Corticosteroids Flashcards
Learning outcomes
- Describe how corticosteroids are released and act on cells
- Contrast Gluco versus Mineralocorticoid actions using examples
- Describe the properties of steroids used in the clinic
- Give details of the uses of steroids to treat inflammatory conditions in muscle and bone
- List the common side-effects of steroids, and the features of Cushing’s syndrome
How are endocrine hormone systems controlled? (e.g Hypothalamic-pituitary axis)
Negative feedback loop
Hyp releases CRH (corticotrophin releasing hormone) > pituitary gland > ACTH (adrenocorticotropic hormone) > adrenals > cortisol
Cortisol influences tissue action or can negatively feedback to pituitary/hypothalamus ( this is affected by stress or circadian rhythm also)
Adrenal gland
Cortex and medullary regions- cortex responsible for corticosteroid production, medulla responsible for catecholamine production (nora/drenaline)
Outer layer- Glomerulosa- mineralocorticoids
Fasciculata- glucocorticoids
Reticularis- Adrenal androgens
Histologically- Glomerulosa > fasciculata > reticularis > adrenal medulla
Glucocorticoids versus mineralocorticoids
Gc receptors- widely expressed
Mc receptors- mainly expressed in epithelial cells of kidney, colon and bladder
GCS widely used in pain relief/ anti-inflamm drugs
MCS (aldosterone) used in electrolyte balance in kidneys (e.g fludocortisone)
CCsteroids have similar structure related to cholestrol- hydrocortisone (cortisol)- large, hydrophobic molecules
Glucocorticoids- pharmacological examples
Hydrocortisone- prednisolone, methylprednisolone deflazacort, betamethasone, dexamethasone (rheumatic etc), beclomethasone (astmha)
- binds to GC receptors in cytoplasm (widely expressed) - ANTI INSULIN
Mineralocorticoids- pharmacological examples
Aldosterone, fludocortisone
Bind to MC receptor mainly in kindey, colon and bladder epithelial cells- regulating electrolyte balance
- Inc Na+ reabsoprtion in DT of kidney
- Inc K+ and H+ excretion
If excess MC secretion, spironolactone used- K+ sparing agent used in CHF
How does the activated Glucocorticoid receptor identify its target genes in the nucleus?
Steroid hormone receptors found in cytosol
GC receptor dimers bind to specific hormone response elements (HRE’s) on target genes- helps find ligand to activate target cells
What are the 3 main clinical uses of steroids?
- Metabolic
- Anti-inflammatory
- Immunosuppresive
- Protect glucose dependent tissue (brain/heart) from starvation- affect carbohydrate and protein metabolism
- affect protein synthesis and increase breakdown
liver- decrease glucose uptake and utilisation/ increase gluconeogenesis (muscle wastage in cushing’s)
AA + glycerol > gluconeogenesis
Fat redistribution in Cushing’s
Clinically used steroids
-Replacement therapy for Addison’s disease (adrenal failure) hydrocortisone (GC), fludrocortisone (MC)-anti-inflammatory/immunosupressive therapy
methylprednisolone, dexamethasone-asthma: beclometasone(inhalation)
-eczema
-allergic conjunctivitis
-rhinitis
-autoimmune disease
-rheumatoid arthritis, inflammatory bowel disease
-transplant patients to prevent graft v host reactions
Addison’s disease
Primary hypoaldosteronism
No steroids are produced from the adrenal cortex
How do corticosteroids reduce inflammation and how are they administered?
Routes of admin include oral, rectal, intramuscular, intraarticular/lesional, IV, respiratory or topical
Steroids suppress inflammation (calor, rubor, tumor, dolor, functiona laesia)
Dec. no of activated macrophages and T cells (esp helper/ CD4+ cells)
Decreased IL-1/2 (lymphocyte activation)
decreased transcription of COX-2, PLA2, IL-2R via inhibition ofAP-1, NFkBsignalling
How is chronic inflammation suppresed?
Increased lipocortin > inhibits phospholipase A2 : reduces arachidonic acid levels
reduces prostaglandin/leukotriene levels
Overall effect of corticosteroids is to reduce pain and inflammation
Steroid- side effects + cushings’ syndrome
Large doses or prolonged action > exogenous GC levels suppressing normal HPA axis
- PHASED GC withdrawal- patients carry
