adrenal pharm Flashcards
- Describe the metabolic effects of glucocorticoids and explain how these effects can result in serious adverse effects when they are used as pharmacotherapeutic agents.
Carbohydrate: Stimulate gluconeogenesis –> increased blood glucose–> ↑ insulin release. Stimulates gluconeogenesis and glycogen synthase activity–>increased liver glycogen deposition.
* [In excess, can lead to diabetes-like state.]
Protein: Increase AA uptake into liver and kidney, decreased protein synthesis (except liver) –>net transfer of AA from muscle / bone to liver (into glucose).
* [In excess, can lead to muscle wasting, while catabolic effects in skin and connective tissue result in atrophy.]
Lipid: Inhibit uptake of glucose by fat cells –> stimulate lipolysis (but net effect is lipogenesis due to increased insulin release). Greater lipogenic effect in central tissues.
*[In excess, can see as centripetal obesity (buffalo hump, increased abdominal fat).]
Net Physiologic Result: Maintenance of glucose supply to brain (insulin antagonism)
- Discuss the structure-activity relationship of the following adrenocorticosteroids, especially those modifications that affect pharmacodynamic activity (mineralocorticoid vs glucocorticoid activity) or route of administration (requirement for hepatic activation), including hydrocortisone (Solu-Cortef®), prednisone-prednisolone, Dexamethasone (Decadron®), and fludrocortisone (Florinef®).
A: 11-hydroxy glucocorticoids are physiologically active
-cortisol, prednisolone, methylprednisolone, dexamethasone, fludrocortisone
B: 11-keto glucocorticoids are prodrugs that must be activated by 11β hydroxysteroid dehydrogenase I (11β-HSD I)
-prednisone, cortisone
C: Double bond between C-1 and C-2: Increases anti-inflammatory effects 4-5 fold (prednisolone vs cortisol).
D: Addition of α-methyl group to carbon 6: Increases anti-inflammatory effects 5-6 fold (methylprednisolone vs cortisol).
E: Addition of fluorine to C-9: Enhances glucocorticoid and especially mineralocorticoid activity. Fludrocortisone is the drug of choice for mineralocorticoid effects.
F:Addition of fluorine to C-9 plus addition of α-methyl group on C-16: Increases anti-inflammatory effects 18 fold and essentially eliminates mineralocorticoid activity (dexamethasone vs cortisol).
kidney and fetus both have 11β-HSD2 to protect form GC effects
Adrenocortical Insufficiency.
Physiologic replacement therapy in chronic or acute conditions
Chronic (Addison’s disease): 20-30 mg/day cortisol (often 15-20 mg AM, 5-10 mg PM). -Dose should be increased dose by 2-4 fold during periods of stress.
- fludrocortisone is usually required for sufficient salt-retaining effect.
- DHEA may have benefits in some patients.
Acute: Life-threatening, so immediate treatment needed. Large amounts IV cortisol (100 mg q 6-8 hrs) until stable; must correct fluid/electrolyte abnormalities. Fludrocortisone may be required in some patients after switch to lower oral maintenance doses of cortisol (hydrocortisone).
Cushing’s Syndrome (Hypercortisolism)
Tx
early
later
- Surgery is treatment of choice
- Pharmacotherapy - generally reserved for adjunctive therapy in refractory or inoperable cases
Glucocorticoid synthesis inhibitors: Divided into agents affecting early (broad effects) or later (more specific effects) steps in steroid biosynthesis.
Early:
- Mitotane (Lysodren®):
- Ketoconazole (Nizoral®):
- Aminoglutethimide (Cytadren®):
Later:
- Metyrapone:
- Trilostane:
- Mifepristone
Mitotane (Lysodren®)
Glucocorticoid synthesis inhibitors
adrenal mitochondrial toxin, also inhibits cholesterol oxidase
Ketoconazole (Nizoral®)
Glucocorticoid synthesis inhibitors
inhibits cholesterol to pregnenolone step (+ androgen synthesis)
Aminoglutethimide
Glucocorticoid synthesis inhibitors
inhibits cholesterol to pregnenolone step
Metyrapone
Glucocorticoid synthesis inhibitors
inhibits 11β-hydroxylase - 11-deoxycortisol to cortisol step
Trilostane
Glucocorticoid synthesis inhibitors
inhibits 3β-hydroxysteroid dehydrogenase , pregnenolone to progesterone
Mifepristone (RU-486):
Glucocorticoid receptor antagonist -
anti-progestational drug that blocks glucocorticoid receptors at higher doses. Not first-line agent - approved to control hyperglycemia secondary to hypercortisolism. Can increase cortisol secretion via block of negative feedback at pituitary. Contraindicated for use during pregnancy - women of child-bearing age should use contraception.
Adrenocortical Hyperfunction: Pheochromocytoma.
Tx
alpha-adrenergic receptor blockade to avoid a hypertensive crisis during surgery.
Phenoxybenzamine-an irreversible α1-α2 receptor antagonist, is given twice daily with upward dose titration every 3 days until blood pressure controlled
Beta-blockade (e.g., metoprolol) - after adequate alpha-adrenergic receptor blockade has been achieved - can be employed 2-3 days preoperatively to control tachycardia and other arrhythmias.
Calcium channel blockers (nifedipine) can be used to supplement alpha- and beta-blockade if blood pressure control is inadequate or side effects of alpha-blockade with phenoxybenzamine are not tolerated
17α-hydroxylase
takes pregnenalone down cortisol and DHEA pathway
3β-hydroxysteroid DH
takes 17-OH-pregnenalone down cortisol pathway
21-hydroxylase
takes progesterone down aldosterone pathway
11β-hydroxylase
takes 11 deoxycortisol to cortisol
