COPD Therapeutics II PDF

Chronic Obstructive Pulmonary Disease Therapeutics II Abdulkarim Alshammari, Pharm.D., MS, PhD Reference: DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition Joseph T. DiPiro, Gary C. Yee, Stuart T. Haines, Thomas D. Nolin, Vicki L. El...

Chronic Obstructive Pulmonary Disease Therapeutics II Abdulkarim Alshammari, Pharm.D., MS, PhD Reference: DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition Joseph T. DiPiro, Gary C. Yee, Stuart T. Haines, Thomas D. Nolin, Vicki L. Ellingrod, L. Michael Posey Chapter 45: COPD Free access to Accesspharmacy is provided via Saudi Digital Library (SDL) 2  COPD: Pharmacotherapeutics § In contrast to survival benefit conferred by supplemental oxygen therapy and tobacco cessation, there is no medication available for the treatment of COPD that has been conclusively shown to modify lung function decline or prolong survival § There is some evidence that chronic treatment with pharmacotherapy may reduce the rate of lung function decline in a subset of patients, although more definitive studies are needed to confirm these observations. § The primary goal of pharmacotherapy is to improve patient symptoms, reduce the frequency and severity of exacerbations, and improve the patient’s exercise tolerance. § Due to the progressive nature of COPD, pharmacotherapy tends to be chronic and cumulative 3  COPD: Pharmacotherapeutics § International guidelines recommend a stepwise approach to the use of pharmacotherapy based on disease severity determined by an assessment of symptom burden and exacerbation risk § The impact of recurrent exacerbations on accelerating disease progression is increasingly recognized as an important factor to be considered § There is inadequate evidence to support the routine use of more aggressive pharmacotherapy early in the course of the disease because of the lack of a disease-modifying benefit. § Pharmacotherapy for COPD involves the use of inhaled medications that require patient knowledge and skill using various inhalation devices § Treatment regimens with multiple inhalation devices add complexity and may adversely impact adherence and disease management. § For patients requiring therapy with multiple inhaled medications, clinicians should prescribe devices with a similar administration technique or containing combinations of medications. 4 Pharmacotherapeutics: Recommended initial therapy 5 Pharmacotherapeutics: Recommended initial therapy 6 Pharmacotherapeutics: Recommended escalation therapy 7  Pharmacotherapeutics: Bronchodilator § Bronchodilators represent the mainstay of drug therapy for COPD and are used to relieve patient symptoms, improve exercise tolerance, and quality of life. § For patients with COPD, clinical benefits of bronchodilators include increased exercise capacity, decreased air trapping in lungs, and relief of symptoms such as dyspnea. § The use of bronchodilators does not produce significant improvements in pulmonary function measurements of expiratory airflow such as FEV1. § Bronchodilator classes available for the treatment of COPD include § Short- and long-acting β2-agonists § Short- and long-acting anticholinergics, and § Methylxanthines. § Short-acting bronchodilators relieve symptoms and increase exercise tolerance. § Long-acting bronchodilators relieve symptoms, reduce exacerbation frequency, and improve quality of life and health status 8  Bronchodilator: Short-Acting Bronchodilators § The initial recommended therapy for COPD patients who experience occasional symptoms (category A) is a bronchodilator, either long- or short-acting § Short-acting bronchodilators are also recommended for all patients for use as rescue or as-needed therapy to manage symptoms (category A, B, C, D). § Among short-acting bronchodilators, choices include short-acting β2-agonist or short-acting anticholinergic agents. § Short-acting bronchodilators do not reduce the frequency or severity of exacerbations in COPD. § Both classes are equally effective for symptom management. When a patient does not achieve adequate management of symptoms with one agent, a combination of a short-acting β2-agonist and short-acting anticholinergic is reasonable. 9  Bronchodilator: Short-Acting Sympathomimetics (β2-Agonists) § Short-acting inhaled β2-agonists cause only a small improvement in FEV1 acutely but may improve respiratory symptoms and exercise tolerance despite the small improvement in spirometric measurements. § Choices for short-acting, selective β2-agonists are albuterol and levalbuterol. § Albuterol is the most frequently used short-acting β2-agonist § Despite years of clinical use, there is no compelling evidence to suggest that levalbuterol offers a clear advantage in terms of clinical effectiveness or safety over albuterol, and it is more expensive. § The preferred route of administration for short-acting, selective β2-agonists is inhalation. The use of oral and parenteral β-agonists in COPD is discouraged because they are no more effective than properly used inhalation devices, and the incidence of systemic adverse effects such as tachycardia and hand tremor is greater. § Older patients may be more sensitive and may experience palpitations, skeletal muscle tremors, and “jittery” feelings after β2-agonist use. 10  Bronchodilator: Short-Acting Anticholinergics § When given by inhalation, anticholinergics, also referred to as antimuscarinics, produce