Pharm 2 Unit 3 Endocrine drugs Flashcards
Leuprolide (Lupron)
long acting GnRH agonist
*inhibit HPG axis (initial surge, then @ 3 wk ultimate inhibition)
Goserelln (Zoladex)
long acting GnRH Agonist
*inhibit HPG axis (initial surge, then @ 3wk ultimate inhibition)
Cetrorelix (cetrolide)
GnRH Antagonist
*inhibit HPG axis from onset (4-5d)
Ganirelix (Antagon)
GnRH Antagonist
*inhibit HPG axis from onset (4-5d)
Purpose of both GnRH agonist and GnRH antagonists
- ART tx (so full control over exogenous GnRH and thus FSH, LH)
- sex steroid dependent cancers
- note: if using GnRH agonist, also give antiandrogen to protect against initial surge
- precocious puberty
- endometriosis
difference bw GnRH agonist and GnRH antagonist
3 wk for suppression of gotro vs 4-5 days
SE of both GnRH agonist and GnRH antagonists
Menopausal sx, testicular atrophy
What happens in the follicular phase (what drives folliculognenesis and what does this result in) and what is another name for this phase
aka proliferative phase:
- FSH drives folliculogenesis –> increase estrogen (FSH eventually inhibited as estrogen levels increase)
- estrogen causes endometrial development
What happens during ovulation
Sustained and high amts of estrogen –> positive feedback on LH –> LH surge = ovulation and lutenization (LH controls progesterone secretion from corpus luteum)
What happens during the luteal phase (what maintains the CL and endometrium) and what is another name for this phase
Luteal phase aka Secretory Phase
- LH maintains the corpus luteum (CL)
- CL secretes progesterone and estrogen, maintain the endometrium
How does menstruation occur
no pregnancy, loss of LH –> CL degenerates and is shed during menstuation–> loss of progesterone and estrogen
how does progesterone influence FSH, LH and GnRH
progesterone neg inhibits FSH, LH and GnRH (overrides estrogen)
FSH in males stimulates
spermatogenesis
FSH in females stimulates
ovarian follicular development
LH in males stimulates
steroid (testosterone) synthesis
LH in females stimulates
ovulation, lueiinization of follicules, steroid (progesterone) production
hMG (human Menopausal Gonadotropin)
Gonadotropin: FSH
*used for infertility, ART (stimulates ovaries and estrogen production 9-12 d), spermatogenesis (takes months)
*made of LH and LH (menotropins)
Urofollitropin (uFSH, Bravelle)
Gonadotropin: purified FSH
*used for infertility, ART (stimulates ovaries and estrogen production), spermatogenesis
hCG (Pregnyl)
Gonadotropin: LH
*Ovulation, luteinization of follicules aka maintains corpus luteum, steroid (progesterone, testosterone up to 1 yr)
In general, what are gonadotropins used for
reversing infertility
in males specifically, how are gonadotropins used
Inducing spermatogenesis
LH: increases testosterone (up to a yr)
FSH: induces spermatogenesis (about 2-3 mth)
In females, how are gonadotropins used
IVF (ART)
FSH: stimulate ovaries and estrogen production (9-12 d)
LH: single dose to induce ovulation
What are the steps for Ovarian hyperstimulation for ART
Begin a baseline GnRH agonist (longer) or GnRH antagonist (shorter)
- Once woman starts Menses
- initiate gonadotropin, FSH 9-12 d
- single dose hCG (LH) to induce ovulation
- retrieve oocyte and fertilize with male sperm
- give progesterone
- implant 3 embryos (embryo transfer)
What are the side effects of Gonadotropins
ovarian enlargment
OVARIAN HYPERSTIMULATION SYNDROME* (life threatening)
*multiple births (20%)
*Gynecomastia (men)
*HA/depression, edema, precocious puberty
What would keep you from prescribing gonadotropins
sex-steroid dependent cancers
What are the major endogenous estrogens and what is their mechanism. Are they orally active
- Estradiol
- Estriol
- Estrone
* not orally active
Mechanism: nuclear receptors (lipophilic/hydrophobic, crosses through CM and binds to receptors in cytoplasm or nucleus, interacts with DNA - protein synthesis)
*enterohepatic circulation
How are estrogens metabolized
- conjugated by liver (excreted in bile)
- enterohepatic circulation, reverses conjugation and increases bioavailability
What is ovarian hyperstimulation syndrome
sudden ovarian enlargement, increased vascular permeability, rapid accumulation of fluid in peritoneal/pleural/pericardial cavities, hypovolemia, fever, shock
Estrogen function on the ovary, uterus, and endocervical gland?
