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ER Week 2 > Adrenocortical Pharmacology > Flashcards

Adrenocortical Pharmacology Flashcards

1
Q

Why can’t you just take a blood cortisol and ACTH level?

A

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

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2
Q

What are two tests you can do to measure the cortisol level is an interpretable way?

A
  1. 24 hour urine sample measurement of the free cortisol level (do twice)
  2. late night salivary cortisol (do twice)
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3
Q

What result from a urine test would confirm hypercortisolism?

A

high level of cortisol - duh

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4
Q

What result from a late night salivary cortisol test would confirm hypercortisolism?

A

loss of the circadian rhythm and absence of the late night nadir

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5
Q

Why would you not do a dexamethasone test in those who have epilepsy?

A

antiepileptic drugs are known to enhance dexamethasone clearance

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6
Q

If you suspect hypocortisolism, how can you determine if the adrenal gland is functioning?

A

do a short ACTH stimulation test

inject tetracosactide, which is just synthetic ACTH

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7
Q

What would be the response to an ACTH stimulation test if the adrenal gland is functioning?

A

you would see an increase in blood cortisol

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8
Q

If the short ACTH stimulation test does not yield an increase in cortisol, what test do you do next? WHY

A

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

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9
Q

So if a patient has Addison disease, will the long ACTH stimulation test yield an increase in cortisol?

A

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

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10
Q

Back to hypercortisolism, let’s talk about dexamethasone. What is dexamethasone?

A

it’s a synthetic glucocorticoid that has very potent effects on the glucocorticoid receptor (and none on the mineralocorticoid receptor)

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11
Q

What are the two “flavors” of the dexamethasone challenge test?

A

low dose and high dose

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12
Q

What is measured in the blood after a dex test - ACTH or cortisol?

A

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.

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13
Q

If you give the low dose dex test and cortisol is seen to decrease, what is the itnerpretation?

A

it means the axis is working and the patient does NOT have Cushing syndrome

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14
Q

If you give the low dose dex test and cortisol does NOT suppress, what are the possibilities?

A

two possibilities:

  1. pituitary adenoma
  2. ectopic ACTH production
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15
Q

So what test do you do next?

A

the high dose dex test

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16
Q

If you give high dose Dex and cortisol is suppressed, what is the diagnosis? If it is not suppressed, what is the diagnosis?

A

suppressed = pituitary adenoma

nos suppressed = ectopic ACTH production

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17
Q

What are the major caveats with the dex test?

A

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

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18
Q

So in Cushing syndrome caused by an adrenal tumor,

ACTH level is ___
Low does Dex test is ——

A

ACTH level is low

Low dose Dex test does not show suppression

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19
Q

IN Cushing syndrome related to ectopic ACTH production…

ACTH is _____
Low dose Dex shows _____
High dose Dex shows ____

A

ACTH is high
Low dose Dex shows no suppression
High dose Dex shows no suprpession

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20
Q

Cushing syndrome caused by a pituitary tumor (Cushing Disease) ….

ACTH is ___
Low dose Dex shows ____
High dose Dex shows_____

A

ACTH is high
Low dose Dex shows no suppression
High dose Dex shows suppression

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21
Q

What additional stimulation test can you use after the diagnosis of cushing syndrome is established?

A

the CRH stimulation test

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22
Q

What does CRH allow us to distinguish between?

A

Cushing disease (pituitary adenoma) and ectopic ACTH producing tumors

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23
Q

What would be the normal response to a CRH stimulation test?

A

you would expect an increase in cortisol and ACTH

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24
Q

What will be the result of a CRH stimulation test if the diagnosis is a pituitary adenoma?

A

You would expect the ACTH and cortisol to increase

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25
Q

What would the CRH stim result be if the diagnosis is ectopic tumor?

A

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

26
Q

What would the CRH stimulation result be if the diagnosis is an adrenal tumor?

A

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

27
Q

Why is the CRH stimulation test not done very often?

A

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.

28
Q

What are the effects of glucocorticoids on the cardiovascular system?

A
  1. positiev ionotropic effect

2. increase in BP (because it has some mineralocorticoid effect, causing Na and water retention)

29
Q

What are the efects of glucocorticoids on the CNS?

A
  1. lowers seizure threshold

2. behavioral change: mood depression/elevation is common; euphoria and restlessness, anxiety and psychosis is possible

30
Q

What are the effects of glucocorticoids on the GI system?

A
  1. increase in gastric acid and pepsin production
  2. suppress local immune response against H pylori, resulting in ulcer formation
  3. decreased Ca2+ absorption from the gut
31
Q

What are the effects of glucocorticoids on bone metabolism?

