Sexy drugs

Name / Use / Mechanism / Side-effects / Notes
Gonadotropins overview
GnRH
-Leuprolide
-Gonadorelin / -Pulsatile IV/SC admin à FSH, LH secretion
-Continuous admin à gonatropin suppression / T1/2 = 4 mins
Leuprolide 15x > potetency
Menotropins / Urofollitropin – ONLY FSH activity / Contain naturally-modified FSH/LH activity of low potency
hCG / Ovulation and progesterone secretion / LH activity
Gonadotropin uses
Induction of ovulation / Gonadorelin
In vitro fertilization / Continuous leuprolide to suppress LH/FSH temporarily
Controlled gonadotropin doses Urofollitropin and hCG à follicle development and ovulation
Precocious puberty / Continuous leuprolide
Endometriosis / Continuous leuprolide à reduced estrogen
Prostate cancer / Leuprolide à suppresses testosterone secretion

-Natural Estrogens (estradiol) – quickly inactivated by liver via conjugation, rapidly excreted by kidneys – not orally effective, given IM or transdermal

-Conjugated estrogens – comes from pregnant mare’s urine (GROSS); 60% sulfated estrone; orally effective at high concentrations

-Premarin, Prempro (premarin + progesterone)

-Esters of Estradiol – longer absorption time à longer duration of action

-benzoate, valerate, etc.

-Synthetic, steroidal E’s: ethinyl estradiol – potent agonist, slower metabolization by liver à longer duration of action; orally effective

-Synthetic, non-steroidal E’s: Diethylstilbestrol (DES) – moderately potent agonist, slowly inactivated by liver, orally effective

Therapeutic uses of Estrogens
Dysmenorrhea / Caused by overstimulation of uterus by prostaglandins
-usual Rx = NSAIDs
-for intractable dysmenorrhea: inhibit ovulatory cycle by chronic administration of low dose E’s and P’s
Post-partum breast engorgement (niiiice) / Estrogens at high doses for 8-10 days post-partum to inhibit prolactin secretion
Hirsutism / Excess androgen production by ovary or adrenals
-Rx: High dose estrogen to antagonize androgens
Menopause / Estrogen replacement therapy (ERT), usually in conjunction with progestin
Postmenopausal Osteoporosis / Chronic or cyclic estrogen and progestin immeadiately after menopause or at onset of bone loss
--Withdrawal of therapy may result in accelerated bone loss

Non-steroidal drugs for osteoporosis (OP)

Name / Use / Mechanism / Side-effects / Notes
Bisphosphonates – Alendronate, pyrophosphate, etidronate, pamidronate
Alendronate / -Postmenopausal OP
-Preventing male vertebral fractures / Retards dissolution of hydroxyapatite crystals
-given orally / EXTREMELY selective for bone (50% absorbed by bone, 50% excreted in urine) so few SE’s / Bisphosphonates also for:
-Paget’s disease
-hypercalcemia (malignancy)

Anti-Estrogens – antagonize action of E at the receptor (but not true receptor antagonists) – rather, Selective Estrogen Receptor Modulators

Name / Use / Mechanism / Side-effects / Notes
SERMs – Tamoxifen, clomiphene, raloxiphene
Tamoxifen / -steroid-dependent (ER positive) breast cancer – both pre and post MP / Inhibits E stimulation of Ca growth / Hypercalcemia
Bone pain
Increased risk of endometrial cancer
-Resistance can develop: add aromatase inhibitor (to completely block E productn) / Orally effective
As effective as cytotoxic anti-neoplastics w/o the SE’s
Clomiphene / Anovulatory infertility (due to too much circulating estradiol) / Inhibits E-mediated repression of GnRH release
-rise in plasma LH/FSH by 5th day / -repeated dosing required for more than one ovulation / NOT effective in pt.’s w/ pituitary or ovarian disfunction
80% effective in ovulation
Raloxifene / Agonist for PMOP
Antagonist at uterus / Possibly antag at boob
Name / Use / Mechanism / Side-effects / Notes
Aromatase inhibitors – Anastrozole, Letrozole, Exemestane, Aminoglutethimide – inhibit biosynthesis of estrogen
Anastrozole
Letrozole / -Adjunct to tamoxifen in Tx of steroid-dependent breast Ca. / Competitive non-steroidal inhibtors of aromatase
-Blocks conversion of androgens to estrogens / Exemestane – non-reversible steroidal inhibitor of aromatase
Aminoglutethimide / Blocks conversion of cholesterol to pregnenolone / Reduces all steroid synthesis / Hydrocortisone replacement required

Synthetic Progestins

I. Progesterone derivatives: medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate

II. Derivatives of Nortestosterone: Norethindrone, L-norgestrel, Norgestimate

-can stimulate Δ’s in endometrium but cannot support pregnancy in test animals

-more effective as inhibitors of gonadotropin secretion (majority of OC’s use a nortestost. derivative)

-Importance of Progesterone in preg. – P supports secretory endometrium; inhibits synthesis of prostaglandins, thus inhibiting contractility of uterus; firms cervix (prevents dilation)

Anti-Progestins

1. RU486 (Mifepristone) – abortifacient

-binds P and glucocort. R’s, preventing gene transcription

-antagonizes progesterone’s action on endometrium à decline in hCG production à decline in P production of CL

-often given w/ Prostaglandin E1 to further stimulate uterine contraction, expelling the baby (sorry Brian Burke!!!)

-Other uses: fibroid tumors, Cushing’s disease, post sexy time birth control, inhibition of P and GC dependent tumors

Post-coital birth control

-E+P’s taken at high doses for 5-6 days, 99% effective when begun 72 hours post sexy time (I liiiike!)

-Typically use conjugated E’s, ethinyl estradiol; some say L-norgestrel (“Plan B”) more effective

-Mech: disruption of implantation by altering endometrium (sorry Brian Burke!!!)

-SE’s: strong – N/V, severe cramps

Transdermal Contraception: Ortho Evra

-uses norelgestromin and ethinyl estradiol

-patch applied weekly

-Pros: Bypasses hepatic metabolism, lower peak plasma [drug] than COCs, lower rate SE’s, compliance, similar failure rates to COCs in typical use

-Cons: skin allergies, higher steady state [drug] than COCs

NuvaRing – flexible ring inserted into lady’s box

-Take out after 3 weeks to allow for menses

-Etonorgestrel (active metabolite of norgestrel) and ethinyl estradiol @ lower steady state concentrations than COCs

-pros: lower SE’s, very high compliance, ~equal efficacy to COCs

Norplant II – Intradermal injection of capsules containing norgestrel

-effective for up to 5 years

-serum [steroid] are 1/5 – 1/3 of COCs, fewer side effects, VERY effective

Combined Oral Contraceptives – see lecture (sorry, way too much going on in this part of lecture to try to condense it)

Anti-androgens

-Finasteride – blocks conversion of testosterone to DHT – used for BPH and male-pattern baldness (androgens stimulate prostate growth; additionally, in MPB, follicles very sensitive to androgens – they destroy follicles)