Obstructive Lung Diseases

1. destruction of small airways alveolar walls abnormalities Chronic obstructive bronchitis Obstructive Lung Diseases allergens Irritants infections (esp. smoking) Genetic Predisposition bronchospasm Emphysema Asthma COPD

2. ASTHMA PATHOGENESIS GENES ENVIRONMENT INFLAMMATION AIRWAY AIRWAY SYMPTOMS HYPERREACTIVITY OBSTRUCTION

3. destruction of small airways alveolar walls abnormalities Chronic obstructive bronchitis Obstructive Lung Diseases allergens Irritants infections (esp. smoking) Genetic Predisposition bronchospasm Emphysema Asthma COPD

5. Gross Appearance of Human Lung Normal Asthma Emphysema

8. PHARMACOLOGIC AGENTS • BRONCHODILATORS • Beta2-adrenergic agonists • Anticholinergics • Theophylline • Leukotriene modifiers • ANTI-INFLAMMATORY AGENTS • Corticosteroids • (Cromolyn/Nedocromil)

9. Bronchoconstriction Before 10 Minutes After Allergen Challenge

10. ADRENERGIC AGENTS

11. LONG-ACTING BETA2-AGONISTS

13. ROUTE OF ADMINISTRATION

14. BETA-AGONISTS: ADVERSE EFFECTS • Tremor • Palpitations • Hypokalemia • Arrhythmias ?

15. PHARMACOLOGIC AGENTS • BRONCHODILATORS • Beta2-adrenergic agonists • Anticholinergics • Theophylline • Leukotriene modifiers • ANTI-INFLAMMATORY AGENTS • Corticosteroids • (Cromolyn/Nedocromil)

18. Parasympathetic Nervous System

20. Parasympathetic Nervous System

21. Comparison: Beta-agonists / Anticholinergics • Beta2-adrenergic agonists most effective bronchodilators in chronic asthma • Anticholinergics and beta2-adrenergic agonists effective in COPD • Anticholinergics often added to beta-agonists in acute asthma exacerbations • Tiotropium-long duration of action

24. Comparison: Beta-agonists / Anticholinergics • Beta2-adrenergic agonists most effective bronchodilators in chronic asthma • Anticholinergics and beta2-adrenergic agonists effective in COPD • Anticholinergics often added to beta-agonists in acute asthma exacerbations • Tiotropium-long duration of action

26. PHARMACOLOGIC AGENTS • BRONCHODILATORS • Beta2-adrenergic agonists • Anticholinergics • Theophylline • Leukotriene modifiers • ANTI-INFLAMMATORY AGENTS • Corticosteroids • (Cromolyn/Nedocromil)

28. THEOPHYLLINE • Mechanism of Action • Pharmacokinetics • Volume of distribution 0.5L/kg • Thus, 1 mg/kg increases serum level ~2 mcg/ml • Loading dose 5 mg/kg • Clearance • Liver • Differs not only between individuals but in same individual over time

30. THEOPHYLLINE • Mechanism of Action • Pharmacokinetics • Volume of distribution 0.5L/kg • Thus, 1 mg/kg increases serum level ~2 mcg/ml • Loading dose 5 mg/kg • Clearance • Liver • Differs not only between individuals but in same individual over time

31. Decreased Elimination Liver Disease Congestive Heart Failure Cor Pulmonale Ciprofloxacin Erythromycin Increased Elimination Cigarette Smoking Conditions and Drugs Affecting Theophylline Elimination

33. Indications for Theophylline

34. ASTHMA PATHOGENESIS GENES ENVIRONMENT INFLAMMATION AIRWAY AIRWAY SYMPTOMS HYPERREACTIVITY OBSTRUCTION

36. Airway Inflammation

37. PHARMACOLOGIC AGENTS • BRONCHODILATORS • Beta2-adrenergic agonists • Anticholinergics • Theophylline • Leukotriene modifiers • ANTI-INFLAMMATORY AGENTS • Corticosteroids • (Cromolyn/Nedocromil)

40. Systemic Corticosteriods • Oral (usually prednisione) or parenteral (hydrocortisone, methylprednisolone) • Most effective therapy in serious exacerbations of asthma • Basically, any patient sick enough for hospitalization (and most that go to ER) treated with short course of systemic corticosteroid therapy

43. Inhaled Corticosteroids

45. Cromolyn / Nedocromil • Anti-inflammaory effects in asthma, but minimal compared with inhaled corticosteroids • Mechanism of action poorly defined • Prevent mediator release from mast cells and other inflammatory cells • Can protect against allergen and exercise challenge • No adverse effects

46. PHARMACOLOGIC AGENTS • BRONCHODILATORS • Beta2-adrenergic agonists • Anticholinergics • Theophylline • Leukotriene modifiers • ANTI-INFLAMMATORY AGENTS • Corticosteroids • (Cromolyn/Nedocromil)

47. CYSTEINYL LEUKOTRIENES airway narrowing mucus secretion vascular leak 5-Lipoxygenase Pathway Membrane Phospholipids zileuton PG, TX AA FLAP 5-HPETE 5-LO LTC4 LTA4 synthase LTB4 LTC4 LTD4 LTE4 montelukast Cys LT1 zafirlukast

48. PEF or FEV1 PEF Variability Symptoms/Day Symptoms/Night Continual Frequent  60% >30% Daily >1 night/week >60% - <80% >30% >2/week but <1x/day >2 nights/month  80% 20% - 30%  2 days/week  2 nights/month  80% <20% Step 1 Mild Intermittent Stepwise Approach for Adults and Children (>5 years) Daily Medications Severity Class • Preferred treatment: • High-dose ICS + LABA AND, if needed, corticosteroid tablets or syrup long term Step 4 Severe Persistent • Preferred treatment: • Low-to-medium dose ICS + LABA Step 3 Moderate Persistent • Alternative treatment: Increase ICS dose within med dose range OR low-to-med dose ICS + LTM or theophylline • Preferred treatment: • Low-dose inhaled corticosteroid Step 2 Mild Persistent • Alternative treatment: cromolyn, LTM, nedocromil OR theophylline SR (serum concentration of 5-15 mcg/mL) • No daily medication needed Guidelines for the Diagnosis and Management of Asthma—Update on Selected Topics 2002. NIH, NHLBI. June 2002. NIH publication no. 02-5075.

49. Therapy of COPD • Symptomatic patients: bronchodilator • Anticholinergic or beta-agonist • Inhaled steroids in moderate-severe patients with multiple exacerbations • Acute exacerbations • Bronchodilators • Systemic corticosteroid - short course

50. RHINITIS • Inflammation of the nasal mucosa • Diagnosis • Rhinorrhea • Nasal blockage or stuffiness • Pruritus • Sneezing