Adrenocorticoid Drugs

Question 1

How do cortisol and other glucocorticoids mediate their effects?

Answer 1

They readily cross the plasma membrane and mediate their effects through specific glucocorticoid receptors (GR) that act as transcription factors

Question 2

What other activity does cortisol exhibit?

Answer 2

Mineralocorticoid - it is not a pure glucocorticoid

Question 3

What is the function of 11ß-HSD2 in aldosterone-sensitive tissues?

Answer 3

Converts cortisol (active) to cortisone (inactive) and prevents cortisol from binding MR in aldosterone-sensitive tissues

Question 4

What is the function of 11ß-HSD1?

Answer 4

Converts cortisone (inactive) back into cortisol (active) in the liver, adipose tissue and brain

Question 5

What synthetic corticosteroid will be active in the fetus?

Answer 5

Dexamethasone - it is not a substrate for 11ß-HSD2 found in the fetus

Question 6

Chronic Adrenal Insufficiency

Answer 6

Life threatening disorder caused by the inability of the adrenal cortex to produce adequate amounts of hormones

Question 7

What is the most common cause of chronic adrenal insufficiency?

Answer 7

Addison’s Disease - autoimmune destruction of the adrenal cortex

Question 8

What is the main cause of secondary adrenal insufficiency?

Answer 8

Suppression of HPA axis by exogenous glucocorticoids

Question 9

Adrenal Crisis

Answer 9

Loss of endogenous cortisol production from prolonged use of glucocorticoids and abrupt removal of drug uncovers the lack of endogenous cortisol production resulting in adrenal insufficiency and ADRENAL CRISIS

Question 10

Is aldosterone used for replacement therapy?

Answer 10

NO - high cost and rapid hepatic metabolism to inactive metabolites make it not suitable

Question 11

What is the drug of choice for aldosterone replacement therapy?

Answer 11

Fludrocortisone (synthetic mineralocorticoid)

Question 12

What are the main drugs used for primary adrenal insufficiency therapy?

Answer 12

• Hydrocortisone
• Dexamethasone
  with
• Fludrocortisone (aldosterone replacement)

Question 13

What are the main drugs used for secondary adrenal insufficiency therapy?

Answer 13

• Hydrocortisone
• Dexamethasone
  (aldosterone replacement usually not necessary as it is controlled by the RAA system not the HPA axis)

Question 14

Congenital Adrenal Hyperplasia

Answer 14

Genetic disorder caused by a deficiency in the activity of enzymes involved in the synthesis of corticosteroids. Impaired production of cortisol results in a lack of negative feedback and ACTH expression, resulting in adrenal hyperlasia and excess production of other hormonally active steroid hormones like androgens.

Question 15

What is the treatment for a female in utero with 21-hydroxylase deficiency?

Answer 15

Dexamethasone - it will inhibit pituitary ACTH secretion which will prevent androgen over expression and virilization of the female

Question 16

What is the effect of glucocorticoids on the inflammatory response?

Answer 16

Glucocorticoids induce the expression of IkB a specific inhibitor of NF-kB leading to inhibition of the inflammatory response

Question 17

What is the drug of choice for treatment of rheumatoid disorders?

Answer 17

Prednisone

Question 18

What are the main SE of glucocorticoids?

Answer 18

• Acute flare-up of the underlying disease with withdrawal of the drug
• Acute adrenal insufficiency
• Cushing syndrome-like symptoms (weight gain, HTN, CV disease, etc.)

Question 19

What are the 4 main causes of Cushing syndrome?

Answer 19

• Exogenous cortisol treatment
• ACTH pituitary adenoma
• Cortisol-secreting adrenal tumor
• ACTH secreting small cell lung cancer

Question 20

Ketoconazole MOA

Answer 20

Antifungal inhibits fungal CYP450 and at high doses inhibits adrenal CYP11A1 (rate-limiting enzyme) and CYP11B1 which blocks synthesis of all adrenal steroids

Question 21

Ketoconazole SE

Answer 21

Hepatotoxicity, gynecomastia impotence, teratogenic

Question 22

Etomidate MOA

Answer 22

Inhibits adrenal CYP11A1 and CYP11B1

Question 23

Metyrapone MOA

Answer 23

• Inhibits CYP11B1 and CYP11B2

- Inhibits both cortisol and aldosterone

Question 24

What is the only adrenal inhibitor that is safe in pregnancy?

Answer 24

Metyrapone

Question 25

Mitotane MOA

Answer 25

It is metabolized in the adrenal cortex into the active form which destroys mitochondria and leads to necrosis of adrenocortical cells

Question 26

Mitotane Indications

Answer 26

• used to achieve medical adrenalectomy
• cases of severe Cushing’s Disease
• patients not cured by surgery/refuse surgery

Question 27

Mitotane Contraindications

Answer 27

Pregnancy

Question 28

Mitotane SE

Answer 28

NOT well tolerated - nausea, vomiting, anorexia, rash, diarrhea, ataxia

Question 29

Mifepristone MOA

Answer 29

• Antagonizes glucocorticoid receptor at high doses

- Prevents excessive activation of GR in Cushing’s

Question 30

Mifepristone Indications

Answer 30

Refractory Cushing’s Syndrome

Question 31

Mifepristone SE

Answer 31

Adrenal insufficiency

Question 32

Mifepristone Contraindications

Answer 32

Pregnancy - it causes abortion

Question 33

What is the primary effect of cortisol on glucose?

Answer 33

Increases blood glucose levels

Question 34

What drug has the most MR potency?

Answer 34

Fludrocortisone