L58: Drugs Used In Treatment Of Asthma + COPD

Question 1

Asthmatic airway inflammation vs COPD airway inflammation

Answer 1

Asthma (caused by sensitizing agent):

• CD4+ T-lymphocyte + Eosinophil
• Airway inflammation and remodelling
• epithelial loss, thickened RBM
• Reversible

COPD (caused by noxious agent):

• CD8+ T-lymphocyte + Macrophage + Neutrophil
• Loss of alveolar wall —> decrease in elastic recoil
• epithelial metaplasia, normal RBM
• Irreversible

Question 2

Early and late asthmatic reactions

Answer 2

Asthma patients may have 2 phases of asthmatic reaction after initial bronchial challenge / inhalation of allergen

• Early phase: much sharper decrease: mast cell degranulation
• Late phase: occur after recovery from early phase, slower decrease and more prolonged: inflammatory cells infiltrate

Question 3

Spirometry of COPD

Answer 3

Post-bronchodilator FEV1/FVC <70% indicate presence of airflow obstruction that is not fully reversible

Positive response towards bronchodilator: FEV1 >200ml and >=15 % increase from pre-bronchodilator value

Question 4

Combined assessment of COPD

Answer 4

1. Post-bronchodilator spirometry (FEV1/FVC) —> diagnosis for COPD

2. FEV1 % predicted to determine stage of COPD
>=80% stage 1
50-79: stage 2
30-49: stage 3
<30: stage 4

3. Assessment of symptoms + risk of exacerbation

Question 5

Bronchodilator

Answer 5

1. Beta agonists (1st line)
   - SABA: Salbutamol, Terbutaline
   - LABA: Salmeterol, Formoterol
2. Methylxanthines / PDE inhibitor (2nd line)
   - Theophylline, Aminophylline
3. Muscarinic antagonist
   - SAMA: Ipratropium
   - LAMA: Tiotropium
4. Leukotriene pathway
   - Cysteinyl leukotriene receptor anatagonist: Montelukast
   - 5-lipoxygenase inhibitor: Zileuton
5. Glucocorticoid
   - Inhaled: Budesonide, Fluticasone
   - Oral: Prednisolone, Prednisone
6. Mast cell stabilisers
   - Cromolyn sodium
7. Monoclonal antibody
   - Anti-igE
   - Anti-IL4
   - Anti-IL5

Question 6

Beta agonist

Answer 6

Inhalation / IV

1. Smooth muscle relaxation
2. Reduce vascular permeability —> reduce oedema
3. Increase mucociliary clearance by increase ciliary beat frequency

SABA: 4-6 hours, rapid relief
LABA: >12 hours, decrease rescue medication, improve lung function, steroid-sparing

Adverse effects:

• tremor
• tachycardia
• hypokalaemia
• tachyphylaxis: reduced responsiveness of beta-2 receptor
• down-regulation of beta-2 receptor

Question 7

Methylxanthines

Answer 7

• PDE inhibitors
  1. ↑ cAMP —> smooth muscle relaxation
  2. block adenosine receptor —> ↓ smooth muscle contraction + ↓ histamine release

Adverse effects:

• narrow therapeutic index
  1. CNS: nervousness
  2. CVS: chronotropic and inotropic
  3. GI: N+V
  4. Kidney: diuresis

Question 8

Muscarinic antagonist

Answer 8

1. decrease Vagal cholinergic tone —> smooth muscle relaxation
2. ↓ mucus secretion

Few adverse effects with inhalation

Question 9

Leukotriene pathway

Answer 9

1. Cysteinyl leukotriene receptor antagonist: Montelukast, Zafirlukast
   —> bind to LTC4 + LTD4 receptor
   —> block leuktriene action
2. 5-lipoxygenase inhibitor: Zileuton
   —> taken orally

Question 10

Glucocorticoid

Answer 10

Particularly aim at late phase asthmatic response

1. Suppress inflammation
   - ↓ synthesis and release of inflammatory cytokines
   - ↓ infiltration and activity of inflammatory cells
   - ↓ oedema of mucosa
2. ↓ Mucus production
3. ↑ number of beta2-receptor

Inhaled: Budesonide, Fluticasone
Oral: Prednisolone, Prednisone

Adverse effects: Oral&raquo_space;> inhaled

• osteoporosis
• depressed immunity
• Cushing’s syndrome

Mechanism: bind to glucocorticoid receptor GR (inhibitory cytosolic receptor) —> inhibit cytokine transcription

Inflammatory cells:

• ↓ number of eosinophil, mast cell, dendritic cell
• ↓ cytokines from T-lymphocyte, macrophage

Structural cells:

• ↓ cytokines mediators from epithelial cells
• ↓ leak from endothelial cells
• ↓ mucus production
• ↑ beta-2 receptor synthesis

Question 11

Mast cell stabilisers

Answer 11

• Cromolyn sodium, Nedocromil
• Inhalation
• Prophylactic treatment

1. inhibit mast cell degranulation
2. depress exaggerated neuronal reflexes by irritant receptors

Adverse effects:

• dry mouth
• irritating cough

Question 12

Monoclonal antibodies

Answer 12

1. Anti-IgE: Omalizumab
   - reduction of circulating IgE to reduce IgE receptors on mast cells —> prevents release of inflammatory mediators
   - prophylactic for severe uncontrolled asthma
   - SC injection every 2-4 weeks
   - Adverse effects: anaphylaxis
2. Anti-IL5: Mepolizumab (IgG1), Reslizumab (IgG4), Benralizumab (target alpha subunit of IL5 receptor)
3. Anti-IL4: Dupilumab (IgG4, target alpha subunit of IL4 receptor)

Question 13

Combination therapies

Answer 13

1. LABA + ICS (restore beta-2 agonist number)
   - Symbicort (budesonide/formoterol)
   - Seretide (fluticasone/salmeterol)

Controller (long term)

• LABA + ICS
• LAMA
• ICS
• sustained release theophylline
• Montelukast
• Mast cell stabiliser
• Anti-IgE

Reliever (as required)

• SABA (1st line)
• SAMA

Question 14

COPD medication

Answer 14

Bronchodilators

1. Beta-agonist
   - Salbutamol
   - Salmeterol
   - Indacaterol (Ultra LA)
2. Muscarinic antagonist
   - Ipratropium
   - Tiotropium
   - Aclidinium (Ultra LA)
   - Glycopyrronium (Ultra LA)

Decrease inflammatory response
3. ICS

4. PDE4 inhibitor
   - Roflumilast
5. Theophylline

Combination therapy:

• BA/MA
• ICS + LABA
• ICS + LABA + LAMA