Obstructive Lung Diseases infectionsIrritantsallergens (esp. smoking) Genetic Predisposition bronchospasm AsthmaEmphysema destruction of alveolar walls small airways abnormalities Chronic obstructive bronchitis COPD

INFLAMMATION GENESENVIRONMENT AIRWAY HYPERREACTIVITY SYMPTOMS AIRWAY OBSTRUCTION ASTHMA PATHOGENESIS

Obstructive Lung Diseases infectionsIrritantsallergens (esp. smoking) Genetic Predisposition bronchospasm AsthmaEmphysema destruction of alveolar walls small airways abnormalities Chronic obstructive bronchitis COPD

NormalAsthmaEmphysema Gross Appearance of Human Lung

PHARMACOLOGIC AGENTS BRONCHODILATORS – Beta 2 -adrenergic agonists – Anticholinergics – Theophylline – Leukotriene modifiers ANTI-INFLAMMATORY AGENTS – Corticosteroids – (Cromolyn/Nedocromil)

Bronchoconstriction Before 10 Minutes After Allergen Challenge

ADRENERGIC AGENTS

LONG-ACTING BETA 2 -AGONISTS

ROUTE OF ADMINISTRATION

BETA-AGONISTS: ADVERSE EFFECTS Tremor Palpitations Hypokalemia Arrhythmias ?

PHARMACOLOGIC AGENTS BRONCHODILATORS – Beta 2 -adrenergic agonists – Anticholinergics – Theophylline – Leukotriene modifiers ANTI-INFLAMMATORY AGENTS – Corticosteroids – (Cromolyn/Nedocromil)

Parasympathetic Nervous System

Comparison: Beta-agonists / Anticholinergics Beta 2 -adrenergic agonists most effective bronchodilators in chronic asthma Anticholinergics and beta 2 -adrenergic agonists effective in COPD Anticholinergics often added to beta- agonists in acute asthma exacerbations Tiotropium-long duration of action

Comparison: Beta-agonists / Anticholinergics Beta 2 -adrenergic agonists most effective bronchodilators in chronic asthma Anticholinergics and beta 2 -adrenergic agonists effective in COPD Anticholinergics often added to beta- agonists in acute asthma exacerbations Tiotropium-long duration of action

PHARMACOLOGIC AGENTS BRONCHODILATORS – Beta 2 -adrenergic agonists – Anticholinergics – Theophylline – Leukotriene modifiers ANTI-INFLAMMATORY AGENTS – Corticosteroids – (Cromolyn/Nedocromil)

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

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

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

Indications for Theophylline

INFLAMMATION GENESENVIRONMENT AIRWAY HYPERREACTIVITY SYMPTOMS AIRWAY OBSTRUCTION ASTHMA PATHOGENESIS

Airway Inflammation

PHARMACOLOGIC AGENTS BRONCHODILATORS – Beta 2 -adrenergic agonists – Anticholinergics – Theophylline – Leukotriene modifiers ANTI-INFLAMMATORY AGENTS – Corticosteroids – (Cromolyn/Nedocromil)

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

Inhaled Corticosteroids

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

PHARMACOLOGIC AGENTS BRONCHODILATORS – Beta 2 -adrenergic agonists – Anticholinergics – Theophylline – Leukotriene modifiers ANTI-INFLAMMATORY AGENTS – Corticosteroids – (Cromolyn/Nedocromil)

airway narrowing mucus secretion vascular leak LTC 4 LTD 4 LTE 4 Cys LT 1 montelukast FLAPFLAP 5-LO LTC 4 synthase zileuton AA 5-HPETE LTA 4 LTB 4 PG, TX CYSTEINYL LEUKOTRIENES 5-Lipoxygenase Pathway Membrane Phospholipids zafirlukast

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

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

RHINITIS Inflammation of the nasal mucosa Diagnosis – Rhinorrhea – Nasal blockage or stuffiness – Pruritus – Sneezing

CLASSIFICATION OF RHINITIS ALLERGIC NON-ALLERGIC – Vasomotor – Medicamentosa INFECTIOUS – Common Cold

DRUGS FOR RHINITIS DECONGESTANTS ANTIHISTAMINES CROMOLYN CORTICOSTEROIDS ANTICHOLINERGICS

DECONGESTANTS Oral  -adrenergic receptor agonists – activate  -receptors in nasal resistance vessels – produce vasoconstriction and decreased nasal blockage – common (only) agent--pseudoephedrine – phenylpropanolamine (withdrawn by FDA-stroke risk) – side effects--restlessness, insomnia, increased blood pressure, urinary retention – caution in patients with hypertension or BPH – contraindicated in patients taking MAO inhibitors

DECONGESTANTS Imidazoline agents (e.g. oxymetazoline) can be applied topically   -receptor agonists Repeated application leads to rebound congestion Prolonged use--”rhinitis medicamentosa”

DRUGS FOR RHINITIS DECONGESTANTS ANTIHISTAMINES CROMOLYN CORTICOSTEROIDS ANTICHOLINERGICS

H1 RECEPTOR ANTAGONISTS Histamine--important mediator in allergic rhinitis, urticaria, atopic dermatitis Effects in respiratory tract via H1 histamine receptors Well absorbed from GI tract--given orally 1st Generation--block muscarinic receptors (producing anticholinergic side effects) and CNS H1 receptors (producing sedation) Effective for relief of sneezing, pruritus, and rhinorrhea but less effective for nasal blockage

Ann Intern Med, 2000

2nd Generation H1 Antihistamines Decreased sedation and anticholinergic side effects Syndrome of torsades de pointes – Polymorphic ventricular arrhythmia – terfenadine and astemizole (now off market) – Block delayed rectifier potassium current – QT-prolongation, ventricular tachycardia, death – All currently available 2nd generation H1 antihistamines are safe – Dose related effect with first generation H1 antihistamines

TERFENADINE TORSADES DE POINTES TERFENADINE CARBOXY METABOLITE Blocks delayed rectifier K channels Antihistamine effects CYP3A4 liver disease ketoconazole itraconazole erythromycin clarithromycin other CYP3A4 drugs

QTc Prolongation / Torsades de Pointes

DRUGS FOR RHINITIS DECONGESTANTS ANTIHISTAMINES CROMOLYN CORTICOSTEROIDS ANTICHOLINERGICS

Relative Effectiveness of Medications on Symptoms of Allergic Rhinitis Medication Antihistamines Decongestants Cromolyn Corticosteroids +++ Anticholinergics Symptom SneezingRhinorrheaPruritus Nasal Blockage