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Medicinal Chemistry 3 > Exam #02 (Steroids) > Flashcards

Exam #02 (Steroids) Flashcards

1
Q

List the intermediates in the biosynthesis of cholesterol.

A

(1) Acetyl-CoA + acetoacetyl-CoA (hydrated to form) HMG-CoA (reduced to form) Mevalonate (converted to) Isoprene units (3 units condense to form) Cholesterol

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2
Q

Give the hierarchy of where glucocorticoids, mineralocorticoids, and androgens are derived?

A

Cholesterol –> Pregnenolone –> Progesterone –> (Glucocorticoids + Mineralocorticoids + Androgens)

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3
Q

Pregnenolone can be converted to what major secretory product of the androgens?

A

DHEA (Dehydroepiandrosterone)

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4
Q

Testosterone can be converted to what major secretory product of the androgens via 5alpha-reductase?

A

DHT (Dihydrotestosterone)

Important in controlling prostate and hairgrowth

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5
Q

What enzyme converts testosterone to estradiol?

A

Aromatase

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6
Q

Progesterone can be converted into what (2) major secretory products in the glucocorticoids and mineralocorticoids?

A

Glucocorticoids: Cortisol (HYDROcortisone)
Mineralocorticoid: Aldosterone

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7
Q

LH stimulates the release of what (2) steroids?

A
  1. androgens

2. progestins

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8
Q

FSH stimulates the release of what steroid?

A

esterogen

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9
Q

Chorionic gonadotropin (HCG) stimulates the release of what steroid?

A

progestins

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10
Q

Name the (3) regions of the adrenal cortex and which steroid(s) produced in each region.

A
  1. Zona glomerulosa - produces mineralocorticoids (aldosterone)
  2. Zona fasciculata - produces glucocorticoids (cortisol, cortisone)
  3. Zona reticularis - produces sex hormones (androgens)
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11
Q

Renin/angiotensin stimulates the release of what steroid?

A

mineralocorticoids (aldosterone)

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12
Q

True or False - The MOA of steroids is based soley on having a “genomic” mechanism in which binding of steroids to glucocorticoid receptors interacts with the transcription of target genes?

A

False - steroids have a “genomic” mechanism that accounts for the long term effects, and also a non-genomic MOA involving 7TM-GPCR responsible for the rapid response of steroids

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13
Q

What component of a steroid receptor is involved with the correct fitting of steroids into the receptor?

A

Zn fingers

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14
Q

Cortisol can exist as free cortisol in plasma and protein-bound cortisol in plasma. Which protein does cortisol primarily bind to?

A

corticosteroid-binding globulin (CBG) also called transcortin

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15
Q

True or False - synthetic steroids are highly protein bound?

A

True - synthetic steroids are highly bound to albumin

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16
Q

What are the (3) main routes glucocorticoids are metabolized?

A
  1. oxidation
  2. glucuronidation
  3. sulfation

*glucocorticoids are highly metabolized

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17
Q

Describe the pathway leading to the release of cortisol initiated by trauma via nociceptive pathways, drive for circadian rhythm, or emotion via the limbic system?

A

Initiation of the pathway stimulates the Hypothalamus to release CRH which stimulates the Anterior Pituitary to release ACTH which stimulates the Adrenal Cortex (Zona Fasciculata) to release cortisol

CRH = corticotropin releasing hormone
ACTH = adrenocorticotropic hormone
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18
Q

Describe the negative feedback mechanism of cortisol.

A

Release of cortisol by the adrenal cortex has a negative feedback mechanism. Cortisol inhibits the hypothalamus and anterior pituitary from releasing stimulating hormones (CRH and ACTH, respectively) to cause the adrenal cortex to release more cortisol

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19
Q

Cushing’s syndrome describes the signs and symptoms associated with prolonged exposure to inappropriately high levels of the hormone cortisol. This can be caused by taking glucocorticoid drugs, or diseases that result in excess cortisol, adrenocorticotropic hormone (ACTH), or CRH levels. What would you expect to happen to ACTH and cortisol levels in a patient with Cushing’s given dexamethasone?

