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The following common respiratory disorders are discussed within this module:

• Asthma
• Chronic obstructive pulmonary disease
• Pulmonary arterial 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 United States.^1,2 These disorders may have a considerable negative impact on patients’ quality of life and carry a substantial burden on health care 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 United States.^1,3 In 2016, 8.3% of the US population had asthma.³ Children, especially boys, are particularly susceptible, comprising approximately 23% of all U.S. patients with asthma. Asthma accounted for 1.7 million emergency department (ED) visits in 2015. The estimated national medical cost of asthma from 2002 to 2007 was $50.1 billion, and prescription drugs accounted for the largest direct medial expenditure.¹ A disproportionate share of ethnic minorities are affected by asthma.³ Similarly, the likelihood of hospitalization or death from asthma is approximately 3 times greater in black compared with white patients, 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.^1,2 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 (eg, 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.^1,2 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. This leads to airway remodeling, which may be irreversible or may respond to early use of inhaled corticosteroids (ICS). 

Clinical presentation of asthma is composed of characteristic intermittent symptoms of dyspnea, wheezing, coughing (particularly at night), and chest tightness.^1,2 Clinical signs include wheezing on auscultation, tachypnea, other signs of atopy (eg, allergic rhinitis), and compromised measures of spirometry.

Two guidelines form the basis for diagnosis, classification, and treatment of asthma in the United States – the National Asthma Education and Prevention Program Expert Panel Report-3 (NAEPP EPR-3) and the Global Initiative for Asthma (GINA) report.^4,5  In addition to the full guideline report on asthma, GINA also published a 2019 pocket guide on diagnosis and management of difficult-to-treat and severe asthma in adolescents and adult patients.⁶ Diagnosis of asthma is confirmed by airflow limitation as demonstrated by spirometric testing, at least partly reversible airflow obstruction, and exclusion of other causes.^4,5 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 COPD.

A crucial step in appropriate asthma management is classification of disease severity.^4,5 The NAEPP EPR-3 provides a classification scheme for asthma severity based on domains of impairment and risk (Table 1).⁴ Classification differs for patients in distinct age groups, including those aged 0 to 4, 5 to 11, and ≥ 12 years. In contrast, the GINA report categorizes asthma severity based on the step of treatment necessary to maintain control of symptoms.⁵ Mild, moderate, and severe asthma requires treatment from step 1 to 2, 3, and 4 to 5, respectively. Table 2 presents the medications used in each step of asthma treatment per the GINA report. Of note, the GINA pocket guide for the management of difficult-to-treat and severe asthma emphasizes that severe asthma is a subset of difficult-to-treat asthma.⁶ Difficult-to-treat asthma is defined as “uncontrolled despite GINA step 4 or 5 treatment or that requires such treatment to maintain good symptom control and reduce the risk of exacerbations.” Severe asthma was defined as asthma that is “uncontrolled despite adherence with maximal optimized therapy and treatment of contributory factors, or that worsens when high-dose treatment is decreased.”

Treatment

Goals of asthma treatment are generally to minimize the manifestations of asthma by reducing impairment (eg, pulmonary function and activity levels), reducing risk of exacerbations, and minimizing adverse events.^4,5  Uncontrolled asthma leads to impaired quality of life, increased disease burden, and greater use of health care resources. The NAEPP EPR-3 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.⁴ 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.^4,5 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. Patients should be aware that some drugs, including beta-blockers, aspirin, and other nonsteroidal anti-inflammatory drugs (NSAIDs) may also worsen asthma symptoms.⁵

Both NAEPP EPR-3 and GINA reports present 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.^4,5 Historically, patients with mild asthma were treated with SABA monotherapy. However, there has been a recent major change to the GINA report, and ICS-containing controller treatment is now recommended for all adults and adolescents with asthma (Table 2).⁵ As therapy is escalated through steps, the dose of ICS may be increased and/or ICS therapy may be combined with other agents (eg, long-acting beta-agonist [LABA], leukotriene receptor antagonists [LTRA]). Other recommendations made in the GINA report are similar to those in NAEPP EPR-3, with the exception of a step 6 included in the EPR-3 but not the GINA report.^4,5 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 (poor inhaler technique, etc). Difficult-to-treat asthma may be managed by improving factors such as incorrect inhaler technique, suboptimal adherence, certain comorbidities, regular or over-use of SABAs, anxiety, depression, social/economic difficulties, medication adverse events, or modifiable factors such as smoking and pollution.⁶

