55,57,59,60 Anticoagulation should be considered in patients with idiopathic pulmonary arterial hypertension (IPAH), patients with other underlying processes (e.g., congenital heart disease), or patients with an indwelling catheter for administration of prostanoids; target international normalized ratio (INR) ranges are typically 1.5 to 2.5.^56,60 Warfarin remains the anticoagulant of choice due to little study of new oral anticoagulants in PH. ³¹ While up to 70% of patients with PAH receive diuretics as needed, they should be used judiciously to target euvolemia.⁵⁵ No data support improvement in outcomes with digoxin, though it may be used clinically to improve symptoms or slow ventricular rate.

Patients with IPAH should be tested for reactivity to vasodilators; those with a positive response can receive oral calcium channel blockers (CCBs).^55,57,59,60 While few patients (approximately 10%) respond positively, CCB treatment has shown improved survival.⁶² Amlodipine or long-acting nifedipine or diltiazem at maximum tolerated doses are preferred; verapamil should be avoided due to potential negative inotropy.^57,60 Reassessment should occur after approximately 3 months of therapy. Patients with negative vasoreactivity tests or who do not improve to functional class I or II with CCB therapy should receive other therapy to treat the underlying pulmonary disorder and prevent disease progression in patients with persistent symptoms (Table 10).

Prostanoids promote pulmonary vasodilation and inhibit platelet aggregation (Table 10).⁵⁵ These agents have been shown to improve exercise tolerance, though only epoprostenol has improved survival. Important considerations for prostanoids include their short half-life (3 to 5 minutes versus 4 hours for epoprostenol and treprostinil, respectively), the risk for infection and catheter obstruction with those requiring continuous parenteral infusion, and high dosing frequency with those administered via inhalation.  Doses should be titrated until patients respond or experience dose-limiting toxicity. Treprostinil was recently approved as an oral tablet (Orenitram) for treatment of patients with functional class III symptoms, although it has received low recommendations for use from guidelines because of limited data. ^47,57,59,60 Another new oral agent, selexipag, is a selective prostacyclin receptor agonist that is distinct from prostacyclin, yet has similar actions; selexipag may be an option for patients that are not candidates for non-oral prostanoids.⁶³ During a phase III clinical study, selexipag alone or combined with endothelin receptor antagonists (ERAs) and/or phosphodiesterase (PDE) inhibitors reduced a combined endpoint of mortality and morbidity (hospitalization or worsening disease) by 40%.⁵⁷

The ERAs ambrisentan, bosentan, and macitentan target the vasoconstricting and mitogenic peptide endothelin-1, resulting in improved exercise capacity and delayed time to clinical progression.^5564,65 All ERAs may cause hepatotoxicity and are pregnancy category X.⁹ Phosphodiesterase inhibitors cause vasorelaxation and antiproliferative effects; both offer reduced mPAP and improved functional class and exercise capacity, while tadalafil has additionally shown improved time to disease worsening.⁶² Riociguat is a guanylate cyclase stimulator that has shown improved walk distance and functional class; it is approved for PAH and is the only approved therapy for chronic thromboembolic pulmonary hypertension.⁹