A

cortisol levels would be relatively low and ACTH levels would be similar to normal, morning (relatively high)

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20
Q

Interpret these results from a dexamethasone suppression test:

No change to cortisol levels when patient administered low-dose dexamethasone, but lower levels of cortisol seen on high-dose dexamethasone.

A

Patient has Cushing’s disease

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21
Q

Interpret these results from a dexamethasone suppression test:

Patient administered low-dose and high dose dexamethasone, but cortisol levels remained unchanged.

A

Patient has a cortisol secreting adrenocortical tumor OR ectopic ACTH syndrome

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22
Q

Name (2) metabolic effects of glucocorticoids

A
  1. stimulate gluconeogenesis by inducing PEPCK, glucose-6-phosphatase, fructose-2, 6-bisphosphatase
  2. stimulates lipolysis AND lipogenesis resulting in MOON FACE & BUFFALO HUMP
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23
Q

True or False - In addition to the metabolic effects, glucocorticoids have immunosuppressive, anti-inflammatory effects, and stimulates gastric acid secretion?

A

True - inhibits transcription factors necessary for production of cells that generate the inflammatory response AND inhibits enzyme responsible for releasing arachidonic acid (precursor of inflammatory mediators)

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24
Q

Name 12 AE associated with long-term/high dose glucocorticoids?

A
  1. increase acid in GI
  2. edema
  3. osteoporosis
  4. gluconeogenesis
  5. growth inhibition
  6. CNS effects (euphoria, insomnia, depression)
  7. myopathy
  8. ocular effects
  9. moon face
  10. acne
  11. hirsutism (extra growth of hair esp in females)
  12. purpura (purple skin)
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25
Q

Cortisol (active-binds to MR and GR) is converted to Cortisone (inactive-does not bind to MR and GR) in the kidneys what enzyme isoform?

A

Type 2 isoform 11B-HSD2

11B-hydroxysteroid dehydrogenase-2

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26
Q

Cortisone (inactive-does not bind to MR and GR) is converted to Cortisol (active-binds to MR and GR) in the liver and fat by what enzyme isoform?

A

Type 1 isoform (11B-HSD1)

11B-hydroxysteroid dehydrogenase-1

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27
Q

Which 11B-HSD isoform protects the MR from the high circulating concentrations of cortisol?

A

Type 2 isoform 11B-HSD2

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28
Q

Lack of Type 2 isoform 11B-HSD2 can lead to what (2) conditions?

A
  1. HTN
  2. Hypokalemia (from overstimulation of MR)

If you’re lacking Type 2 isoform, you can’t convert the active cortisol to in the inactive cortisone resulting in over stimulation of MR

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29
Q

What is the most frequent problem associated with steroid withdrawal?

A

flare-up of the underlying disease for which steroids were prescribed to treat

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30
Q

What is the most SEVERE complication of rapid steroid cessation?

A

HPA shock (adrenal insufficiency)

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31
Q

What type of dosing regimen is employed when large doses of steroids are required for Tx for prolonged periods of time?

A

alternate-day administration to allow body recovery time in between doses

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32
Q

True or False - the longer one has been taking steroids, the slower the taper needs to be when coming off the steroids?

A

True

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33
Q

True or False - a single dose of glucocorticoid has virtually no harmful effects?

A

True - even a short course of therapy (up to 7 days) is unlikely to cause harm (excluding contraindications)

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34
Q

Which adrenocortical antagonist is used in Cushing’s and blocks conversion of cholesterol to pregnenolone?

A

Cytadren

35
Q

Name the (3) gonadal hormones.

A
  1. estrogens
  2. progestins
  3. androgens
36
Q

List which reproductive hormone is produced in the following locations:

Zona reticularis
Leydig cells
Ovaries
Placenta

A

Zona reticularis - androgens
Leydig cells - testosterone
Ovaries - estrogens
Placenta - estrogens and progestins

Estrogens primarily made in ovaries

37
Q

True or False - androgens and estrogens are secreted by both sexes?

A

True

38
Q

Name the (3) naturally occurring estrogens.