ovary: prepare follicle cells for ovulation w/ FSH
Uterus: inuce ENDOMETRIAL CELL DIVISION AND GROWTH during follicular phase
endocervical gland: mucous
how does estrogen influence breast, puberty and growth
Breasts: growth (pregnancy and puberty)
Puberty: CLOSES EPIPHYSES
Bone: MAINTENANCE
how does estrogen influence blood, and metabolism
Blood: SYN OF CLOTTING PROTEINS,
^ PLATELET ADHESIVENESS
Metabolic: liver - clotting factors, HORMONE BINDING PROTEINS, INCREASES HDL and DECREASES LDL, Na/H20 retention
Are naturally occuring estrogens orally active? if not, what have we done
not orally active we developed forms: 1. synthetic (contraceptives) 2. Conjugated (postmeno HRT) 3. Estradiol (creams/patches)
what are exogenous estrogens used for
contraception, postmeno HRT, stimulating pubertal development, decrease uterine bleeding, suppress ovulation in dysmenorrhea
SE of estrogen include
- endometrial hyperplasia
- Nausea/ breast tender
- **MIGRAINES (vasodilation in brain)
- gallbladder dz
- HTN
- **THROMBOEMBOLISM, accl blood CLOTTING
MIGRAINES, THROMBOEMBOLISM, CLOTTING
primary SE of estrogen to know
migraines, thromboemolism, accelerated blood clotting
Contraindicated to rx estrogen when
- estrogen dep breast cancer**
- uncontrolled HTN
- liver dz
- THOMBOEMBOLIC disorders
- smoking and >35
- preg (excess estrogen increases baby’s risk for cancer)
Tamoxifen (Nolvadex) *class and Use
Antiestrogen:
- SERM (selective estrogen receptor modulator)
- antagonist: breast cancer (palliative, prophylactic)
- agonist: bone (limits bone loss) uterus (may increase risk uterune cancer)
*might decrease HDL :(
tami’s happy bc helps breast cancer and osteoporosis but her HDL is now lower and her uterus has cancer
Instead of tamoxifen, what other antiestrogen SERM is better for reducing likelihood of uterine cancer
Raloxifene (Evista)
*antagonist of uterine cancer
also antagonizes breast cancer and is good for osteoporosis
Raloxifene: decrease uterine/breast cancer, helps osteoporosis
Instead of tamoxifen which may decrease HDL, what other antiestrogen SERM is better for HDL
Toremifene (Fareston)
this SERM is similar to Tamoxifen but INCREASES HDL as well
Clomiphene (Clomid) *class and MOA
Antiestrogen: SERM
*antagonizes neg feedback of estrogen in hypothalamus
*Fertility drug: stimulates LH and FSH, induces Ovulation
*MULTIPLE PREGNANCIES
(clomiphene, clone, mult preg)
main use for Raloxifene (Evista) SERM
decrease uterine/breast cancer, OSTEOPOROSIS
Fulvestrant (faslodex) class and MOA
Antiestrogen FULL estrogen receptor antagonist *use when want to fully antagonize estrogen -not used much Fulvestrant FULL EST antagonist
what is aromatase
final converting enzyme for estrogen production
aromatase inhibitors generally speaking do what
inhibit estrogen synthesis
Anastrozole (Arimidez)
class, use
Aromatase inhibitor
(inhibit estrogen but NOT adrenal steroid synthesis)
DOC: breast cancer tx POSTMENO (CI in premeno)
*2nd line adv breast cancer tx after tamoxifen failure in postmeno women
Letrozole (femara)
class, use
Aromatase Inhibitor:
(inhibits estrogen syn but not adrenal steroid synth)
DOC: breast cancer in postmeno (CI in premeno)
*2nd line breast cancer tx after tamoxifen failure in postmeno women
Exemastane (Aromasin)
Aromatase Inhibitor:
(inhibits estrogen syn but not adrenal steroid synth)
*Exemastane is an irreversible aromatase inhibitor**
DOC: breast cancer Postmeno
*2nd line breast cancer tx after tamoxifen failure
SE of aromatase inhibitors
essentially menopause sx
-Diarrhea, abdominal pain, N/V, hot flashes, joint pain
Contraindication aromatase inhibitors
Premenopausal
CATX
*if tamoxifen fails and women is premeno and has breast cancer.. go in and do ovarian ablation to make woman postmeno so that aromatase inhibitor can be used
What is progesterone produced by and what mechanism does it use
