L12.2 Asthma

Question 1

What is asthma characterised by

Answer 1

• Asthma = chronic inflammatory disorder of the airways
• Hyperresponsive airway → narrowing the airways

Question 2

Asthma pathogenesis

Answer 2

• Overproduce IgE
• APC → lymphocyte clonal expansion:
  
  • B cells (under influence of IL4) → IgE → IgE made chronically → re-exposure to antigen → mast cell → airway obstruction
  • Th2 → pro-inflam cytokines → eosinophil recruitment and activation → airway obstruction

Question 3

Airway obstruction caused by:

Answer 3

• Bronchspasm
• Mucous hypersecretion → mucous plugs
  
  • Untreatable in small airways → ∴ anti-asthmatics given prohylactically
• Hyperaemia → causes oedema
• Vascular leak
• Cellular proliferation
• Fibrosis

Question 4

Features of eosinophils

Answer 4

• Released Cytotoxic substances → acts on epithelial cells → nerve activation
  
  • Involves central and local neural reflex (cholingeric reflex) → release mediators → bronchoconstriction

Question 5

Host/env factors influencing asthma development and expression

Answer 5

• Host:
  
  • Genetic/Gender/Obesity
• Environmental:
  
  • Indoor allergens
  • Outdoor allergens
  • Occupational sensitisers
  • Tabacco smoke
  • Air pollution
  • Resp Infections
  • Diet

Question 6

FEV1 and hyperresponsiveness

Answer 6

• ↓FEV1 → shows that airways are narrowed (greater resistance to air being expired)
  
  • Bronchoconstrictors shifts FEV1 curve to the left with airway hyperresponsiveness (AHR)
    
    • Normal and mild AHR ↓FEV1 → but still maintain minimal FEV1 response (plateaus)

Question 7

What does chronic inflammation cause

Answer 7

• Chronic inflammation → causes remodelling → airway narrowing

Question 8

Treatment of asthma

Answer 8

• *Difficult to prevent development of allergy
  
  • Relievers (SABA)
  • Controller (LABA - background bronchodilatation)
  • Preventer (Anti-inflammatory agents - i.e. GC)
    
    • Targets broncho SM and the oedema aspect of asthma

Question 9

Routes of drug admin for anti-asthmatics

Answer 9

• Oral once a day is ideal → ↑compliance
• Parenteral treatment (injections) → for more severe diseases

Question 10

Balance of relaxation and constriction

Answer 10

• ↑bronchodilation (via ↑adrenaline and PGE2) > bronchoconstriction (from histamine/leukotriences/ACh)

Question 11

SABA

Answer 11

• Salbutamol/Terbutaline
• Selective for β2 adrenoceptors
• A.E:
  
  • B1 → would produce tachycardia
  • B2 → causes tremors

Question 12

Regulation of muscle tone

Answer 12

• Contractile agonists
• Constrictors work through Gq protein → Ca osscilations → X-bridge cycle (countered by MLC-P → turns off ATPase)
• β-agonists → cAMP → PKA → phos MLC-P → ↓Ca to activate MLC K → ↓Contractions

Question 13

Important clinical features of b-agonists

Answer 13

• Low degree of tachyphylaxis (low response to drug after admin = tolerane) on ASM
• High degree of tachyphylaxis on inflammatory cells → mast cell action relativel unimportant
  
  • Caused by:
    
    • Induction of PDEs
    • ↓receptor number
    • ↓coupling to adenylate cyclase
    • βARK activity higher in mast cells than ASM

Question 14

LABA (controllers)

Answer 14

• Salmeterol (slow)/Formoterol (rapid)
• Combined with inhaled GCS in single actuator
• Tolerance may develop to bronchoprotective effects
  
  • But not significant enough to not use controllers

Question 15

GC features

Answer 15

• Suppresses:
  
  • Inducible enzymes of inflammation (PLA2)
  • Inflammatory cytokines (TNF α)
  • Adhesion molecules (ICAM1)
• Induces:
  
  • Annexin-1 & β2 R

Question 16

GC (inhaled)

Answer 16

• Budesonide, fluticasone propionate
• Slow onset and max benefit
• Usually inhaled GCS if need β2 agonist >3x a week (mild persistent asthma)
  
  • Now use even in mildest intermittent forms (use low does → control event)
  • Start at effect dose → step down

Question 17

GC (oral GCS)

Answer 17

• Acute exacerbations
• Prednisolone: not the same A.E as GCS used chronically
  
  • Addition effect may be due to effects on bone marrow

Question 18

Stepwise therapy

Answer 18