Antiinflammatory Steroids

Front 1

site of androgen synthesis?

Back 1

reticulans

Front 2

site of cortisol synthesis?

Back 2

fasciculata

Front 3

site of aldosterone synthesis?

Back 3

glomerulosa

Front 4

chemical differences between adrenal steroids?

Back 4

minor oxidation points but these differences have major effects

Front 5

mechanism of action of adrenal steroids?

Back 5

bind to chaperone proteins
work as trxn factors
direct alteration of gene products
each cell has 10-100 GCC-responsive genes

Front 6

why do adrenal steroids have so many effects?

Back 6

each cell has 10-100 GCC-responsive genes

Front 7

effects of GCC on metabolism?

Back 7

stimulates hepatic glucose formation
diminish glucose utilization in periphery

Front 8

hepatic glucose formation from?

Back 8

glycerol (gluconeogenesis)
amino acids

Front 9

how do GCC diminish glucose utilization in periphery?

Back 9

enhance protein catabolism in muscle
enhance lipolysis in fat

Front 10

end/side effects of GCC?

Back 10

increase plasma glucose (steroid diabetes);
fat mobilization leading to accumulation at 'trunk';
muscle wasting (at high doses)

Front 11

antiinflammatory effects of GCC?

Back 11

inhibit synthesis of leukotrienes, PGs;
decrease cellular content and release of histamine;
decrease the synthesis of interleukins and cytokines;
decrease the synthesis of MCF, MAF;
decrease activity of MIF;
decrease the release of lytic enzymes;
decrease release of reactive O2 products

Front 12

MCC mechanism?

Back 12

increase Na+ reuptake creating positive Na+ balance;
increase extracellular fluid volume

Front 13

high levels of MCC result in?

Back 13

increased blood pressure
hypokalemia
hypernatremia
alkalosis

Front 14

low levels of MCC result in?

Back 14

decreased blood pressure
hyperkalemia
hyponatremia
acidosis

Front 15

uses of synthetic adrenocorticosteroids?

Back 15

replacement therapy
antiinflammatory therapy
immunosuppressive therapy
diagnostic purposes

Front 16

major goals of medicinal chemist?

Back 16

develop synthetic corticosteroids
separate MCC, GCC actions

Front 17

relative potencies of:
prednisolone
9α-fluorocortisol
dexamethasone

Back 17

prednisolone: 4xGCC; 0.5xMCC
9α-fluorocortisol: 10xGCC; 125xMCC
dexamethasone; 30xGCC; 0xMCC

Front 18

addison's disease?

Back 18

primary adrenal insufficiency;
autoimmune in 70-80%

Front 19

causes of addison's disease?

Back 19

autoimmune
TB and other infections
surgery

Front 20

treatment for addison's disease?

Back 20

replacement therapy with cortisol;
usually sufficient for GCC and MCC activity;
MCC supplement may be required

Front 21

fludrocortisone?

Back 21

MCC supplement

Front 22

how is replacement dose of cortisol given?

Back 22

2/3 in morning and 1/3 in late afternoon to mimic the normal pattern

Front 23

what may require dose adjustment of cortisol?

Back 23

illness or stress usually requires 2-3 times normal dose

Front 24

most common enzyme deficiency?

Back 24

21 hydroxylase

Front 25

how can cortisol levels be normal when there is an enzyme deficiency?

Back 25

compensatory increase in ACTH that causes adrenal hyperplasia resulting in normal cortisol concentration

Front 26

consequence of most adrenal enzyme deficiencies?

Back 26

increased androgen secretion because their production doesn't require the deficient enzymes and more cholesterol is shunted into the alternate pathways

Front 27

treatment for adrenal enzyme deficiencies?

Back 27

100 mg/day initially (~5 days) to decrease ACTH production;
then reduced to replacement therapy levels

Front 28

toxicity of GCC steroids?

Back 28

CNS effects (euphoria)
steroid diabetes
skeletal effects
increased infectivity
ulcers
delayed wound healing
adrenal atrophy

Front 29

CNS effects of GCC?

