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Adrenal Hormones and Related Drugs


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What controls the secretion of ACTH?
1. diurnal rhythms
2. negative feedback by cortisol
3. stress override system
what composes the stress override system?
immune and inflammatory system (inc. infection, inflammation, injury, hemorrhage, pain, cold, hypoglycemia, surgery)
Arginine vasopressin (AVP) from pituitary synergizes to increase ACTH during stress
What is the function of ACTH?
1. stimulates adrenal cortex to make glucocorticoids
2. maintains the functional integrity if zona fasciculata and zona reticularis
increased doses of ACTH leads to adrenal hypertrophy and hyperplasia
What are the strucural properties of ACTH?
39 AA chain, singe chain
biological activity in first 24 AA's (if remove N-terminal serine, you remove its activity) the first 13 AA's are called alpha-MSH
What is MSH?
melanocyte stimulating hormone, stimulated by increased ACTH, leads to hyperpigmentation in primary adrenal insufficiency
Primary vs. secondary adrenal insufficiency
primary- problem at target organ/gland
secondary- problem with stimulating hormone
pig ACTH
synthetic ACTH, contains only the first 24 AA's, AA's 24-39 eliminated to reduce immune respponse, administered parenterally because degraded if taken orally, and short half life (15 min) if given by infusion, therefore give in repository injections in gelatin (lasts 18 hrs) or zinc oxide (lasts days)
Side effects of ACTH drugs
hypersensitivy rxns, swelling at site of repository injections, GC related toxicities and effeccts due to inc GC;s with ACTH
Adrenal steroid types
From adrenal cortex: GC's (21-C; cortisol)
MC's (21-C; aldosterone)
from adrenal medulla and cortex: Androgens( 19-C; testosterone)
Estrogens (18-C; estradiol)
Progestins (21-C; progesterone)
major source of estrogen in all children, adult males and postmenopausal women
(if increased in women= masculinized)
Glucocoricoid Function
1. provide glucose to brain and other organs by stimulating conversion of glycogen, fats adn proteins to glucose
2. Deal with stress
Effects of GC on glucose metabolism
in muscle cells- decrease glucose uptake; increase protein breakdown to AA
in fat cells: decrease glucose uptake, increase fat breakdown to free fatty acids
in liver cells: increase enzymes for gluconeogenesis so glucose goes to blood, uses AA's and FFA's from reactions in rest of body
Mechanism of Action of GC's
GC receptor is nuclear transcrition factor, the cotisol in blood is bound to CBG (corticosteroid binding globulin), it dissociates, enters cell, binds to inactive GC receptors in cytosol. The activated receptor migrates into nucleus, binds to the GC-responsive elements in promoter region of genes. the GC receptor forms a dimer with another GC receptor and gegins transription of genes, produces proteins that change cell function
Addison's disease
primary adrenal insufficiency, from adrenal destruction or error in metabolism
secondary adrenal insufficiency, decrease ACTH release and/or synthesis
iatrogenic adrenal insufficiency
surgical adrenal removal or drug-induced, or atrophy from negative feedback
oral cortisol
treatment for adrenal insufficiency, for chronic hormone replacement (5-10 mg tid or more under stress)
main drug used to treat adrenal insufficiency with mineralcorticoid insufficiency, for chronic hormone replacement
acute hormone replacement
aka Addisonian crisis
higher dose of cortisol used
situations of stress (ie car accident, surgery, etc)
100 mg until patient stable, also give water and electrolytes and glucose
Cushing's syndrome
too much GC activity, caused by adrenocortical hyperplasia or neoplasm, avnormal or ectopic ACTH release, or overdosage of GC or ACTH, treatment: surgery, steroid syth inhibitors or change dosage
stimulation tests
cosyntropin (ACTH 1-24 AA)
corticrelin (ovine CRH)-
60 min screening test and 24 hour infusion test, if get productio of GC then problem at ACTH production, in no GC's production the problem is at the adrenals
test for primary response to CRH or to differentiate between pituitary and ectopic ACTH production which is not stimulated by sheep CRH
supression test (dexamethasone (DEXA))
long acting synthetic GC; documents hypersecretion, give it overnight, test urine 17-hydroxycortisol in morning, should decrease definitive 24/48 hr test if not decreased after low dose, then it is indicative of non-idiopathic Cushings; if not decreased after high dose, indicates adrenal hyperplasia
steroid syntesis antagonist, inhibits cortisol synthesis by inhibiting 11B-hydroxylase, administered orally, can diagnose HPA axis functions and Cushing's if administration causes increased 11deoxycortisol in plasma or 17 hydroxycortisol in urine then its a physiological release of ACTH; side effects= dizziness, GI disturbance, increased MC and androgens;
adrenocorticoid antagonist, isomer of DDT, selective toxicity for adrenal cortex therefore destroys cortex and need lifelong GC & MC because irreversible; used in anti-cancer treatment
side effects: CNS depression, 15% skin rashes and 80% GI disturbance
block steroidgenesis by inhabiting p450sec which is first step in steroid synthesis; used to decrease gonadal hormones in breast cancer patients, and to decreae adrenal cortical hormones in adrenal carcinoma, do not get complete inhibition therefore cortisone is added to block increases in ACTH
steroid antagonist, widely used, first used as antifungal, higher doses inhibit p450scc and other biosynthetic enzymes, used in treating cushings
reversble inhibitor of 3B-HSD, blocks cortisol and aldosterne synthesis, administered orally, used when more definitive treatment cant be used, reversible so not as effective
metyrapone- test ACTH b/c blocks p450-11B so build up of 11-deoxycortisol into plasma
Trilostane- dec aldosterone & cortisol
aminoglutethimide & ketoconazole- blocks rate-limiting enzyme so in theory, get nothing

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