Anti-inflammatory steroids - Ceryak Flashcards
Where are adrenal corticosteroids synthesized
adrenal cortex
- cortisol
- aldosterone
Are glucocorticoids inflammatory?
no they are anti-inflammatory
- cortisol
What do mineralocorticoids affect?
water, electrolyte balance
What is the largest zone of the adrenal cortex?
zona fasciulata
Which zone of the adrenal cortex is cortisol synthesized in
zona fascicolata
What stimulates cortisol synthesis
ACTH
Which zone is the aldosterone synthesized in?
zona glomerulosa
What stimulates aldosterone synthesis
angiotensin II and K+
What are the steps of HPA axis
- stress stimulus
- NT are released and activate the hypothalamus to release releasing hormones
- releasing hormones act on the ant. pit.
- ant. pit. releases ACTH
- ACTH acts on the adrenal cortex
Where is ACTH released from
anterior pituitary
Where is CRH released
hypothalamic neurons
What are cortisol levels at 8 am
16 micrograms/100 ml
What are cortisol levels at 4 am?
4 micrograms/100 ml
What happens when ACTH binds to its receptor in the adrenal cortex
adenylyl cyclase is activated
- increased cAMP leads to increased PKA
What does PKA phosphorylate in the adrenal cortex?
phosphorylates cholesterol ester hydrolase (CEH) which increases its activity
What does cholesterol ester hydrolase (CEH) activation lead to
free cholesterol is formed to serve as a substrate for corticosteroid synthesis
What is cholesterol converted to to form cortisol
pregnelone
Where is cholesterol converted to pregnelone
mitochondria
What is the effect of ACTH on cholesterol?
ACTH frees up cholesterol as a substrate for corticosteroid synthesis
Where do glucocorticoids bind their receptor?
cytosol
- can freely pass the plasma membrane
What happens when glucocorticoids bind their receptor
the steroid-receptor dimerized complex is translocated into the nucleus
- inside the nucleus it binds to a GRE on the regulatory portion of the gene
- affect protein synthesis
Transrepression by glucocorticoid
directly interact with and alter the function of other transcription factors, such as NF-Kb in the nucleus of cells
What is a glucocorticoid response element
a specific nucleotide sequence that is recognized by the receptor complex
What is the effect of glucocorticoids on the liver
increased synthesis of glucose, glycogen deposition
What is the effect of glucocorticoids on skeletal muscles
increased protein breakdown and inhibit protein synthesis
What is the effect of glucocorticoids on fatty acids
increased free fatty acids, permissive for lipolytic signals (epinephrine, growth hormone)
What do you see at high levels of glucocorticoids
muscle wasting, redistribution of body fat (back of neck and face)
What is the effect of glucocorticoids of on the CV system
- hypertension with prolong high levels
What is the effect of glucocorticoids on calcium homeostasis
decreased renal absorption, decreased Ca/ Mg/ PO4 absorption in the GI
What is the effect of glucocorticoids on collagen and bone deposition
inhibit collagen synthesis and bone deposition = osteoporosis in adults
- slows bone growth in children
What is the effect of glucocorticoids on CNS
modulate perception and mood and behavior
What does aldosterone bind to
renal cortical collecting duct mineralocorticoid receptor
- translocates into the nucleus and binds to the GRE and functions as a transcription factor
What does aldosterone do to the cell?
increased Na transporter on the lumen of the cell
- pump more Na+ into extracellular space
- uptake of potassium and export of sodium
= increase in H2) and volume = hypertension
What do mineralocorticoid target tissues express
11-beta hydroxysteroid dehydrogenase type 2
- inactivates cortisol to cortisone to prevent excessive stimulation of the mineralocorticoid receptor
Why can eating large amount of licorice lead to hypertesnion
cortisol can’t be deactivated
- cortisol binding MR which leads to extracellular fluid volume
- licorice inhibits enzyme so cortisol can act like aldosterone and induce hypertension
What happens to the eNac and Na/k+ transporters with aldosterone?
both are upregulated
- allowing more Na+ to be reabsorbed and more water
- increases blood volume
Do clinically used corticosteroid bind the same receptors?
yes
What are glucocorticoids primarily used for
anti-inflammatory and immunosuppressive actions
fludrocortisone
potent GC and MC activity
What is dexamethasone used for
diagnose various causes of hypercorticism
Where are corticosteroids metabolized and excreted?
liver metabolism and urine excretion
Is dexamethasone more potent than hydrocortisone?
yes, 30x more potent in terms of anti-inflammatory
Is fludrocortisone more potent than hydrocortisone?
yes 250x in the salt retaining properties
Which drug is the mineralocorticoid of choice for mineralocorticoid replacement therapy
fludrocortisone
What do pro-inflammatory cytokines act on in the HPA axis?
hypothalamus to induce CRH release
- ant. pit. to release ACTH
- circulating cortisol also has direct effects on immune suppression
How do glucocorticoids decrease production of prostaglandin and leukotriene?
inhibition of phospholipase A2 and decreased synthesis of COX2
Which proteins transcription is activated in the presence of glucocorticoids
anti-inflammatory proteins:
IL-10
annexin A1
IxB
Which proteins are suppressed in the presence of glucocorticoids
IL-1, IL-2, IL-6, IL-8 VEGF COX-2 prostaglandins TNF IFN-gamma
What happens to COX2 and TNF alpha in the presence of glucocorticoids
transcriptionally repressed
What is the role of TNF
inflammation induction
- activates immune cell
What happens with COX 2 in the presence of glucocorticoids
- decreased COX 2
- decreased prostaglandin
What happens to annexin A1 (lipocortin 1) production in the presence of glucocorticoids
- decreasd lipocortin 1
decreased arachidonic acid - decreased prostaglandin
What does annexin A1 lipocortin inhibit
phospholipase A2
- AA can’t be cleaved so downstream mediators aren’t formed
How can you tell if something wrong is coming from the HPA axis in the dexamethasone suppression test
- ACTH and CRH production will be supressed
How can you tell if something is an ectopic tumor that is producing ACTH in the dexamethasone suppression test
- not going to be suppressed by dexamethasone
At what time point do glucocorticoids start to have a negative effect
greater than 2 weeks
What causes AE of glucocorticoids
- cessation of therapy - abrupt withdrawal
- continued use for supraphysiological doses for inflammation (mimic Cushing syndrome)
What can cause acute adrenal insufficiency
suppression of the HPA by prolonged therapy with high doses of glucocorticoids
How to recover from taking glucocorticoids
slowly tapering the dose
What are the drug induced Cushing’s syndrome symptoms
altered fat deposition, muscle weakness and atrophy, striae (protein in dermis is being degraded), bruising, acne
What are the metabolic effects of Cushing’s
fluid/electrolyte imbalance
- hypertesion
- hyperglycemia due to increased gluconeongesis
- growth suppression
- osteoporosis
- decreased wound healing
- suppression of immune system