A
  1. direct inhibition of osteoblasts
  2. 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

32
Q

What are the glucocorticoid effects on skeletal muscle?

A

weakness and fatigue via:

  1. hypokalemia
  2. muscle wasting (promotes proteolysis)
33
Q

Why do glucocorticoids increase susceptibility to infection?

A

lymphocyte levels decrease

as do eosinophils and basophils

34
Q

Which decrease more - T cells or B cells?

A

T cells

35
Q

Which blodd cell types actually increase with glucocorticoids?

A

neutrophils and erythrocytes

36
Q

In general, how do glucocorticoids promote anti-inflammatory effects?

A
  1. inhibit COX2 expression, so decreased AA metabolites
  2. decrease in immune factor productoin (platelet activating factor, tumor necrosis factor, interleukins)
  3. reduced edema (maintain capillary cell wall integrity)
  4. lysosomal membrane stabilized, so fewer proteases released and less fibrosis
  5. reduction in the release of vasoactive factors that promote vasodilation and shock
37
Q

When is the maximal anti-inflammatory effect when giving glucocorticoids?

A

6 hours after treatment administration

38
Q

How do glucocorticoids manage their anti-allergic effects?

A

synthesis of histamine by mast cells is inhibited

39
Q

In general, how do synthetic glucocorticoids differ from natural glucocorticoids?

A
  1. increased potency
  2. less protein bound (leads to potency)
  3. metaoblism is slower - longer half life
40
Q

What is the synthetic preparation of cortisol?

A

hydrocortisone

41
Q

What is dexamethasone’s potency compared to cortisol?

A

25-80 times

42
Q

True or false: like cortisol, dexaethason has a 1:1 effect on glucocorticoids and mineralocorticoids.

A

false - it’s super potent with glucocorticoids but has almost no activity with the mienralocorticoids

43
Q

What synthetic glucocorticoid has more mineralocorticoid effect than glucocorticoid effect?

A

Fludrocortisone

44
Q

True or false: prednisone is in the active form.

A

false - it needs to be reduced to the active prednisolone form by 11beta-hydroxydehydrogenases

45
Q

What is the inhaled glucocorticoid we know?

A

beclomethasone

46
Q

How should you give cortisol replacement in acute adrenal insufficiency?

A

IV

47
Q

What major point do you need to keep in mind when weening someone off glucocorticoids?

A

they may require additional supplementation during periods of stress

2-fold for minor stress and 10-fold for major stress

48
Q

In general, what are hte common side effects of gluoccorticoid treatments and which would make you stop the med?

A
  1. hyperglycemia (give insulin if necessary
  2. infection (give Abx)
  3. Peptic ulcer (treat, or discontinue steroids if possible)
  4. Myopathy (discontinue - it will become permanent otherwise)
  5. osteoporosis
  6. behavioral disturbances
  7. cataracts
  8. hypertension with hypernatremia and hypokalemia
49
Q

What food will augment cortisol effect?

A

licorice

it inhibits 11betaHSD2, so you have slower conversion of cortisol to inactive cortisone

50
Q

How much ACTH be administered and why?

A

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

51
Q

What are the therapeutic uses for ACTH?

A

Not many….mostly used for diagnostic testing

  1. anticonvulsant for infantile spasms
  2. 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

52
Q

What is the general treatment strategy for Cushing disease?

A
  1. surgery (with support of glucocorticoids until recovery of own ACTH function)
  2. Irraditaion for those who are poor surgical candidates
  3. Medical treatment for those who fail surgery
53
Q

What are some of the medical options?

A 
Ketoconazole
Aminoglutethimide
Etomidate
Metyrapone
Cabergoline
Mifepristone
Mitotane
54
Q

What is ketoconazole?

A

an antifungal that inhibits side chain cleavage enzyme (among other CYP eyzmes)

55
Q

What other drug works by this mechanism for this context?

A

aminoglutethimide

56
Q

What does Etomidate do in this context?

A

inhibits 11 beta hydroxylase

57
Q

What other drug does the same as Etomidate and is preferred?

A

Metyrapone

58
Q

What does Cabergoline do and what type of Cushing syndrome is it used for?

A

It’s a dopamine agonist

It’s used (along with somatostatin) to bind the D@ receptor on a pituiary adenoma and shut it off

59
Q

What is Mifepristone usually used for and why can it be used in this context?

A

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

60
Q

What is Mitotane? What’s it used for in this context?

A

it’s actualy a DDT class of insecticides, but it has nonselective adrenal toxicity

used against adrenal carcinoma in this context

ER Week 2 (10 decks)

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