Drugs Used for Treatment of Asthma

Overview
• Commonly encountered respiratory disease
• Characterized by hyper-responsive airways.
• Drugs can be delivered:
— Topically to nasal mucosa
— Inhaled into lungs
— Orally or parenterally for systemic absorption.
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DRUGS AFFECTING THE RESPIRATORY SYSTEM

DRUGS USEDTO TREAT ASTHMA

 ß2-Adrenerg ic agoni Sts
 Corticosteroids
 Cromolyn, nedocromil
 Ipratropium
 Montelukast, zafirlukast, zileuton
 Omalizumab
Theophylline
Role of Inflammation
• Airflow obstruction is due to bronchoconstriction:
— Contraction of bronchial smooth muscle
— Inflammation of bronchial wall
— Increased mucous secretion
Classification
 Reliever:
— Used for treatment of acute exacerbation
— Cause bronchodilation
Controller
— To prevent acute exacerbation
— Anti-inflammatory effects
1. RELIVERS
a) ß Adrenergic Agonist
— Nonselective: Isoproterenol, Epinephrine
— Short acting ß2 Agonist: Salbutamol (Albuterol)
— Long Acting ß2 Agonist: Salmeterol
Formoterol
b) Methylxanthines:
— Theophylline
— Aminophylline
c) Antimuscarinics
— Ipratropium Bromide
— Tiotropium
d) Magnesium Sulphate
2. CONTROLLERS
e) Corticosteroids:
— Inhaled: ,Budesonide, Fluticasone
— Systemic: Hydrocortisone, Prednisone
f) Mast Cell Stabilisers:
— Nedocromil
— Cromolyn Sodium
g) Leucotriene Antagonist:
- MONTELUKAST, ZAFIRLUKAST
h) lgE Antagonist:
— Omalizumab

ß2 Adrenergic Agonist
• Inhaled forms are drugs of choice for mild asthma (Occasional intermittent symptoms).
• Potent bronchodilators (smooth muscle relaxation)
BRONCHO- RESULTS OF PEAK QUICK RELIEF OF
LONG-TERM
CLASSIFICATION CONSTRICTIVE FLOW OR SYMPTOMS
CONTROL
EPISODES SPIROMETRY
Mild Less than Near normat• No daity medication Short-acting
intermittent two per Near normat• Low-dose inhaled agonist
week
Mild persistent 60 to 80 percent Short-acting
More than
Moderate two per of Low- to medium- agonist
persistent Less than 60 percent dose inhaled Short-acting
week
corticosteroids
Severe Daily of agonist
and a long-acting
persistent agonist Short-acting
High-dose inhaled agonist
corticosteroids and a
long-acting agonist
• Rapid onset of action (5 - 30min)
Relief for 4 - 6 hours
• Symptomatic treatment of acute bronchoconstriction.
• No anti-inflammatory effects
• Monotherapy with short-acting in mild intermittent asthma, exercise-induced asthma.
— Pirbuterol
— Terbutaline
— Albuterol (salbutamol)
• Minimal a or ßl stimulation.

Adverse effects (less with inhalation):

— Tachycardia
— Hyperglycemia
— Hypokalemia
— Hypomagnesemia

Long Term Control

• Include:
— Salmeterol xinafoate
— Formoterol
• Chemical analogs of albuterol

Corticosteroids

Inhaled are drugs of choice in persist asthma

Severe asthma may require short course of oral glucocorticoid

Actions on Lung
• Targets airway inflammation:
— Decreases inflammatory cascade
— Reverses mucosal edema
— Decreases capillary permeability
— Inhibits leukotrienes release
— Reduces airway
hyperresponsiveness
(chronic use)

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1. Route of Administration – Inhalation

• Markedly reduced need for systemic corticosteroids

• Appropriate inhalation technique is critical

— Metered Dose Inhaler: Slow and deep inhalation

— Dry powder Inhaler: Quick and deep inhalation

Adverse effects:
— Deposition on oral, pharyngeal mucosa:
• Oropharyngeal candidiasis
• Hoarseness.

2. Route of Administration — Oral/ Systemic

• Severe asthma exacerbation (status asthmaticus)
• IV methylprednisolone, oral prednisone.
• Taper dose (discontinue in 2 weeks) So
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• Inhaled have few systemic effects.
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3. Alternative Drugs
• Treatment of moderate — severe asthma that is:
— Poorly controlled by conventional therapy
— Adverse effects due to high dose or prolonged corticosteroid treatment.
• Used in conjunction with ICS (not monotherapy)
Leukotriene Antagonists
 • Products of 5-lipoxygenase
• Leucotriene effects:
— Bronchoconstriction
— Increase endothelial permeability
— Promote mucous secretion
— Chemoattractant
• Zileuton:
— 5-lipoxygenase inhibitor
— prevent formation of LTB4, cysteinyl leukotrienes
• Zafirlukast, montelukast:
— reversible inhibitors of cysteinyl leukotriene-l receptor
— block effects of cysteinyl leukotrienes
• Used for prophylaxis of asthma (not effective in acute bronchoconstriction)

Cysteinyl-
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Pharmacokinetics
• Given orally (food impairs absorption of zafirlukast)
• 90% bound to plasma protein
• Extensively metabolized
• Zileuton is excreted in urine
• Zafirlukast, montelukast undergo biliary excretion.

Adverse Effects
• Elevations in hepatic enzymes (monitor)
• Eosinophilic vasculitis (Churg-Strauss syndrome) — when steroid dose is reduced
• Headache, dyspepsia
• Zafirlukast, zileuton CYP450 inhibitors
— Increase warfarin levels

Cromolyn, nedocromil
• Prophylactic anti-inflammatory agents (not useful in acute bronchospasm)
• Block initiation of immediate and delayed asthmatic reactions
• Mast cells stabilisers
• Given as inhalation
• Poorly absorbed
• Pretreatment blocks allergen and exercise induced bronchoconstriction.
• Efficacy after 6 weeks

Adverse Effects:
• Mild
— Bitter taste
— Irritation of pharynx, larynx
• Short duration of action (frequent dosing)

Cholinergic Antagonists

• Less effective than ß2 agonists

• Block vagally mediated bronchoconstriction and mucus secretion
• Inhaled ipratropium:
— Quaternary derivative of atropine
— Useful in those unable to tolerate ß2 agonist
— Slow onset
— More effective in COPD

Theophylline

Bronchodilator (chronic asthma)

Well absorbed
Narrow therapeutic window
Overdose — seizures, arrhythmias
Metabolized by CYP450 (drug interaction)
INFLAMMATORY CELLS

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Inhibits release of allergic mediatorsP
• Decreased binding of lgE on mast cells, basophils.
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• Used for treatment of refractory moderate — severe asthma
• Expensive