Progesterone:
- produced by CL
- produced by fetal/placenta in pregnant women
MOA: nuclear receptor
what are the biological functions of progesterone
Uterus: converts endometrium to secretory state, maintains pregnancy (suppresses contractility)
- regulates cervical mucus, lobulolveolar development in mammary duct, increases body temp (thermogenic)
is natural progesterone orally active? if not, what have we done medically
not orally active so we made Progestins:
- 19-nortestosterone (progestin& andogenic activity)
- Progesterone derivatives (varying levels of androgen activity)
Use of Progestins
Contraception, prevent endometrial hyperplasia in HRT
SE: HTN, reduced HDL (19-nortestos), depression, drowsiness
in general, antiprogestins are
abortion like drugs
Mifepristone (RU 486)
*class, use, SE
Antiprogestin:
*progesterone/glucocorticoid receptor antagonist
USE - terminate pregnancy (w/ prostglandin)
SE: vomiting, dirrhea, pelvic pain, vaginal bleeding
Danazol (Danocrine)
*class, use, SE
Antiprogestin:
weak progestin and androgen, suppresses ovarian function
USE: ENDOMETRIOSIS***
SE: lots
Contraception options
combination of estrogen and progestin
*DROSPIRENONE/ETHINYL ESTRADIOL
Drospirenone/ethinyl estradiol use, MOA
- Yasmin?
- 9% effective CONTRACEPTION
* INHIBIT OVULATION bc no LH surge
- change cervical mucus to block sperm
- change endometrium to decrease implantation
*progestin w/drawal initiates bleeding
what contraception combo tx is typically used and how is it dosed
estrogen: usu ethinyl estradiol or mestranol
Progestin: levonorgestrel or norethindrone
*used to due high estrogen, but had lots of SE
E:P ratio more important than amt (use minimal)
*vary E:P in 3 stages (in 21 d) to mimic normal hormonal cycle
*estrogen stays same throughout (20-35 ug or for HRT 5-10 ug), increase progestin each stage
Seasonal
class, cycle time
newer combination oral contraceptive
84 d on, 7 d off
Seasonique
class, timing
New combo oral contraceptive
84 d on, 7 d estrogen only (to minimize bleeding)
Lybrel
class, timing
New combo oral contraceptive
ALWAYS on
Adverse SE of new oral contraceptivies
increased breakthrough bleeding (esp 1st yr), hard to tell if you are pregnant or just missing period
Yasmin (Yaz)
class, use, advantages
Combination oral contraceptive
- ethinyl estradioal and drospirenone (mineralcorticoid antagonist)
- advantage: less water retention, FDA approved for PMDD**, very little androgenic properties
- think spironolactone, dospirenone
Natazia
class, use, info
Newest oral combination contraceptive
- uses estradiol valerate to produce E2 in vivo (bioidentical hormone0
- uses dienogest as progestin, weird 4 cycle regimen
Nuvaring
class, info
Vaginal ring contraceptive
*3 wk supply etonogesterel and ethinyl estradiol
Progestin only contraception options include
- Mini pills
- Depo-provera
- Implanon
- Mirena
what are mini-pills
progestin only contraception
- 87-98% effective
- adolescents and breast feeding
what is depo-provera
Progestin only contraception 3 mth depot injection of medroxyprogesterone
what is implanon
Progestin only contraception - single silastic tube implanted in art
>99% effective 3 yr
What is mirena
Progestin only IUC containing levonorgesterel
99.9% effective up to 5 yr
What are Post-Coital contraceptive options
- Plan B
- Preven
- Mifeprisotone (RU 486, Mifeprix)
Plan B
class, use
Post-coital emergency contraceptive option
- levonorgestrel only pill
- take w/in 72 hr (sooner=better)
- available to 18+ w/o rx
Preven class use
similar to Plan B post coital emergency contraceptive option, but also has ethyinyl estradiol
Mifepristone (RU-486)
post-coital emergency contraceptive option
- also used to prevent implantation if admin 1/in 72 hr post intercourse
- antiprogestin normally used to terminate preg
