Department of Pharmacology Drugs Used in Asthma Dr. Sasan Zaeri (PharmD, PhD) Department of Pharmacology

Asthma A chronic inflammatory disorder of bronchial airways that result in bronchospasm in response to external stimuli (pollen, cold air, tobacco smoke etc.)

Symptoms of asthma Asthma produces recurrent episodic attack of Acute bronchoconstriction Shortness of breath Chest tightness Wheezing Rapid respiration Cough

Pathophysiology of Immunologic Asthma

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Aims of Anti-asthmatic Drugs To relieve acute episodic attacks of asthma (bronchodilators, quick relief medications) To reduce the frequency of attacks, and nocturnal awakenings (anti-inflammatory drugs, prophylactic or control therapy )

Anti-inflammatory Agents (control medications or prophylactic therapy) Anti-asthmatic Drugs Bronchodilators (Quick relief medications) treat acute episodic attack of asthma 2-agonists Antimuscarinics Methylxanthines Anti-inflammatory Agents (control medications or prophylactic therapy) reduce the frequency of attacks Corticosteroids Mast cell stabilizers Leukotrienes antagonists Anti-IgE monoclonal antibody

- adrenoceptor agonists Mechanism of Action Direct 2 stimulation  stimulate adenyl cyclase  Increase cAMP  bronchodilation

Classification of  agonists Non selective  agonists epinephrine - isoproterenol Selective 2 – agonists (Preferable) Salbutamol (Albuterol) Terbutaline Salmeterol Formeterol

Nebulizer Inhaler

Selective 2 –agonists Short acting ß2 agonists (salbutamol, terbutaline) Drugs of choice for acute attack of asthma Long acting ß2 agonists (salmeterol, formoterol) Used for nocturnal asthma (long acting relievers) Combined with inhaled corticosteroids to control asthma (decreases the number and severity of asthma attacks)

Adverse effects of selective 2 –agonists Skeletal muscle tremor Tachycardia and arrhythmia Tolerance and tachyphylaxis

Muscarinic antagonists Ipratropium Act by blocking muscarinic receptors Given by aerosol inhalation Quaternary derivatives of atropine Do not enter CNS Does not diffuse into the blood Minimal systemic side effects

Effects Uses Inhibit bronchoconstriction and mucus secretion Less effective than β2-agonists Uses Main choice in chronic obstructive pulmonary diseases (COPD) In acute severe asthma combined with β2-agonists & steroids

Theophylline - Aminophylline Methylxanthines Theophylline - Aminophylline Mechanism of Action Phosphodiestrase (PDE) inhibition   cAMP  bronchodilation Adenosine receptor antagonists

Uses Second line drug in asthma (theophylline in nocturnal asthma) For status asthmatics (aminophylline is given as slow infusion)

Side Effects CVS: arrhythmia GI: nausea & vomiting, ↑ gastric acid secretion CNS: tremors, nervousness, insomnia, convulsion Kidney: ↑renal blood flow, weak diuretic action

↓ metabolism of theophylline Drug interactions Metabolized by Cyp P450 enzymes in liver Enzyme inducers e.g. phenobarbital, rifampin, tobaco smoke → ↑metabolism of theophylline Enzyme inhibitors e.g. erythromycin→ ↓ metabolism of theophylline

Anti - inflammatory Agents (control medications / prophylactic therapy) By reducing inflammation, they reduce bronchial hyper-reactivity and bronchospasm

Anti-inflammatory Agents Glucocorticoids Leukotrienes antagonists Mast cell stabilizers Anti-IgE monoclonal antibody (Omalizumab)

Glucocorticoids Mechanism of action Inhibition of phospholipase A2 → ↓ prostaglandin and leukotrienes Mast cell stabilization →↓ histamine release Upregulation of β2 receptors

Routes of administration Inhalation Budesonide, Fluticasone, Beclomethasone Less side effects Oral Prednisolone Parenteral Hydrocortisone, Methylprednisolone Status asthmaticus (IV infusion)

Glucocorticoids Are not bronchodilators Given as prophylactic medications, used alone or combined with beta-agonists

Side effects of systemic corticosteroids Adrenal suppression Growth retardation in children Osteoporosis Fluid retention, weight gain, hypertension Hyperglycemia Susceptibility to infections Glaucoma Cataract Fat distribution, wasting of the muscles Psychosis

Inhalation therapy has less side effects Oropharyngeal candidiasis (thrush) Dysphonia (voice hoarseness) Withdrawal Abrupt stop of corticosteroids should be avoided and dose should be tapered (adrenal insufficiency syndrome)

Mast cell stabilizers Act by stabilization of mast cell membrane Cromolyn - Nedocromil Act by stabilization of mast cell membrane Have poor oral absorption Given by inhalation

Mast cell stabilizers Not bronchodilators Not effective in acute attack of asthma Prophylactic anti-inflammatory drugs Children respond better than adults

Uses Prophylactic therapy in asthma especially in children Allergic rhinitis Conjunctivitis Side effects Bitter taste minor upper respiratory tract irritation (burning sensation)

Leukotrienes antagonists Leukotriene B4 chemotaxis of neutrophils Leukotrienes C4 and D4 bronchoconstriction

Leukotriene receptor antagonists Zafirlukast, Montelukast Taken orally Are bronchodilators Are NOT effective to relieve acute attack of asthma Have anti-inflammatory action

Uses Prophylaxis of Mild to moderate asthma Aspirin-induced asthma Antigen and exercise-induced asthma Can be combined with glucocorticoids (low dose of glucocorticoids can be used)

Anti-IgE monoclonal antibody Omalizumab A monoclonal antibody directed against human IgE It binds to the IgE on sensitized mast cells and prevents activation by asthma triggers and subsequent release of inflammatory mediators Expensive-not first line therapy

Summary