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  • Decrease airway inflammation that is linked with increased airway responsiveness

Transcript

  • 1. Respiratory Pharmacology Review
  • 2. Asthma Widespread reversible narrowing of bronchial airways Increased bronchial responsiveness to inhaled stimuli Lymphocytic, eosinophilic inflammation of bronchial mucosa
  • 3. Physiology of Asthma
  • 4. Asthma treatment by timing of presentation Short 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 airways Increased bronchial responsiveness to inhaled stimuli Lymphocytic, eosinophilic inflammation of bronchial mucosa
  • 13. Omaluzimab, cromolyn and nedocromil Reduce 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)