1. Respiratory Pharmacology Review

2. Asthma Widespread reversible narrowing of bronchial airwaysIncreased bronchial responsiveness to inhaled stimuliLymphocytic, eosinophilic inflammation of bronchial mucosa 3. Physiology of Asthma 4. Asthma treatment by timing of presentationShort Term Treatment: Goal = relax airway smooth muscle (Short Acting Beta Agonists most common, also can use Methyxanthines or anti-muscarinics)Chronic Treatment: Goal = reduce airway inflammation (Inhaled corticosteroids most effective, can also use cromolyn or nedocromil) 5. Beta 2 agonists- most widely used for treatment for asthma! Short Acting: Albuterol, piralbuterol, metaproterenol and levalbuterol Long Acting: Salmeterol, Formeterol, Arformeterol Multiple Mechanisms of Beta 2 activation: Relaxes airway smooth muscle Inhibits mediator release Activates the Na/K pump Side Effects Tachycardia, tremor (flight or flight!) Hypokalemia Transiently decreases PaO2 as they may increase perfusion to poorly ventilated areas supplemental oxygen helpful Important note: DO NOT use long acting beta agonists by themselves, as they do not have an effect on inflammation. Combine them with corticosteroids Long Acting Beta Agonists have a BLACK BOX WARNING: can cause increased risk of death or near-death from asthma attack, especially in African American population 6. Mechanism of Beta 2 agonists 7. Directly relax airway smooth muscle (sympathomim etic agents, theophylline) 8. Mechanism of Methylxanthines (Theophylline) 9. Methylxanthines (theophylline) Multiple other mechanisms Inhibition of PDE4 on inflammatory cells reduces cytokine and chemokine release Enhancement of histone deacetylation decreased inflammatory cell gene transcription Narrow therapeutic window! Toxicity: anorexia, N/V, abdominal discomfort, HA, anxiety More severe toxicity: seizures and arrhythmias 10. Inhibit the effect of acetylcholine from vagal motor nerves (muscarinic antagonists) 11. Anti-Muscarinics Ipratropium: primarlily M3 receptor Tiotropium (longer acting): primarily M1 and M3 receptors Treatment of COPD, potential use in asthma but not approved SE: dry mouth, exacerbation of narrow angle glaucoma and myasthenia gravis 12. Pathophysiology of Asthma Widespread reversible narrowing of bronchial airwaysIncreased bronchial responsiveness to inhaled stimuliLymphocytic, eosinophilic inflammation of bronchial mucosa 13. Omaluzimab, cromolyn and nedocromilReduce amount of IgE bound to mast cells (anti-IgE antibodyomaluzimab) OR Prevent mast cell degranulation (cromolyn or nedocromil) 14. Cromolyn sodium and Nedocromil sodium (insoluble salts) Alter delayed chloride channels in cell membrane (inhibits activation): Airway nerves inhibits cough Mast cells inhibits early response to antigens (degranulation) Eosinophils inhibits inflammation NO effect on smooth muscle tone ONLY useful for prophylaxis of asthma Also has some benefit in allergic rhinoconjunctivitis SE: throat irritation, cough, dry mouth, wheezing prevented by pre-treatment of beta agonist 15. Omalizumab: IgG monoclonal antibody Inhibits IgE from binding to IgE receptor on mast cells and basophils Used for refractory asthma BLACK BOX WARNING: anaphylaxis! (2-24 hours after administration) 16. Decrease airway inflammation that is linked with increased airway responsiveness (inhaled corticosteroids) 17. Inhaled Corticosteroids Budesonide, Triamcinolone, Fluticasone, Mometasone, Flunisolide, Beclomethasone, Ciclesonide *First line treatment for asthma!* (except exercise induced asthma) Reduce bronchial reactivity and reduce frequency of asthma exacerbations when taken regularly Used as controller asthma medications- not curative Inhibit infiltration of airways by lymphocytes, eosinophils and mast cells UNIQUE SIDE EFFECT of Inhaled Corticosteroids!!! Oropharyngeal candidiasis- prevented by gargling and spitting water after use 18. Leukotriene inhibitors Leukotriene B4: neutrophil chomoattractant Leukotriene C4 and D4: cause bronchoconstriction, increased bronchial reactivity, mucosal edema and mucous hypersecretion Leukotriene D4 receptor antagonists inhibit these effects: zafirlukast and montelukast 5-lipoxegenase is the enzyme involved in leukotriene synthesis: inhibition by zileuton inhibits the above effects These agents are less effective than inhaled corticosteroids, but similar efficacy in reducing frequency of asthma exacerbations Shown to be particularly effective in aspirin-induced asthma *Zileuton MAJOR SE: LIVER TOXICITY!!! (less often used)- zafirlukast has some hepatotoxicity, but less than zileuton Monteleukast UNIQUE SE: eosinophilia and Churg Strauss Syndrome 19. COPD Differences from asthma: NOT reversible with bronchodilator treatment Occurs in older patients Neutrophil mediated Less responsive to inhaled corticosteroid treatment Acute symptoms SABA, anti-cholinergic (ipratropium) or both Persistent symptoms LABA or tiotropium (long acting) Severe airflow obstruction inhaled corticosteroid Theophylline is also useful (improves contractility of the diaphragm improved ventilatory capacity) Oxygen is needed with progression 20. Protease inhibitors 21. Protease inhibitors Helpful in patients with emphysema caused by alpha 1 anti-trypsin deficiency SE: anaphylaxis and low grade fever (especially in patients with IgA deficiency) 22. Pulmonary Hypertension Treatment Epoprostenol: FIRST LINE for severe pulmonary hypertension Mechanism: vasodilation and inhibition of clotting SE: Jaw pain, chest pain, weakness, shortness of breath, arrhythmias, flushing, hypotension Treprostinil: prostanoid- pulmonary and systemic vasodilation; inhibits platelet aggregation Iloprost: Prostaglandin- vasodilation, suppression of vascular smooth muscle proliferation, inhibition of platelet aggregation Bosentan: non-selective endothelin receptor antagonist SE: hepatotoxicity Ambrisentan: selective type A endothelin-1 receptor antagonist Sildenafil and Tadalafil: cGMP phosphodiesterase inhibitor (prolongs nitric oxygen prolonged vasodilation)