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Pharmacology Test 2 > Androgens & Anti-Androgens > Flashcards

Androgens & Anti-Androgens Flashcards

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1
Q

Androgens

A

19C compound derived from cholesterol

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2
Q

Androgenic Precursors

A
  • DHEA: dehydroepiandrosterone
  • Androstnedione
  • inactive; must be converted
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3
Q

DHEA: dehydroepiandrosterone

A
  • androgenic precursor
  • adrenal cortex; testes
  • inactive
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4
Q

Androstenedione

A
  • androgenic precursor
  • adrenal cortex; testes
  • inactive
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5
Q

Androgens

Name two

A
  • Testosterone

- DHT: dihydrotestosterone

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6
Q

Testosterone

A
  • testes

- MOST ABUNDANT

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7
Q

DHT

Dihydrotestosterone

A
  • androgen target cells and tissues
  • – paracrine/autocrine manner
  • MOST POTENT natural androgen
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8
Q

Adult male [testosterone]

A

[T]testes 100x > [T]serum

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9
Q

17-B-hydroxysteroid dehydrogenase (17B-HSD)

A
  • converts DHEA and androstenedione to testosterone

- expressed in testicular leydig cells

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10
Q

5-a-reductase

A

testosterone -> DHT

  • androgen-responsive target tissues
  • most DHT production occurs outside the testes
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11
Q

How much testosterone is produced in the adrenal cortex?

A

<5%

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12
Q

Aromatase (CYP19)

A

androgens are OBLIGATE precursors to estrone and estradiol

- more fat = more estradiol

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13
Q

Androgen Receptor: males express

A

only 1

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14
Q

Regulation of Androgen Production from Testes

A
  • Hypothalamus = pulse generator
  • – GnRH: hypothalamus -> pituitary (+)
  • FSH: pituitary -> testes/seminiferous tubules (+)
  • LH: pituitary -> testes/Leydig cells
  • – C -> T
  • Testosterone: testes -> pituitary & hypothalamus (-)
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15
Q

Testosterone secreted by Leydig cells play critical role in ____

A

spermatogenesis

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16
Q

Androgen Signaling Pathways

A

1) ligand binding triggers loss of heat shock proteins
2) nuclear localization
3) coactivators lead to transcription

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17
Q

T -> DHT

A

5-a-reductase

- DHT binds 5x more tightly to AR

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18
Q

T -> Estradiol

A

Aromatase

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19
Q

Androgen Actions

Developmental (males)

A
  • Embryonic/Fetal: masculinize internal and external male genitalia
  • Puberty
  • – regulate growth and development of male reproductive tract
  • – regulate linear growth and physical development
  • – imprint male behavior and libido
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20
Q

Androgen Actions
Metabolic Adult Males
Bone

A
  • maintains and strengthens bone mass by increasing osteoblast proliferation and decreasing bone resorption by osteoclasts
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21
Q

Androgen Actions
Metabolic Adult Males
Muscle

A
  • increases protein synthesis
  • increases size and length of muscle fibers
  • increases muscle mass
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22
Q

Androgen Actions
Metabolic Adult Males
Blood

A
  • increases erythropoietin
  • increases maturation of erythrocytes
  • increases number of red blood cells
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23
Q