Back 29

may produce a euphoria that makes it difficult to wean the patient

Front 30

skeletal effects of GCC?

Back 30

osteoporosis develops due to decreased Ca2+ absorption with resulting increased PTH and bone resorption

Front 31

therapy approach to circumvent adrenal atrophy?

Back 31

alternate-day steroid therapy using double the daily dose

Front 32

benefits of alternate-day steroid therapy?

Back 32

adrenals do not atrophy
stress response remains normal
other side effects are decreased

Front 33

causes of cushings?

Back 33

pituitary adenoma
nonendocrine tumors secreting ACTH (metastatic cancer)
abnormal adrenal gland responses (hyperplasia)
ectopic adrenal tissue (mets from adrenal tumor)

Front 34

true cushing's disease?

Back 34

pituitary adenoma secreting ACTH

Front 35

dexamethasone suppression test?

Back 35

low dose turns off ACTH in normal;
4x needed in cushing dz;
not turned off with high dose then suspect cancer

Front 36

diagnosis of cushings?

Back 36

urinary free cortisol test (>50-100 mg/day)
dexamethasone suppression test
petrosal sinus testing

Front 37

petrosal sinus testing?

Back 37

blood sample from veins directly draining pituitary;
CRH give and ACTH measured;
compare with peripheral venous blood;
tell if ACTH is coming from pit or ectopic location

Front 38

signs of GCC/MCC excess?

Back 38

truncal obesity
muscle wasting
steroid diabetes
bone demineralization
growth retardation
CNS manifestations
HTN
delayed wound healing
hypokalemic alkalosis

Front 39

signs of androgen excess?

Back 39

hirsutism
amenorrhea

Front 40

treatment of cushings?

Back 40

pharmacological intervention until make diagnosis;
then remove source of ACTH

Front 41

why is pharmacological treatment of cushings best utilized as bridging therapy to ablation?

Back 41

although decrease cortisol production this results in more ACTH;
therapeutic effects can be overridden;
upregulation of other corticosteroids

Front 42

mitotane?

Back 42

adrenostatic drug
derivative of DDT
reacts nonspecifically with hydroxylases
destroys tissue (so ACTH does not overcome)
removed from US market

Front 43

amphenone B?

Back 43

adrenostatic drug
more potent derivative of mitotane
blocks hydroxylases
does not destroy tissue (ACTH leads to hypertrophy)
removed from US market

Front 44

metyrapone?

Back 44

adrenostatic drug
specific inhibitor of 11β hydroxylase
rarely used as therapy
used in cortisol excess before known cause;
test for pituitary reserve of ACTH

Front 45

aminoglutethimide?

Back 45

adrenostatic drug
inhibits cholesterol --> pregnenolone
reduces MCC, GCC, androgen secretion
not specific to adrenal
overcome by ACTH
used with dex to decrease androgen synthesis

Front 46

used primarily for cushings syndrome secondary to adrenal cancer?

Back 46

aminoglutethimide

Front 47

used to test of pituitary reserve of ACTH?

Back 47

metyrapone

Front 48

ketoconazole?

Back 48

adrenostatic drug;
blocks many of steroid synthesis P450s;
displace estrogen, testosterone from binding proteins;
increases estrogen:testosterone ratio

Front 49

side effects of ketoconazole?

Back 49

compensatory increase in ACTH --> increased androgens and aldosterone;
increased estrogen:testosterone ratio --> gynecomastia and oligospermia in males and altered menstrual cycle in females

Front 50

mifepristone (RU486)?

Back 50

GCC receptor antagonist

Front 51

spironolactone?

Back 51

MCC receptor antagonist

Front 52

spironolactone use in cushings?

Back 52

treats excessive aldosterone secretion

Front 53

captopril?

Back 53

ACE inhibitor

Front 54

losartan?

Back 54

ARB

Front 55

other mechanisms of treatment?

Back 55

GCC receptor antagonist
MCC receptor antagonist
ACEI
ARBs