Inhaled corticosteroids (ICS) are the mainstay of pharmacotherapy therapy in patients with asthma.⁵ This drug class has the largest effect in the maintenance of asthma control by suppressing pathologic airway inflammation. A variety of ICSs are available both as single-entity inhalation therapies and in combination with other agents (Tables 4 and 5).^5-8 For newer preparations, the prescribing information may be consulted to determine whether products with the same active ingredient are clinically equivalent.

Patients uncontrolled with ICS monotherapy may benefit from addition of a LABA, which is the preferred therapy among adjunctive agents added to ICSs.⁵ 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.^9,10 Importantly, use of LABAs without an ICS is contraindicated in patients with asthma, as this results in unsuppressed airway inflammation, high rates of asthma exacerbations, and a potentially increased risk of asthma-related death.^11,12 Alternative agents may be utilized in patients with asthma of varying severity (Table 2).^5,6 The LTRAs (montelukast and zafirlukast) prevent asthma induced by environmental exposures.^7,13 Cromolyn sodium is another alternative, though it has not shown consistent benefit vs placebo in clinical trials.⁵ Its main advantage is a favorable safety profile; however, clinical response may take up to 4 to 6 weeks.⁴ Theophylline use has waned due to its narrow therapeutic index, drug interactions, and monitoring requirements.¹ Any use of theophylline should utilize the sustained-release product and target serum concentrations of 5 to 15 mcg/mL.⁴ Agents that are approved by the US Food and Drug Administration (FDA) for EIB prevention include albuterol, cromolyn sodium, montelukast, and salmeterol.^7,8

Recommendations for the use of biologic agents are provided by the GINA pocket guide on diagnosis and management of difficult-to-treat and severe asthma in adolescents and adult patients.⁶ This pocket guide is recommended to be used in conjunction with the 2019 GINA full report (not yet published), so it is likely that the 2019 report will have more detailed recommendations on biologic agents compared to the 2018 report. Because biologic therapy is expensive, GINA recommends first considering nonbiologic options if there is evidence of type 2 inflammation after using high-dose ICS (ie, objectively measuring adherence, consider add-on treatment for clinical type 2 phenotypes, or increasing the ICS dose and then reviewing after 3 to 6 months). The guideline recommends that if available and affordable, consideration should be given to adding a targeted biologic therapy in patients lacking symptom control or with exacerbations taking high-dose ICS/LABA and have eosinophilic and/or allergic biomarkers or require maintenance oral corticosteroids. Specific recommendations are provided in Table 6.

Because of the cost of the biologic agents, GINA also recommends considering whether patients satisfy payer eligibility criteria.⁶ Each therapy is recommended to have a trial of at least 4 months. The guideline provides 3 options if there is not a good response to the initial trial of an add-on agent: 1) the trial can be extended 6 to 12 months if the response is uncertain, 2) the agent may be stopped if there is no response, or 3) the agent may be switched to a different type 2 targeted therapy. Response to biologic therapy should be monitored every 3 to 6 months.

