Respiratory Pharmacology: Asthma/COPD Fall 2024 PDF
Document Details
LSUHSC
2024
Keira F Weed
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Summary
This document is lecture notes on Respiratory Pharmacology covering asthma and chronic obstructive pulmonary disorder (COPD). It details the pathophysiology, different types of medications, and treatment approaches for both conditions. Topics such as learning objectives, outlines, and mechanisms of action are also discussed.
Full Transcript
Respiratory Pharmacology: Asthma / Chronic Obstructive Pulmonary Disorder Keira F Weed, PhD, MPH [email protected] Learning Objectives 1. Briefly review the pathophysiology of asthma and biochemical mechanisms responsible for asthma s...
Respiratory Pharmacology: Asthma / Chronic Obstructive Pulmonary Disorder Keira F Weed, PhD, MPH [email protected] Learning Objectives 1. Briefly review the pathophysiology of asthma and biochemical mechanisms responsible for asthma symptoms and triggers. 2. Describe and understand the categorization of asthma medications based upon bronchodilators/anti-inflammatory action along with indication for acute relief versus long-term control of symptoms. 3. Classify the primary and secondary medications used for quick relief of asthma symptoms. 4. Classify the primary and secondary medications used for long-term control of mild to severe asthma symptoms. 5. Demonstrate understanding why a specific medication would be preferred based upon symptom presentation. 6. Briefly review the pathophysiology of chronic obstructive pulmonary disease (COPD). 7. Understand how treatment of COPD differs from asthma and alters preferred medication choices. Outline Asthma Pathology Routes of Administration Pharmacology Bronchodilators Corticosteroids Leukotriene Antagonists Biologics/Immunotherapies Chronic Obstructive Pulmonary Disorder (COPD) Pathology Pharmacology The Inflamed Lung: An Example of Excess Inflammation is important in protecting the lungs against pathogens Excessive inflammation and its resulting lung injury are an essential component of many lung diseases Mucus is an important for defending airways against pathogens, where it immobilizes invading pathogens. Excess mucus alters gas exchange. Bronchoconstriction For example, in asthma, airways become hyper-responsive to mediators such as histamine and cholinergic stimulation. Pathology of Asthma Pathology of Asthma Normal Lung Efficient gas exchange Asthmatic Lung Inflammation Lower airways obstruction: inflammation, constriction, mucus Airway hyperresponsiveness Airway remodeling Chronic and PROGRESSIVE! The Heterogeneity of Asthma Immunopathogenesis of Asthma Outline Asthma Pathology Routes of Administration Pharmacology Bronchodilators Corticosteroids Leukotriene Antagonists Biologics/Immunotherapies Chronic Obstructive Pulmonary Disorder (COPD) Pathology Pharmacology Routes of Administration - Inhalation Preferred route Localized administration minimize systemic adverse effects β2 Receptor Agonists Corticosteroids Muscarinic Receptor Antagonists Routes of Administration - Inhalation Delivery Devices: Pressurized Metered-Dose Inhalers delivery with propellant Spacer Chambers spacer between pMDI and mouth reduces velocity/size of drug particles before reaching upper airways Dry Powder Inhalers delivery as micronized dry powder (requires minimum inspiratory flow) Nebulizers produce nebulized form of drug that can be delivered during tidal breathing / in higher doses than pMDI Routes of Administration - Oral Systemic administration Require larger doses than inhaled Corticosteroids Leukotriene Antagonists Methylxanthines Routes of Administration - Parenteral Reserved for severely ill/emergency situations Corticosteroids Adverse effects more frequent than other routes Methylxanthines For long-term moderate-to-severe asthma control Immunotherapies Outline Asthma Pathology Routes of Administration Pharmacology Bronchodilators Corticosteroids Leukotriene Antagonists Biologics/Immunotherapies Chronic Obstructive Pulmonary Disorder (COPD) Pathology Pharmacology Therapeutic Mechanisms of Action Medications Used for Asthma Relief Bronchodilators β Adrenergic Agonists 2 Muscarinic M3 Antagonists