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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
- taper off!
- 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
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