Corticosteroids Flashcards
Glucocorticoid action
carbohydrate and protein metabolism, anti-inflammatory response (cortisol)
mineralocorticoid action
Na+ retention (Aldosterone)
Adrenal Androgen Increased release occurs in concert with cortisol, not aldosterone
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Dihydroandrostenedione (DHEA)
weak androgenic activity, some converted to testosterone and estradiol outside adrenal glad
regulates mineralocorticoid release
RAAS system
Regulation of glucocorticoid and androgen release
ACTH from pituitary released following CRH from hypothalamus
CRH is released in response to sleep-wake cycles
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Curculating corticosteroids (endogenous and exogenous) cause negative feedback to the release of ACTH
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STRESS response can override negative feedback and produce an increase release of steroids
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Glucocorticoid pathway is substrate limited, the rate-limiting step is…
Conversion of cholesterol to pregnenolone - ACTH stimulates this in zona fasiculata and reticularis
Mineralocorticoid Pathway is stimulated independent of ACTH, ANG II stimulates conversion of
cholesterol to pregnenolone and corticosterone to aldosterone
Glucocorticoid MOA (widely distributed receptors)
Steroid (S) binds intracellular receptor (R) – forms S-R complex that gets transported to nucleus – binds glucocorticoid response element on DNA – activates or inhibits gene transcription to increase or decrease protein synthesis – alters cellular function in hours or more
Glucocorticoid metabolic effects on carbohydrates
Stimulates gluconeogenesis (in fasting state) --> increases BGL and insulin release Stimulates gluconeogenesis and glycogen synthase --> increased liver glycogen deposition
Glucocorticoid metabolic effects on lipids
Inhibits uptake of glucose by adipocytes –> stimulates lipolysis (but NET effect is lipogenesis from increased insulin)
Greater effect on central tissues –> central obesity
Glucocorticoid metabolic effect on protein
Increased AA uptake into liver and kidney, decreased protein synthesis (except liver) –> net transfer of AA from muscle to liver
Can lead to muscle wasting and atrophy in connective tissue
Glucocorticoid NET physiologic results are to maintain glucose to the brain (insulin antagonism)
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permissive effects are…
responses that occur in presence of glucocorticoids but are not further stimulated with increased amount of glucocorticoids
Permissive effects of glucocorticoids
vasoconstriction and bronchodilation response to catecholamines
fat cell lipolytic response to catecholamines, ACTH, GH
Cortisol effects via mineralocorticoid receptors
cortisol also induces formation of mRNA to synthesize and insert membrane proteins to increase reabsorption of Na+ from renal distal tubules, loosely coupled to increased secretion of H+ and K+
adverse effects of steroids acting on mineralocorticoid receptors
hypertension (fluid retention) and edema. hypokalemia, metabolic alkalosis
for use in physiologic replacement, use an agent with both mineralocorticoid and glucocorticoid activity
(Cortisol aka hydrocortisone)
For use in anti-inflammatory or immunosupressive actions, select an agent with minimal or no mineralocorticoid activity
(Dexamethasone)
It is not possible to have anti-inflammatory activity without glucocorticoid activity
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Aldosterone (longer acting: Fludrocortisone) possesses essentially all mineralocorticoid activity
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glucocorticoid analogs: structural changes can affect receptor specificity, potency, abs, membrane permeability, elimination
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11-hydroxy glucocorticoids are physiologically active. Examples are:
Cortisol, prednisolone, methylprednisolone, dexamethasone, fludrocortisone
11-keto glucocorticoids are prodrugs that must be activated by 11-B-hydroxysteroid dehydrogenase 1 (11B-HSD1) examples are
Prednisone and Cortisone
level of activity of endogenous and EXOGENOUS cortisol in various tissues can be determined by which type of 11B-HSD is expressed in the tissue
Helps to decipher which route to give it
Liver has 11B-HSD1
Activates Prednisone and Cortisone - so can be given PO and activated via first pass. CANT activate via topical or IV
Kidney has 11B-HSD2
INACTIVATES cortisol to cortisone to protect kidneys from unregulated MC activity
Fetus/Placenta 11B-HSD2 - fetal liver (11B-HSD1) inactive
can treat mother without effect on baby
to treat baby: must use drug that is a poor substrate for 11B-HSD2 to it will not become inactivated (for lung development or prior to premature delivery)
Cortisol must circulate bound to…
Corticosteroid binding protein and albumin. Must be bound to circulate w/o being metabolized, but must be free to diffuse into cells
Cortisol (Hydrocortisone) Use
Replacement therapy and emergencies: IV and PO.
1:1 GC:MC action
Prednisone Use
Most commonly used steroid burst PO agent
GC:MC 13:1. inactive until 1st pass effect in liver
Methylprednisolone (Solu-Medrol parenteral, Medrol PO)
Used if parenteral desired for steroid burst. minimal MC action
Dexamethasone (Decadron) Use
Most potent anti-inflammatory. Cerebral edema, chemo-induced vomiting, GREATEST suppression of ACTH secretion at pituitary. NO MC action
Triamcinolone (Kenalog) Use
Excellent topical activity. POTENT systemic action. NO MC action
Adrenal Insufficiency treatment
Chronic - Addison’s: Cortisol daily, increase during times of stress. Fludrocortisone (long acting) usually required for MC effect.
Acute - Life threatening. Immediate TX IV
Adrenocortical Hyperfunction (Cushing’s Syndrome from tumor secreting ACTH or Cortisol) TX
Surgery is TX of choice.
Glucocorticoid synthesis inhibitors. IE: Ketoconozol
Glucocorticoid receptor antagonist: Mifepristone. NOT 1st line. Contra in pregnancy
Adrenocortical Hyperfunction (Congenital Adrenal Hyperplasia, decreased cortisol synthesis (multiple congenital enzyme defects) –>to increased ACTH and overstimulation of adrenals) TX
Replace deficient steroids while minimizing adrenal sex hormone (overproduction) and glucocorticoid excess (overtreatment)
Depending on the enzyme deficiency: virulization (»androgens), hypotension (>MC)
Adrenocortical Hyperfunction (Pheochromocytoma - excess catecholamine) TX
Surgery, after alpha-adrenergic receptor blockade to avoid HTN crisis in surgery
Phenoxybenzamine - irreversible A-receptor antagonist
Beta-blockers after A-adrenergic receptor block
CCB can supplement alpha and beta blockers
