Steroids

• What is cholesterol?

  Endogenous steroid
• What do glucocorticoids do?

  Widespread effects

  Maintain homeostasis

  Manage stress
• What do mineralocoricoids do?

  Electrolyte homeostasis

  Renin-angiotensin system

  Increase Na+ & H2O reabsorption in kidney

  Increase K+ & H+ excretion in kidney
• What are the metabolic effects of glucocorticoids?

  Breakdown protein/carbohydrate

  Stimulate gluconeogenesis -> hyperglycaemia

  Breakdown & deposition of lipids

  Increases appetite -> obesity
• What are the cardiovescular effects of glucocorticoids?

  Increase BP
• What are the immune effects of glucocorticoids?

  Stress protective responses

  Decreases immune/inflammatory response -> slows wound healing & increases infection
• What are the other effects of glucocorticoids (not metabolic, CV or immune)?

  Bone growth -> osteoporosis

  Cell growth -> pro apoptotic

  CNS effects (neurodegeneration, mood etc)
• How do steroids have systemic effects?

  Steroids are lipid soluble -> so distributed throughout entire body -> influence function of ALL cells
• MOA steroids

  Lipid soluble -> widespread

  Bind to steroid hormone receptors (in cytoplasm) -> dissociation of HSP (heat shock protein) & dimerisation -> translocation to nucleus -> bind to defined sequences on DNA (GRE (glucocorticoid response elements)) -> modifies target gene transcription (either increases or decreases)
• What is transactivation?

  Increased transcription
• What is transpression?

  Decrease transcription
• Where are corticosteroids produced?

  Adrenal cortex
• What are the 3 types of corticosteroids?

  Glucocorticoids

  Mineralocorticoids

  Sex steroids
• Where are glucocorticoids produced (specific)?

  Adrenal cortex - zona fasciculata
• Where are mineralocorticoids produced (specific)?

  Adrenal cortex - zona glomerulosa
• Where are sex steroids produced (specific)?

  Gonads

  Adrenal cortex - zona reticularis
• What does the adrenal medulla produce>?

  Adrenaline (epinephrine)
• What are the effects of steroids on immune & inflammatory responses (humoral)?

  Humoral

  • decreased mediators of inflammation
  • decreased prostaglandin synthesis, histamine release, NO generation
  • decreased complement
• What are the effects of steroids on immune & inflammatory responses (cellular)?

  Cellular

  • decreased neutrophil migration into tissues
  • decreased T cell activation/proliferation
  • decreased B cell activation/proliferation & decrease IgG production
• What are the effects of steroids on immune & inflammatory responses (substantial & comprehensive)?

  Substantial & Comprehensive

  • very effective anti-inflammatory agents
  • wide-ranging clinical usage
• What is Cushing's Syndrome?

  Over-exposure to glucocorticoids

  Can be pathological (adrenal tumour) or iatrogenic (excessive use of exogenous glucocorticoids)
• Which genes are modulated by glucocorticoids?

  Approx. 10% of genes (not all are related to immunity/inflammation)
• Give 2 examples of proteins upregulated by glucocorticoids.

  Annexin A1

  Anti-inflammatory cytokines
• Give 4 examples of proteins down-regulated by glucocorticoids.

  COX-2

  iNOS (inducible nitric oxide synthase)

  PLA2

  Pro-inflammatory cytokines
• Give 7 drugs that can be used for gout & hyperuricaemia.

  Allopurinol

  Febuxostat

  Colchicine

  Probenecid

  Rasburicase

  Canakinumab

  Lesinurad