2023_RS1_Asthma_COPD_LEO.pptx

Drugs That Affect the Bronchi Goal To provide an overview of the drugs acting on the bronchi as bronchodilators or as anti-inflammatory drugs and to discuss the mechanisms of action of such drugs. Objectives • Discuss the mechanism of action, adverse effects, contraindications, and potential dru...

Drugs That Affect the Bronchi Goal To provide an overview of the drugs acting on the bronchi as bronchodilators or as anti-inflammatory drugs and to discuss the mechanisms of action of such drugs. Objectives • Discuss the mechanism of action, adverse effects, contraindications, and potential drug interactions of drugs used in the treatment of asthma and COPD. Pathophysiology: Bronchial Asthma or other inflammatory stimuli edema mucus secretion Treatment Strategy in Asthma • The treatment strategy is to avoid bronchoconstriction by: – Identification and avoidance of noxious stimuli – Prophylactic anti-inflammatory treatment • Bronchodilators are used primarily to cure acute asthma attacks (short-acting drugs) but are sometimes (in more severe cases) also needed for maintained bronchodilation (long-acting drugs). Pathophysiology: COPD α1-antitrypsin deficiency Alpha1-antitrypsin Deficiency Augmentation Therapy • Alpha1-antitrypsin (AAT) is an endogenous protease inhibitor. • In lungs of patients with AAT deficiency, an imbalance between neutrophil elastase and the elastase inhibitor AAT, can lead to alveolar wall destruction and emphysema. • Four pooled human plasma AAT products are available: – Aralast NP – Prolastin-C (also available as Prolastin C – Liquid) – Zemaira – Glassia • These AAT products are given as weekly infusions to augment the AAT levels in the blood and lung interstitium. Treatment Strategy in COPD • In contrast to asthma, the inflammation in patients with COPD is largely corticosteroid resistant, and there are currently no effective anti-inflammatory treatments. • In COPD, fibrosis of the small airways together with mucus hypersecretion severely impedes airflow through the small airways. • Thus, the most important therapeutic strategy in COPD is to induce persistent chronic bronchodilation. Remember ! • The first-line treatment strategy – In asthma is prophylactic (chronic) anti-inflammatory treatment with ICSs. – In COPD is chronic bronchodilation with LAMA (preferred) or LABA. Controllers • Corticosteroids • Mast cell degranulation blockers • Leukotriene pathway inhibitors • Anti-IgE antibodies • IL-5 inhibitors • PDE-4 inhibitors Rescue agents • β2-agonists • M3-antagonists • Methylxanthines • PDE-4 inhibitors Overview of Classes of Drugs for Asthma / COPD • Controllers (Anti-inflammatory / immune modulators) – Corticosteroids – Leukotriene pathway inhibitors – Mast cell degranulation blockers – Anti-IgE antibodies – IL-5 and PDE-4 inhibitors • Rescue Agents (Bronchodilators) – β2-adrenergic agonists – Muscarinic antagonists – Methylxanthines – PDE-4 inhibitor (roflumilast) Corticosteroids in Bronchial Asthma • Inhaled corticosteroids (ICSs) constitute a first-line therapy for chronic asthma. • ICSs are much less effective in COPD ! • Sensitization of β2-receptors (less bronchoconstriction) • Inhibition of mucus glycoprotein secretion (less mucus). • Reduction in number of mast cells lining the surfaces of airway mucosal cells. • Reduction in chemotaxis and activation of eosinophils • Reduction in cytokine production by eosinophils, monocytes, mast cells, and lymphocytes. • Corticosteroids do not relax bronchial smooth muscle ! Anti-inflammatory Actions of Glucocorticoids • Glucocorticoids affect: – Macrophages / dendritic cells (biggest effect) – B-cells and T-lymphocytes • Modulation of immune cell function – Expression of surface receptors on immune cells – Transcription of anti-inflammatory proteins/cytokines (e.g., lipocortin) – Reduced expression of pro-inflammatory cytokines – Release of vasoactive substances (reduced capillary permeability, preventing edema) – Inhibition of lysosomal enzymes and activity Lipocortins Synthesis and action of prostaglandins COX-1 COX-2 • Phospholipase A2 forms arachidonic acid from phospholipids of the cell membrane. • Cyclooxygenases (COX) convert arachidonic acid to cyclic endoperoxides from which prostaglandins, prostacyclin and thromboxan A2 are synthesized. • Lipoxygenases convert arachidonic acid to leukotrienes. Glucocorticoids and Blood Cells • Decreased concentration of: – Lymphocytes (T- and B-cells), monocytes, eosinophils, basophils – Efflux from blood to lymphatic tissue  – Increased apoptosis • Increased concentration of: – Neutrophils, erythrocytes, platelets – Efflux from bone marrow  – Migration out of blood vessels  Inhaled Glucocorticoids • Drugs: fluticasone (e.g., Flovent), flunisolide (e.g., Aerobid) beclomethasone (e.g., Qvar), BA budesonide (e.g., Pulmicort), <20% mometasone (e.g., Asmanex) ciclesonide (e.g., Alvesco, less systemic effects) • Mechanism of action: • Inhibition of synthesis of cytokines (interleukins, TNF), phospholipase A2, and cyclooxygenase. • Stimulation of synthesis of lipocortin. Lipocortin inhibits the enzyme phospholipase A2 and, therefore, inhibits the arachidonic acid pathway and reduces synthesis of prostaglandins and leukotrienes. • Caveat: Rinse mouth after use to prevent oral thrush. • Systemic side effects are rare with inhaled application. Side Effects of Inhaled Corticosteroids Local side effects (frequent) • Dysphonia (weakness of voice, 40% of patients) • Oropharyngeal candidiasis (5% of patients) • Cough (mostly with metered dose inhalers) Systemic side effects (rare) • Adrenal suppression and insufficiency (taper dose) • Growth suppression • Bruising • Osteoporosis • Cataracts, Glaucoma • Metabolic abnormalities (glucose, insulin, triglycerides) • Psychiatric disturbances (euphoria, depression) • Pneumonia Inhibition of Leukotriene Synthesis Zileuton “Lukasts” COX-1 COX-2 • Phospholipase A2 forms arachidonic acid from phospholipids of the cell membrane. • Cyclooxygenases (COX) convert arachidonic acid to cyclic endoperoxides from which prostaglandins, prostacyclin and thromboxan A2 are synthesized. • Lipoxygenases convert arachidonic acid to leukotrienes. Leukotriene Pathway Inhibitors • Indications: Asthma (controller therapy), seasonal allergies Particularly effective in aspirin- and exercise-induced asthma • Drugs: montelukast (once a day, e.g., Singulair) zafirlukast (twice a day, e.g., Accolate) • Mechanism: cysteinyl-leukotriene receptor antagonists that antagonize the actions of LTC4, LTD4, and LTE4 on airway smooth muscle and vascular endothelium. • Zileuton (e.g., Zyflo CR): Lipoxygenase (LOX)-inhibitor. • Application: oral as tablets • Unwanted effects: hepatic dysfunction (particularly with zileuton, rare, monitor liver enzymes ALT), unusual weakness, stomach upset, diarrhea, dizziness, cough, headache, nausea, vomiting, insomnia, flu-like infections, Churg-Strauss syndrome (vasculitis), neuropsychiatric adverse effects (depression). Mast Cell Degranulation Blockers Mast Cell Degranulation Blockers • Drug: cromolyn sodium (e.g., Intal) • Mechanism: block mast cell degranulation Anmi visnaga (toothpickweed) by suppressing release of mediators of bronchoconstriction and reducing eosinophil recruitment through membrane stabilization and inhibition of chlorine channels. • Can be used in atopic and non-atopic asthma because they act on mast cells, basophils, eosinophils, and T-cells. • Also effective in exercise-induced asthma. • Less frequently used because ICSs are more effective. • Application: Only locally (e.g., nebulizer inhalation) no absorption with oral application ! • Unwanted effects: Chest tightness, cough. Anti-IgE Antibody - Omalizumab Anti-IgE Antibodies • Indications: Atopic (extrinsic, allergic) asthma – Less effective for intrinsic asthma (not IgE-mediated !) – Safety and effectiveness for other allergic indications remain to be demonstrated. • Drugs: Omalizumab (=rhuMAb-E25) • Mechanism: Recombinant humanized monoclonal antibody to IgE. Binds to circulating IgE in the blood and blocks release of inflammatory mediators by keeping IgE from binding to mast cells. • Administration: parenteral injections every 2-4 weeks. • Cost: $500 - $3,000 per month! Anti-IL-5 Therapy in Eosinophilic Asthma Anti-interleukin-5 Therapy for Severe Asthma: A new Therapeutic Option / month What About Anti-Histamines ? Little effect on allergic bronchospasm in humans ! Rescue Agents (Bronchodilators) Groups of drugs: • β2-adrenergic agonists (e.g., albuterol, salmeterol, formoterol) • Muscarinic (parasympathetic) antagonists (e.g., ipratropium bromide) • Xanthines (e.g., theophylline) • PDE-4 inhibitors (e.g., roflumilast) β-adrenergic Agonists α1 α2 β1 β2 α1 α2 β1 β1 β2 Inhaled β2-adrenergic Agonists • Most frequently used bronchodilators ! • Systemic β agonists (e.g., isoproterenol) are “last resort” drugs. • Short-acting β2-agonists (SABAs,~3-4 hours): albuterol, terbutaline, metaproterenol administered through metered-dose inhaler • Long-acting β2-agonists (LABAs, >12 hours): Can be used as mono-therapy in COPD but not in asthma ! In asthma LABAs are usually used in combination with an ICS in a fixed-dose combination inhaler. formoterol, salmeterol (~12-15 