Adrenocortical Pharmacology Flashcards
Why can’t you just take a blood cortisol and ACTH level?
You can, but the levels vary so much througout the day in an unpredictable manner, that it’s impossible to set a “normal” value for these test
the only way you can interpret a blood cortisol and ACTH level is in the context of a stimulating/suppressing test
What are two tests you can do to measure the cortisol level is an interpretable way?
- 24 hour urine sample measurement of the free cortisol level (do twice)
- late night salivary cortisol (do twice)
What result from a urine test would confirm hypercortisolism?
high level of cortisol - duh
What result from a late night salivary cortisol test would confirm hypercortisolism?
loss of the circadian rhythm and absence of the late night nadir
Why would you not do a dexamethasone test in those who have epilepsy?
antiepileptic drugs are known to enhance dexamethasone clearance
If you suspect hypocortisolism, how can you determine if the adrenal gland is functioning?
do a short ACTH stimulation test
inject tetracosactide, which is just synthetic ACTH
What would be the response to an ACTH stimulation test if the adrenal gland is functioning?
you would see an increase in blood cortisol
If the short ACTH stimulation test does not yield an increase in cortisol, what test do you do next? WHY
the long ACTH stimulation test
tests for the possibility that hypopituitarism caused atrophy of the adrenal gland, but such an adrenal gland could produce cortisol eventually - just takes longer
so it helps differentiate between primary and secondary adrenal insufficiency
So if a patient has Addison disease, will the long ACTH stimulation test yield an increase in cortisol?
no - cortisol will be low at all the time points because the adrenal gland just can’t respond to the ACTH no matter how long you give it
Back to hypercortisolism, let’s talk about dexamethasone. What is dexamethasone?
it’s a synthetic glucocorticoid that has very potent effects on the glucocorticoid receptor (and none on the mineralocorticoid receptor)
What are the two “flavors” of the dexamethasone challenge test?
low dose and high dose
What is measured in the blood after a dex test - ACTH or cortisol?
cortisol
note that the direct effect of dexamethasone is a decrease on ACTH via feedback inhibition. But in response, cortisol should decrease, so that’s what we measure because it’s easier.
If you give the low dose dex test and cortisol is seen to decrease, what is the itnerpretation?
it means the axis is working and the patient does NOT have Cushing syndrome
If you give the low dose dex test and cortisol does NOT suppress, what are the possibilities?
two possibilities:
- pituitary adenoma
- ectopic ACTH production
So what test do you do next?
the high dose dex test
If you give high dose Dex and cortisol is suppressed, what is the diagnosis? If it is not suppressed, what is the diagnosis?
suppressed = pituitary adenoma
nos suppressed = ectopic ACTH production
What are the major caveats with the dex test?
there is a wide individual variation in dexamethasone drug clearance
estrogen will increase cortisol-binding globulin and can make blood levels low, leading to false positives - so stop estrogen-containing drugs 6 weeks before test
antiepileptics and alcohol can induce hepatic clearance of dex
liver disease reduces clearance of dex
So in Cushing syndrome caused by an adrenal tumor,
ACTH level is ___
Low does Dex test is ——
ACTH level is low
Low dose Dex test does not show suppression
IN Cushing syndrome related to ectopic ACTH production…
ACTH is _____
Low dose Dex shows _____
High dose Dex shows ____
ACTH is high
Low dose Dex shows no suppression
High dose Dex shows no suprpession
Cushing syndrome caused by a pituitary tumor (Cushing Disease) ….
ACTH is ___
Low dose Dex shows ____
High dose Dex shows_____
ACTH is high
Low dose Dex shows no suppression
High dose Dex shows suppression
What additional stimulation test can you use after the diagnosis of cushing syndrome is established?
the CRH stimulation test
What does CRH allow us to distinguish between?
Cushing disease (pituitary adenoma) and ectopic ACTH producing tumors
What would be the normal response to a CRH stimulation test?
you would expect an increase in cortisol and ACTH
What will be the result of a CRH stimulation test if the diagnosis is a pituitary adenoma?
You would expect the ACTH and cortisol to increase
What would the CRH stim result be if the diagnosis is ectopic tumor?
no change in the cortisol level
this is because the ectopic production of ACTH has put inhibition on the hypothalamus, so the anterio pituitary hasn’t been stimulated to make its own ACTH in a long time and can’t do it right away in this stim test
What would the CRH stimulation result be if the diagnosis is an adrenal tumor?
Cortisol would not be expected to increase because the adrenal tumor is functioning independently of the axis - doesn’t care how much ACTH there is
Why is the CRH stimulation test not done very often?
because of logistics - you have to sample venous drainage from the pituitary for ACTH and compare it to a simultaneous venous sample - totally not feasible.
What are the effects of glucocorticoids on the cardiovascular system?
- positiev ionotropic effect
2. increase in BP (because it has some mineralocorticoid effect, causing Na and water retention)
What are the efects of glucocorticoids on the CNS?
