Asthma

Question 1

Define broadly what asthma is

Answer 1

• Chronic inflammatory condition of lung airways
• Causing bronchial muscle contraction, mucosal swelling/ inflammation and increased mucus production → Obstructing airways
• Characterized by recurrent episodes of dyspnoea, cough and wheeze

Question 2

What is the pathogenesis of asthma?

Answer 2

Antigen;

• Antigen presenting cells pick it up
  
  • Present to naive CD4+ T_H cells, +IL4 → T_H2 cells → produce IL4,5,13
  • IL5 recruits oesinophils
  • IL13 stimulates mucus secretion
  • IL4 & IL13 promotes class switching in B cells to IgE
• IgE binds to Fc receptor on mast cells sensitising it
• Repeat exposure → antigen binds to IgE on mast cell and;
  
  • Mast cell degranulation, releasing;
    
    • Histamine (vasoactive)
    • Proteases (damage)
    • Chemotactic factors (inflam)
  • Activated phospholipase A₂ → released membrance phospholipds → arachidonic acid → prostaglandins (vasoactive) & leukotrienes (C/D₄vasoactive B₄ inflam) & PAF
  • Secretes cytokines (inflam)

Question 3

What causes bronchial smooth muscle contraction?

Answer 3

Direct stimulation of subepithelial vagal (parasympathetic) receptors through both central and local reflexes (including those mediated by unmyelinated sensory C fibers)

Question 4

What causes mucosal swelling/ inflammation?

Answer 4

• Antigen presenting cells pick it up
  
  • Present to naive CD4+ TH cells, +IL4 → TH2 cells → produce IL4,5,13
• Mast cell
  
  • Secretes cytokines (inflam)
  • Secretes proteases
• EVERYTHING ELSE…

Question 5

What stimulates increased mucus production?

Answer 5

IL13 release from T_H2 cells stimulates mucus secretion.

Question 6

What are the symptoms & signs of asthma?

Answer 6

Symptoms;

• Intermittent dyspnoea
• Wheeze, cough (often nocturnal) & sputum
• Diurnal variation in symptoms or peak flow
  
  • Marked morning dip of peak flow
• Acid-reflux - 40-60% of asthmatics have reflux
• Precipitants; cold air, exercise, emotion, allergens etc
• Other atopic diseases - eczema, hay fever, allergy, family history

Signs;

• ↑Inflation ↑Resonance ↑RR
• ↓Diminished air entry
• Audible wheeze & polyphonic wheeze (musical on ausc)
• Severe attack;
  
  • Sentences
  • Pulse >110bpm
  • Resp rate >25min
  • PEF33-50% predicted
• Life threatening attack;
  
  • Silent chest
  • Bradycardia, cyanosis, exhaustion
  • PEF <33% predicted

Question 7

What investigations are used to diagnose asthma?

Answer 7

• LFTs
  
  • Variable (>15%) airflow limitation via PEF or FEV1
  • Diurnal PEF, drugs help, exercise hinders
• CXR
  
  • Hyperinflation
• ABG
  
  • Low PaO2
  • Low PaCO2
• Allergy tests
  
  • Histamine/ metacholine inhaled ⇒ FEV1 drops
  • Wheele 15mins after skin prick

Question 8

How do you treat chronic asthma?

Answer 8

Behaviour;

• Quit smoking, avoid precipitants, check inhaler technique, knowledge of treatment/ action plan

British Thoracic Society guidelines;

1. B2 agonist (eg salbutamol)
2. • Steroid (eg beclometasone)
3. • LABA (eg salmeterol)
4. • Theophylline + Leukotrience receptor antagonist
5. • Prednisolone

Question 9

How do B2-adrenoceptor agonists work?

Give examples of short & long acting

Answer 9

Act on B2 adrenergic receptor;

• Activates adenylyl cyclase
• ATP → cAMP
• Activates PKA
• → Bronchodilation

Short acting include Salbutamol, Terbutaline

Long acting include Salmeterol, Formoterol

Question 10

How do anticholinergics work?

Give examples

Answer 10

They are muscarinic antagonists, inhibiting bronchial mucus secretion.

eg Ipratropium, Tiotropium

Question 11

How do methylxanthines work?

Give examples

Answer 11

Inhibit phosphodiesterase

• Stops cAMP → AMP conversion
• Increasing cAMP
• Activates more PKA → bronchodilation

eg Theophylline, Aminophylline

Question 12

How do glucocorticoids work?

Give examples

Answer 12

Bind to glucocorticoid receptor, modifying gene transcription;

• Inhibit COX2, cytokines, cell adhesion molecules
• Upregulate anti-inflam genes
• Inhibit IL4,5,13 release from T_H2 cells

eg Beclometasone, Fluticasone, Prednisolone

Question 13

How do Cromones work?

Give examples

Answer 13

Stablise mast cell & inhibit sensory nerves (block Cl^- channel)

eg Sodium Cromoglycate, Nedocromil

Question 14

How do anti-leukotriene’s work?

Give example

Answer 14

Inhibit 5-lipoxygenase (an enzyme that converts arachidonic acid to Leukotriene A₄)

• eg Zileuton

Antagonist for CysLT1 (a receptor for Leukotrienes)

• eg Zafirlukast, Montelukase

Question 15

How do anti-IgE therapies work?

Give examples

Answer 15

Omalizumab

• Humanized monoclonal anti-human IgE
• Neutralizes circulating IgE
• Suppresses allergic reactions, including chronic allergy underlying asthma