Methylxanthines Immunomodulatory Agents Corticosteroids Leukotriene Pathway Inhibitors Biologics Medications Used for Asthma Relief Long-term Control Quick Relief (RESCUE) Corticosteroids - inhaled Short-acting β2-agonists Long-acting β2-agonists Corticosteroids – IV / oral Methylxanthines - oral Methylxanthines – IV Leukotriene antagonists Short-acting muscarinic antagonists Long-acting muscarinic antagonists Biologics Control and prevent asthma Provide relief of acute asthma symptoms episodes Make airways less sensitive to Bronchodilators triggers and prevent inflammation that leads to an acute asthma episode (Immunomodulatory) Taken on a daily basis Combination Therapies Use of Single Therapies Rare Instead combine different pharmacological therapies with different mechanisms of action together Example Combination Inhalers: long-acting β2 agonist (LABA) + inhaled corticosteroid (ICS) Inhaled corticosteroid (ICS) + long-acting muscarinic antagonist (LAMA) For COPD: short-acting muscarinic antagonist (SAMA) + short-acting β2 agonist (SABA) long-acting muscarinic antagonist (LAMA) + long-acting β2 agonist (COPD) Rescue – “quick” relief drugs Primarily bronchodilators – open airways quickly Usually do not treat inflammation of the airways Short-acting β2 receptor agonists (SABA) Short-acting muscarinic receptor antagonists (SAMA) Emergency treatments: I.V. methlyxanthines I.V. corticosteroid – treat inflammation Long-Term Control Drugs Primarily treat inflammation of the airways Long acting β2 receptor agonists (LABA) Long-acting muscarinic receptor antagonists (LAMA) Sustained-release oral methylxanthines Inhaled corticosteroids Leukotriene antagonists Biologics β2 Adrenergic Receptors β2 Adrenergic Receptors Short-Acting β2 Agonists (SABAs) Acute Relief: albuterol (ProAir, Proventil, Ventolin), levalbuterol (Xenopex) Others: ephedrine, epinephrine, metaproterenol, terbutaline Therapeutic Indications: Prevention of exercised-induced asthma; rapid relief of asthma / bronchospasm Intermittent asthma symptoms Long-term control of asthma (oral albuterol/terbutaline) Pharmacokinetics: Onset: within 5 min (depending upon formulation) Duration: 3 - 6 h Administration: inhaled, oral Adverse Effects: tremor, tachycardia/angina (cardiac β1 receptors) Long-Acting β2 Agonists (LABAs) Controllers: formoterol, salmeterol, indacaterol, vilanterol, olodaterol Therapeutic Indications: Long-term control of asthma (NOT monotherapy) Pharmacokinetics: Onset: 5 - 30 m Duration: 12 -24 h Administration: inhaled Adverse Effects: (dose-dependent) hypotension, hypertension, vascular headaches, tremors, arrhythmia, angina Warning: increased chance of serious/fatal asthma when used alone LABAs should never be used alone to control asthma Muscarinic (M3) Pulmonary Receptors Short-Acting Muscarinic Antagonists (SAMAs) ipratropium (Atrovent HFA) Therapeutic Uses: COPD greater effect than inhaled β2-adrenergic agonists due to inhibition of vagal airway tone Asthma (off-label) not responsive to inhaled β2-adrenergic agonists / theophylline not sufficient; inhaled β agonists contraindicated (i.e. cardiac ischemia/arrhythmia, severe tremor) Administration: inhaled Pharmacokinetics Onset: within 15 m Duration: meter-dose inhaler 2-4 h; nebulizer 4-5 h Adverse Effects: dry mouth, hoarseness, bitter taste Consideration for patients w/ narrow-angle glaucoma Long-Acting Muscarinic Antagonists (LAMAs) tiotropium (Spiriva HandiHaler), glycopyrrolate (Lonhala Magnair, Seebri Neohaler), umeclidinium (Incruse Ellipta) aclidinium (Tudorza Pressair) Therapeutic Uses: COPD greater effect than inhaled β2-adrenergic agonists due to inhibition of vagal airway tone often combined w/LABA Asthma if poor response to inhaled β2-adrenergic agonists / theophylline not sufficient inhaled β agonists are contraindicated (i.e. cardiac ischemia/dysrhythmia; severe tremor) Administration: inhaled Pharmacokinetics: Onset: 5-15 m Duration: > 24 h Adverse Effects: dryness of mouth, hoarseness Consideration for patients w/ narrow-angle glaucoma Methylxanthines Mechanisms of Action: Inhibits Phosphodiesterase Raise levels of intracellular cAMP Bronchial smooth muscle relaxation Inhibits IgE release of mast cell