L3.2 Glucocoritcoids Flashcards Preview

Pharmacology > L3.2 Glucocoritcoids > Flashcards

Flashcards in L3.2 Glucocoritcoids Deck (19):
1

Pharmacological roles of glucocorticoid

  • Anti-inflam
  • Immunosuppressant
  • Anti-cancer

2

What is cortisol

  • 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

3

Regulation of cortisol

  • 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

4

Speed of action of cortisol and GC

  • 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)

5

Anti-inflam uses of GC

  • 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)

6

Mechanism of GC

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

7

Transactivation

  • 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

8

Transactivator resultant anti-inflam products

  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

9

Pro-inflammatory genes include:

  • 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

10

Transrepression

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

11

GC AE

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

12

Transpression/activation benefits and AE

  • 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

13

Annexin-1

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

14

Distribution of Annexin 1

  • Cytoplasm
  • Plasma mem
  • Extracellularly

15

Actions of Annexin 1

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

16

Significance of transactivation

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

17

"Dissociated steroids"

  • 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

18

What happens when GR has not dimerisation

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

19

GC resistance

  • From chronic use of steroids → impairs GC actions