Pathophysiology of Asthma

Chronic inflammation of airway bronchial

hyperreactivity bronchoconstriction

Strategies of Asthma Bronchodilators : to treat acute asthmatic bronchospasm Antiinflammatory drugs : to control of the inflammation process in the airway longterm preventive treatment

Drugs used in asthma

Bronchodilators : agonists (beta adrenoceptor agonists) Muscarinic antagonists Methylxanthines Antiinflammatory drugs : Corticosteroids Chromolyn & nedocromil Others : IgE antibodies Leukotriens anagonists

Beta-adrenoceptor Agonists
Pharmacokinetics : Reverse asthmatic bronchoconstriction The important sympathomimetics in asthma are 2-selective agonists Classification 2-selective agonists: - short acting (albuterol, terbutaline, metaproterenol) - long acting (salmeterol, formoterol) Usually given by inhalation The inhalation route decrease systemic dose & adverse effects

Mechanism & Effects Stimulating adenylcyclase & increasing cAMP in smooth muscle bronchodilator response Clinical Use : Short-acting 2 agonists should be used only for acute episodes of bronchospasm Long-acting 2 agonists should be used for prophylaxis, not for acute episodes Toxicities Skeletal muscle tremor (2 effects) Cardiac effect/tachycardia When used excessively, arrhythmias may occur

Methylxanthines
The three major methylxanthines in plants: theophylline, caffeine, & theobromine Theophylline is important in the treatment of asthma

Mechanism and Effects : Inhibit phosphodiesterase (PDE), the enzyme degrades cAMP increase cAMP bronchodilation Other effects : CNS stimulation, cardiac stimulation, vasodilaton, increase BP and GI motility

Clinical use & Toxicities

Clinical use : Asthma Toxicities : GI distress Tremor Insomnia Very large overdosage are potentially lethal because of the arrhythmias & convulsions Antidote : beta-blocker

Muscarinic Antagonists
Prototype : Atropine, alkaloid belladona, ipratropium Pharmacokinetics : Ipratropium designed for aerosol use (has little systemic action) Mechanism & Effects : - competitively blocks muscarinic receptors in the airways - effective prevents bronchoconstriction mediated by vagal discharge - Effects : reverse bronchoconstriction in asthma & COPD - no effects on the inflammation

Clinical use & Toxicities

Clinical use : Asthma (for acute bronchospasm, but 2 agonist usually preferred) Chronic Obstructive Pulmonary Disease (COPD) more effective and less toxic than 2 agonists Toxicities : Minor atropine-like toxic effect (excessive dosage) Ipratropium does not cause tremor or arrhythmias

Cromolyn & Nedocromil

Pharmacokinetics Insoluble minimal systemic blood levels Given by aerosol in asthma Mechanism & Effects : Decrease in the release of mediators (leukotriene and histamine) from mast cells Have only local effects Effective for preventing food allergy (orally)

Clinical use & Toxicities

Clinical use Prevent bronchoconstriction caused by allergic Hay fever (nasal & eyedrop formulation) Food allergy (orally) Toxicities : cough, irritation of the airway when given by aerosol

Corticosteroid
All of the corticosteroids are potentially beneficial in

severe asthma Systemic (oral) corticosteroid are used only if other therapies are unsuccesfull (because their toxicities) Local aerosol administration (beclomethasone, budesonide, dexametasone, flunisonide, fluticasone, mometasone) are relatively safe

Mechanism, Effects & Toxicities

Mechanism : reduce the synthesis of arachidonic acid

by phospholipase A2 Effects : antiinflammatory Clinical use : moderate asthma that not responsive to aerosol beta-agonists Toxicities : adrenal supression (small degree)

Leukotriene Antagonists
Prototype : Leukotriene receptor blockers (zafirlukast, montelukast) Inhibitor lipoxygenase (zileuton)

Leukotriene Receptor Blockers

Zafirlukast and montelukas are antagonists at the LTD4 and LTE4 leukotriene receptor Effective in preventing exercise-, and antigeninduced bronchospasm Not recommended for acute episodes of asthma Given orally

Zileuton
Selectively inhibits 5-lipoxygenase It is also effective in preventing exercise- and antigen-

induced bronchospam Given orally Toxicities : elevation of liver enzymes

Anti-IgE antibody
Prototype : Omallizumab It is a humanized murine monoclonal antibody to human Ig E Prevent activation by asthma triggers and release of inflammatory mediators