bronchodilation by competitively inhibiting muscarinic receptors in bronchial smooth muscle and mucus glands. § Ipratropium is the most prescribed short-acting anticholinergic agent for COPD in the United States. § Studies comparing ipratropium with inhaled β2-agonists have generally reported similar improvements in pulmonary function, although ipratropium has a slower onset of action and a more prolonged bronchodilator effect. § Because of the slower onset of effect (15-20 minutes compared with 5 minutes for albuterol), ipratropium may be less suitable for as-needed use § In contrast to albuterol, ipratropium exhibits a dose-response effect with increasing dose rather than increasing frequency. § Patients may experience additional symptom improvement with a higher number of inhalations (ie, 6 puffs Q6 hours, maximum 24 puffs/day), whereas no additional improvement is seen with increasing the frequency (ie, more frequent than Q6 hours). 11 Bronchodilator: Short-Acting Bronchodilators 12  Bronchodilator: Long-Acting Bronchodilators § For patients with COPD who experience persistent symptoms, or in whom short-acting therapies do not provide adequate relief, long-acting bronchodilator therapies are recommended § Long-acting agents are also recommended as initial therapy for patients at high risk for exacerbation (category C and D). § Long-acting inhaled bronchodilator therapy can be administered as an inhaled β2-agonist (LABA) or an anticholinergic (LAMA). § For symptom management, both LABAs and LAMAs are equally effective. § Compared with short-acting agents, long-acting inhaled bronchodilator therapy is more convenient for patients with persistent symptoms and has shown superior outcomes in: § Improving lung function § Relieving symptoms § Reducing exacerbation frequency, and § Improving quality of life. 13  Bronchodilator: Long-Acting Inhaled β2-Agonists § Multiple LABAs are currently available in the United States and differ primarily by dosing frequency (twice daily vs once daily) and device type (SMI, DPI, nebulizer). § One LABA, vilanterol, is currently available in the United States only in combination with an inhaled corticosteroid (fluticasone) or long-acting anticholinergic (umeclidinium). § Arformoterol, formoterol, indacaterol, and olodaterol have an onset of action similar to albuterol (less than 5 minutes), whereas salmeterol has a slower onset (15-20 minutes). § None of these agents are recommended for acute relief of symptoms in COPD § There is no dose titration for any of these agents; the starting dose is the effective and recommended dose for all patients. § The use of the long-acting agents should be considered for patients with frequent and persistent symptoms and those at higher risk for exacerbation 14  Bronchodilator: Long-Acting Anticholinergics § Multiple LAMAs are currently available in the United States and differ primarily by dosing frequency (twice daily vs once daily) and device type (SMI, DPI, nebulizer). § Long-acting anticholinergic agents are more selective than ipratropium at blocking important muscarinic receptors. § They dissociate slowly from M3 receptors, resulting in prolonged bronchodilation with once or twice a day dosing. § Aclidinium, glycopyrrolate, and umeclidinium have a faster onset of action (5-15 minutes) compared to tiotropium (80 minutes) § There is no dose titration for any of these agents; the starting dose is the effective and recommended dose for all patients. 15  Bronchodilator: Long-Acting Anticholinergics § Long-acting anticholinergics provide similar improvements ins symptoms and health status when compared to long-acting β2-agonists § Either class is an appropriate choice for patients with persistent symptoms or those needing a step-up from short-acting agents. § When evaluating exacerbation outcomes, LAMAs (primarily tiotropium) provide a greater reduction in exacerbation frequency compared to LABAs and should be considered as first-line monotherapy for patients at high risk for exacerbation 16  Dual Bronchodilator: Combination Anticholinergics and β-Agonists § Long-acting anticholinergics provide similar improvements ins symptoms and health status when compared to long-acting β2-agonists § Combination regimens of bronchodilators are often used in the treatment of COPD as symptoms worsen over time. § Combining bronchodilators with different mechanisms of action allows the lowest possible effective doses to be used and reduces potential adverse effects from individual agents § Short-acting bronchodilators may be combined for patients experiencing persistent symptoms, although step-up to long-acting bronchodilator monotherapy is usually preferred 17  Dual Bronchodilator: Combination Anticholinergics and β-Agonists § Current clinical practice guidelines recommend combining long-acting bronchodilators for patients who have persistent symptoms or recurrent exacerbations on bronchodilator monotherapy § Combination of long-acting bronchodilators (LAMA/LABA) provides significant improvement in lung function, symptoms, and quality-of-life measures compared with LABA or LAMA monotherapy § dual long-acting bronchodilator therapy has been shown to decrease the frequency of moderate-to-severe exacerbations compared to either LAMA or LABA monotherapy. 