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Respiratory Drugs

Respiratory Drugs. Stephania Cormier, PhD scorm1@lsuhsc.edu. Outline. Asthma Chronic Bronchitis Emphysema COPD Chronic bronchitis Emphysema. Asthma. 23 million Year 12.4 million “attack” 1.8 million ER visits $21 billion health care costs & meds >5000 deaths. Asthma .

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Respiratory Drugs

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  1. Respiratory Drugs Stephania Cormier, PhD scorm1@lsuhsc.edu

  2. Outline • Asthma • Chronic Bronchitis • Emphysema • COPD • Chronic bronchitis • Emphysema

  3. Asthma • 23 million • Year • 12.4 million “attack” • 1.8 million ER visits • $21 billion health care costs & meds • >5000 deaths

  4. Asthma • Normal Lung • Efficient gas exchange • Asthmatic Lung • Inflammation • Lower airways obstruction: inflammation, constriction, mucus • Airway hyperresponsiveness • Airway remodeling • Chronic and PROGRESSIVE!

  5. Immunopathogenesis of Asthma

  6. Allergen Mast Cell BRONCHOSPASM • Mediators • Histamine • Leukotrienes • Prostaglandins • Interleukins • Triggers • Cold air • Exercise • Tobacco smoke • Other smoke • Pollutants Airflow Limitation • Inflammatory cell recruitment • Eosinophils • Leukocytes • macrophages • Mediators • Cytokines • Interleukins • Leukotrienes Bronchial hyperreactivity INFLAMMATION

  7. COPD • 12 million • 4th leading cause of death • Year • $26 billion / year • >127,000 deaths

  8. Medications Used for Asthma Relief • Control and prevent asthma symptoms • Make airways less sensitive to triggers and prevent inflammation that leads to an acute asthma episode (Immunomodulatory) • Taken on a daily basis • Provide relief of acute asthma episodes • Bronchodilators

  9. β2 Adrenergic Receptor Agonists • Inflammatory Cells • Vasoactive amines • Lipid mediators • SMC hyperplasia

  10. β2 Adrenergic Receptor Agonists • Relievers: short-acting (SABAs) • Adrenaline (epinephrine)….ephedrine (Ma-Huang): α, β1,β2 • Stimulates cAMP production • Terbutaline, albuterol, pirbuterol, bitolterol, levalbuterol (R-albuterol): β2 >β1 (220- 400 x) • Pharmacokinetics • Onset: 5 -10 m • Effect: 30 m • Duration: 4 - 6 h • Administration: inhaled, oral (terbutaline:SC) • Side Effects: tremor, tachycardia – cardiac β1 receptors. S-albuterol more active at β1

  11. β2 Adrenergic Receptor Agonists • Controllers: long-acting (LABAs); selective β2 agonists • Formoterol • Salmeterol • Pharmacokinetics • Onset: 15 - 30 m • Peak Effect: 22 h • Duration: 12 -24 h • Administration: inhaled • Side Effects: hypotension, hypertension, vascular headaches, tremors. Tolerance over time. • Warning: increased chance of serious or fatal asthma

  12. Salmeterolxinafoate (SEREVENT) formoterol(FORADIL)

  13. Methylxanthines • MOA • Inhibits PDE • High levels cAMP • SM relaxation • Inhibits IgE release of mast cell mediators • Competitive antagonist at adenosine (A2) receptors • Adenosine • Bronchoconstriction • Potentiate inflammatory mediator release • Forms • Theophylline, Caffiene (>) • Synthetic: Aminophyline (>theophylline) , Dyphilline, Oxtriphyline

  14. Methylxanthines • Use: very limited (CNS stimulants) • Administration: Oral, Inhaled, (rectal, IV) • Pharmacokinetics: • Onset: unknown • Effect: 1-2 h • Duration: varies • Side Effects: nausea, vomiting, anorexia • Cardiac effects: sinus tachycardia, extrasystole, palpitations, arrhythmia • Kidney: weak diuretic • Skeletal Muscle: increase contractions