hours duration) indacaterol, olodaterol, vilanterol (>24 h duration) • Adverse effects: rare with inhalation, hypokalemia, lactic acidosis, tremor, tachycardia (in excessive amounts) Anti-inflammatory Effects of β2-Agonists Journal of Allergy and Clinical Immunology 1999 104, S10-S17 What About Tachyphylaxis With β2 agonists? • Chronic treatment with long-acting β2 agonists can result in downregulation of β2 receptors (tachyphylaxis). • Corticosteroids sensitize the bronchial smooth muscle for β2 agonists by upregulating β2 adrenergic receptor density ! • Thus, long-acting β2 agonists are usually combined with ICS in asthma, because the upregulation of β2-receptors in response to ICS compensates for the downregulation of the receptors (tachyphylaxis) in response to chronic β2 stimulation. Anticholinergics Anticholinergics Muscarinic Receptor Antagonists Muscarinic Antagonists • Particularly effective in COPD, because COPD is usually a problem of the small airways. • A small change in bronchiole diameter has a huge effect on airway resistance (Hagen-Poiseuille). Anticholinergics M3 Muscarinic Receptor Antagonists • Indications: COPD (main indication), asthma (if β2-agonists are not tolerated or if asthma is not controlled on ICS/LABA) • SAMA (6-8 h): ipratropium bromide LAMA (12-24 h): tiotropium, aclidinium, umeclidinium, glycopyrrolate • Mechanism: – Prevention of parasympathetic bronchoconstriction (M3). – Blockade of Nn receptors at parasympathetic ganglia. – Decrease in mucus secretion. • Application: Inhalation • Side effects: Generally, well tolerated when inhaled. On stopping inhaled anticholinergics, a small rebound increase in airway responsiveness has been described. Dry mouth with LAMAs, urinary retention can occur in elderly patients. Muscarinic and Anti-muscarinic Effects DUMBBELLS • • • • Diarrhea Urination Miosis Bronchorrea - Constipation - Urinary Retention - Mydriasis - Dry Bronchi and - Bronchodilation - Anti-emetic - Dry Eyes - Constipation - Dry Skin Xerostomia • • • • • Bronchospasms Emesis Lacrimation Laxation Sweating Indacaterol – Glycopyrrolate Combination (Utibron Neohaler) • Indacaterol (IND): selective β2-agonist that relaxes bronchial smooth muscle with little effect on heart rate; acts locally in the lung. • Glycopyrrolate (GLY): M1,3-muscarinic receptor antagonist that causes bronchodilation in COPD. • IND/GLY is a fixed LABA/LAMA combination, that is only indicated for COPD and not for asthma. • In COPD, LABA/LAMA combinations can significantly improve lung function, dyspnea, symptoms and health status and reduce exacerbations compared to an inhaled corticosteroid/LABA. Methylxanthines and Caffeine The effects of methylxanthines on asthma were discovered based on the observation that consumption of strong coffee reduces the symptoms of asthma. Theophylline Caffeine Methylxanthines (Theophylline, Aminophylline) Gi l Adenyly e s la cyc • PDE inhibition  cAMP   bronchodilation • Blockade of A1-adenosine receptors  bronchodilation • IL-10 release  • NF- B translocation to nucleus  • Histone deacetylase activity  Methylxanthines (=Xanthines) • Developed based on the observation that strong coffee relieves the symptoms of asthma. Now rarely used. • Drugs: theophylline (e.g., Elixophyllin), aminophylline • Application: i.v. or per os (as slow-release preparation) • Duration of action of slow-release preparations: 16-18 h • Narrow therapeutic window (therapeutic plasma concentration: 10 μg/mL; adverse effects at 20 μg/mL). • Adverse effects: nausea, cardiac arrhythmias (cardiotoxicity), convulsions (neurotoxicity). • Drug interactions: – barbiturates, benzodiazepines (enzyme inducers)  plasma concentration of xanthines  – cimetidine, erythomycin, ciprofloxacin, allopurinol (enzyme inhibitors)  plasma concentration of xanthines  Unwanted Effects of Methylxanthines (think coffee) • • • • • • Convulsions Increased alertness Fatigue deferral Nervousness Tachyarrhythmias Increased gastric acid and digestive enzyme secretion  GI upset • Increased muscle contractility  muscle cramps • Diuresis Phosphodiesterase 4 (PDE4) Inhibitor Roflumilast (e.g., Daliresp) • FDA approved for COPD with severe disease. • PDE4 inhibitors relax smooth muscle and inhibit inflammatory cells through an increase in intracellular cAMP. • PDE4 is the predominant PDE isoform in inflammatory cells. • Can be effective on top of LABA/LAMA and ICSs. • Dose: 500 mcg once per day, per os. • Side effects: diarrhea, headaches, nausea. • Cost: $300-$500 per month. • Caveat: Roflumilast differs from theophylline, because theophylline is a non-specific PDE inhibitor. The End