Androgen Actions
Metabolic Adult Males
skin

A

increases sebum production in sebaceous glands

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24
Q

Androgen Actions
Metabolic Adult Males
Liver

A
  • increases LDL
  • decreases HDL
  • implications for CV function
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25
Androgen Actions Metabolic Adult Males Reproduction
- maintains and regulates the male reproductive tract
26
Androgen Actions Metabolic Adult Females
- normal patterns of body hair growth, muscle growth, libido | - maintain bone density
27
Breakdown of Creation of Androgens in Females
50% adrenal cortex | 50% ovaries
28
Therapeutic uses of ANdrogens
- Male Hypogonadism | - Andropause
29
Male Hypogonadism
- defect in testicular function that leads to testosterone deficiency
30
Andropause
- male senescence; late onset hypogonadism; LOH
31
Androgen Replacement Therapy for Andropause
CONTROVERSIAL
32
Therapeutic Androgenic Drug Preparations
- when oral, rapidly degraded by liver, limiting oral bioavailability Effective androgen therapy requires: 1) testosterone in a slow continuously absorbed form 2) chemically modified testosterone derivatives that bypass metabolism in the body
33
3 types of T modifications
1) Type A: esterification of C17 hydroxyl group 2) Type B: alkylation of the C17a position 3) Type C: modifications of the A, B, or C rings Type B+C= very effective
34
Type A Modifications | Esterification of C17 Hydroxyl Group
- make more hydrophobic/lipophilic - allows slow and continuous release into the bloodstream - the longer the ester carbon chain, the more prolonged the action - T esters must be hydrolyzed back into free testosterone to become biologically active
35
Testosterone undecanoate
- Type A Modification - lasts the longest because longest C chain - intramuscular injection every 6-8 weeks
36
Type B Modifications | Alkylation of the C17a position
- increases oral availability; VERY TOXIC to liver - inhibits hepatic catabolism = higher bioavailability - Drawback: prolonged use is associated with liver toxicity
37
Methyltestosterone
Type B Modification
38
Type C ad B Modifications | Modification of A/B/C rings AND C17 a-alkylation
MOST POTENT - enhances the androgenic potency - usually found in combination with C17 a-methylation, thus increasing bioavailability - can increase affinity for receptor OR - can make not a substrate for aromatase, causing it to hang around longer
39
Oxandrolone
C/B modification | - does not aromatize
40
Stanozolol
B/C modification | - does not aromatize
41
Fluoxymesterone
B/C modification - 5x potency of T - does not aromatize
42
Danazol
B/C modification | - does not aromatize
43
Anabolic Steroid Misnomer
there are no purely anabolic steroids | - initial studies done on animals
44
Side Effects of Androgenic Drugs
- prostate enlargement/malignancy - dyslipidemia - severe acne - thinning of hair on scalp/baldness - fluid retention/edema - high BP - liver damage (esp C17 a-alkylated derivatives) - erythrocytosis
45
Anti-Androgens | 2 Classes
- drugs that block endogenous androgen production | - drugs that block the androgen receptor
46
Therapeutic uses of Anti-Androgens
- prostate cancer - benign prostate hyperplasia (BPH) - male-patter hair loss - hirsutism (females)
47
Prostate Cancer
- most commonly diagnosed malignancy | - initially dependent on androgens for growth and survival
48
Huggins and Hodges Key Findings
- reduction of testosterone levels by surgical orchiectomy (castration) or by injection of estrogens results in regression of prostate cancer - exogenous testosterone injections results in progression of prostate cancer
49
Drugs that Block Endogenous Androgen Production | 3 Classes
1) Inhibitors of Hypothalamic-Pituitary-Testes Signaling 2) Inhibitors of Androgen Biosynthesis 3) Inhibitors of DHT Biosynthesis
50
1) Inhibitors of Hypothalamic-Pituitary-Testes Signaling
- GnRH receptor agonists and antagonists | - estrogenic treatment
51
Ketoconazole
2) Inhibitors of Androgen Biosynthesis First Generator - prevents oxidation - -- sterically occludes anything from getting into active site - potent NONSELECTIVE inhibitor - inhibits 3 out of 4 enzymes involved in testosterone biosynthesis - if female took it would also inhibit estrogen - also inhibits CYP3A4: could interfere with drug metabolism
52
Finesteride
3) Inhibitors of DHT Biosynthesis - 90% DHT reduction in prostate - can act as androgen receptor antagonist
53
Duasteride
3) Inhibitors of DHT Biosynthesis - 99% DHT reduction in the prostate - prevents most hairloss
54
