Adrenal Pharmacology Flashcards
How do glucocorticoids mediate anti-inflammation? (Biochemical)
Glucocorticoids inhibit expression of COX-2 and Phospholipase A2 in inflammatory cells, leading to decreased prostaglandin and leukotriene formation
Also block activation of TH0 to TH1/TH2 and reduces release of cytokines from TH1/TH2
How do glucocorticoids mediate anti-inflammation? (Vascular)
Decreased vasodilation
Decreased fluid exudation
How do glucocorticoids mediate anti-inflammation? (Cellular)
Overall decrease in accumulation and activation of inflammatory cells in peripheral tissues
Decreased proliferation of blood vessels
Decreased fibrosis
11-hydroxy glucocorticoids - 5 agents
Cortisol (hydrocortisone) Prednisolone Methylprednisolone Dexamethasone Fludrocortisone
11-keto glucocorticoids - 2 Agents
Prednisone
Cortisone
Must be activated by 11B-HSDI in the liver; this enzyme is not found in the skin so these drugs cannot be used as topicals
11B Hydroxysteroid Dehydrogenase I (11B-HSDI)
Hepatic enzyme that activates 11-keto glucocorticoids (Prednisone, Cortisone) to 11-hydroxy glucocorticoids
Cortisol (Hydrocortisone)
50% Glucocorticoid / 50% Mineralocorticoid activity
Preferred agent for physiological replacement, i.e. in Addison’s Disease
Can be administered orally, IV/IM, or topical
Prednisolone
Product of prednisone activation in the liver
4-5x more potent glucocorticoid activity than cortisol with less mineralocorticoid activity
Available oral, injectable; most commonly used oral agent for steroid burst therapy
Methylprednisolone
5-6x more potent glucocorticoid activity than cortisol with less mineralocorticoid activity
Oral, injectable
Often used for parenteral administration of steroid burst
Dexamethasone
Longest acting, highest potency glucocorticoid activity with essentially no mineralocorticoid activity
Used in cerebral edema, chemotherapy-induced vomiting
Available oral, injectabe, topical
Fludrocortisone
Addition of fluorine enhances mineralocorticoid activity; retains a low level of glucocorticoid activity
Available oral only
Addison’s Disease - Treatment
Cortisol - baseline dose must be increased 2-4x during periods of physiological stress
Fludrocortisone
+/- DHEA
Treatment of acute adrenal crisis
IV Cortisol until stable, then switch to lower oral maintenance doses of hydrocortisone and add fludrocortisone
Cushing’s Syndrome - Etiology
Pituitary tumor secreting excess ACTH - 70%
Non-pituitary tumor secreting excess ACTH (Ectopic Cushing’s, often small cell carcinoma) - 15%
Adrenal tumor secreting excess cortisol - 15%
Cushing Syndrome - Treatment
- Surgery to remove ACTH / ectopic / adrenal tumor
Ketoconazole - inhibits rate limiting conversion of cholesterol to pregnenolone in cortisol synthesis
Mifepristone - Glucocorticoid receptor antagonist
Mifepristone
Glucocorticoid receptor antagonist
Approved for control of hyperglycemia secondary to hypercortisolism
Can cause increased cortisol secretion via block of negative feedback at the pituitary
21 hydroxylase deficiency
21 hydroxylase is necessary for both cortisol and aldosterone synthesis
Lack of cortisol synthesis leads to increased ACTH, causing adrenal hyperplasia and virilization via shunting of pregnenolone down the androgen synthesis pathway
Lack of aldosterone synthesis causes hypotension
17-alpha hydroxylase deficiency
17a hydroxylase is necessary for both cortisol and adrenal androgen synthesis
Enzyme deficiency causes increased ACTH (adrenal hyperplasia) and increased mineralocorticoid synthesis, leading to hypertension
11B-hydroxylase deficiency
11B-hydroxylase is required for cortisol synthesis
Enzyme deficiency causes increased ACTH (adrenal hyperplasia) with shunting of pregnenolone toward androgen production (virilization) and aldosterone production (hypertension)
Pheochromocytoma - Special surgical considerations
Requires pharmacologic preparation with alpha-adrenergic receptor blockade to avoid hypertensive crisis, i.e. phenoxybenzamine
Selective beta blocker (metoprolol) given after adequate alpha-adrenergic receptor blockade to control tachycardia
+/- Calcium channel blockers (Nifedipine) if blood pressure control is inadequate
Metyrosine - Mechanism & Uses
Competitive inhibitor of catecholamine synthesis
Reduces synthesis of catecholamines in inoperable or metastatic pheochromocytoma
11B-hydroxysteroid dehydrogenase 2 (11B-HSD2)
Inactivates cortisol by conversion to cortisone in the kidney
11B-hydroxysteroid dehydrogenase 1 (11B-HSD1)
Activates cortisone by conversion to cortisol in the liver
11B-HSD1 is inactive in fetuses; therefore, can treat pregnant women with betamethasone without effect on fetus
Effects of epinephrine
Primarily binds beta-adrenergic receptors
B1 - Increased cardiac contractility, heart rate
B2 - Gluconeogenesis, lipolysis; smooth muscle dilation in muscule arterioles, GI/GU, and bronchial tree
Effects of norepinephrine
Primarily binds alpha-adrenergic receptors (Alpha-1)
Increased gluconeogenesis, glycogenolysis, lipolysis
Arteriolar vasoconstriction, hypertension
Smooth muscle contraction - GI/GU
CNS - Dilation of pupils, arousal
Autoimmune Polyendocrine Syndrome 1 (APS-1)
Addison’s
Hypoparathyroidism
T1DM
Mucucutaneous Candidiasis
Autoimmune Polyendocrine Syndrome 2 (APS-2)
Addison’s
Hypothyroidism
T1DM
MEN2A
Pheochromocytoma
Medullary thyroid carcinoma
Hyperparathyroidism
MEN2B
Pheochromocytoma
Medullary thyroid carcinoma
Mucosal neuromas
Phenoxybenzamine
Alpha blocker - used to pre-operatively lower BP in pheochromocytoma patients
Lower BP may cause reflex tachycardia, which can be treated with Beta Blockers; however, BBs must be given only after alpha blockers to avoid unopposed alpha-agonism and hypertensive crisis
MEN1
Pituitary Adenoma
Parathyroid adenoma / hyperplasia
Pancreatic endocrine neoplasm
