Professional Documents
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Objectives
Review briefly the adrenal gland Name the different adrenocorticotropic hormones and discuss their effects Identify uses of adrenocorticotropic hormones
Adrenal Gland
Adrenal cortex mineralocorticoids, glucocorticoids, adrenal androgens Adrenal medulla - catecholamines
Adrenal Cortex
Outer zone (zona glomerulosa) secretes mineralocorticoids - receptors for angiotensin II and express aldosterone synthase; do not atrophy Inner zone (zona fasciculata and reticularis) secrete glucocorticoids and adrenal androgens - expresses 17-hydroxylase and 11-hydroxylase;
results in atrophy
ACTH
a peptide of 39 amino acids amino acids 15 18: high affinity binding amino acids 6 10: receptor activation synthesized from pro-opiomelanocortin (POMC)
ACTH
Stimulates the synthesis and release of adrenocortical hormones Human ACTH G-protein coupled receptor family activates adenyl cyclase intracellular cyclic AMP (2nd messenger for most steroidogenesis)
Steroid hormones
All steroid hormones are derived from cholesterol and differ only in the ring structure and side chains attached to it. All steroid hormones are lipid soluble
Extracellular lipoprotein
LH
Cholesterol pool
acetate
ATP cAMP
cholesterol PKA+
Pregnenolone
3bHSD
Progesterone Androstenedione
P450c17
17bHSD
TESTOSTERONE
Steroidogenic Enzymes
Common name
Side-chain cleavage enzyme; desmolase 3 beta-hydroxysteroid dehydrogenase 17 alpha-hydroxylase/17,20 lyase 21-hydroxylase 11 beta-hydroxylase Aldosterone synthase
"Old" name
P450SCC 3 beta-HSD P450C17 P450C21 P450C11 P450C11AS
Current name
CYP11A1 3 beta-HSD CYP17 CYP21A2 CYP11B1 CYP11B2
Aromatase
P450aro
CYP19
Adrenocorticosteroids
Classification:
A. Mineralocorticoids
Aldosterone electrolyte-balance regulating, saltretaining activity
- promotes reabsorption of Na+ from the distal convoluted tubules and proximal collecting tubules; loosely coupled with K+ and H+ ions excretion - secreted at a rate of 100-200ug/d - t 15-20mins - excreted in the urine as tetrahydroaldosterone and 3-oxo-glucoronide
B. Glucocorticoids
Cortisol carbohydrate metabolism regulating,; intermediary metabolism; immune function
- 10-20 mg daily; circadian rhythm - bound to CBG (90%), albumin (5%) - t =60-90 mins.; - liver (glucoronic acid or sulfates) - 1/3 excreted as 17-hydroxysteroids while 1% is unchanged
CBG (transcortin)
Elevated: pregnancy, hyperthyroidism, estrogen administration Diminished: hypothyroidism, protein deficiency, genetic defects
C. Adrenal Androgens
- Dehydroepiandrosterone (DHEAs) and androstenedione androgenic-estrogenic activity - they do not stimulate or support major androgen dependent pubertal changes in humans) - used in SLE and women with adrenal insufficiency
Dynamics: MOA - bind to cytosol receptors (steroid receptor complex) - alters gene expression by binding to glucocorticoid-response element (GREs)
Physiologic effects
Carbohydrate metabolism: - protect glucose-dependent tissues from starvation - stimulate gluconeogenesis, glycogen synthesis in the fasting state glucose lipolysis FFA insulin release periphery: glucose utilization and lipogenesis ( fat deposition) Protein metabolism: - protein breakdown (amino acids) - catabolic effects: decrease muscle mass, atrophy of lymphoid tissue, negative nitrogen balance, thinning of the skin
Other effects: amounts: - insomnia, euphoria, depression, pseudomotor cerebri, roid rage - peptic ulcer, promote fat redistribution - vit D antagonist on Ca absorption (bone resorption) - # of platelets and RBCs amounts: - psychiatric depression absence: - impaired renal function and fetal lung effects
Synthetic Steroids
