Flashcards in Adrenal Deck (102):
What are the chemicals that are synthesized by the adrenal cortex?
What are the two chemicals that are secreted by the medulla of the adrenal glands?
Epi and norepi (catecholamines)
What is the function of the mineralocorticoids (aldosterone)? (3)
Increases Na reabsorption in the collecting tubule
Increases K excretion
What are the physiological effects of glucocorticoids?
Restoring homeostasis after exposure to stress:
Increases BG levels
Counterbalance immune system
What are the two glucocorticoids?
What are the two drug targets of corticosteroid biosynthesis?
17 alpha hydroxlaye
11 beta hydroxylase
What are the relative levels of aldosterone and cortisol in the blood normally?
High cortisol, low aldosterone
What is the effect of ACTH that is release from the anterior pituitary on the adrenal cortex?
Increased steroidogenic enzyme expression
Stimulates production of cortisol and adrenal androgens
What is the problem with long term use of corticosteroids?
What is the MOA of glucocorticoids and mineralocorticoids?
Freely cross the lipid membrane, and interact with receptors in the cytoplasm, and then enter the nucleus to alter expression
What is the intracellular messenger that is inhibited in glucocorticoid/mineralocorticoid use, to immune suppress pts?
True or false: cortisol binds and activates mineralocorticoids and glucocorticoids
What enzyme activates cortisol into inactive cortisone?
What is the enzyme that converts cortisone into cortisol?
What is the function of 11beta HSD1?
Activates cortisone to cortisol
What is the function of 11beta HSD2?
Inactivates cortisol into cortisone
What are the two short acting glucocorticoids? Which effect is predominant: anti inflammatory or salt retention?
What are the four intermediate acting corticosteroids? Which effect is predominant: anti inflammatory or salt retention?
What are the two long acting corticosteroids? Which effect is predominant: anti inflammatory or salt retention?
No salt retention
What is the use of fludrocortisone?
Increase salt retention (BP)
What makes the glucocorticoids prodrugs?
Adding a hydroxyl group to the ring
Is dexamethasone a prodrug? Prednisolone? cortisone? Prednisone?
Prednisone and cortisone are.
What are the causes the Addison's disease?
Autoimmune or TB causes deficiency in cortisol, aldosterone, and androgens
What happens to ACTH and CRH levels in primary (Addison's) adrenal insufficiency? Aldosterone? Why? What does this lead to?
Elevated-- adrenal cortex is lacking a mechanism for feedback
Aldosterone decreases, leading to K retention and Na loss
What is the treatment for Addison's? (2)
Fludrocortisone and oral cortisol
What are the effects of Addison's?
Hypotension from unresponsiveness of vascular smooth muscle to catecholamines
What are the two causes of secondary adrenal insufficiency? What are CRH and ACTH levels in these?
Either decrease in ACTH from pituitary, causing an increase in CRH, and a decrease in cortisol
No CRH from the hypothalamus, lowering ACTH, and lower cortisol
What is the treatment for secondary adrenal insufficiency? Why?
NOT fludrocortisone, since aldosterone function is still retained
When is Glucocorticoid levels highest physiologically? What is the effect on the dosing regimen with this?
In the morning
Higher doses then
What is the cause of Cushing's syndrome?
Chronic glucocorticoid excess
-Pituitary tumor that secretes ACTH
-SCLC secretion of ACTH
-Adrenal tumor that hypersecrete cortisol
What are the ssx of Cushing's?
-Increased abdominal fat
-Poor wound healing
-Thinning of the skin
What happens to bones in Cushing's?
What happens to BP with Cushing's? Why?
Increased d/t increased cortisol levels in the adrenal cortex (swamped 11bHSD2)
What happens with CRH and ACTH with: pituitary hypersecretion of ACTH
What happens with CRH and ACTH with: adrenal adenoma?
Decreased in both ACTH and CRh
What happens with CRH and ACTH with: ectopic ACTH production
Increased ACTH from ectopic production
What happens if dexamethasone is injected into a pt wit pituitary hypersecretion of ACTH? Why?
Usually around 50% reduction in cortisol
The pituitary is still somewhat responsive to dexamethasone.
What happens if dexamethasone is injected into a pt with ectopic production of ACTH? Why?
No reduction in cortisol
ACTH secreting adenoma has no regulatory function like the pituitary
What happens if dexamethasone is injected into a pt with adrenal adenoma? Why?
No reduction is cortisol
Tumors in the adrenal cortex would have no regulatory function with dexamethasone
What is the MOA of ketoconazole in treating Cushing's?
Inhibits 17 alpha hydroxylase, which can lower cortisol production.
What is the major side effect of Ketoconazole?
What is the MOA of Metyrapone in treating Cushings?
Inhibits 11beta hydroxylase leading to decreased aldosterone and cortisol production
Draw out aldosterone pathway
What is the MOA of Mifepristone? What is it normally used for? What is its basis for the use in cushing's?
Anti-progestin effects (abortion)
Glucocorticoid receptor antagonist at high doses
What is the main use of glucocorticoids?
Reduce histamine release
What is the use of glucocorticoids in preterms?
Increased lung maturation
What is the effect of glucocorticoids on: macrophages?
Decrease cytokine release
What is the effect of glucocorticoids on: PMNs?
