class estrogens and antiestrogens
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Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR
DEPT. OF PHARMACOLOGYSSIMS & RC.
ESTROGENS AND ANTIESTROGENS
Natural estrogens
Estradiol (17-β-estradiol)-most potent –secreted by ovaries
Esterone –formed by extra-glandular conversion of androstenedione in peripheral tissues
Estriol is a conjugated metabolite of estrone and estradiol
Biosynthesis and Metabolism of Estradiol and Progesterone
OH
CH3
CH3
CH3CH3
CH3
OH
CH3
CH3
CH3 O
CH3
CH3OH
O
CH3OH
OH
OH
CH3
OH
O
CH3
OH
OH
cholesterol pregnenolone testosterone estradiol
estriol
Conjugation to glucuronides, sulfates, etc….
CH3
O
CH3
CH3
O
OH6a-hydroxymetabolite
CH3
O
CH3
CH3
OH
20a/b-hydroxy metabolite
CH3
OH
CH3
CH3
OH
H
5b-metabolite
estrone
CH3
O
CH3
CH3
O
progesterone
Estrogen preparations
Natural steroidal Estrogens Estradiol
benzoate/cypionate/valarate-IM Esterone and Esteriol
Synthetic steroidal Estrogens Ethinyl Estradiol-oral Mestranol-prodrug Quinesterol and Tibolone
Estrogen preparations
Synthetic nonsteroidal EstrogensDiethyl stilbestrol-oralDienestrol-topicalChlorotrainiseneMethallenesril
Synthetic Estrogens
CH3OH
RO
CHC
CH2
CH2OH CH3
CH3 OH
CH
CHOH
OH
CH3
CH3OMe
MeO
Cl
OMe
Ethinyl-estradiol R = H DiethylstilbestrolMestranol R = CH3
Chlorotrianisene Dienestrol
Distribution of ERα and ERβ
Estrogen Receptors Trigger Gene Activation
Estrogen Targets Tissues
Estrogen Replacement in Menopause
Therapeutic uses
Osteoporosis-conjugated equine estrogens-(0.625mg/day) or estradiol
Vasomotar symptoms-short term conjugated equine estrogen therapy
Cardiovascular disease-estradiol Esterified estrogens-sodium esterone sulfate Urogenital atropy-
Therapeutic uses
Neuroprotective and CNS effects- ins0mnia, fattigue-Tibolone-synthetic norsteroid derivative-estrogenic, progestrogenic, and weak androgenic properties
Dose-2.5mg OD
ERT in primary ovarian failure- Estrogens in cyclical pattern- Ethinyl estradiol-0.01mg- 3 wk for 4 m -0.02mg- 3wk for 1yr
Therapeutic uses
Dysfunctional Uretine Bleeding -Mainly progestins Dysmennorrhoea- mainly NSAIDS, cyclic estrogens
Acne and hirsuitism-cyclic estrogens
CH3Na+-O3PO
CH3 OPO3-Na+
Diethylstibesterol diphosphate - Stilphostrol®
CH3 OPO3Na2
ON
OCl
Cl Estermustine Sodium PhosphateEmcyt® - Pharmacia & Upjohn
Indications: inoperable prostate cancer
Absolute contraindication in women
MOA: Non-steroidal estrogen that binds to cytosolic estrogen receptor with the complex being transported to the nucleus where androgenic activity is antagonized by receptor competition
Primary hepatic metabolism with conjugated renally excreted
Contraindicated in men with cancer of the breast, any estrogen dependent neoplasm, thromboembolitic disorders
Estrogens – Prostate Ca
Estrogen adverse effects
Gynacomastia, Feminisation Prostatic Ca, Migraine, Breast tenderness Ammenorrhoea, Gall stones, hepatic dysfunctionC/I- diabetes, hepatic failure, thromboembolic disorder
Antiestrogens Block estrogen receptors Breast cancer ONLY All estrogen agonist/antagonists Selective Estrogen Receptor Modulators
SERM’s
Selective Estrogen Receptor Modulators (SERM)
Single Receptor Single Response …. May not be valid!
– Tissue specific activity …. Estrogenic for bone
growth; anti-estrogenic for uterine endometrial growth
N
SOH
O
O
OH
OH
NO
NO
Cl
CH3
CH3
Raloxifene Nafoxidine Toremifene
SERMs
Tamoxifen citrate - Nolvadex®
CH3
ON
CH3
CH3
Indications: Adjunctive treatment of breast cancer, prevention of breast cancer in genetically predisposed women and men
MOA: non-steroidal anti-estrogen that competes with estradiol for estrogen receptors in target breast tissues
Hepatic metabolism to conjugates that are renally excreted, hepatic failure possible, thromboembolism especially PE’s, have regular gynecologic exams, use only non-hormonal contraceptive methods
Tamoxifen citrate
Tamoxifen
Receptor deactivation can: Increase bone density Reduce LDL levels – bad lipids Increase HDL levels – good lipids Increase cancer risk▪ Endometrial carcinoma▪ Thromboembolism
Dose = 20 mg p.o. q.d.
Tamoxifen and Cancer
Toremifene citrate - Fareston®
ON
CH3
CH3
Cl
Toremefin citrate
Indications: Breast cancer ( ER + or unknown)
MOA: similar
Extensively metabolized by
CYP3A4, extensive enterohepatic
recirculation
Watch for thromboembolism,
leukopenia, may cause endometrial
hyperplasia, patients with metastatic
bone lesions may suffer hypercalcemia
Raloxifene
Developed for breast cancer for the treatment and prevention of osteoporosis in
postmenopausal women.
Tamoxifen and Raloxifene share antagonist properties in breast and agonist properties in bone,
but differ at the uterus in that tamoxifen acts as a partial agonist, while raloxifene is an antagonist.
In addition to the benefits in bone health, a 75% reduction in the development of new breast cancer in women who did not have a prior history of breast cancer was observed.
Raloxifene is as effective as Tamoxifen in breast cancer Chemoprevention .
Raloxifene
25
Thank you
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