Prior to stepping up therapy, the influence of medication adherence, inhaler technique, and environmental factors on symptom control should be considered.^5,6 Patients with asthma controlled for at least 3 months should be considered for therapy step-down; however, this should be done carefully by utilizing a written asthma action plan and close monitoring.⁵ Patients uncontrolled on step 5 therapy may require chronic oral corticosteroids to achieve asthma control.^5,6 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 with severe asthma and/or 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.^5,6 The NAEPP EPR-3 and GINA report recommend that clinicians consider inactivated influenza vaccination for patients with asthma due to their increased susceptibility to influenza complications.^4-6 The vaccine is safe for children 6 months and older and adults.⁷ Other vaccinations, such as pneumococcal vaccine, may be warranted based on the patient’s age and type of asthma controller therapy.^4,5

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.⁵ Two treatments of 2 to 6 puffs of a SABA may be administered 20 minutes apart, with an assessment of response after 30 minutes.^4,5 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. Peak expiratory flow rate (PEFR) monitoring may also be beneficial in patients who have severe asthma, experience frequent or sudden exacerbations, have difficulty identifying asthma symptoms, or want to identify environmental or occupational exposures.⁵

Monitoring Parameters

Monitoring of outcomes in asthma is related to the severity of disease, extent of symptom control, and responsiveness of symptoms to therapy.^4,5 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.^4,5,14-17 While all are validated and quantify asthma control, pharmacists and advanced practice registered nurses (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.^4,5,14-18

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.^4,18 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.⁵ Increases in FEV₁ of 12% or greater are generally considered indicative of treatment effectiveness.

The GINA report and NAEPP EPR-3 generally recommend 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.^4,5 Spirometry should be performed at the time of diagnosis, after treatment initiation and lung function stabilization, and during periods of worsening control.

The GINA report and NAEPP EPR-3 recommend the development of written asthma action plans for all patients with asthma.^4,5 Action plans instruct patients on how to recognize asthma symptoms and adjust medications accordingly. Action plans should incorporate PEFR 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.⁸ Adverse events related to LABAs include tachycardia, headache, and cramps; these agents should be used for the shortest duration possible and discontinued when asthma is controlled.^1,12 Of note, a boxed warning previously found on all ICS-LABA combination products warning about the increased risk of asthma-related death has been removed after post-marketing studies did not reveal an increased risk of death with these combinations vs ICS monotherapy.¹²

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.^7,8 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.^19,20 Other ICS-related adverse events include cough, sore throat, and hoarseness; incidence may vary with individual ICSs.^7,8 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 metered-dose inhaler (MDI). Cromolyn sodium and LTRAs are considered extremely safe, with low potential for adverse events; however, LTRAs have been associated with neuropsychiatric 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.^1,7,8 As a class, drug interactions are few among ICSs, though levels of budesonide, fluticasone, and mometasone may be increased by strong 3A4 inhibitors.⁷ 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. No known interactions exist for cromolyn.⁸

Inhaler technique is of paramount importance in optimizing drug efficacy.^1,5,21 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.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Overview

The prevalence of COPD has increased in recent decades, particularly among elderly patients, and currently affects over 15 million Americans.^22-25 COPD ranks as the third leading cause of death by disease in the United States, and predictions estimate that COPD will rise to the third most common cause of death worldwide by 2030.^25,26 In the United States, COPD accounts for 15 million physician office and over 700,000 hospitalizations annually.²²

The etiology of COPD includes host and environmental factors, though the latter confer the majority of risk.²² 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.²² An imbalance between destructive and protective processes in the lung may lead to progressive loss of elasticity. 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.^22,24 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.²³ 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.²⁴ Spirometry is required, as the presence of a post-bronchodilator FEV₁/FVC < 70% confirms a diagnosis of COPD.

The 2019 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 7).²⁴ 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 the occurrence of exacerbations to stratify patients and determine appropriate therapy (Table 8).^22,24 Patients should be categorized in the stage with criteria corresponding to the most severe combined assessment criteria.

Treatment

Treatment goals in stable COPD address symptoms and risk.²⁴ 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 8), COPD assessment criteria, medication availability, and patient response.

