Adrenocorticoid Drugs Flashcards
How do cortisol and other glucocorticoids mediate their effects?
They readily cross the plasma membrane and mediate their effects through specific glucocorticoid receptors (GR) that act as transcription factors
What other activity does cortisol exhibit?
Mineralocorticoid - it is not a pure glucocorticoid
What is the function of 11ß-HSD2 in aldosterone-sensitive tissues?
Converts cortisol (active) to cortisone (inactive) and prevents cortisol from binding MR in aldosterone-sensitive tissues
What is the function of 11ß-HSD1?
Converts cortisone (inactive) back into cortisol (active) in the liver, adipose tissue and brain
What synthetic corticosteroid will be active in the fetus?
Dexamethasone - it is not a substrate for 11ß-HSD2 found in the fetus
Chronic Adrenal Insufficiency
Life threatening disorder caused by the inability of the adrenal cortex to produce adequate amounts of hormones
What is the most common cause of chronic adrenal insufficiency?
Addison’s Disease - autoimmune destruction of the adrenal cortex
What is the main cause of secondary adrenal insufficiency?
Suppression of HPA axis by exogenous glucocorticoids
Adrenal Crisis
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
Is aldosterone used for replacement therapy?
NO - high cost and rapid hepatic metabolism to inactive metabolites make it not suitable
What is the drug of choice for aldosterone replacement therapy?
Fludrocortisone (synthetic mineralocorticoid)
What are the main drugs used for primary adrenal insufficiency therapy?
- Hydrocortisone
- Dexamethasone
with - Fludrocortisone (aldosterone replacement)
What are the main drugs used for secondary adrenal insufficiency therapy?
- Hydrocortisone
- Dexamethasone
(aldosterone replacement usually not necessary as it is controlled by the RAA system not the HPA axis)
Congenital Adrenal Hyperplasia
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.
What is the treatment for a female in utero with 21-hydroxylase deficiency?
Dexamethasone - it will inhibit pituitary ACTH secretion which will prevent androgen over expression and virilization of the female
What is the effect of glucocorticoids on the inflammatory response?
Glucocorticoids induce the expression of IkB a specific inhibitor of NF-kB leading to inhibition of the inflammatory response
What is the drug of choice for treatment of rheumatoid disorders?
Prednisone
What are the main SE of glucocorticoids?
- 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.)
What are the 4 main causes of Cushing syndrome?
- Exogenous cortisol treatment
- ACTH pituitary adenoma
- Cortisol-secreting adrenal tumor
- ACTH secreting small cell lung cancer
Ketoconazole MOA
Antifungal inhibits fungal CYP450 and at high doses inhibits adrenal CYP11A1 (rate-limiting enzyme) and CYP11B1 which blocks synthesis of all adrenal steroids
Ketoconazole SE
Hepatotoxicity, gynecomastia impotence, teratogenic
Etomidate MOA
Inhibits adrenal CYP11A1 and CYP11B1
Metyrapone MOA
- Inhibits CYP11B1 and CYP11B2
- Inhibits both cortisol and aldosterone
What is the only adrenal inhibitor that is safe in pregnancy?
Metyrapone
Mitotane MOA
It is metabolized in the adrenal cortex into the active form which destroys mitochondria and leads to necrosis of adrenocortical cells
Mitotane Indications
- used to achieve medical adrenalectomy
- cases of severe Cushing’s Disease
- patients not cured by surgery/refuse surgery
Mitotane Contraindications
Pregnancy
Mitotane SE
NOT well tolerated - nausea, vomiting, anorexia, rash, diarrhea, ataxia
Mifepristone MOA
- Antagonizes glucocorticoid receptor at high doses
- Prevents excessive activation of GR in Cushing’s
Mifepristone Indications
Refractory Cushing’s Syndrome
Mifepristone SE
Adrenal insufficiency
Mifepristone Contraindications
Pregnancy - it causes abortion
What is the primary effect of cortisol on glucose?
Increases blood glucose levels
What drug has the most MR potency?
Fludrocortisone