mediators Competitive Antagonist at Adenosine Receptors Bronchial smooth muscle relaxation IL-10 Release Inflammatory mediator suppression Enhancement of Corticosteroid Anti- Inflammatory Effect Methylxanthines theophylline (Elixophyllin, Theocron), aminophylline (synthetic) Therapeutic Uses: Oral: mild persistent asthma, COPD (alternative; not as effective as β2 adrenergic agonists) IV: emergency for rapid relief (alternative; not as effective as β2 agonists / corticosteroids) Administration: oral (theophylline), intravenous (theophylline, aminophylline) Pharmacokinetics: Onset and Duration: variable Effect: 1-2 h (oral); 30 min (IV) Adverse Effects: restlessness, GI upset Corticosteroids Corticosteroid Effects on Asthma Corticosteroids Mechanism of Action: Alter gene regulation Reduce mediators of inflammation Immunosuppression Administration: Inhaled Intravenous Oral Inhaled Corticosteroids beclomethasone (Quvar RediHaler), fluticasone (Flovent Diskus, Arnuity Ellipta), budesonide (Pulmicort), mometasone (Asmanex) Therapeutic Use: persistent asthma (first line) COPD (second line) Adverse Effects: mostly throat/mouth oropharyngeal candidiasis, dysphonia, cough Risk of systemic effects with overuse Often combined with long-acting β2 Intravenous Corticosteroids hydrocortisone (Cortef); methylprednisolone rapid onset: within one hour Therapeutic Use: Severe acute asthma attacks (< 30% lung function w/ no improvement from quick relief medications) Adverse Effects: Mood disturbances, increased appetite, impaired glucose control in diabetics, and candidiasis Long-term use: see Corticosteroid lecture Used short term and at lowest doses Oral Corticosteroids prednisone, prednisolone (Millipred, Pediapred) Duration: 6-8 h Therapeutic Uses: Exacerbations of asthma symptoms One-two week regimen Adverse Effects: Mood disturbances, increased appetite, impaired glucose control in diabetics, and candidiasis Long-term use: see Corticosteroid lecture Used short term and at lowest doses Corticosteroids Inhalation: Spacer Benefits - large-volume spacers Use Lowest Dose Necessary to Control Asthma Minimizing Adverse Effects Inhalation Rinse / Gargle with water after administration Oral Bone loss: adequate intake of calcium and Vitamin D and participate in weight bearing exercise Anti-Leukotrienes Anti-Leukotrienes – 5’-lipoxygenase Enzyme Inhibitor zileuton (Zyflo) Therapeutic Indications: chronic asthma Administration: oral Pharmacokinetics: Half-Life: 3 h Requires frequent dosing (4x/day) due to short Duration of Action Extended Release formulations available (2x/day) Adverse Effects: headache, pain, UTI, hepatic dysfunction (rare) Drug Interactions: warfarin, theophylline (reduce metabolism) Anti-Leukotrienes – Leukotriene Receptor Antagonists montelukast (Singulair), zafirlukast (Accolade) Therapeutic Indications: mild chronic asthma in adults / children Administration: oral Pharmacokinetics: Half-Life: ~ 5-10 h Duration of Action: 12-24 h Adverse Effects: headache, infection (rare) Drug Interactions: montelukast – phenytoin (inhibit effects) zafirlukast – warfarin, theophylline (inhibit metabolism) Outline Asthma Pathology Routes of Administration Pharmacology Bronchodilators Corticosteroids Leukotriene Antagonists Biologics/Immunotherapies Chronic Obstructive Pulmonary Disorder (COPD) Pathology Pharmacology Anti-IgE Therapy omalizumab (Xolair) high cost > $10,000 / yr Therapeutic Use: moderate-to-severe persistent asthma w/ IgE- mediated hypersensitivity IgE levels must be high enough to be impacted by treatment Requires skin testing / radioallergosobent test (RAST) to perennial allergens Administration: SC; every 2 or 4 weeks Pharmacokinetics: Peak Plasma: 7-8 days Adverse Effects: injection-site reaction, infections, anaphylaxis, cancer Anti-IL-5 Therapy mepolizumab (Nucala) SC every 4 weeks reslizumab (Cinquair) IV every 4 weeks benalizumab (Fasenra) SC every 8 weeks high cost > $15,000 / yr Therapeutic Use: severe eosinophilic (type-2) asthma Adverse Effects: hypersensitivity, anaphylaxis (0.3%) Other Immunotherapies dupilumab (Dopixent) Mechanism of Action: antibody against IL-4 / IL-13 Therapeutic Uses: moderate-to-severe asthma with severe eosinophilia; or severe uncontrolled asthma Administration: SC every 2 weeks Adverse Effects: Local site reaction, anaphylaxis Outline Asthma Pathology Routes of Administration Pharmacology Bronchodilators Corticosteroids Leukotriene Antagonists Biologics/Immunotherapies Chronic Obstructive Pulmonary Disorder (COPD) Pathology Pharmacology Chronic Obstructive Pulmonary Disorder (COPD) Chronic Obstructive Pulmonary Disease (COPD) Approx. 