  15. Anticholinergics • 1896: asthma cigarettes • Stramonium • Atropine, ipratropium, and tiotropium • MOA: Competitive antagonists of muscarinic Ach receptors • Use: • Asthma • not responsive to inhaled β2-adrenergic agonists • inhaled β agonists are contraindicated (i.e. cardiac ischemia or arrhythmia) • Chronic bronchitis/emphysema/COPD • Administration: A: IV, I, T:inhalation, T: oral • Pharmacokinetics: • Onset: 5-15 m • Effect: 1-2 h • Duration: 4-5 h • Side Effects: dryness of mouth and airway, headache. Rarely: tachycardia, dry eyes/blurred vision, urinary retention

  16. Corticosteroids • MOA: gene regulation • Anti-inflammatory • Immunosuppression • Administration • Inhaled: beclomethasone, triamcinolone, fluticasone, budesonide, flunisolide, mometasone • Side Effects: Oropharyngealcandidiasis, dysphonia • oral (most potent): dexamethasone, prednisone • Side Effects: mood disturbances, increased appetite, impaired glucose control in diabetics, and candidiasis • Long-term use: bone resorption • Inhaled Prednisone

  17. Corticosteroids • Pharmacokinetics (inhaled): • Onset: unknown • Effect: unknown • Duration: 24 h • Warning: compliance poor!

  18. Cromolyns: Mast Cell Stabilizers • Cromolyn, nedocromil • MOA: • Alter fxn of delayed Cl- channels (inhibiting their activation) • Blocks release of inflammatory mediators: mast, eosinophil, basophil, lymphocyte • Use: • prophylactic therapy for mild-moderate allergic asthma • Allergic rhinitis (C) • Administration: Inhalation • Pharmacokinetics: • Effect: wks • Side Effects: • C: safest of all • increased coughing, wheezing • Age matters: • Cromolyn: children, adolescents • Nedocromil: ≥12 yoa

  19. Leukotriene Modifiers • Strategies • Leukotriene-Synthesis Inhibitors • Zileuton • Leukotriene Receptor Antagonists • Montelukast, zafirlukast • Use: • “responder” mild chronic asthma • allergic rhinitis • Administration: Inhalation (, oral (M,Z) • Pharmacokinetics: • Onset: 3-6 h • Effect: 4 h • Duration: 24h • Side Effects: Churg-Strauss syndrome … happens in the unLUcKiest

  20. Drug Interactions • Montelukast (Singulair) • Phenobarbital • Rifampin • MOA • Increased metabolism • Result • Decreased montelukast levels • Zafirlukast (Accolate) • Drugs • Aspirin: Zafir • Erythromycin: Zafir • Tolbutamide, phenytoin, carbamazepine: levels • Warfarin: levels • Zileuton (Zyflo) • Drugs: levels • Propranolol • Theophylline • Warfarin

  21. Antagonism of IgE • Anti-IgE: omalizumab • 95% humanized • High cost >$10K/yr • Use: moderate-to-severe persistent asthma • Administration: SC • Pharmacokinetics: • Pk Plasma: 7-8d • Duration: 26 d • Side Effects: injection-site reaction, infections, anaphylaxis, cancer

  22. Drug Delivery Metered Dose Inhaler Nebulizers Injection Dry Powder Inhaler

  23. MDI 21% lung

  24. Monotherapy

  25. Combi-therapies • Budesonide + formeterolfumerate • Refer to each component • Moderate-severe uncontrolled asthma • Fluticasoneproprionate + salmeterolxinofate • Refer to each component • Moderate-severe uncontrolled asthma

  26. Potential New Therapies for Asthma • Vaccines (DNA vaccine; Mycobacterium, CpG) • Desensitization (allergen-specific immunotherapy including recombinant gene-manipulated antigens and peptides) • Cytokine modulators (gene, protein) • Anti IL-4, IL-5, IL-13 • IL-12 • IL-10 • Selective phosphodiesterase inhibitors • Selective tryptase inhibitors • Potassium channel activators • Adhesion molecule inhibitors • Gene therapy • Targeting susceptibility genes • Targeting polymorphism of receptors for drugs • Others

  27. Step-wise Approach to Asthma Therapy

  28. Staging COPD - GOLD

  29. Gq-coupled receptor signaling in airway smooth muscle Billington et al. Respiratory Research 2003, 4:2

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