Abiraterone
2) Inhibitors of Androgen Biosynthesis Second Generation - SELECTIVE inhibitor - does NOT inhibit CYP3A4
55
Estradiol
1) Inhibitors of Hypothalamic-Pituitary-Testes Signaling | Estrogenic Treatment
56
DES | Diethylsilbestrol
1) Inhibitors of Hypothalamic-Pituitary-Testes Signaling | Estrogenic Treatment
57
Leuprolide
1) Inhibitors of Hypothalamic-Pituitary-Testes Signaling GnRH receptor agonists D Leu
58
Goserelin
1) Inhibitors of Hypothalamic-Pituitary-Testes Signaling GnRH receptor agonists D Ser
59
Degarelix
1) Inhibitors of Hypothalamic-Pituitary-Testes Signaling | GnRH receptor agonists and antagonists
60
Relugolix
1) Inhibitors of Hypothalamic-Pituitary-Testes Signaling | GnRH receptor agonists and antagonists
61
Inhibitors of Hypothalamic-Pituitary-Testes Signaling
Ranking 1) GnRH Receptor Agonists or Antagonists: chemical castration 2) Orchiectomy: surgical castration 3) Estrogen Treatment - will not bind AR & promote growth of tumor - need v. high levels; nasty side effects
62
Castration Level
<50 ng/dL
63
GnRH Receptor Agonists
- reversible - used clinically for infertility Mechanism of action: - distorts normal pulsatile signaling from hypothalamic GnRH thus desensitizing the pituitary to GnRH - -- overwhelms pituitary and shuts down LH & FSH - painful with metastases
64
GnRH Receptor Antagonists
- reversible - bind GnRH receptor and block gonadotropic secretion Mechanism of Action: competitively and reversibly inhibit GnRH receptors in pituitary gland which blocks FSH, LH, and T release
65
Synthetic GnRH Agonists
>> t1/2 and binding affinity for GnRH receptor than GnRH
66
Advantages of GnRH ANTagonists over GnRH agonists
1) RAPID suppression of FSH, LH, and T 2) no microsurges 3) prolonged suppression of FSH, LH, and T
67
GnRH Antagonist Side Effects
- injection site reaction - hot flashes - fatigue - weight gain - hepatotoxicity
68
Abiraterone vs Ketoconazole at Adrenal Cortex
Ketoconazole: shuts down everything - side effects: blocks cortisol and aldosterone synthesis too - inhibits CYP3A4 actively in liver affecting drug metabolism ``` Abiraterone: inhibit in adrenal cortex - CYP17 - DHEA - Aldosterone ~ Cortisol ```
69
Inhibitors of DHT Biosynthesis
- inhibits 5-a-reductase - target tissue: prostate, scalp Used to treat: - hair loss - benign prostate hyperplasia - prostate cancer
70
``` AR antagonists (aka Anti-androgens) First Generation ```
Flutamide | Bicalutamide
71
``` AR antagonists (aka Anti-androgens) Second Generation ```
Enzalutamide Apalutamide Darolutamide
72
Enzalutamide
nonsteroidal AR antagonist - been around the longest - approved for all stages of prostate cancer - very expensive
73
1st & 2nd Generation AR Antagonists
- work by binding to AR and preventing binding of either - -- DHT - -- Testosterone - Drugs inhibit - -- localization of AR to nucleus - -- ability of receptor to bind to DNA - -- ability to recruit co-activators - -- ability to regulate gene expression
74
1st vs 2nd AR Antagonists | AR Nuclear Import
- 1st: inhibits nuclear import - 2nd: completely blocks AR transport into nucleus - -- if AR can't get into nucleus: ALL STOP
75
1st vs 2nd AR Antagonists | AR Binding Dd
- 1st: 160 - 2nd: 25 - DHT: 5
76
Which 2nd Generation AR Antagonist has highest potency/shortest t1/2?
Darolutamide
77
Which 2nd AR Antagonists can cross brain/blood barrier?
Enzalutamide & Apalutamide | - why such significant CNS side effects
78
Prostate Cancer Treatment Paradigm | Advanced Castration Sensitive Prostate Cancer
Goal: lower serum testosterone to "castrate" levels (<50 ng/dL) Treatment: Androgen Deprivation Therapy #1: Chemical Castration (80%) 2) Surgical Castration (Orchiectomy) 3) Estrogen (last resort; nasty side effects)
79
Castrate Levels
Serum testosterone <50 ng/dL
80
Prostate Cancer Treatment Paradigm | Cancer Progression to Castrate Resistant Prostate Cancer
- increasing PSA levels & metastases - introduce Secondary Hormonal Therapy - Chemotherapy - Immunotherapy
81
Secondary Hormonal Therapies
- 1st & 2nd Gen Anti-Androgen - Androgen Inhibitors - DHT Inhibitors
82
Buserelin
- inhibitor of hypothalamic-pituitary-testes signaling - GnRH Receptor Agonist (increases GnRH released from hypothalamus to pituitary) D-Ser
83
Testosterone Enanthate
Testosterone Ester - esterification of C17 hydroxyl group - Type A modification - Intramuscular injection; every 2-3 weeks
84
Testosterone Cypionate
- testosterone ester - esterification of C17 hydroxyl group - type A modification

Pharmacology Test 2 (8 decks)

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