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65 Cards in this Set
- Front
- Back
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Normal adults make how much cortisol daily?
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about 10mg daily
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About ____% of circulating cortisol is bound to _______.
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75%
Cortisol-binding globulin (CBG) |
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CBG synthesis?
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Synthesized by the liver
Synth increased by -- estrogen -- pregnancy |
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Free cortisol acts to inhibit...?
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1. CRH release from the hypothalamus = feedback inhibition
2. ACTH release from the pituitary = feedback inhibition |
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Synthetic glucocorticoids are bound to...?
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albumin
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Cortisal half life? Degradation?
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Half-life of 60-90min
Degraded by the liver (synthetic corticosteroids have longer half-lives) |
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Glucocorticoid MOA?
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1. Glucocorticoid receptor is located in the cytoplasm and is inhibited from migrating to the nucleus by a heat-shock protein (HSP 90)
2. When cortisol binds to the GR-HSP 90 complex, the HSP 90 is released, and the cortisol-GR complex migrates to the nucleus where it acts as a transciptional regulator at glucocorticoid-responsive elements of DNA |
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Cortisol enhances gene expression for...?
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1. lipocortin -- inhibits the enzyme phosopholipase A2
-- thus prevents liberation of arachidonic acid -- prevents synth of PGs and LTs 2. enzymes involved in gluconeogenesis 3. glycogen synthetase in the liver |
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Cortisol inhibits gene expression for...?
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1. CRH in the hypothalamys
2. ACTH precursor POMC in the pituitary gland 3. Cox-2 in leukocytes 4. IL-1, IL-6, collagenase, and TNF in macrophages |
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Because changes in protein synthesis are involved, the biological effects of cortixol and the synthetic glucocorticoids...?
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1. will develop over a period of days
2. persist much longer than the half-life of these compounds in the blood |
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"Permissive" effects of glucocorticoids?
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1. Ability of catecholamines to
-- contract vascular smooth muscle -- relax bronchial smooth muscle -- induce lipolysis 2. maintenance of GFR and free water clearance 3. contraction of skeletal muscle Absence of these "permissive" effects helps to explain the hypotension and skeletal weakness seen in patients w/ Addison's disease |
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Overarching metabolic effect of cortisol?
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Maintains plasma glucose concentration for the brain, even if this means destroying other tissues in the process
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Cortisol maintains plasma [glucose] in the fasting state by...?
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1. proteolysis of skeletal muscle and release of a.a.
2. stimulation of lypolysis to release glycerol 3. activation of gene transcription for enzymes responsible for gluconeogenesis 4. inhibition of peripheral glucose uptake in multiple tissues via ↓ expression of the GLUT-2 transporter 5. stimulation of glycogen synthetase for glycogen storage |
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Cortisol and protein metabolism?
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1. produces proteolysis in skeletal muscle
2. ↑ a.a. uptake by the liver and kidney 3. ↑ hepatic glucose production from a.a./glycerol |
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Lipid metabolism in hypercortisolism?
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1. NET effect is redistribution of fat from extremities to thorax and abdomen
2. Proteolysis of skeletal m provides a.a. for gluconeogenesis 3. ↑ in plasma [glucose] causes insulin release 4. peripheral fat cells respond primarily to cortisol which stimulates lipolysis 5. truncal fat cells respond primarily to insulin which stimulates fat storage via inhibition of extracellular lipase |
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Other catabolic effects which occur during Cushing's syndrome or during prolonged glucocorticoid therapy?
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1. Catabolic effects of lymphoid and connective tissue, muscle, fat, and skin
2. osteoporosis 3. aseptic necrosis of femoral head 4. small p.o. doses can reduce linear growth in children |
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How do corticosteroids cause osteoporosis?
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1. inhibit activity of osteoblasts so less new bone is formed
2. indirectly increase activity of osteoblasts to resorb bone -- inhibit Ca absorption from GI tract and ↑ Ca excretion by kidneys -- ↓ Ca stores enhances release of parathyroid hormone (PTH) -- PTH activates osteoclasts which destroy bone |
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Immunosuppressive effects of cortisol?
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1. ↓ circulating T- and B-lymphocytes, monocytes, eosinophils, and basophils.
-- These cells move from the blood to lymphoid tissue 2. inhibit ability of leukocytes to respond to Ag 3. inhibit ability of macrophages to phagocytose and kill microorganisms 4. reduce production of IL-1, collagenase, elastase, and TNF by macrophages 5. inhibit IL-2 production by lymphocytes -- indirect via inhibition of gene expression for IL-1 and IL-6 by macrophages 6. inhibit Ab production by lymphocytes |
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The anti-inflammatory effects of cortisol?
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Obligatorily linked to the immunosuppressive effects b/c both involve inhibition of WBC fxn.
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CNS effects of cortisol?