The most important determinant in preventing the onset and progression of COPD is smoking cessation, which is an essential nonpharmacologic management strategy.²⁴ Physical activity is recommended in all patients. 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.²⁴ 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.^22,24 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).²⁴ Patients with symptoms that are chronic or unresponsive to short-acting bronchodilators may benefit from long-acting agents, which offer greater convenience. Long-acting muscarinic antagonists (LAMAs) have demonstrated greater decreases in exacerbation rates and hospitalizations and are preferred to LABAs for COPD. Also, long-term use of LAMAs does not lead to tolerance, as seen with long-term LABA therapy.^22,24 Tiotropium, a LAMA, is specifically recognized by the GINA guideline for improving exercise performance.²⁴

Although COPD pathophysiology involves inflammation, monotherapy with ICSs should be avoided due to its poor risk-to-benefit profile in this population.^22,24 Use should be limited to patients with moderate to very severe COPD and frequent exacerbations, and should be combined with inhaled bronchodilator therapy.²⁴ 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. Patients with inherited AAT deficiency are treated with weekly infusions of replacement AAT preparations.²²

Treatment of COPD exacerbations includes intensification of the dose and/or frequency of bronchodilator therapy and initiation of short-term oral corticosteroids.^22,24 Prednisone 40 mg (or equivalent) for 5 to 7 days appears effective for most patients.²⁴ Antibiotic courses of 5 to 7 days, although controversial, may be appropriate for patients with all 3 of the following symptoms: increased sputum production, increased sputum purulence, or increased dyspnea; antibiotics may also be appropriate if any 2 of these symptoms are present so long as sputum purulence is increased, and in patients who require mechanical ventilation. The most common pathogens are treated with macrolides, amoxicillin with clavulanic acid, or tetracyclines. Some patients may receive chronic prophylaxis (no data beyond 1 year) 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.^24,27 The benefits of chronic use (≤ 1 year) of azithromycin are also lessened in active smokers.²⁴ Expectorants have not consistently shown benefits. Influenza and pneumococcal immunization should be offered to all eligible COPD patients.

Monitoring Parameters

Patients with COPD should be monitored for changes in symptoms, exacerbations, and objective airflow measurements.²⁴ Symptoms can be scored by using the COPD Assessment Test at every office visit. Pulmonary function testing should occur at least annually and with any change in dose or addition or deletion of medications. 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.

Adverse events due to inhaled LABAs, SABAs, and ICSs used in COPD are equivalent to those in asthma. Inhaled LAMAs may cause paradoxical bronchospasm, exacerbation of glaucoma, or urinary retention.^7,22 Inhaled ICSs may increase the risk for pneumonia and fracture.^22,28 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.²²

A theoretical concern exists regarding the concomitant use of systemic beta-blockers and inhaled beta-agonists in COPD.²⁴ 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.^29,30 Therefore, COPD patients with indications for beta-blockers should not be denied therapy, nor should COPD patients with hypertension be treated differently.²⁴ 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.^7,8 Roflumilast may also cause weight loss and neuropsychiatric effects.

Inhaler technique is as important in COPD as in asthma, and poor technique is associated with worse COPD control.³¹ 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.³² Elderly COPD patients with osteoarthritis who have problems connecting or activating inhalers may benefit from the use of breath-activated inhalers (eg, Maxair Autohaler, Table 4).³³

PULMONARY ARTERIAL HYPERTENSION

Overview

Pulmonary hypertension prevalence approximates up to 26 cases per million people, with more cases being idiopathic in nature rather than secondary to other causes.³⁴ The disease typically occurs in the third to sixth 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 1 of 5 groups based on mechanism (Table 10).³⁵  Group 1 pulmonary hypertension, also known as pulmonary arterial hypertension (PAH) is the focus of this module.

Pathophysiologic changes in PAH include endothelial cell dysfunction, platelet activation, vasoconstriction, hypertrophy, fibrosis, and inflammation.³⁴ Mediators in dysfunctional pathways include prostacyclins, endothelin-1, nitric oxide, and serotonin. 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.³⁴ 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.^34,35 Findings diagnostic of PAH include a mean pulmonary artery pressure (mPAP) > 20 mm Hg at rest, a pulmonary artery wedge pressure ([PAWP], also referred to as pulmonary artery occlusion pressure) ≤ 15 mm Hg, and a pulmonary vascular resistance (PVR) ≥ 3 wood units.³⁶

The WHO classification of PAH categorizes patients based on the extent of activity limitation.³⁵ 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 11).

