Adrenal Pharmacology - Trachte

Question 1

When does the maximal effect of Glucocorticoid administration occur?

Answer 1

maximal effect is 6 h after treatment, dissipated by 24 h.

Question 2

Are synthetic or natural glucocorticoids more effective?

Answer 2

Synthetic glucocorticoids > natural

increase glucocorticoid potency (ratio of glucocorticoid to mineralocorticoid effect)

synthetics are less protein bound

metabolism is slower

Question 3

What glucocorticoid actually has more mineralocorticoid potentcy?

Answer 3

Fludrocortisone

Question 4

What glucocorticoids are used for Substitution/Replacement of Adrenal Insufficiency (e.g. acute, chronic primary, secodnary, congenital hyperplasia)?

Answer 4

acute adrenal insufficiency; i.v. cortisol

chronic primary adrenal insufficiency: cortisol, fludrocortisone (mineralocorticoid) if needed

secondary adrenal insufficiency: cortisol

congenital adrenal hyperplasia due to 21-hydroxylase deficiency (partial or complete): cortisol and fludrocortisone

Question 5

What are the hematologic effects of glucocorticoids?

Answer 5

Lymphocyte levels decrease, Increasing susceptibility to infection => T-cells decrease more than B-cells

eosinophil and basophil levels decrease

neutrophil and erythrocyte levels increase

Inhibit leukocyte extravasation

Question 6

What effect does licorice have on glucocorticoids?

Answer 6

Cortisol effects augmented by licorice

Licorice slows down the conversion of cortisol to cortisone (due to reduction of 11bHSD2)

Question 7

When are basal cortisol levels highest?

Answer 7

Morning

Question 8

What happens if you give ACTH in the ACTH stimulation test (for diagnosing hypocortisolism) and you get cortisol production?

Answer 8

Adrenal glands are working!

Question 9

What are the five tests to establish hypercortisolism and determine the origin of Cushing Syndrome?

Answer 9

1. 24h Urine sample measurement of ”free” cortisol level (> 2 tests)
2. Late night salivary cortisol (> 2 tests)
3. Special populations
   Pregnancy: Urine free cortisol
   Epilepsy: not dexamethasone (antiepileptic drugs known to enhance dexamethasone clearance). Use urine or salivary cortisol.
4. Once hypercortisolism is established a baseline plasma ACTH is obtained.
   Low level ACTH indicates ACTH independent disease.
   High ACTH level indicates ACTH dependent disease.
5. Dexamethasone Challenge Test:
   - One of the gold standard screening tests: failure to suppress (ACTH) & cortisol after a dose of dexamethasone (DEX)
   - Cortisol levels are measured post-test; if blood levels of cortisol are lower than normal, then the axis works and Cushing syndrome can be ruled out.

Question 10

What are the Dexamethasone Test interpretations if Low-dose test: no change and ACTH level: low?

Answer 10

Cushing syndrome caused by an adrenal tumor

Question 11

What are the Dexamethasone Test interpretations if Low-dose test = no change, ACTH level = high, and High-dose test = no change?

Answer 11

Cushing syndrome related to an ectopic ACTH producing tumor

Question 12

What are the Dexamethasone Test interpretations if Low-dose test: no change and High-dose test: normal suppression (if there is no suppression another test is needed)?

Answer 12

Cushing syndrome caused by a pituitary tumor (Cushing disease)

Question 13

What is the CRH stimulation test used for?

Answer 13

CRH stimulation test is used to distinguish between Cushing’s disease (pituitary origin) and ectopic ACTH-secreting tumors

• tumors of the pituitary are responsive - CRH is administered at high doses and ACTH/cortisol increases
• ectopic tumors show no response
• adrenal tumors show no response

Question 14

What are the Glucocorticoid effects on the cardiovascular system?

Answer 14

positive inotropic effect

increase in BP (Na/water retention) => maintains the sensitivity of small vessels to catecholamines to retain tone and blood pressure

Question 15

What are the Glucocorticoid effects on the CNS system?

Answer 15

lowers seizure threshold

behavioral changes: mood depression/elevation is common; euphoria and restlessness in some; anxiety and psychosis is possible

Question 16

What are the Glucocorticoid effects on the GI system?

Answer 16

increase in gastric acid and pepsin

may suppress the local immune response against h.pylori resulting in ulcer formation

decreased Ca++ absorption from the gut

Question 17

What are the therapeutic uses of ACTH?

Answer 17

***distinguishes 1° from 2° adrenal insufficiency

anticonvulsant for infantile spasms and to prevent neurotoxicity with cisplatin

Not used to increase adrenocorticoid levels for therapeutic benefits

Question 18

What are the potential treatment options for Cushing disease?

Answer 18

Surgery with support of glucocorticoids until recovery of ACTH function

Irradiation for those that are poor surgical candidates

Medical treatment for those who fail surgical treatment or are ineligible:

• adrenal steroidogenesis inhibition (ketoconazole, metyrapone, mitotan (cancer cases), etomidate)
• suppression of ACTH (SST analog: pasireotide, D2 agonist: cabergoline)
• glucocorticoid receptor antagonism (mifepristone)

Question 19

What are the four Enzyme inhibitors of steroidogenesis used in the medical treatment of Cushing Disease?

Answer 19

1. ***Ketoconazole –inhibits side chain cleavage and other CYP enzymes
   is a bis-triazole; antifungal azole
2. ***Metyrapone- inhibits 11 beta hydroxylase in the adrenal gland with the goal of interfering with cortisol production
3. Aminoglutethimide – inhibits side chain cleavage enzyme
4. Etomidate –inhibits 11 beta hydroxylase

Question 20

What are the Iatrogenic Glucocorticoid Toxicities?

Answer 20

Iatrogenic acute adrenal insufficiency => can be induced by rapid withdrawal after prolonged administration of exogenous preparations

-Adrenal gland shrinkage with chronic treatment of glucocorticoids

Iatrogenic Cushing Syndrome => Effects of long-term, high-dose glucocorticoid therapy (> 2 weeks)