- lowers seizure threshold
2. behavioral change: mood depression/elevation is common; euphoria and restlessness, anxiety and psychosis is possible
What are the effects of glucocorticoids on the GI system?
- increase in gastric acid and pepsin production
- suppress local immune response against H pylori, resulting in ulcer formation
- decreased Ca2+ absorption from the gut
What are the effects of glucocorticoids on bone metabolism?
- direct inhibition of osteoblasts
- secondary stimulation of parathyroid hormone, which stimualtes osteoclasts (via decreased Ca2_ absorption in the gut)
so you get net absorption of the bone matrix without remodelling = osteoporosis
What are the glucocorticoid effects on skeletal muscle?
weakness and fatigue via:
- hypokalemia
- muscle wasting (promotes proteolysis)
Why do glucocorticoids increase susceptibility to infection?
lymphocyte levels decrease
as do eosinophils and basophils
Which decrease more - T cells or B cells?
T cells
Which blodd cell types actually increase with glucocorticoids?
neutrophils and erythrocytes
In general, how do glucocorticoids promote anti-inflammatory effects?
- inhibit COX2 expression, so decreased AA metabolites
- decrease in immune factor productoin (platelet activating factor, tumor necrosis factor, interleukins)
- reduced edema (maintain capillary cell wall integrity)
- lysosomal membrane stabilized, so fewer proteases released and less fibrosis
- reduction in the release of vasoactive factors that promote vasodilation and shock
When is the maximal anti-inflammatory effect when giving glucocorticoids?
6 hours after treatment administration
How do glucocorticoids manage their anti-allergic effects?
synthesis of histamine by mast cells is inhibited
In general, how do synthetic glucocorticoids differ from natural glucocorticoids?
- increased potency
- less protein bound (leads to potency)
- metaoblism is slower - longer half life
What is the synthetic preparation of cortisol?
hydrocortisone
What is dexamethasone’s potency compared to cortisol?
25-80 times
True or false: like cortisol, dexaethason has a 1:1 effect on glucocorticoids and mineralocorticoids.
false - it’s super potent with glucocorticoids but has almost no activity with the mienralocorticoids
What synthetic glucocorticoid has more mineralocorticoid effect than glucocorticoid effect?
Fludrocortisone
True or false: prednisone is in the active form.
false - it needs to be reduced to the active prednisolone form by 11beta-hydroxydehydrogenases
What is the inhaled glucocorticoid we know?
beclomethasone
How should you give cortisol replacement in acute adrenal insufficiency?
IV
What major point do you need to keep in mind when weening someone off glucocorticoids?
they may require additional supplementation during periods of stress
2-fold for minor stress and 10-fold for major stress
In general, what are hte common side effects of gluoccorticoid treatments and which would make you stop the med?
- hyperglycemia (give insulin if necessary
- infection (give Abx)
- Peptic ulcer (treat, or discontinue steroids if possible)
- Myopathy (discontinue - it will become permanent otherwise)
- osteoporosis
- behavioral disturbances
- cataracts
- hypertension with hypernatremia and hypokalemia
What food will augment cortisol effect?
licorice
it inhibits 11betaHSD2, so you have slower conversion of cortisol to inactive cortisone
How much ACTH be administered and why?
IV - because it’s half life is only 10-15 minutes
most of it is hydrolyzed by blod and tissue enzymes since it’s a peptide hormone an dnot a steroid
What are the therapeutic uses for ACTH?
Not many….mostly used for diagnostic testing
- anticonvulsant for infantile spasms
- prevent neurotoxicity with cisplatin
replacement is not feasible for therapeutic increase of adrenocorticoid levels. Also not useful to prevent adrenal atrophy during chronic glucocorticoid therapy
What is the general treatment strategy for Cushing disease?
- surgery (with support of glucocorticoids until recovery of own ACTH function)
- Irraditaion for those who are poor surgical candidates
- Medical treatment for those who fail surgery
What are some of the medical options?
Ketoconazole Aminoglutethimide Etomidate Metyrapone Cabergoline Mifepristone Mitotane
What is ketoconazole?
an antifungal that inhibits side chain cleavage enzyme (among other CYP eyzmes)
What other drug works by this mechanism for this context?
aminoglutethimide
What does Etomidate do in this context?
inhibits 11 beta hydroxylase
What other drug does the same as Etomidate and is preferred?
Metyrapone
What does Cabergoline do and what type of Cushing syndrome is it used for?
It’s a dopamine agonist
It’s used (along with somatostatin) to bind the D@ receptor on a pituiary adenoma and shut it off
What is Mifepristone usually used for and why can it be used in this context?
it’s an anti-progesterone that is used as an abortifacent
At high doses it can also bind to the glucocorticoi receptors as an antagonist
What is Mitotane? What’s it used for in this context?
it’s actualy a DDT class of insecticides, but it has nonselective adrenal toxicity
used against adrenal carcinoma in this context
