Why is corticosteroid-induced Cushing's syndrome more common in pts on ritonavir
Because ritonavir inhibits CYP3A4 - enzyme involved in the metabolism of corticosteroids.
Bone concerns for corticosteroid use?
They can cause osteopenia/osteoporosis because they suppress bone remodeling and decrease calcium reabsorption.
Caution on removing a pt from corticosteroids use
Adrenal suppression makes this a must-do or the pt will crash
Mechanism of action of Ketoconazole?
- net effect of this mechanism?
A Non-selective adrenal steroid synthesis inhibitor - to reduce cortisol levels
net effect - all of aldosterone, cortisol and androgens will be reduced
Concerns when using ketoconazole?
CYP450 inhibitor. Major 3A4 inhibitor therefore hepatotoxicity is a major concern.
Can have antiandrogenic effects since it reduced androgens too. i.e. gynecomastia in males
Metyrapone - mechanism?
Blocks 11B hydroxylase to decrease cortisol
Concerns in using metyrapone?
blocking 11Bhydroxylase causes the buildup of 11deoxycortisol which is an aldosterone receptor agonist - can therefore cause hypertension
May also increase androgens - hirsutism in females
Blocks rate-limiting conversion of cholesterol to prenenolone and increases steroid clearance.
Non-selective and will decrease other adrenal hormones. Therefore it's often used in conjunction with metyrapone
Mechanism of mitotane?
Non-selective blocker of several steps in the synthesis of cortisol and aldosterone
Side effects of Mitotane?
Wipes out adrenal. Several. Also low TI, therefore only used as a 3rd line tx. Sometimes used in carcinomas and secondary cushing's like lung cancer if otherwise inoperable and other therapies fail
Adverse effects of Aminogluthomide
blocks thyroxine synthesis - hypothyroidism
Induced CYP3A4 - possible drug interactions
May be too effective in combo with metyrapone - adrenal insufficiency
What is the mechanism of action of hydrocortisone?
activates glucocorticoid receptors??
Given in two doses to mimic natural cycle of cortisol
What is the mechanism of action of fludrocortisone?
it's a hydrocortisone agonist. Specific for the aldosterone receptor.
It activates the mineralocorticoid receptor to increase the expression of the Na/K ATPase.
Increases salt retention, and K excretion - necessary in Addison's if oral hydrocortisone has insufficient MR activity
Adverse effect of Fludrocortisone?
If the dose is too high, it can cause edema/hypertension, and hypokalemia.
Hypokalemia predisposes pt to cardiac events
Pharm for Adrenal deficiencies including cushing's and addison's