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Deficit can cause
-- apathy -- depression -- irritability Pts treated w/ glucocorticoids have elevated mood. -- some experience euphoria, insomnia, restlessness, and increased motor activity |
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Glucocorticoids exert a negative feedback on the hypothalamus, resulting in...?
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1. inhibition of CRH release and thus release of ACTH
-- ↓ in plasma [cortisol] -- atrophy of adrenal cortex 2. inhibition of TRH releae and thus release of TSH -- ↓ in plasma [thyroxine] -- possibility of hypothyroidism 3. inhibition of GnRH release -- ↓ plasma [FSH] -- amenorrhea in females -- azoospermia in males |
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Glucocorticoid effect on bone marrow?
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stimulates erythropoiesis --> increased RBCs and platelets
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Glucocorticoid effect on lungs?
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stimulates fetal production of pulmonary surfactant
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List the glucocorticoids that can be given systemically.
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p.o., i.m., or i.v.
bethamethasone cortisone -- converted to hydrocortisone by hepatic 11β-hydroxysteroid dehydrogenase dexamethasone fludrocortisone hydrocortisone methylprednisolone prednisolone prednisone -- converted to prednisolone by 11β-hydroxysteroid dehydrogenase |
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Glucocorticoids given by inhalation for asthma?
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beclomethasone
budesonide dexamethosone flunisolide fluticasone triamcinolone |
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Which asthma inhalant is best to treat children? Why?
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flunisolide
fluticasone Both have high first-pass metabolism and are less likely to stunt growth in children **TQ |
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Glucocorticoid nasal preps?
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beclomethasone
budesonide dexamethosone fluticasone flunisolide |
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Glucocorticoid opthalmic preps?
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dexamethasone
fluorometholone hydrocortisone prednisolone |
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Glucocorticoid optic preparations (usually contain an antibiotic)?
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dexamethasone
hydrocortisone |
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Glucocorticoid topical preps?
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clobetasol -- good for scalp dermatitis b/c comes in alcoholic suspension
fluticasone |
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Glucocorticoid formulations?
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1. rapidly absorbed from the GI tract
2. Phosphate and succinate sodium esters are water-sol and given by i.m., s.c., and i.v.. -- rapid absorption after i.m. and s.c. injection 3. acetate cmpds have low water sol and exert prolonged effect after injection into soft tissues and joints -- NOT for i.v. use |
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Which glucocorticoids are short acting?
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8-12h
cortisone hydrocortisone |
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Which glucocorticoids are intermediate acting?
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12-36h; used most for chronic p.o. therapy
methylprednisolone prednisolone prednisone triamcinolone |
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Which glucocorticoids are long acting?
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36-72h
betamethasone dexamethasone paramethasone |
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Which glucocorticoids have the greatest antiinflammator activity and longest duration of biological effect?
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betamethasone
dexamethasone **TQ |
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Which glucocorticoids have the most potent mineralocorticoid activity?
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fludrocortisone
**TQ |
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Absorption of glucocorticoid topical preps?
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Absorbed at different rates from different areas of the body.
Greatest absorption -- groin -- axilla -- face Absorbed 10-20 times more rapidly in groin or perianal area than forearm Occlusive dressings enhance cutaneous absorption |
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Acute adrenal insufficiency?
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Characterized by:
-- dehydration -- hyponatremia -- hyparkalemia -- weakness -- lethargy -- hypotension Can be precipitated by infection, trauma, or hemorrhage |
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Treatment of adrenal insufficiency?
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Immediate therapy
1. fluids 2. electrolytes 3. hydrocortisone (i.v.) |
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Chronic adrenal insufficiency is caused by?
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AIDS
autoimmune disease bilateral adrenal hemorrhage |
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What is Addison's disease?
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Chronic, wasting autoimmune disease caused by gradual destruction of adrenal cortex
Pt deficient in both cortisol and aldosterone |
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Characteristics of Addison's?
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hyperpigmentation
weakness fatigue weight loss hypotension inability to maintain plasma glucose conc during fasting |
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How do we treat Addison's disease?
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1. hydrocortisone or cortisone
2. fludrocortisone Replacement therapy required for life and must be increased in times of stress **TQ |
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How do we diagnose Cushing's disease?
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Dexamethasone suppression test
1. give dexamethasone and measure plasma cortisol concentration 2. In Cushing's, will suppress plasma cortisol by 50% 3. In pts w/ ectopic ACTH-secreting tumor or adrenal carcinoma, will NOT suppress plasma [cortisol] |
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How do we deal with surgery in pts w/ hypercortisolism?
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1. continuous i.v. infusion of hydrocortisone given on the day of the surgery
2. dose gradually reduced until normal replacement values are obtained |
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What is congenital adrenal hyperplasia?
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A genetic abnormality of cortisol synthesis (21β-hydroxylase defienciency) causes elevated ACTH
-- in turn causes adrenals to become hyperplastic 2. Excessive ACTH stim cayses excessive production of 17-hydroxy-progesterone which is shunted to androgen synth -- virilization of female fetus results |
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Trtmt for congenital adrenal hyperplasia?
