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Module 6: Repro/Endocrine > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Where are androgens produced in the male body?

A

95% in Leydig cells - in the form of testosterone
(in response to LH released by Anterior Pituitary)

5% in adrenal glands - in the form of Dehydroepiandrosterone (DHEA)
(in response to Adrenocorticotrophic hormone (ACTH) released by Anterior Pituitary)

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2
Q

Where are androgens produced in the female body?

A

Equal parts of androgen are produced in:

  • *Ovaries** (testosterone from corpus luteum in response to LH)
  • *Adrenal Cortex** (DHEA in response to ACTH)

Note: Majority of testosterone made in ovaries is made and swiftly converted to estrogen

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3
Q

What is the mechanism of androgens?

A
  • Androgens are steroids that readily cross through the cell membrane
  • They bidn to cytosolic receptors and translocate to the nucleus
  • Activated androgen receptors bind to specific response elements and activate specific genes
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4
Q

How is testosterone activated?

A

Testosterone –> Dihydrotestosterone (DHT)
Enzyme: 5alpha reductase

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5
Q

What are the types of 5alpha reductase enzymes?

A

Type I: non-genital skin, liver and bone enzyme

Type II: urogenital tissue (prostate) in men and genital skin in men and women

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6
Q

Where does Dihydrotestosterone act?

A

Androgen receptors on:

  • *External Genetalia**: (Type II 5a reductase)
  • Differentiation during gestation
  • Maturity during puberty (growth of penis and scrotum)
  • Acne
  • Adulthood prostatic disease
  • *Hair Follicles**: (Type I 5a reductase)
  • Increased growth during puberty
  • After delay, facial hair and male pattern baldness
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7
Q

Where does testosterone act?

A

Androgen receptors on:

  • *Internal Genetalia**:
  • Wollfian development during gestation (seminiferous tubules, seminal vesicles, epididymus, vas deferens)
  • *Skeletal Muscle:**
  • Increased muscle mass and strength during puberty
  • *Larynx:**
  • Deepens voice during puberty

Erythropoiesis

Bone

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8
Q

How is estradiol created?

A

Testosterone –> Estradiol
Enzyme: CYP19 (aromatase)

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9
Q

Where does estradiol act?

A

It acts on an estrogen receptor on:

  • *Bone**
  • Epiphyseal closer
  • Increased density
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10
Q

What are the developmental effects of androgen?

A
  • *In Utero:**
  • Large increase in Testosterone during 2nd trimester
  • Androgens cause virilization of the urogenital tract

From birth to puberty:
Testosterone levels are very low

  • *Puberty:**
  • Testosterone influences internal reproductive characteristics
  • DHT regulates external male characteristics
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11
Q

What are female side effects of androgen use?

A
  • Growth of facial and body hair
  • male-pattern baldness
  • enlarged larynx (irreversible)
  • Enlarged clitoris (reversible)
  • Increased musculature (esp. shoulder girdle)
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12
Q

What is the downside of oral preparations of androgens?

A

They are rapidly metabolized (during first pass by the liver)

–> therefore, they are modified at the 17alpha position by a methyl or ethinyl group

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13
Q

What are oral forms of active androgens?

A

Methyltestosterone

Danazol

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14
Q

What makes oral androgens less useful?

A
  • Relatively weak. Too weak to induce spermatogenesis
  • May cause liver damage with long-term use
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15
Q

What is Delatestryl?

A

Injectable form of androgen

  • esterified with fatty acids at the hydroxyl group in the 17ß position to prolong absorption
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16
Q

What are transdermal options for androgen delivery?

A
  • Testoderm patch
    applied to scrotum (must shave first)
  • Androderm patch
    applied anywhere on skin
  • some skin irritation results from permation enhancers
  • AndroGel
    gel of testosterone and permeation enhancers are rubbed on shoulders
  • Testosterone buccal system (Striant®)
    adheres to gum; allows slow release of T to buccal mucosa and drains to SVC
  • Topical Testosterone Solution (Axiron®)
    solution applied to axilla
17
Q

What are clinical uses of androgens?

A
  1. Replacement in hypogonadism (lack of LH/FSH)
    or loss of testicles due to trauma
    - Large doses induce speratogenesis in hypo.
  2. Congential Adrenal Hyperplasia - Androgen excess
    21-hydroxylase deficiency –> insufficient synthesis of adrenal steroids and an increase in androgenic intermediates; lack of biofeedback leads to increased release of ACTH
    Males = precocious puberty
    Females = virilization of urogenital tract in utero and masculinization in post-pubescent
  3. Andropause
  4. Catabolic/Wasting states
    HIV-related wasting
  5. Hereditary Angioedema
    due to Testosterone effect on liver
  6. Anemia (men only)
18
Q

What are adverse effects of androgen therapy?

A
  • AndroGel can be transferred to children –> cause precocious puberty
  • Virilicatino in women (hirsutism, acne, clitoral enlargement, deepening voice)
  • Jaundice (reversible) from orally active preps
  • Sexual effects:
    Decreased libido
    Impotence
    Testicular Atrophy
    Gynecomastia
19
Q

What are anti-androgens used to treat?

A
  • Counter excess androgens (mostly in females)
  • Block DHT formation in BPH
  • Block androgen recetors in cancerous tissue (prostate cancer)
20
Q

What is the mechanism of Leuprolide?

