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65 Cards in this Set

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Normal adults make how much cortisol daily?
about 10mg daily
About ____% of circulating cortisol is bound to _______.
75%

Cortisol-binding globulin (CBG)
CBG synthesis?
Synthesized by the liver

Synth increased by
-- estrogen
-- pregnancy
Free cortisol acts to inhibit...?
1. CRH release from the hypothalamus = feedback inhibition

2. ACTH release from the pituitary = feedback inhibition
Synthetic glucocorticoids are bound to...?
albumin
Cortisal half life? Degradation?
Half-life of 60-90min

Degraded by the liver

(synthetic corticosteroids have longer half-lives)
Glucocorticoid MOA?
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
Cortisol enhances gene expression for...?
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
Cortisol inhibits gene expression for...?
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
Because changes in protein synthesis are involved, the biological effects of cortixol and the synthetic glucocorticoids...?
1. will develop over a period of days

2. persist much longer than the half-life of these compounds in the blood
"Permissive" effects of glucocorticoids?
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
Overarching metabolic effect of cortisol?
Maintains plasma glucose concentration for the brain, even if this means destroying other tissues in the process
Cortisol maintains plasma [glucose] in the fasting state by...?
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
Cortisol and protein metabolism?
1. produces proteolysis in skeletal muscle

2. ↑ a.a. uptake by the liver and kidney

3. ↑ hepatic glucose production from a.a./glycerol
Lipid metabolism in hypercortisolism?
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
Other catabolic effects which occur during Cushing's syndrome or during prolonged glucocorticoid therapy?
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
How do corticosteroids cause osteoporosis?
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
Immunosuppressive effects of cortisol?
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
The anti-inflammatory effects of cortisol?
Obligatorily linked to the immunosuppressive effects b/c both involve inhibition of WBC fxn.
CNS effects of cortisol?
Deficit can cause
-- apathy
-- depression
-- irritability

Pts treated w/ glucocorticoids have elevated mood.
-- some experience euphoria, insomnia, restlessness, and increased motor activity
Glucocorticoids exert a negative feedback on the hypothalamus, resulting in...?
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
Glucocorticoid effect on bone marrow?
stimulates erythropoiesis --> increased RBCs and platelets
Glucocorticoid effect on lungs?
stimulates fetal production of pulmonary surfactant
List the glucocorticoids that can be given systemically.
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
Glucocorticoids given by inhalation for asthma?
beclomethasone
budesonide
dexamethosone
flunisolide
fluticasone
triamcinolone
Which asthma inhalant is best to treat children? Why?
flunisolide

fluticasone

Both have high first-pass metabolism and are less likely to stunt growth in children

**TQ
Glucocorticoid nasal preps?
beclomethasone
budesonide
dexamethosone
fluticasone
flunisolide
Glucocorticoid opthalmic preps?
dexamethasone
fluorometholone
hydrocortisone
prednisolone
Glucocorticoid optic preparations (usually contain an antibiotic)?
dexamethasone
hydrocortisone
Glucocorticoid topical preps?
clobetasol -- good for scalp dermatitis b/c comes in alcoholic suspension

fluticasone
Glucocorticoid formulations?
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
Which glucocorticoids are short acting?
8-12h

cortisone

hydrocortisone
Which glucocorticoids are intermediate acting?
12-36h; used most for chronic p.o. therapy

methylprednisolone
prednisolone
prednisone
triamcinolone
Which glucocorticoids are long acting?
36-72h

betamethasone
dexamethasone
paramethasone
Which glucocorticoids have the greatest antiinflammator activity and longest duration of biological effect?
betamethasone
dexamethasone

**TQ
Which glucocorticoids have the most potent mineralocorticoid activity?
fludrocortisone

**TQ
Absorption of glucocorticoid topical preps?
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
Acute adrenal insufficiency?
Characterized by:
-- dehydration
-- hyponatremia
-- hyparkalemia
-- weakness
-- lethargy
-- hypotension

Can be precipitated by infection, trauma, or hemorrhage
Treatment of adrenal insufficiency?
Immediate therapy
1. fluids
2. electrolytes
3. hydrocortisone (i.v.)
Chronic adrenal insufficiency is caused by?
AIDS

autoimmune disease

bilateral adrenal hemorrhage
What is Addison's disease?
Chronic, wasting autoimmune disease caused by gradual destruction of adrenal cortex

Pt deficient in both cortisol and aldosterone
Characteristics of Addison's?
hyperpigmentation
weakness
fatigue
weight loss
hypotension
inability to maintain plasma glucose conc during fasting
How do we treat Addison's disease?
1. hydrocortisone or cortisone

2. fludrocortisone

Replacement therapy required for life and must be increased in times of stress

**TQ
How do we diagnose Cushing's disease?
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]
How do we deal with surgery in pts w/ hypercortisolism?
1. continuous i.v. infusion of hydrocortisone given on the day of the surgery

2. dose gradually reduced until normal replacement values are obtained
What is congenital adrenal hyperplasia?
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
Trtmt for congenital adrenal hyperplasia?
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
Glucocorticoids and fetal lung maturation?
When delivery expected prior to 34wks gestation, maternal treatment w/ BETAMETHASONE reduces incidence of fetal respiratory distress syndrome
Other medical uses?
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
Glucocorticoid toxicity?
1. adrenal suppression

2. Iatrogenic Cushing's syndrome
Glucocorticoids and adrenal suppression?
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
Withdrawal of therapy w/ corticosteroids can result in...?
1. acute adrenal insufficiency

2. reappearance of inflamm disease

3. malaise, fever, myalgia, arthralgia
What are the symptoms of iatrogenic Cushing's syndrome?
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
Glucocorticoid drug-drug interactions?
FUROSEMIDE and HCTZ enhance hypokalemia caused by corticosteroids

Inducers of CYP450 enhance glucocorticoid metabolism
How do we manage glucocort toxicity?
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
Bisphosponates?
alendronate
-- p.o. tablets
-- p.o. solution

ibandronate
-- p.o. tablets
Bisphosponate MOA?
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
Bisphosponate therapeutic use?
1. corticosteroid-induced osteoporosis (**TQ)

2. postmenopausal osteoporosis

3. Paget's disease

4. hyercalcemia assoc w/ cancer
Bisphosphonate contraindications?
1. decreased renal fxn

2. disorders of esoph motility

3. peptic ulcer disease
Correct dosing of bisphophonates?
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
Bisphosponate toxicity?
osteonecrosis of jaw
What can inhibit adrenal steroid synthesis?
aminogluthetimide
Aminoglutethimide MOA?
"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"
What is body response to aminoglutethimide?
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
Therapeutic use of aminoglutethimide?
1. Amino- + dexamethasone used to suppress androgen and estrogen synth in pts w/ breast cancer

2. Trtmt of Cushing's syndrome (adrenal carcinoma)