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Treatment of pregnant female at high risk for children w/ this condition protects the female fetus from virilization
At birth, acute adrenal insufficiency must be treated aggressively w/ HYDROCORTISONE -- replacement therapy muust be continued to ensure normal growth and development |
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Glucocorticoids and fetal lung maturation?
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When delivery expected prior to 34wks gestation, maternal treatment w/ BETAMETHASONE reduces incidence of fetal respiratory distress syndrome
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Other medical uses?
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arthritis
rheumatic carditis nephrotic syndrome collagen diseases allergic diseases asthma ocular diseases skin diseases (eczema, seborrheic keratosis) UC and Crohn's disease adjunctive therapy in ALL sarcoidosis cerebral edema organ transplantation |
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Glucocorticoid toxicity?
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1. adrenal suppression
2. Iatrogenic Cushing's syndrome |
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Glucocorticoids and adrenal suppression?
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1. occurs after 4-7days, but recovery is usually prompt
-- use descending dose pack for short-term therapy 2. prolonged therapy severely depresses the adrenal cortes, and drug therapy must be w/d very slowly -- adrenal responsive after 2-3 months -- plasma cortisol may not recover for another 6-9 months Time needed to recover adrenocortical fxn is HIGHLY VARIABLE |
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Withdrawal of therapy w/ corticosteroids can result in...?
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1. acute adrenal insufficiency
2. reappearance of inflamm disease 3. malaise, fever, myalgia, arthralgia |
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What are the symptoms of iatrogenic Cushing's syndrome?
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PREDNISONE
P = peptic ulcers R = retention of salt/water + hypokalemia + hypochloremia + metabolic alkalosis; also hypotension E = extra deposit of fat in trunk and face (moon facies) D = diabetes and changes in CHO metab N = neurosis and psychosis I = infection prone S = suppression of pituitary-adrenal axis O = osteoporosis, esp ribs and vertebrae (30-50% of pts) N = negative N balance w/ muscle wasting; may affect respiratory muscles E = eye - posterior subcapsular cataracts and glaucome |
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Glucocorticoid drug-drug interactions?
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FUROSEMIDE and HCTZ enhance hypokalemia caused by corticosteroids
Inducers of CYP450 enhance glucocorticoid metabolism |
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How do we manage glucocort toxicity?
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1. Use smallest possible dose, but remember that daily dose will need to be increase during stress.
2. alternate day therapy 3. high protein diet and possibly anabolic steroids t ocounteract muscle wasting 4. K supplements to prevent hypokalemia from mineralocort activity 5. diet and insulin for control of hyperglycemia 6. misoprostol for trtmt of peptic ulcer 7. periodic slit-lamp exam for cataract detection 8. periodic meas of intraocular pressure 9. Vitamin D, Ca supplement, and bisphosphonates to prevent osteoporosis |
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Bisphosponates?
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alendronate
-- p.o. tablets -- p.o. solution ibandronate -- p.o. tablets |
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Bisphosponate MOA?
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1. prevents bone resoption by retarding dissolution of hydroxyapetite crystals in bone by osteoclasts
2. these drugs may increase bone formation via increased activity of osteoblasts |
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Bisphosponate therapeutic use?
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1. corticosteroid-induced osteoporosis (**TQ)
2. postmenopausal osteoporosis 3. Paget's disease 4. hyercalcemia assoc w/ cancer |
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Bisphosphonate contraindications?
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1. decreased renal fxn
2. disorders of esoph motility 3. peptic ulcer disease |
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Correct dosing of bisphophonates?
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1. take p.o. w/ ONLY 8-10oz water and remain upright for 30 minutes
2. must be taken on empty stomach since F = 10% 3. food decreases the absorption after p.o. dosing |
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Bisphosponate toxicity?
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osteonecrosis of jaw
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What can inhibit adrenal steroid synthesis?
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aminogluthetimide
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Aminoglutethimide MOA?
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"medical adrenalectomy"
1. blocks conversion of cholesterol to pregnenolone (inhibits CYP450scc) 2. blocks CYP45011β 3. blocks extra-adrenal aromatase which converts androgens to estrogens Blocks ALL adrenal and extra-adrenal steroid synth to cause a "medical adrenalectomy" |
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What is body response to aminoglutethimide?
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Responds w/ increased ACTH secretion which partially overcomes the blockade of adrenal steroidogenesis
-- dexamethasone or hydrocortisone is usually administered w/ it to suppress the compensatory increase in ACTH |
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Therapeutic use of aminoglutethimide?
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1. Amino- + dexamethasone used to suppress androgen and estrogen synth in pts w/ breast cancer
2. Trtmt of Cushing's syndrome (adrenal carcinoma) |