Table 10. Pharmacotherapy of Pulmonary Hypertension47,55,66
Drug	Mode of administration	FDA-approved class of PH	Adult dosage and titration
Prostanoids
Epoprostenol (Flolan, Veletri)	Infusion via CVC	III, IV	2 ng/kg/min increased by 2 ng/kg/min every 15 minutes until dose-limiting toxicity
Treprostinil (Remodulin)	Infusion via CVC	II, III, IV	1.25 ng/kg/min increased by 1.25 ng/kg/min weekly for first month, then by 2.5 ng/kg/min afterward
Treprostinil (Tyvaso)	Inhaled	III	3 inhalations 4 times daily, increased every 1 to 2 weeks by 3 inhalations 4 times daily until therapeutic or maximum 9 inhalations 4 times daily
Treprostinil (Orenitram)	Oral	II, III	0.25 mg twice daily with food or 0.125 mg three times daily, increased to highest tolerated dose in increments of 0.25 to 0.5 mg twice daily or 0.125 mg three times daily every 3 to 4 days; avoid abrupt discontinuation
Iloprost (Ventavis)	Inhaled	III, IV	2.5 mcg 6 to 9 times daily (no more frequently than every 2 hours), titrated to maximum 5 mcg 6 to 9 times daily
Selexipag (Uptravi)	Oral	II-III	200 mcg twice daily; dose is increased in increments of 200 mcg twice daily, at weekly intervals, to the highest tolerated dose up to 1600 mcg twice daily
Endothelin receptor antagonists
Bosentan (Tracleer)	Oral	II, III, IV	62.5 mg twice daily; increase to 125 mg twice daily after 4 weeks
Ambrisentan (Letairis)	Oral	II, III	5 mg daily; increase to 10 mg if tolerated
Macitentan (Opsumit)	Oral	II, III	10 mg once daily
Phosphodiesterase inhibitors
Sildenafil (Revatio)	Oral	II, III	20 mg 3 times daily
Tadalafil (Adcirca)	Oral	II, III	40 mg once daily (do not divide dose)
Calcium channel blockers
Nifedipine (Procardia XL, Nifedical XL, Adalat CC)	Oral	OL	30 mg twice daily titrated to 120 to 240 mg daily
Diltiazem (Cardia XT; Cardizem CD, LA, SR; Taztia XT)	Oral	OL	60 mg 3 times daily titrated to 240 to 720 mg daily
Amlodipine (Norvasc)	Oral	OL	2.5 mg daily titrated to maximum 40 mg daily
Other agents
Riociguat (Adempas)	Oral	II, III	0.5 to 1 mg 3 times daily initially; titrate every 2 weeks in 0.5-mg increments to maximum 2.5 mg 3 times daily
CVC = central venous catheter; FDA = Food and Drug Administration; OL = off-label; PAH = pulmonary arterial hypertension.

Combination therapy may be utilized to maximize efficacy and decrease toxicity in patients with class III or IV disease unresponsive to initial therapy or with worsening disease.^56,60 Combination therapy may include sequential drug combination therapy in non-responsive patients, as well as upfront combination therapy (particularly in patients with functional class III or IV symptoms) because of the known mortality of PAH.^57,60 Data are emerging on combination therapy that have yielded recommendations, although no consensus exists on ideal sequencing or combinations. Combination therapy that has received a Class I (beneficial) recommendation from the 2015 ESC/ERS guideline includes upfront combination therapy with ambrisentan and tadalafil in functional class II and III PAH, as well as sequential therapy with macitentan added to sildenafil, riociguat added to bosentan, and selexipag added to ERAs and/or PDE inhibitors in functional class II and III PAH.⁵⁷ In functional class III PAH only, sildenafil is considered beneficial when added to epoprostenol. Recently, ambrisentan was approved by the FDA for treatment of PAH in combination with tadalafil to reduce risk of disease progression and hospitalization, based on a trial evaluating its use as initial combination therapy compared to initial monotherapy with either agent alone. ^67,68

Monitoring Parameters

Exercise capacity should be measured at baseline to determine functional status class (Table 9), periodically every 3 to 12 months, when there is clinical worsening, and 3 to 6 months after changes in therapy to assess response.^55,57,60 Other monitoring parameters include assessments of drug-specific adverse events. Liver function testing should be performed monthly and indefinitely with bosentan and occasionally with other ERAs.^50,57-59 Complete blood counts should also be taken every 3 months with bosentan due to the potential for anemia.^55,69 Blood pressure may be monitored in patients receiving PDE inhibitors. Electrolytes should be assessed in patients receiving digoxin, as well as serum drug levels to target a range of 0.5 to 0.8 ng/mL.⁵⁵

Common side effects due to prostanoids (including oral treprostinil) include flushing, headache, nausea, and hypotension.⁵⁵ Injectable prostanoids may be associated with infusion site reactions, infection, and catheter occlusion. Inhaled iloprost and treprostinil can be used to avoid infectious complications, though they may cause throat irritation, cough, and hypotension; they should be used with caution in patients with pulmonary infection or other lung disease. Common ERA-related adverse reactions include edema, flushing, and palpitations; hepatotoxicity may rarely occur and warrants monthly monitoring, though risk is lower with ambrisentan.^31,55 Because selexipag is administered orally, it is not associated with many adverse events related to traditional prostanoids; the most common adverse events reported were headache, jaw pain, and gastrointestinal symptoms.⁶³ Adverse events due to PDE inhibitors include headache, flushing, dyspepsia, and epistaxis. Rare changes in vision (e.g., blue-tinted vision) warrant immediate discontinuation.⁵⁵

