L3.2 Glucocoritcoids

Question 1

Pharmacological roles of glucocorticoid

Answer 1

• Anti-inflam
• Immunosuppressant
• Anti-cancer

Question 2

What is cortisol

Answer 2

• Physiological GC
• Synthesised by adrenal cortex → affects carbs & protein synthesis
• Acts on 2 types of receptors:
  
  • GCR: Anti-inflammatory
  • MCR (mineralocorticoid R): promotes Na/H2o retention

Question 3

Regulation of cortisol

Answer 3

• Stress → CRH → ACTH (from ANT pituitary) → adrenal cortex → cortisol
• Coritsol sends FB to hypothalamus which regulates the level of cortisol
• Cortisol acts as own -ve FB

Question 4

Speed of action of cortisol and GC

Answer 4

• Rapid metabolism but synthetic GCs have a longer duration
  
  • GCs used to treat local areas need short 1/2 life → quickly metabolised into local area
• GC has a slow onset of action & maximum benefit
  
  • Some actions are rapid - i.e systemic hydrocortisone in shock (from non-genomic actions of GC)

Question 5

Anti-inflam uses of GC

Answer 5

• Physiological replacement - Addison’s disease
• Anti-inflammatory uses:
  
  • Asthma (particularly the allergic type)
  • Skin, eye inflammation
  • Hypersensitivity states
  • R.A - Non-allergic condition where GC are indicated (Prednisolone)

Question 6

Mechanism of GC

Answer 6

• ↓ inflam cell #
• ↓ probability & severeity of inflamm

Question 7

Transactivation

Answer 7

• GC crosses mem → binds to GR → HSP90 dissociates → Dimerisation → translocation into nuclues → interacts with GRE (GC response element)
• Transactivator resultant gene products:
  
  • β-adrenoceptors
  • Annexin-1
  • PDGFBB

Question 8

Transactivator resultant anti-inflam products

Answer 8

1. Enac
   
   • Important for reabsorption of Na
2. MKP1
   
   • Dephosphorlates ERK → inhibits cytokine production
3. GILZ
   
   • Inhibits NF-kB → ∴↓pro-inflammatory genes
4. IkBa
   
   • Keeps NF-kB in nuclues → preventing it from reaching site of action

Question 9

Pro-inflammatory genes include:

Answer 9

• IL8
• COX2
• ICAM1 - adhesion protein for leukocytes, contributes to leukocyte infiltration
• NOS2 - produces NO
  
  • Produced extracellularly → causes indiscriminate damage
  • Produced within compartment → Physiological regulation of infections/vasoprotection

Question 10

Transrepression

Answer 10

• GR binds to HDAC2 → compacts chromatin → inhibits transcription → ↓pro inflam products

Question 11

GC AE

Answer 11

• Suppress GC synthesis
• Suppress response to infection/injury
• Behavioural disturbances
• Cataracts, glaucoma
• Metabolic

Question 12

Transpression/activation benefits and AE

Answer 12

• Adverse effect from transactivation associated with metabolic effects
  
  • Osteoporosis, fat deposit, muscle wasting, hyperglycaemia, inhibition of growth in children
• Adverse effect from transrepression associated with ↓leukocytes/eicosanoids

Question 13

Annexin-1

Answer 13

• Pro-resolution & Anti-inflam
• Mediator of GC action
• Ca2+ dependent activation
  
  • Unique N-terminus to regulate bioavailability & distribution

Question 14

Distribution of Annexin 1

Answer 14

• Cytoplasm
• Plasma mem
• Extracellularly

Question 15

Actions of Annexin 1

Answer 15

• ↓PLA2 activity
• Mem repair
• Mem fusion
• Phagocytosis + ↓cytokines
  
  • Acts by binding to FPR2
    
    • Triggers/binds lipoxins → ↓ leukocytes & macrophage phagocytose neutrophils
    • Suppress neutrophil activation

Question 16

Significance of transactivation

Answer 16

• Deleted annexin-1 genes in mice
  
  • ↓intensity of anti-inflam response
  • Shows that transactivation has significant contribution twd anti-inflammation

Question 17

“Dissociated steroids”

Answer 17

• Concept of separate beneficial anti-inflammatory & detrimental metabolic effects of GC
  
  • ↑transrepression but ↓transactivation
    
    • Flawed. No transactivation → lack anti-inflam & high transrepression leads to poor repair
    • Both needed

Question 18

What happens when GR has not dimerisation

Answer 18

• GR without dimerisation → non-lethal
  
  • Shows that transrepression more important than transactivation

Question 19

GC resistance

Answer 19

• From chronic use of steroids → impairs GC actions