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Renal 2 Test 1 > Renal 2 Pharmacology 2 > Flashcards

Renal 2 Pharmacology 2 Flashcards

1
Q

Male Hypothalamic-Pituitary-Gonadal Axis

A
  • release/secretion of hypothalamic and anterior pituitary hormone is pulsatile
  • GnRH in hypothalamus stimulates pituitary to Release FSH and LH which stimulates sertoli cells and leydig cells
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2
Q

Anterior pituitary LH stimulates

A

Leydig cells testosterone biosynthesis and secretion

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3
Q

Testosterone + pituitary FSH stimulates

A

sertoli cells–>sperm maturation

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4
Q

Sperm maturation in Sertoli cells

A
  • depends on FSH and testosterone, but also on precisely controlled estrogen levels
  • Aromatase in sertoli cells uses testosterone to make estradiol
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5
Q

GnRH (LHRH)

A
  • released by hypothalamus

- stimulates anterior pituitary to produce and secrete FSH and LH

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6
Q

FSH

A
  • released by anterior pituitary

- stimulates sertoli cells and sperm maturation

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7
Q

LH

A
  • released by anterior pituitary

- stimulates testosterone hormone synthesis and secretion by leydig cells

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8
Q

Continual high concentrations of LH result in

A

reduced secretion of testosterone due to down regulation of LH receptors in Leydig cells

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9
Q

Androgens, testosterone

A
  • released by adrenals and testes

- stimulates Sertoli cells (other cells responsive to androgens, e.g. prostate epithelium)

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10
Q

Estrogens, estradiol

A
  • released by adrenals and testes

- formed by aromatase catalyzed conversions of androgens to estrogens

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11
Q

Aromatase

A

-converts androstenedione to estrone and testosterone to estradiol

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12
Q

Synthesis of dihydrotestosterone

A
  • androstenedione converted to testosterone by 17B-hydroxylase
  • testosterone converted to DHT by 5a-reductase
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13
Q

Synthesis of estradiol in males

A

-estrone converted to estradiol by 17B-hydroxylase or testosterone converted to estradiol by aromatase

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14
Q

High concentrations of testosterone in the circulation

A

-inhibit the release of GnRH, FSH, and LH, by negative feedback control

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15
Q

When circulating concentrations of testosterone are low,

A

-higher levels of GNRH, FSH, and LH are released

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16
Q

Testicular levels of testosterone are

A

100-500x greater than those found in blood

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17
Q

An in crease in PSA level over time may indicate

A

prostate cancer

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18
Q

Androgens stimulate

A

prostate cancer cells to grow

  • lowering androgen levels or stopping androgens from signaling in prostate cancer cells often makes tumors shrink or grow more slowly for a time.
  • Androgen deprivation therapy alone does not cure prostate cancer
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19
Q

GnRH antagonist

A

Degarelix

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20
Q

GnRH agonist

A

Leuprolide

-Nafarelin (nasal)

21
Q

Natural replacement of GnRH

A

Gonadorelin

22
Q

Degarelix

A
  • GnRH antagonist (blocks receptor on pituitary)
  • reduces testosterone levels below detectable levels quickly (2-3 days)
  • used to treat advanced prostate cancer
  • given subcutaneously as a monthly injection
  • counters reflex to try to produce more T because receptor is blocked
23
Q

Degarelix Side effects

A

-problems at injection site (pain, redness, swelling) and increased levels of liver enzymes on lab tests

24
Q

Continuous administration fo a GnRH agonist (Leuprolide)

A

-eventually desensitizes receptors for GnRH and LH after an initial ‘surge’ in androgen biosynthesis

25
Q

Leuprolide

A
  • causes circulating testosterone to surge initially, then drop later due to desensitization of GnRH and LH receptors
  • cause testicles to shrink over time (chemical castration)
  • other GnRH agonists include goserelin, triptorelin, and histrelin
26
Q

How to manage testosterone flare that coincides with administration of GnRH receptor agonists

A

-concurrent administration of androgen receptor antagonists

27
Q

Androgen receptor antagonists include

A

Bicalutamide
Flutamide
Nilutamide

28
Q

Bicalutamide

A
  • used with leuprolide or other GnRH agonists
  • favored
  • 1x a day
29
Q

Flutamide

A

used with GnRH/LHRH agonists

30
Q

Nilutamide

A

-used in combination with surgical castration

31
Q

Non-steroidal (anti-androgens)–androgen receptor antagonists

A
  • compete with testosterone and DHT for receptor
  • No AR dimerization, transport
  • No transcription
  • suppress effects of residual adrenal testosterone, or testosterone flare from GnRH agonists
  • palliative for metastatic prostate cancer: reduced bone pain, better performance status, increased sense of well being
32
Q

