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Obstructive Lung DiseasesinfectionsIrritantsallergens
(esp. smoking)
Genetic Predisposition
bronchospasm
Asthma Emphysema
destruction of alveolar walls
small airways abnormalities
Chronic obstructive bronchitis
COPD
INFLAMMATION
GENES ENVIRONMENT
AIRWAYHYPERREACTIVITY
SYMPTOMS AIRWAYOBSTRUCTION
ASTHMA PATHOGENESIS
Obstructive Lung DiseasesinfectionsIrritantsallergens
(esp. smoking)
Genetic Predisposition
bronchospasm
Asthma Emphysema
destruction of alveolar walls
small airways abnormalities
Chronic obstructive bronchitis
COPD
Normal Asthma Emphysema
Gross Appearance of Human Lung
PHARMACOLOGIC AGENTS
• BRONCHODILATORS– Beta2-adrenergic agonists– Anticholinergics– Theophylline– Leukotriene modifiers
• ANTI-INFLAMMATORY AGENTS– Corticosteroids– (Cromolyn/Nedocromil)
Bronchoconstriction
Before 10 Minutes After Allergen Challenge
ADRENERGIC AGENTS
LONG-ACTING BETA2-AGONISTS
ROUTE OF ADMINISTRATION
BETA-AGONISTS: ADVERSE EFFECTS
• Tremor
• Palpitations
• Hypokalemia
• Arrhythmias ?
PHARMACOLOGIC AGENTS
• BRONCHODILATORS– Beta2-adrenergic agonists– Anticholinergics– Theophylline– Leukotriene modifiers
• ANTI-INFLAMMATORY AGENTS– Corticosteroids– (Cromolyn/Nedocromil)
Parasympathetic Nervous System
Parasympathetic Nervous System
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
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
PHARMACOLOGIC AGENTS
• BRONCHODILATORS– Beta2-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 EliminationLiver Disease
Congestive Heart Failure
Cor Pulmonale
Ciprofloxacin
Erythromycin
• Increased EliminationCigarette Smoking
Indications for Theophylline
INFLAMMATION
GENES ENVIRONMENT
AIRWAYHYPERREACTIVITY
SYMPTOMS AIRWAYOBSTRUCTION
ASTHMA PATHOGENESIS
Airway Inflammation
PHARMACOLOGIC AGENTS
• BRONCHODILATORS– Beta2-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– Beta2-adrenergic agonists– Anticholinergics– Theophylline– Leukotriene modifiers
• ANTI-INFLAMMATORY AGENTS– Corticosteroids– (Cromolyn/Nedocromil)
airway narrowingmucus secretionvascular leak
LTC4 LTD4 LTE4
Cys LT1
montelukast
FLAP
5-LO
LTC 4synthase
zileutonAA
5-HPETE
LTA4
LTB4
PG, TX
CYSTEINYL LEUKOTRIENES5-Lipoxygenase PathwayMembrane 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 FEV1
PEF VariabilityDaily Medications
Step 4Severe 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 2002. NIH, NHLBI. June 2002. NIH publication no. 02-5075.
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
TERFENADINETORSADES DE POINTES
TERFENADINECARBOXY 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 ++ ++ ++ 00
Decongestants 0 0 0 +++
Cromolyn + + + +
Corticosteroids +++ +++ +++ +++
Anticholinergics 0 + 0 0
SymptomSneezing Rhinorrhea Pruritus Nasal Blockage
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