6% of US population 6th leading cause of death per year $26 billion / year Approx. 108,000 deaths Chronic Obstructive Pulmonary Disease (COPD) Chronic Obstructive Pulmonary Disorder (COPD) Risk Factors Cigarette Smoking (tobacco and other products) Exposure to Tobacco Smoke via Passive Smoking Biomass / Other Pollution Exposure Household, ambient air, wildfire smoke, occupational hazard pollutions Genetic Factors Age – lung function decreases later in life Asthma – greater risk of developing COPD later in life Chronic Bronchitis – commonly associated with COPD; increased risk of exacerbation Severe Respiratory Infections During Childhood Poverty Chronic Obstructive Pulmonary Disorder (COPD) Clinical Indicators Chronic Cough Typically first presentation symptom; progressive in over time Sputum Production – can be intermittent; timing during more severe symptoms Dyspnea – progressive over time; exercise intolerance; persistent Recurrent Wheeze – can change in severity across days / during day Forced Spirometry FEV1/FVC < 0.7 Recurrent Lower Respiratory Tract Infections History of Risk Factors (Previous Slide) Chronic Obstructive Pulmonary Disorder (COPD) Clinical Indicators Dyspnea Progressive over time Exercise intolerance Persistent Recurrent Wheeze Chronic Cough May be intermittent, unproductive (no sputum) Recurrent Lower Respiratory Tract Infections History of Risk Factors (Previous Slide) COPD Chronic Obstructive Pulmonary Disorder (COPD) Non-Drug Therapies Smoking cessation – Reduces development of symptoms and improves survival Pulmonary rehabilitation – improves patients following hospitalizations due to COPD-related exacerbations Improves dyspnea, health status, exercise tolerance in stable patients Reduces hospitalization time among patients with recent exacerbation events Long-term oxygen therapy – PaO2 ≤ 55 mmHg or < 60 mmHg with cor pulmonale Increases survival in patients w/ severe resting arterial hypoxemia Noninvasive positive pressure ventilation – stable COPD w/ marked hypercapnia Improve hospitalization-free survival in patients w/daytime persistent hypercapnia after recent hospitalization (PaCO2 > 53 mmHg) Chronic Obstructive Pulmonary Disorder (COPD) Pharmaceuticals: Preferred (improve symptoms for all patients) Long-acting muscarinic antagonists (LAMAs) / short-acting muscarinic antagonists (SAMAs) Long-acting β2-agonists (LABA) / short-acting β 2-agonists (SABAs) Phosphodiesterase Inhibitor (roflumilast) – moderate-severe exacerbations Vaccines (influenza, COVID-19, pneumococcal, Tdap) – respiratory disease protection Antibiotics (azithromycin) – exacerbation reduction Second Line Inhaled Corticosteroids – reserved for patients with moderate-severe COPD; combined with bronchodilator) Phosphodiesterase-4 Inhibitor roflumilast (Daliresp) Mechanism of Action: prodrug for roflumilast N-oxide; nonselective PDE4 inhibitor Anti-inflammatory action – improved respiratory function + reduces frequency of exacerbations Therapeutic Use: COPD w/ severe disease (FEV1 < 50%), chronic bronchitis moderate-severe COPD + uncontrolled symptoms, even on triple therapy (LABA + LAMA + ICS) Administration: oral Pharmacokinetics: Half-Life: 17 h (active metabolite roflumilast N-oxide t1/2 30 h) Adverse Effects: diarrhea, nausea, headaches Contraindication: patients with liver dysfunction Chronic Obstructive Pulmonary Disorder (COPD) Combination Therapies: Acute Relief Short-acting Muscarinic Antagonist (SAMA) + Short- Acting Beta-2 Agonist (SABA) Long-Term Control Long-Acting Muscarinic Antagonist (LAMA) + Long- Acting Beta-2 Agonist (LABA); Long-Acting Beta-2 Agonist (LABA) + Inhaled Corticosteroid (ICS); Triple Therapy: Long-Acting Beta-2 Agonist (LABA) + Long-Acting Muscarinic Agonist (LAMA) + Inhaled Corticosteroid (ICS) QUESTIONS?