A

GnRH analog with agonist properties when used in pulsatile fashion

–> antagonist propertie when used in continous fashion (downregulates GnRH receptor in pituitary, leading to decreased FSH/LH)

21
Q

What is the clinical use and toxicity of Leuprolide?

A

Clinical Use:
Infertility (pulsitile)
Prostate Cancer (continuous and used with flutamide)
Uterine fibroids

Toxicity:
Antiandrogen
nausea
vomiting

22
Q

What is the mechanism of Finasteride?

What is it used to treat?

A

A 5a-reductase inhibitor
(decreased conversion of testosterone to DHT)

Useful in BPH and male pattern baldness (promotes hair growth)

23
Q

What is the mechanism of Flutamide, bicalutamide, and enzalutamide?

What is it used to treat?

A

A nonsteroidal competitive inhibitor of androgens at the testosterone receptor

Used in prostate carcinoma

Risk of hepatotoxicity

24
Q

What is the mechanism of Ketoconazole and Spironolactone?

What is it used to treat?

A

Inhibits steroid synthesis

Used to treat:
Polycystic ovarian syndrome
Prevent Hirsutism
(Note: Also used as a K-sparing diuretic)

Side effects:
Gynecomastia and amenorrhea

(inhibits desmolase)

25
Q

What mechanisms can be used to improve urine flow caused by BPH?

A
  1. a1 adrenergic receptor antagonist:
    Tamsulosin blocks constriction of smooth muscle in lining of urethra by endogenous norepinephrine
    Side effect: floppy iris syndrome
  2. 5a-reductase Inhibitor:
    Finasteride blocks production of DHT, thus reducing teh size of teh prostate due to BPH
    Side effect: erectile dysfunction
26
Q

What is the mechanism, clinical use, and side effects of Sildenafil and vardenafil?

A

Mechanism: Inhibit cGMP phosphodiesterase (PDE5), causing increase in cGMP, smooth muscle relaxation in the c. cavernosum, increased blood flow, and penile erection

Clinical Use: Erectile Dysfunction

Toxicity:
headache
flushing
dyspesia
impaired blue-green color vision
Risk of life-threatening hypotension when taken with nitrates

27
Q

Which erectile dysfunction treatments require injection into the penis?

A
  1. Alprostadil: PGE1 analog –> increased cAMP –> relaxation of smooth muscle
  2. Papaverine: Nonselective PDE inhibitor –> increased cGMP and cAMP –> relaxation of smooth muscle
  3. Phentolamine: alpha adrenergic receptor antagonist –> block a1 adrenergic receptor mediated vasoconstriction and relax intracorporal smooth muscle
28
Q

What androgen deficiencies would not benefit from androgen treatment?

A
  • Pseudohermaphroditism
    XY genotype, XX phenotype
    Lack of 5a reductase
    –> T not converted to DHT
    Treatment: Plastic surgery and estrogen

- Mutations in Androgen Receptor
(aka testicular feminization)
External female phenotype
Treatment: surgery and estrogen

29
Q

How is estrogen made orally active?

A

Adding an ethinyl group at the 17alpha position

  • in order to avoid 1st pass metabolism
30
Q

What are orally active estrogen preparations?

A

Ethinyl estradiol

Mestanol

Equilenin and Equilin

31
Q

What are the therapeutic uses of estrogens?

A
  • Contraception
  • Replacement therapy
    (hypogonadism)
  • Menopause
    (ovaries stop producing estrogen)
32
Q

What are the pros and cons of estrogen therapy after menopause?

A
  • *Pros:**
  • prevent osteoporosis
  • reverses vaginal dryness
  • Increaesd HDL, decreased LDL
  • E alone: increased endometrial carcinoma; E+P: decreased endometrial carcinoma

Cons:
- hot flushes
- increased risk of:
breast cancer
blood clots
Heart disease
strokes

33
Q

What are SERMs? What are they used to treat?

A

Selective Estrogen Receptor Modulators

  • Used to treat postmenopausal osteoporosis
  • Used to treat and prevent the recurrence of breast cancer
  • Perhaps could be used to treat symptoms of menopause
34
Q

What is Tamoxifen?

A

SERM - estrogen antagonist in breast but agonist in endometrium

–> used to decrease risk of breast cancer recurrence

  • E agonist on bone; protects against osteoporosis
  • E agonist in increasing clotting factors –> increased risk of thrombosis
  • E antagonist in hypothalamus –> increased hot flashes
35
Q

What is Raloxifene?

A

SERM:

E antagonist in breast and endometrium

E agonist in bone –> protects from osteoporosis

E agonist in increasing clotting factors –> increased risk of VTE (less than tamoxifene)

E antagonist in hypothalamus –> increased hot flashes

36
Q

What is ospemifene?

A

The only SERM taht is an E agonist on vaginal epithelium

–> used to treat Dyspareunia (pain during intercourse due to dryness)

  • E agonist in bone and endometrium
  • antagonist in breast –> decreased risk of Breast cancer
  • E antagonist in hypothalamus–> increased hot flashes
37
Q

What is Clomiphene Citrate?

A

E antagonist in hypothalamus and pituitary gland

–> used to induce ovulation in premenopause by blocking estrogen negative feedback at hypothal. and ant. pituitary resulitng in increased FSH and LH release

Module 6: Repro/Endocrine (28 decks)

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