A
  1. estrone (E1)
  2. estradiol (E2)
  3. Estriol (E3)
39
Q

Where does the main source of estrogen come from in men and post-menopausal women?

A

adipose tissue

40
Q

Cholesterol –> Pregnenolone –> Progesterone –> Androgen –> ENZYME?? –> Estrone

AND

Androgen –> ENZYME?? –> Testosterone

Testosterone –> ENZYME?? –> 17B-Estradiol

Testosterone –> ENZYME?? –> 5alpha-DHT (5A-dihydrotestosterone)

Name each enzyme involved in the above reactions.

A

Androgen –> Aromatase –> Estrone

Androgen –> 17B-hydroxysteroid dehydrogenase (17B-HSD)

Testosterone –> Aromatase –> 17B-Estradiol

Testosterone –> 5alpha-reductase –> 5alpha-DHT (5A-dihydrotestosterone)

41
Q

Which part of the uterus is prepared to be impregnated every month by building up, getting thicker and thicker?

A

endometrial lining

If not impregnated, lining is shed (menstrual cycle)

42
Q

At day 14 of the menstrual cycle, a surge in what hormones is responsible for releasing a mature egg?

A

LH and FSH surge

43
Q

Leading up to ovulation, but right before the LH & FSH surge, there is a surge in what other hormone?

A

17B-Estradiol

44
Q

What is the main product (hormone) during the Follicular Phase (released by the growing ovarian follicle)?

A

Estrogen

45
Q

What is the main products (hormones) during the Luteal Phase (released by corpus luteum)?

A

Progesterone + Estrogen

Corpus Luteum kind of becomes and endocrine gland itself

46
Q

Which hormone do pregnancy test kits detect to see if you’re pregnant (effective 2 weeks after fertilization)? What secretes this hormone?

A

urinary human chorionic gonadotropin (hCG)

Placenta secretes hCG to maintain the corpus luteum for the first 9 weeks of pregnancy

47
Q

From where are LH and FSH released?

A

anterior pituitary

48
Q

Explain how the hypothalamus influences the anterior pituitary which influences the ovaries to release estrogen?

A

Hypothalamus releases GnRH which stimulates the anterior pituitary to release LH and FSH which stimulates the ovaries to release estrogen

49
Q

True or False - high levels of estrogen is involved in a negative feedback mechanism in which estrogen inhibits both the hypothalamus from releasing GnRH and the anterior pituitary from releasing FSH and LH?

A

True

high levels of estrogen inhibit secretion of GnRH, LH, and FSH

50
Q

Describe the (2) ways the Theca Interna of the ovaries is involved in releasing estrogen?

A
  1. Theca interna releases androgens which are converted to estrogen (by aromatase) in the granulosa resulting in indirect release of estrogen
  2. Theca interna converts another androgen to estrogen (by aromatase) resulting in direct release of estrogen

Involves the indirect and direct release of estrogen

51
Q

What enzyme is released from the ovary granulosa that inhibits release of FSH from the anterior pituitary?

A

Inhibin-B

52
Q

During the menstrual cycle, when are the highest levels of estrogen reached?

A

Right BEFORE the LH, FSH surge

53
Q

When would the highest levels of progesterone occur?

A

after the surge during the secretory phase (luteal phase)

54
Q

What hormone do OVULATION kits test for to determine when the best chance of becoming pregnant is?

A

surge in LH

55
Q

True or False - During the follicular stage, pregnenolone is converted into androgen via DHEA intermediate and during the luteal phase, pregnenolone is converted into androgen via progesterone?

A

True - remember the progesterone surge occurs during the Luteal Phase, AFTER the FSH, LH surge.

56
Q

When and from what does the major production of Estriol occur?

A

during pregnancy by the placenta

57
Q

True or False - Estradiol is the most potent endogenous estrogen

A

True

58
Q

Name (6) ADRs of unopposed estrogen therapy (estrogen given with no progesterone)

A
  1. edema and weight gain
  2. breast tenderness
  3. thromboembolism
  4. CNS: HA, migraines
  5. Increase or decrease libido
  6. increase acne (or can be used to treat acne)
59
Q

True or False - the Estrane progestins have low progestin activity and slight estrogenic and androgenic activity?