source cholic acid (cattle) or steroid sapogenins (diosgenin, hecopenin); absorption: oral, IV, IM, sites of local administration - prolonged effects with occlusive dressing - large areas may cause suppression of HPA axis
Classification of Glucocorticoids
I. Short to medium-acting glucocorticoids: a. Hydrocortisone (cortisol) b. Cortisone c. Prednisone d. Prednisolone e. Methylprednisolone f. Meprednisone
IV. Mineralocorticoids
1. Deoxycortisone (DOC) serves as precursor of aldosterone
Uses:
A. Diagnosis and treatment of disorders of adrenal function B. Treatment of inflammatory and immunologic disorders
Therapeutic Uses:
A. Replacement Therapy 1. Adrenal Insufficiency a. Acute adrenal insufficiency (acute adrenal crisis)
ssx: GIT symptoms, dhn, hypoNa, hyperK, weakness, lethargy, hypotension cause: - destructive lesions secondary to surgery; TB of the adrenals; bilateral adrenal hgge - abrupt withdrawal of glucocorticoids at high doses or prolonged use mgt: IV : D5 0.3%NaCl solution Monitor for fluid overload Hydrocortisone (cortisol) 100mg bolus, ffed by 100mg every 8 hrs. ; once stable, may give 25mg IM hydrocortisone every 6-8hrs.; thereafter, same mgt with chronic adrenal insufficiency
Addison described : . general languor and debility . remarkable feebleness of the heart's action . irritability of the stomach . peculiar change of the color of the skin
C. Non-Adrenal Diseases
1. Rheumatic disorders suppress the disease and minimize resultant tissue damage mgt: oral prednisone 10 mg/kg/day (taper thereafter by decreasing 1mg/kg/day every 2-3 wks) - intraarticular injection: triamcinolone acetonide: minimize complications (3-4x/year)
2. Renal Disorders nephrotic syndrome mgt: prednisone: 1-2 mg/kg x 6 wks, ffed. by gradual tapering over 6-8 wks or alternate-day therapy (diminished proteinuria in 85% pts in 2-3 wks and 95% pts will have remission in 3 mos. - membranous glomerulonephritis mgt: alternate-day prednisone 8-10 wks ffed by 1-2 month period of tapering
6. Ocular disease 0.1% dexamethasone - C/I: herpes simplex keratitis (clouding of the cornea) , glaucoma
C. Non-Adrenal Diseases (cont.) 7. Skin diseases inflammatory dermatoses 8. GIT diseases inflammatory bowel disease 9. Hepatic diseases prednisolone 80% histologic remission in pts. with chronic, active hepatitis 10. Malignancies ALL, lymphomas
Toxicity:
Withdrawal of therapy: ssx: fever, myalgias, arthralgias, malaise, pseudomotor cerebri ( ICP, papilledema) Continued use at supraphysiologic doses ssx: fluid and electrolyte abnormalities, hypertension, hyperglycemia, increased susceptibility to infection, myopathy, behavioral disturbances, cataracts, growth arrest and fat redistribution, acne, hirsutism, striae, ecchymoses, osteonecrosis, peptic ulcer Adrenal suppression - >2 wks.
Supplemental measures:
Diet rich in potassium and low in sodium Caloric mgt to prevent obesity High protein intake Appropriate antacid therapy Calcium and vit D, physical therapy Alendronate biphosphonate
Mineralocorticoid Antagonists
1. Spirinolactone diagnosis of aldosteronism (400500mg/day for 5-8 weeks) - preparing for surgery (300-40mg/day x 2 wks to reduce the incidence of arrhythmias) - hirsutism in women (androgen antagonist at 50-200mg/d x 2-6 mos) - diuretic - treatment of primary hyperaldosteronism (Conns syndrome) 2. Eplerenone in clinical trials 3. Drospirenone progestin in a new oral contraceptive, antagonizes the effect of aldosterone
Hyperldosteronism 1. primary hyperaldosteronism due to an adrenal adenoma (ssx: hypoK, alkalosis, hyperNa HPN, weakness and tetany 2. secondary hyperaldosteronism due to low plasma renin, angiotensin II
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