Corticosteroids Flashcards
Adrenal glands
Two adrenal glands above/close to kidneys
adrenal cortex - outside
adrenal medulla - inside
Adrenal Medulla
produces adrenaline + catecholamine/amino acid hormone
Adrenal cortex
generation and release of steroid hormones
zona glomerulosa
zona fasciculata
zona reticularis
Zona glomerulosa
mineralocorticoids
aldosterone
salt balance
(salt)
zona fasciculata
glucocorticoids
cortisol
metabolic and immune effects - inflammatory response
(sugar)
zona reticularis
androgens
precursors for testosterone and estrogens
DHEA - metabolized in sex organs to generate androgens
(sex)
cholesterol
common precursor for all adrenal steroid hormones
HPA axis
hypothalamus, pituitary, + adrenal cortex
controls cortisol release from the zona fasciculata
hypothalamus releases CRH → anterior pituitary releases ACTH → stimulates steroid production (cortisol synthesis) [after meals; circadian rhythm]
HPA axis negative feedback
cortisol exerts negative feedback on CRH release from hypothalamus and ACTH release from pituitary
stress signals that trigger cortisol → hormone release inhibits further release
cortisol
acts on glucocorticoid target tissues → stress response, catabolism, immuno-suppression
release of cortisol inhibits further release through negative feedback
aldosterone
released through RAAS - renin angiotensin aldosterone system: kidney releases renin → cleaves angiotensonigen into angiotensin 1 → ACE converts AT1 into AT2 → triggers aldosterone release
targets kidneys - promotes Na+/water reabsorption + K+ excretion
control of blood pressure/volume
steroid hormone action mechanism
cytoplasmic unliganded receptor in complex with Hsp90
binding of steroid hormone to the receptor causes dissociation → transport into nucleus → dimerized receptors interact with DNA + influence transcription of target genes
Glucocorticoid receptor/response element → targets lipocortin + COX-2
corticosteroid receptors
glucocorticoid receptor - stimulates GC response
mineralocorticoid receptor - stimulates a MC response
spectrum - steroids have different affinities for either receptor
specificity arises from affinity of compound/receptor + metabolism in target tissues
In vivo specificity
glucocorticoid target tissues (adipose, muscle, liver) express 11B-hydroxysteroid dehydrogenase type 1 → activation of cortisol from cortisone
kidney cells express 11BHD type 2 → inactivates cortisol = weak mineralocorticoid effects
don’t want cortisol to act on kidneys - under control of aldosterone
example of corticosteroid action/administration
prednisone is widely used by oral intake or injection → metabolized to prednisolone to become effective (first pass metabolism in liver)
prednisolone is the active form and has a strong topical effect
pseudohyperaldosteronism
inhibition of 11BHD type 2 → active cortisol mimics aldosterone in the kidneys (where it would normally be inhibited)
triggers hypertensive response: increased uptake of water and reabsorption of sodium = high blood pressure
ex. licorice overdose, genetic disease apparent mineralocorticoid excess
metabolic effects of glucocorticoids
- carbohydrate metabolism: increases circulating glucose
- fat/lipid balance: promotes fat deposition in the trunk but fat breakdown in the limbs = loss of muscle and bone mass in limbs
- promote synthesis of glucose in the liver
- block insulin effects
short term: trigger breakdown of fat in adipose tissue but long term: tissue becomes insensitive to glucose → high levels of insulin = fat deposition
anti-inflammatory effects of glucocorticoids
induce lipocortin = inhibit arachidonic acid generation from phospholipids
suppress cox-2 = inhibit prostanoid synthesis
cox-2
important inflammatory mediator (early in process) - metabolizes arachadonic acid to prostanoids
glucocorticoids suppress transcription of the cox-2 gene → long term suppression of expression (do not directly inhibit activity by direct receptor antagonism)
lipocortin
- direct effects on leukocytes (inflammatory cells) inhibits their tissue infiltration
- suppression of phospholipase A2 activity - prevents AA generation = suppresses downstream generation of prostanoids
- protein = expression is induced by GC receptor activation
Addison’s Disease
chronic adrenocortical insufficiency
fatigue, salt + sugar imbalance, skin discoloration (negative feedback leads to excess melanin synthesis)
low production of glucocorticoids and mineralocorticoids
treat with supplementation - hydrocortisone
Cushing’s Syndrome
adrenal overactivity = excessive cortisol
adrenal tumour, pituitary tumour, drug-induced (long term GC treatment), or ectopic tumour
round face + fat deposition in trunk, muscle loss + osteoporosis → protein + bone catabolism
treated by resection of adrenals or pituitary tumour, followed by gradual adjustment towards a maintenance dose of cortisol
therapeutic uses of GCs
powerful anti-inflammatory + immunosuppressive actions of cortisol + analogues
allergic reactions
eye inflammation
reduction of pain + scarring
gastrointestinal diseases
hematologic disorders (leukemia, myeloma)
asthma
organ transplants - immunosuppression
glucocorticoid treatment
mimics endogenous cortisol = exerts negative feedback
→ suppresses production of CRH and ACTH = reduces circulating levels
side effects of glucocorticoid treatment
shut down body’s ability to generate its own cortisol:
- if stopped abruptly = addisonian crisis: hypoglycemia, hyponatremia, hyperkalemia, low blood pressure
- mimics effects of Cushing’s syndrome: metabolic (hyperglycemia), immunosuppressive, catabolic (osteoporosis), anti-inflammatory, and other side effects
tapering - should not abruptly stop taking a glucocorticoid