A

True

60
Q

True or False - Gonane progestins have higher progestin activity and no estrogen, low androgenic activity?

A

True

61
Q

How do oral contraceptives (combinations of estrogens and progestins) work?

A

They suppress the production of LH, FSH, or both by feedback inhibition fooling the body into thinking its pregnant

62
Q

Which component of oral contraceptives suppresses LH release and which component suppresses FSH release from the anterior pituitary?

A

Progestins suppress LH release
-also causes thickening of cervical mucosa providing barrier to passage of sperm

Estrogens suppress FSH release

63
Q

True or False - the primary action of the combination of an estrogen with a progestin is to suppress the hypothalamic-pituitary system, decreasing the secretion of GnRH?

A

True

64
Q

Spotting or breakthrough bleeding after mid-cycle is related to _____ progestin relative to estrogen?

A

too much progestin

fixed by making bi and tri-phasic combos where the E/P ratio changes as cycle progresses

65
Q

Seasonale is a continuous dosage or extended-cycle OC. How long can you continuously take Seasonale?

A

84 days

66
Q

Name the first low dose combination contraceptive pill taken 365 days a year?

A

Lybrel

67
Q

Which OC uses ascending dose ethinyl estradiol to reduce unscheduled spotting and bleeding?

A

Quartette

68
Q

Do inducers of CYP3A4 affect OC?

A

Yes, they would decrease the OC effectiveness since OC is metabolized by CYP3A4

69
Q

Intrauterine system (IUS) releases progesterone from the verticle part of the T. Give one example?

A

Mirena

70
Q

How do IUSs work?

A

it’s thought to be from inflammation. Inflammation occurs after insertion which attracts WBCs to the area which secrete substances toxic to sperm

71
Q

SE of IUSs are limited to the uterus. Name (4)

A
  1. cramps
  2. spotting
  3. heavy menstrual flow
  4. infection
72
Q

How often is the IUS Mirena replaced?

A

every 3-5 years

in contrast, copper Paragard is replaced every 10-12 years

73
Q

Testosterone causes retention of what element by increasing protein synthesis and decreasing protein catabolism?

A

nitrogen retention

74
Q

What (2) therapeutic uses do natural and synthetic androgens have?

A
  1. hormone replacement therapy (HRT)

2. promote weight gain in wasting conditions (AIDS)

75
Q

Toxicity of androgens and anabolic steroids causes what type of cancer?

A

liver carcinoma

76
Q

True or False - all steroid 4-end-3-ones are light sensitive?

A

True

77
Q

The main reason why corticosterone and cortisol are not formed in Leydig cells is?

A

the 11 and 21 hydroxyls enzymes (that are present in the adrenal cortex) are absent in Leydig cells, so only androgens and estrogens are synthesized here

78
Q

Testosterone is converted to what major end product estrogen?

A

Estradiol

79
Q

Describe the pathway from Hypothalamus to testosterone

A

Hypothalamus releases GnRH stimulating anterior pituitary to release LH which stimulates Leydig cells to release testosterone

80
Q

List the indirect effects of testosterone mediated by DHT and estradiol

A

Testosterone –> DHT (via 5-alpha reductase)
-affects external genitalia and hair follicles

Testosterone –> Estradiol (via aromatase)
-affects bone (epiphyseal closure, increased density)

81
Q

List the direct effetcs of testosterone

A

affects internal genitalia, skeletal muscle, and erythropoiesis

82
Q

What is the Hershberger Assay used to measure?

A

measures androgenic vs anabolic effects

method of choice for ID’ing androgen receptor-dependent myoanabolic tissue selective activity

83
Q

If you apply Hershberger Assay to DHT (which is a potent androgen), would the LA/VP ratio be lower or higher than an anabolic androgen?

A

lower

84
Q

What antiandrogen is used to treat female hirsutism?

A

Spironolactone

Medicinal Chemistry 3 (6 decks)

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