Injectable prostanoids may increase the risk of bleeding with concomitant anticoagulation.⁵⁵ Coadministration with monoamine oxidase inhibitors may increase the risk for hypotension. Cytochrome P450 interactions may occur with oral treatments for PAH including the ERAs, PDE inhibitors, and riociguat; while all are metabolized by 3A4, ambrisentan and bosentan are additionally metabolized by 2C19 and 2C9, respectively. Additionally, bosentan induces CYP3A4 and 2C9. Strong CYP2C8 inhibitors may increase exposure to selexipag and oral treprostinil; inhibitors should be avoided in combination with selexipag, and a dose reduction is recommended for orenitram.^47,63 Riociguat and PDE inhibitors may cause excessive hypotension when used with nitrates; their coadministration is therefore contraindicated. Patients who receive anticoagulation therapy with warfarin should avoid variation in vitamin K-containing foods and drugs inhibiting CYP 2C9, 1A2, and 3A4. Females of child-bearing age who have PAH should be counseled to avoid pregnancy due to high rates of maternal mortality (up to 50%) and the teratogenic effects associated with ERAs and riociguat, which are classified as pregnancy category X.⁵⁶

Focus Points for Medication Therapy Management (MTM) in Respiratory Diseases

Asthma

• Pharmacists and APRNs should help patients develop and understand their asthma action plans by explaining the purpose of each medication, documenting and updating the plan, and developing customized plans for children who attend school or attend functions away from parents or caregivers.³² Sample action plans are freely available in the 2007 NAEPP EPR.
• A practical way to ensure patients do not receive LABA monotherapy without an ICS is to recommend combination LABA-ICS products (Table 4).³⁴
• The common practice of administering montelukast at night is not supported by clinical data and is a reflection of dosing regimens utilized in key clinical trials; time of administration may be modified to ensure compliance.⁸
• Although levalbuterol was developed to diminish side effects of the albuterol S-isomer, their side effect profiles are nearly identical.^8,70 Therefore, SABA selection should rely on patient or clinician preference and cost. Similarly, ICSs differ primarily in their convenience of dosing, type of delivery device, flexibility in dosage titration, side effects, and cost.  These factors should drive the selection of ICSs, as therapeutic outcomes do not differ substantially within the class.

COPD

• When applicable, COPD patients should be counseled on the importance of smoking cessation. Guidelines for smoking cessation incorporating non-pharmacologic, over-the-counter, and prescription treatment are available from the Agency for Healthcare Research and Quality.⁷¹
• Respiratory infection is a common precipitating factor for COPD exacerbations; pharmacists and APRNs should administer influenza vaccinations annually to patients with COPD and pneumococcal vaccines to those who are candidates.¹⁵
• Checklists have been developed specifically for COPD patients to ensure proper inhaler technique for various types of inhalational products.⁷²
• Duration of antimicrobial treatment for COPD exacerbation may be discussed with providers in patients at risk for antibiotic-related adverse events. Treatment duration typically encompasses 7 to 10 days, though studies suggest equal efficacy and fewer adverse events with shorter courses (5 days).^15,73
• Consider tapering the dose of corticosteroids if patients are frail, were taking corticosteroids prior to burst therapy, have cushingoid symptoms, or are at risk of autoimmune disease flares.⁷⁴ Taper doses by 5% to 20% every 1 to 2 weeks; slow the taper if flu-like symptoms emerge or disease flares. Regimens may be modified by switching to a shorter-acting agent (e.g., prednisone), substituting multiple daily doses with a single morning dose, and dosing on alternate days.

Pulmonary Hypertension

• Patients receiving continuous infusions of prostanoids should be counseled on infusion pump operation and the importance of avoiding interruptions in therapy. Strategies include maintaining access to a backup infusion pump and always having a second cassette available for patients receiving epoprostenol. ^56,75
• Changes in prostanoid dosage should be accompanied by changes in tubing to avoid mingling of solutions of different concentrations.⁷⁵
• Patients receiving epoprostenol should be counseled on appropriate technique to compound the drug from powder. Depending on whether patients receive epoprostenol as Flolan or Veletri, they should be counseled on appropriate diluents and conditions for storage and administration, which are detailed differently in each package insert. Patients with difficulty performing reconstitution may be candidates for treprostinil, which is available as a solution.
• Infusion site pain is common with treprostinil; local treatment options include ice, warm bath with Epsom salt, hemorrhoid ointment, lidocaine 5% patch, and topical diphenhydramine.⁷⁵
• Considerations should be made for females of child-bearing age treated with certain drugs for pulmonary hypertension. Those receiving ERAs or riociguat should have pregnancy excluded at the start of, monthly during, and 1 month after cessation of therapy.^68,69,76,77
• ERAs and riociguat are only available through restricted distribution systems.^68,69,76,77

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