GnRH antagonists and agonists halt

A

-androgen biosynthesis by testicles, but not other cells in the body

33
Q

Abiraterone

A
  • blockers enzyme CYP17, lowering tumor production of androgens
  • CYP17 in testicular, adrenal and prostatic tumor tissues is required for androgen biosynthesis
  • approved for advanced prostate cancer that is still growing despite low testosterone levels from a GnRH antagonist or agonists
  • need to continue treatment with GnRH agonist or antagonist
  • used with prednisone or other corticoids
34
Q

CYP7 catalyzes 2 sequential reactions

A
  • conversion of pregnenolone and progesterone to their 17a-hydroxy derivatives
  • formation of DHE and androstenedione by C17,20 lyase activity
  • these androgens are precursors of testosterone
  • also deranges corticoid production by adrenals
35
Q

Side effects of Abiraterone

A
  • derives from its inhibition of cortisol biosynthesis and enhancement of aldosterone biosynthesis
  • to avoid these problems, it is administered with prednisone or another comparable corticoid
36
Q

Ketoconazole

A
  • In high doses, blocks production of androgens, similarly to abiraterone
  • most often used to treat men recently diagnosed with advanced prostate cancer
  • lowers testosterone levels promptly
  • can be tried if other forms of androgen deprivation therapy fail
  • also blocks production of cortisol, thus, patients treated with this need to take a corticosteroid to prevent the side effects due to low cortisol levels
  • has signifiant hepatotoxicity!
37
Q

SAR inhibitors in prostate cancer

A

-cause fewer tumors, but more mutations and such that allow more high grade (malignant) tumors

38
Q

Male Infertility can be treated with

A

human chorionic gonadotrophin (hCG)

39
Q

Secondary hypogonadism is associated with

A
  • decreased secretions of the gonadotropins, LH and FSH, causing decreased testosterone secretion and sperm production
  • testosterone replacement alone will not restore spermatogenesis
  • testosterone secretion virtually always increases to normal after replacement of LH, and sperm production more often than not increases after replacement of LH alone or LH plus FSH
40
Q

HCG

A
  • LH analog
  • heterodimeric protein with an alpha subunit identical to LH and FSH, and a unique B subunit
  • has the biologic activity of LH but a longer half-life in the circulation
  • Stimulates Leydig cells to synthesize and secrete testosterone
  • hCG alone may suffice for stimulation of spermatogenesis
  • FSH alone is not effective
  • considerably less expensive than exogenous FSH preparations
41
Q

Secondary Hypogonadism from taking exogenous androgens

A
  • anabolic steroids
  • including androstenedione, testosterone overexposure
  • not pulsatile
  • infertility, potential distortion of estrogen synthesis
  • excess testosterone causes negative feedback
  • can cause excess estradiol because excess testosterone converted to estradiol by aromatase
42
Q

In the setting of secondary hypogonadism and infertility due to abuse or misuse of anabolic steroids,

A
  • aromatase and estrogen receptors can add to the problem, thus drugs that modulate aromatase and estrogen receptors can sometimes have important uses
  • use aromatase inhibitors or SERMS to hide the fact they are using exogenous androgens because these block conversion to estradiol
43
Q

Selective estrogen receptor modulator (SERM)

A

-Clomiphene

44
Q

Aromatase inhibitors

A
  • anastrazole

- letrazole

45
Q

Gonadal testosterone production is regulated by

A

a feedback loop which senses testosterone, other androgens, and also estrogen levels

46
Q

During an anabolic steroid cycle,

A
  • high androgen levels suppress the HPG axis
  • for a few weeks this is tolerable, but extended anabolic steroid exposure can cause testicular atrophy
  • HCG injection to limit typically fails after extended anabolic steroid use
47
Q

Clomiphene

A
  • SERM used for enhanced recovery of testosterone production after anabolic steroid cycles
  • occupies the binding sites of estrogen receptors of cells, without activating them
  • estradiol antagonist
  • thus, it ‘tricks’ the hypothalamus to conclude that estrogen levels are low
  • if androgen levels are not elevated, as indeed they should not be after an anabolic steroid cycle, the hypothalamus is then stimulated to produce LHRH.
  • this will act to increase LH and restart natural testosterone production
  • long half life–thus a loading dose is necessary for initial dose
48
Q

In the presence of clomiphene, the body senses

A

low levels of estrogen, and 17-hydroxyprogesterone, androstenedione, and testosterone are up-regulated

  • because of these hormone-receptor interactions, all aromatase inhibitors, including but not limited to, anastrozole, letrozole, exemestane, are banned substances in athletic competitors.
  • selective estrogen receptor modulators, including but not raloxifine, tamoxifen and toremifene, clomiphene and the anti-estrogenic substances are also banned–but widely used

Renal 2 Test 1 (16 decks)

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