18 Bronchodilator: Long-Acting Bronchodilators 19  Pharmacotherapeutics: Methylxanthines § Methylxanthines have been available for the treatment of COPD for at least five decades and at one time were considered first-line therapy. § With the availability of LABAs and LAMAs, the role of methylxanthine therapy has become more limited. § Because of the risk for drug interactions and significant intrapatient and interpatient variability in dosage requirements, theophylline therapy generally is considered for patients who are intolerant or unable to use an inhaled bronchodilator. § Theophylline is considered an alternative to commonly used inhaled therapies for bronchodilation and improving symptoms § The evidence does not support the use of theophylline to prevent exacerbations § Although theophylline is available in a variety of oral dosage forms, sustained-release preparations are most appropriate for the long-term management of COPD 20  Pharmacotherapeutics: Methylxanthines § Theophylline is a challenging medication to dose, monitor, and manage due to the significant intrapatient and interpatient variability in pharmacokinetics and the potential for drug interactions and toxicities. § The therapeutic range of theophylline has been 10 to 20 mcg/mL § However, because of the frequency of dose-related adverse effects and a lack of a clear benefit when used in higher concentrations, a more conservative therapeutic range of 8 to 15 mcg/mL is now targeted, especially in the elderly § When concentrations are measured, trough measurements should be obtained. § Once a dose is established, serum concentrations should be monitored once or twice a year unless the patient’s disease worsens, medications that interfere with theophylline metabolism are added to therapy, or toxicity is suspected. 21  Pharmacotherapeutics: Methylxanthines § Factors that decrease theophylline clearance and lead to reduced maintenance dose requirements include advanced age, bacterial or viral pneumonia, left or right ventricular failure, liver dysfunction, hypoxemia from acute decompensation, and use of drugs such as cimetidine, macrolides, and fluoroquinolone antibiotics. § Factors that may enhance theophylline clearance and result in the need for higher maintenance doses include tobacco and marijuana smoking, hyperthyroidism, and the use of such drugs as phenytoin, phenobarbital, and rifampin. 22  Pharmacotherapeutics: Corticosteroids § It has been postulated that inhaled corticosteroid therapy might be beneficial in COPD to slow disease progression. § Unfortunately, the results of major clinical trials have failed to demonstrate any clear benefit from chronic treatment with ICS in modifying long-term decline in lung function. § ICS have been associated with improvements in clinical endpoints related to exacerbations, including a decrease in exacerbation frequency and time to first exacerbation. § Clinical benefits of ICS therapy in COPD have been observed with combination therapy, primarily as an addition to LABA monotherapy. § Given the lack of supporting evidence and in contrast to evidence in patients with asthma, ICS monotherapy for patients with COPD is not recommended. § Severe adverse effects, such as adrenal suppression, osteoporosis, and cataract formation, have been reported less frequently than with systemic corticosteroids, but clinicians should monitor patients who are receiving high-dose chronic inhaled therapy. 23  Pharmacotherapeutics: Corticosteroids § ICS therapy is recommended for initial treatment in patients at high risk of exacerbation and with a blood eosinophil count greater than 300 cells per microliter (category D). § For escalation therapy, inhaled corticosteroids may be considered for patients who have recurrent exacerbations despite optimal therapy with inhaled bronchodilators § Subgroup analyses of several trials have indicated that patients with elevated sputum and blood eosinophil counts and those with concomitant asthma have greater therapeutic benefit with ICS therapy compared to other patients 24 Pharmacotherapeutics: Corticosteroids 25 Pharmacotherapeutics: Corticosteroids 26  Combination Therapy: Dual Therapy (LAMA/LABA or ICS/LABA) § For most patients with recurrent exacerbations despite optimal long-acting bronchodilator monotherapy, combination therapy with dual long-acting bronchodilators (LAMA/LABA) is preferred over combination therapy with ICS/LABA § A more recent study appears to contradict the superiority of LAMA/LABA over ICS/LABA for exacerbation prevention. (the IMPACT trial) 27  Combination Therapy: Triple Therapy (LAMA/LABA/ICS) § For patients with persistent symptoms and recurrent exacerbations on dual inhaled therapy, triple therapy with LAMA/LABA/ICS is recommended as initial escalation therapy for patients with blood eosinophil counts greater than 100 cells/μL (0.1 × 109/L) § Evidence for the benefit of triple therapy has emerged from recent studies evaluating combination therapy within a single device, and there is also limited evidence supporting triple therapy given by multiple devices. § Compared to dual therapy with either LAMA/LABA or ICS/LABA, triple therapy with LAMA/LABA/ICS provides additional benefit in reducing the frequency of moderate-to-severe exacerbations in patients with COPD. § Early information suggests that the addition of ICS may provide a survival benefit when compared to combination therapy with LAMA/LABA alone in some patients. 28 Combination Therapy: 29 Combination Therapy: 30 Combination Therapy: 31