Obstructive Lung Diseases
allergens
Irritants
infections
(esp. smoking)
Genetic Predisposition
small airways
abnormalities
Chronic obstructive
bronchitis
COPD
destruction of
alveolar walls
Emphysema
bronchospasm
Asthma
ASTHMA PATHOGENESIS
GENES
ENVIRONMENT
INFLAMMATION
AIRWAY
HYPERREACTIVITY
SYMPTOMS
AIRWAY
OBSTRUCTION
Obstructive Lung Diseases
allergens
Irritants
infections
(esp. smoking)
Genetic Predisposition
small airways
abnormalities
Chronic obstructive
bronchitis
COPD
destruction of
alveolar walls
Emphysema
bronchospasm
Asthma
Gross Appearance of Human Lung
Normal
Asthma
Emphysema
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 betaagonists 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 betaagonists 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 Elimination
Liver Disease
Congestive Heart Failure
Cor Pulmonale
Ciprofloxacin
Erythromycin
•
Increased Elimination
Cigarette Smoking
Indications for Theophylline
ASTHMA PATHOGENESIS
GENES
ENVIRONMENT
INFLAMMATION
AIRWAY
HYPERREACTIVITY
SYMPTOMS
AIRWAY
OBSTRUCTION
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)
CYSTEINYL LEUKOTRIENES
5-Lipoxygenase Pathway
Membrane Phospholipids
zileuton
F
L
A
P
5-LO
PG, TX
AA
5-HPETE
LTC 4
synthase
LTA4
LTB4
LTC4
montelukast
zafirlukast
LTD4
Cys LT1
LTE4
airway narrowing
mucus secretion
vascular leak
•Stepwise Approach for Adults and Children (>5 years)
Severity Class
Step 4
Severe
Persistent
Symptoms/Day
Symptoms/Night
PEF or FEV1
PEF Variability
Continual
 60%
Frequent
>30%
Step 3
Daily
Moderate
Persistent
Step 2
Mild
Persistent
Step 1
Mild
Intermittent
>60% - <80%
>1 night/week
>2/week but <1x/day
>2 nights/month
>30%
 80%
20% - 30%
 2 days/week
 80%
 2 nights/month
<20%
Daily Medications
• Preferred treatment:
High-dose ICS + LABA AND, if needed,
corticosteroid tablets or syrup long term
• 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
• Preferred treatment:
Low-dose inhaled corticosteroid
• 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.
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 a-adrenergic receptor agonists
– activate a-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
a-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
CYP3A4
Blocks delayed
rectifier K
channels
liver disease
ketoconazole
itraconazole
erythromycin
clarithromycin
other CYP3A4
drugs
CARBOXY
METABOLITE
Antihistamine
effects
QTc Prolongation / Torsades de Pointes
DRUGS FOR RHINITIS
• DECONGESTANTS
• ANTIHISTAMINES
• CROMOLYN
• CORTICOSTEROIDS
• ANTICHOLINERGICS
Relative Effectiveness of Medications on
Symptoms of Allergic Rhinitis
Medication
Symptom
Sneezing
Rhinorrhea
Pruritus
Nasal Blockage
Antihistamines
++
++
++
00
Decongestants
0
0
0
+++
Cromolyn
+
+
+
+
+++
+++
+++
+++
0
+
0
0
Corticosteroids
Anticholinergics