Respi - Anti-asthma Drugs

Question 1

Asthma is characterized by (3)

Answer 1

1. Hyper-responsiveness of the airway
2. Recurrent reversible airway obstruction
3. Chronic airway inflammation

Question 2

Classes of anti-asthma drugs used & examples

Answer 2

Controllers (anti-inflammatory)

1. Inhaled Corticosteroids (Fluticasone, Ciclesonide)
2. Leukotriene Receptor Antagonist (Montelukast)
3. Cromolyn
4. Anti-IgE Antibody (Omalizumab)

Relievers (bronchodilators)

1. β2 Agonists (SABA - Salbutamol, LABA - Salmeterol, ULABA - Indacaterol)
2. Methylxanthine (Theophylline)
3. Anti-Muscarinic (Ipratropium Bromide)

Question 3

Mechanism of action of inhaled corticosteroids

Answer 3

1. Binds to steroid receptors in cell cytoplasm - forms a complex that enters nucleus - binds to glucocorticoid response element (GRE) - controls protein synthesis
2. Inhibits enzyme phospholipase A2 (arachidonic acid - inflammation) - Anti-inflammatory effects
   - DECREASED T cells, mast cells, macrophages, eosinophils in the airways; shedding of epithelial cells, macrophage phagocytosis & production of cytokines & proteases, COX2, 5-LOX, iNOS & PLA2 expression
   - INCREASED lipocortin, β2 receptors on airway smooth muscle
   - direct vasoconstriction and decreased plasma exudation/mucus secretion

Question 4

Uses of inhaled corticosteroids (2)

Answer 4

1. 1st line prophylactic Asthma therapy

2. Nocturnal Asthma

Question 5

Toxicity of inhaled corticosteroids (7)

Answer 5

1. Oropharyngeal Candidiasis - immune suppression
2. Dysphonia - problem with vocal cords leading to hoarseness
3. Cough/Throat Irritation
4. Easy bruising of skin (elderly)
5. Adrenal Suppression
6. Posterior Subcapsular Cataracts
7. Osteoporosis

Question 6

Mechanism of action of leukotriene receptor antagonist

Answer 6

Blocks LTD4 in the leukotriene pathway which contributes to the pathogenesis of asthma (bronchoconstriction, inflammation)

Question 7

Uses & toxicity of leukotriene receptor antagonists (3+1)

Answer 7

1. Prophylaxis & chronic treatment of asthma
2. Aspirin-induced asthma
3. Exercise-induced asthma
4. Eosinophilia

Question 8

Mechanism of action of cromolyn

Answer 8

1. Inhibits mast cell degradation induced by IgE-mediated FcεRI cross linking
2. Alters delayed Cl channels - inhibits cellular activation
3. Promotes secretion of Annexin A1/Lipocortin-1 - blocks histamine & eicosanoid release from mast cells
4. Blocks release of inflammatory mediators from eosinophils, neutrophils, macrophages

Question 9

Uses of cromolyn (2)

Answer 9

1. Prophylactic control of Asthma
2. Prophylactic control of Allergic Rhinitis/Conjunctivitis
   - prevents cold, dry air & exercise-induced bronchospasm

Question 10

Toxicity of cromolyn (2)

Answer 10

1. Throat irritation, dry mouth, coughing (preventable by first inhaling β2 agonist)
2. Unpleasant, bitter taste

Question 11

Mechanism of action of anti-IgE antibody

Answer 11

1. Binds to Fc portion of IgE - decreases FcεRI expression on mast cells/basophils - prevents degranulation & asthmatic reaction
2. Depletes free IgE levels in serum

Question 12

Uses of anti-IgE antibody (2)

Answer 12

1. Allergic Asthma

2. Allergic Rhinitis

Question 13

Mechanism of action of β2 agonists

Answer 13

1. Activates β2GPCR - activates adenylyl cyclase - increased cAMP leading to (A) decreased intracellular Ca (B) decreased MLCK (C) increased K+ conductance - leading to airway smooth muscle relaxation
2. Mast cell stabilization, reduced microvascular leakiness, increased mucociliary clearance

Question 14

Uses of β2 agonists (3)

Answer 14

1. SABA - reverses constricted airways (PRN)
2. LABA - prevents exercise-induced asthma + long term maintenance of (nocturnal) asthma
3. ULABA - COPD

Question 15

Toxicity of β2 agonists (6)

Answer 15

1. Fine tremor of skeletal muscle
2. Muscle cramps
3. Peripheral vasodilation
4. Palpitations & tachycardia (cross reaction with β1 receptors)
5. Hypokalemia, Hyperglycemia
6. Tolerance

Question 16

Mechanism of action of theophylline

Answer 16

1. Inhibits PDE which breaks down cAMP - increased cAMP - increased ASM relaxation
2. Inhibits adenosine which causes SM constriction
   - Increased epinephrine release from adrenal medulla
   - Decreased microvascular leakiness
   - Increased contractility of fatigued diaphragm in COPD

Question 17

Uses of theophylline (3)

Answer 17

1. Adjunct/add-on therapy to inhaled β2 agonists/steroids
2. Nocturnal bronchospasm (sustained release)
3. Improve lung function in COPD

Question 18

Toxicity of theophylline (3)

Answer 18

1. GIT-related (nausea, vomiting, anorexia, abdominal discomfort)
2. CNS (nervousness, tremor, anxiety, headache, seizures)
3. CVS (arrhythmias)

Question 19

Mechanism of action of ipratropium bromide

Answer 19

1. Inhibits M3 receptor-mediated bronchospasm (M3R is only expressed in airways)
   - reverses portion of bronchospasm & mucus secretion caused by vagal nerve
2. Inhibits M2-nerve terminal transiently - bronchodilation

Question 20

Uses of ipratropium bromide (2)

Answer 20

1. Adjunct/add-on therapy to inhaled steroids/β2 agonists
2. Patients intolerant of β2 agonists
3. COPD (more bronchodilator effect)

Question 21

Toxicity of ipratropium bromide (4)

Answer 21

1. Unpleasant Taste
2. Dry Mouth
3. Urinary Retention in elderly
4. Paradoxical Bronchospasm