Stabilize lysosomal membrane
Prevent release of catabolic enzymes
What is the effect of glucocorticoids on: mast cells?
Inhibit release of histamine, prostaglandins
Increase annexin 1
What is the effect of glucocorticoids on: eosinophils?
Inhibit release of histamine, prostaglandins
What is the effect of glucocorticoids on: T cells?
Decrease cytokine release
What is the effect of inhibition of phospholipase A2 by glucocorticoids?
Decreased production of lipid mediators
What is the effect of inhibition of COX by glucocorticoids?
Decreased prostaglandin release
What is the effect of inhibition of Cytokine production by glucocorticoids?
Suppression of cell mediated inflammation
What is the effects of corticosteroids on vessels?
What is the use of inhaled corticosteroids?
What are the four inhaled corticosteroids?
Why should you treat asthma with glucocorticoids and not just beta2 receptor agonists?
Beta 2 use will downregulate the receptors, but glucocorticoids will increase it back
What is the MOA of glucocorticoids in the asthma? (3)
Decreased cell leakiness
Decreased proliferation of airway smooth muscle
Decrease mucus secretion
What is the effect of beta2 agonists on Glucocorticoid receptors?
Increase translocation of GRs, and increase binding of GR to GRE on genes
What is Advair?
Fluticasone + salmeterol
What percent of glucocorticoids are bound to albumin? Is this active?
greater than 90%
This is inactive
What is the effect of glucocorticoid on liver disease?
Lower albumin means more available to work
What is the relative affinity of dexamethasone for albumin? What is the significance of this?
Those with liver disease need lower dosages
What are the adverse effects of inhaled glucocorticoids?
True or false: inhaled glucocorticoids have a high first pass effect
True--most is swallowed
What is the effect of glucocorticoids on: K levels
What is the effect of glucocorticoids on:BP
What is the effect of glucocorticoids on: growth in children
What is the effect of glucocorticoids on: glaucoma
What is the effect of glucocorticoids on: appetite?
Why does high doses of glucocorticoids cause hypokalemia? Does this happen with dexamethasone?
Hits the glucocorticoid receptor in the kidneys
Does not occur with dexamethasone
HPA axis suppression may not return for how long?
Over 12 months
What are the measures to minimize the HPA axis suppression?
Use short acting compounds
What is the effect of long term HPA suppression that may lead to death?
Times of stress will not increase BP, with vasodilation, causing death
What are the drugs that induce p450s and thus increase degradation of glucocorticoids?
What are the drugs that increase the effect of glucocorticoids? Why?
Estrogens/androgen d/t competition for p450s
What is the interaction between cyclosporine and glucocorticoids?
Increase levels by inhibiting each other's metabolism
Why is coadministering glucocorticoid with NSAIDs bad?
Increases the risk of PUDs
Which drugs can glucocorticoids reduce the effects of?
What is the MOA of high dose glucocorticoid causing hypertension/hypokalemia? Would this be caused by dexamethasone?
Oversaturation of 11beta-HSD2, leading to inactivation of
What is the therapeutic use and MOA of ketoconazole?
Inhibits 17 beta hydroxylase
The adrenal cortex regulates what?
Steroid hormones are secreted by what organ? What are these?
Catecholamines are what? What organ secretes this?
Epi and NE
What is cholesterol converted into once inside the mitochondria? What enzyme converts this?
Pregnenolone via cholesterol desmolase
After pregnenolone is converted from cholesterol by cholesterol desmolase, what is it next converted to? What enzyme does this?
17alpha-hydroxylase converts it to 17alpha-hydroxypregnenolone
17-alpha-hydroxyPregnenolone is converted to what by what enzyme?
Converted into 17 hydroxyprogesterone via 3beta-HSD
17 hydroxyproGesterone is converted to what by what?
What is the primary molecule that regulates aldosterone synthesis?
Describe the HPA axis in terms of cortisol production?
Diurnal rhythms send signals to the hypothalamus to secrete CRH via the corticotroph cells. CRH causes ACTH release from the pituitary
ACTH binds to what receptor? Where is this located? What does this cause?
MCR2 on the surface of the adrenal cortex, causing an increase in cholesterol import.
Describe the events of the renin-angiotensin axis?
Renin released by kidneys Cleaves angiotensinogen to ang I. ACE converts ang I to II.
How is the HPA axis inhibited with cortisol?
Cortisol will bind to glucocorticoid receptor on corticotrophs
What is the effect of glucocorticoids on plasma glucose levels?
What is the effect of glucocorticoids on liver gluconeogenesis?
Increases gluconeogenesis enzymes
What is the effect of glucocorticoids on protein synthesis?
What is the effect of glucocorticoids on lipolysis?
What is the effect of glucocorticoids on insulin like action?
Inhibits insulin's effects except in the brain and heart
Both cortisol and aldosterone activate the same mineralocorticoid receptor in the adrenal cortex, but cortisol levels are always much higher? How does aldosterone exert its effects? What happens with high exogenous cortisol use?
11beta-HSD2 converts cortisol into inactive cortisone
High cortisol levels can saturate the 11beta-HSD2 enzyme, allowing cortisol to bind to the mineralocorticoid receptor, and allowing HTN and hypokalemia
What happens to aldosterone levels in secondary adrenal insufficiency? What is the significance of this?
Does not lead to K retention and Na loss like primary