Adrenal Pharmacology - Trachte Flashcards
When does the maximal effect of Glucocorticoid administration occur?
maximal effect is 6 h after treatment, dissipated by 24 h.
Are synthetic or natural glucocorticoids more effective?
Synthetic glucocorticoids > natural
increase glucocorticoid potency (ratio of glucocorticoid to mineralocorticoid effect)
synthetics are less protein bound
metabolism is slower
What glucocorticoid actually has more mineralocorticoid potentcy?
Fludrocortisone
What glucocorticoids are used for Substitution/Replacement of Adrenal Insufficiency (e.g. acute, chronic primary, secodnary, congenital hyperplasia)?
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
What are the hematologic effects of glucocorticoids?
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
What effect does licorice have on glucocorticoids?
Cortisol effects augmented by licorice
Licorice slows down the conversion of cortisol to cortisone (due to reduction of 11bHSD2)
When are basal cortisol levels highest?
Morning
What happens if you give ACTH in the ACTH stimulation test (for diagnosing hypocortisolism) and you get cortisol production?
Adrenal glands are working!
What are the five tests to establish hypercortisolism and determine the origin of Cushing Syndrome?
- 24h Urine sample measurement of ”free” cortisol level (> 2 tests)
- Late night salivary cortisol (> 2 tests)
- Special populations
Pregnancy: Urine free cortisol
Epilepsy: not dexamethasone (antiepileptic drugs known to enhance dexamethasone clearance). Use urine or salivary cortisol. - Once hypercortisolism is established a baseline plasma ACTH is obtained.
Low level ACTH indicates ACTH independent disease.
High ACTH level indicates ACTH dependent disease. - 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.
What are the Dexamethasone Test interpretations if Low-dose test: no change and ACTH level: low?
Cushing syndrome caused by an adrenal tumor
What are the Dexamethasone Test interpretations if Low-dose test = no change, ACTH level = high, and High-dose test = no change?
Cushing syndrome related to an ectopic ACTH producing tumor
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)?
Cushing syndrome caused by a pituitary tumor (Cushing disease)
What is the CRH stimulation test used for?
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
What are the Glucocorticoid effects on the cardiovascular system?
positive inotropic effect
increase in BP (Na/water retention) => maintains the sensitivity of small vessels to catecholamines to retain tone and blood pressure
What are the Glucocorticoid effects on the CNS system?
lowers seizure threshold
behavioral changes: mood depression/elevation is common; euphoria and restlessness in some; anxiety and psychosis is possible
What are the Glucocorticoid effects on the GI system?
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
What are the therapeutic uses of ACTH?
***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
What are the potential treatment options for Cushing disease?
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)
What are the four Enzyme inhibitors of steroidogenesis used in the medical treatment of Cushing Disease?
- ***Ketoconazole –inhibits side chain cleavage and other CYP enzymes
is a bis-triazole; antifungal azole - ***Metyrapone- inhibits 11 beta hydroxylase in the adrenal gland with the goal of interfering with cortisol production
- Aminoglutethimide – inhibits side chain cleavage enzyme
- Etomidate –inhibits 11 beta hydroxylase
What are the Iatrogenic Glucocorticoid Toxicities?
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)
