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