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.^34,35

Dietary modification includes restricting daily intake of fluid and sodium to avoid fluid retention.³⁴ Low-impact exercise as tolerated is also recommended.³⁵

European and US treatment guidelines for pharmacologic therapy of PAH were updated in 2015 by the European Society of Cardiology/European Respiratory Society (ESC/ERS) joint task force and more recently in 2019 by the American College of Chest Physicians (ACCP).^35,37 Strongly recommended and alternative initial therapies are presented in Table 11, based on the grading systems employed in each guideline.

Primary therapy for PAH may include oral anticoagulation, diuretic therapy, oxygen, and digoxin.^34,35,37 Anticoagulation should be considered in patients with idiopathic pulmonary arterial hypertension (IPAH), heritable PAH (HPAH), those with other underlying processes (eg, congenital heart disease), or those with an indwelling catheter for administration of prostanoids; warfarin is most commonly used with target international normalized ratio (INR) ranges between 1.5 to 2.5.^34,35 While up to 70% of patients with PAH receive diuretics as needed, they should be used judiciously to target euvolemia.³⁴ No data support improvement in outcomes with digoxin, though it may be used clinically to improve symptoms and slow ventricular rate in patients with right-sided heart failure and atrial arrhythmias, respectively. Of note, the 2019 ACCP guidelines for the treatment of PAH do not make any recommendations for or against the use of anticoagulants, diuretics, or digoxin in patients with PAH.

Patients with IPAH, HPAH, or PAH induced by drugs should be tested for reactivity to vasodilators; those with a positive response can receive oral calcium channel blockers (CCBs).^34,35 While few patients (approximately 13%) respond positively, CCB treatment has shown improved survival.³⁸ Amlodipine or long-acting nifedipine or diltiazem at maximum tolerated doses are preferred; verapamil should be avoided due to potential negative inotropy.^34,35 Reassessment should occur after approximately 3 months of therapy. Patients with positive 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 (Table 11).

Prostanoids promote pulmonary vasodilation and inhibit platelet aggregation (Table 12).³⁴ 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 vs 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 is available as an oral tablet (Orenitram) for treatment of patients with functional class II or III symptoms.^8,35 Another new oral agent, selexipag (Uptravi), 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 nonoral prostanoids.^8,35,39 Due to limited efficacy data, the 2019 ACCP guidelines for the treatment of PAH do not make any recommendations for or against the use of oral treprostinil or selexipag.³⁵

The endothelin receptor antagonists (ERAs) ambrisentan, bosentan, and macitentan target the vasoconstricting and mitogenic peptide endothelin-1, resulting in improved exercise capacity and delayed time to clinical progression (Table 12).^34,40,41 All ERAs may cause hepatotoxicity and are contraindicated during pregnancy.⁷

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 (Table 12).^34,35 Riociguat is a guanylate cyclase stimulator that has shown improved walk distance, functional class, and time to disease worsening; it is approved for PAH and is the only approved therapy for chronic thromboembolic pulmonary hypertension.^7,35

Combination therapy may be utilized to maximize efficacy and decrease toxicity in patients with class III or IV disease.^35,37 Combination therapy may include sequential drug combination therapy in nonresponsive patients, as well as upfront combination therapy (particularly in patients with functional class II, III or IV symptoms) because of the known mortality of PAH.³⁵ There is no consensus on ideal sequencing or combinations, however, some combinations have been recognized and recommended in guidelines. Combination therapy that has received a Class I (beneficial) recommendation in 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.³⁷ In functional class III PAH only, sildenafil is considered beneficial when added to epoprostenol.

In 2015, ambrisentan received an expanded approval from the FDA for the treatment of patients with functional class II or III PAH in combination with tadalafil, to reduce risk of disease progression and hospitalization.⁷ The basis for this approval were results from a clinical trial that demonstrated a lower risk of clinical-failure events (death, hospitalization, disease progression, or unsatisfactory clinical response) with initial combination therapy consisting of ambrisentan plus tadalafil compared to initial monotherapy with either agent alone.⁴² Following the publication of this trial, the 2019 ACCP guidelines for the treatment of PAH have been updated to provide a weak recommendation for initial combination therapy with ambrisentan plus tadalafil for treatment-naïve patients with class II or III PAH.³⁵ These guidelines also suggest that the addition of tadalafil for patients who are receiving background therapy with ambrisentan may improve walk distance, based on results from a separate trial.^35,43

Monitoring Parameters

Exercise capacity should be measured at baseline to determine functional status class (Table 11), periodically every 3 to 12 months, when there is clinical worsening, and 3 to 6 months after changes in therapy to assess response.^34,35 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.^7,34 Complete blood counts should also be taken every 3 months with bosentan due to the potential for anemia. 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.³⁴

Common side effects due to prostanoids (including oral treprostinil) include flushing, headache, nausea, and hypotension.⁸ 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. 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. Common ERA-related adverse reactions include anemia, edema, flushing, and headache; hepatotoxicity may rarely occur and warrants monthly monitoring, though risk is lower with ambrisentan and macitentan. Adverse events due to PDE inhibitors include headache, flushing, dyspepsia, and epistaxis. Rare changes in vision (eg, blue-tinted vision) warrant immediate discontinuation. Lastly, headache, gastrointestinal symptoms, and dizziness are the most commonly observed adverse events with riociguat.

Injectable prostanoids may increase the risk of bleeding with concomitant anticoagulation.³⁴ 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. Inhibitors of CYP2C8 may increase exposure to selexipag and oral treprostinil; inhibitors should be avoided in combination with selexipag, and a dose reduction is recommended for oral treprostinil.^8,34 Likewise, exposure to IV and inhaled treprostinil may increase or decrease when administered with strong inhibitors or inducers of CYP2C8.⁸ Riociguat and PDE inhibitors may cause excessive hypotension when used with nitrates; their coadministration is therefore contraindicated. The combination of riociguat and a PDE inhibitor is also 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.^7,8

Focus Points for Medication Therapy Management 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.¹⁸ Sample action plans are freely available in the 2018 GINA Implementation ToolBox.⁴⁴
• A practical way to ensure patients do not receive LABA monotherapy without an ICS is to recommend combination LABA-ICS products (Table 4).¹²
• The GINA report for asthma management and prevention now recommends ICS-containing controller treatment for all adults and adolescents with asthma.⁵
• Although levalbuterol was developed to diminish side effects of the albuterol S-isomer, their side effect profiles are nearly identical.^13,45 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.
• Recommendations for the use of biologic agents are provided in the GINA pocket guide on diagnosis and management of difficult-to-treat and severe asthma.⁶

COPD

• When applicable, COPD patients should be counseled on the importance of smoking cessation.²⁴ Guidelines for smoking cessation incorporating nonpharmacologic, over-the-counter, and prescription treatment are available from the US Preventive Services Task Force (USPSTF).⁴⁶
• 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.²⁴
• Checklists have been developed specifically for COPD patients to ensure proper inhaler technique for various types of inhalational products.⁴⁷
• Duration of antimicrobial treatment for COPD exacerbation may be discussed with providers in patients at risk for antibiotic-related adverse events.²⁴ Treatment duration typically encompasses 5 to 7 days.
• 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.⁴⁸ 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 (eg, prednisone), substituting multiple daily doses with a single morning dose, and dosing on alternate days.

Pulmonary Arterial 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.³⁵
• Changes in prostanoid dosage should be accompanied by changes in tubing to avoid mingling of solutions of different concentrations.⁴⁹
• Patients receiving epoprostenol should be counseled on appropriate technique to compound the drug from powder.⁷ 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.⁵⁰
• Considerations should be made for females of child-bearing age treated with certain drugs for pulmonary arterial hypertension. Those receiving ERAs or riociguat should have pregnancy excluded at the start of, monthly during, and 1 month after cessation of therapy.⁷
• ERAs and riociguat are only available through restricted distribution systems.⁵¹

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