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38 Cards in this Set

  • Front
  • Back
1. MOA of antiestrogens
a. Bind to the estrogen receptor
• Block binding of estradiol to its receptor.
b. Act as antagonists, partial agonists or agonists
1. List the antiestrogens
a. Clomiphene
b. Tamoxifen
c. Toremifene
1. Clomiphene, tamoxifen, and Toremifene belong to the _______________class of drugs.
a. Triphenylethylene
1. Trans vs Cis conformation of the Triphenylethylene class
a. Trans conformations of these drugs have antiestrogenic activity
b. Cis conformations display estrogenic activity.
1. Tamoxifen (NOLVADEX) is marketed using what isomer
a. the pure trans isomer.
1. Clomiphene (CLOMID) is marketed as what isomer
a. a racemic mixture of both cis and trans isomers.
1. Therapudic uses of CLOMIPHENE
a. INFERTILITY
• Used to induce ovulation in women with intact hypothalamic-pituitary-ovarian axis function who are anovulatory
• Given orally 50-100 mg qd for 5 days beginning on day 5 of the menstrual cycle
1. Pharmacological Actions of CLOMIPHENE
a. Slight estrogenic activity, moderate antiestrogenic activity
b. Enlargement of the ovaries
c. Induces ovulation in women with functional hypothalamic-pituitary-ovarian axis
d. Competitively binds to estrogen receptor.
e. Acts primarily at the pituitary level to block inhibitory actions of estrogen on gonadotropin release.
f. May also increase secretion of GnRH.
g. Actions at pituitary and hypothalamus result in increased LH/FSH release and ovulation
1. ROA for CLOMIPHENE
• Oral administration, well absorbed
1. Half life of CLOMIPHENE
a. Long plasma half-life (5-7 days):
• Extensive plasma protein binding
• Enterohepatic recirculation
• Accumulation in fatty tissues.
• Metabolized in the liver and eliminated primarily in the feces
1. ADVERSE EFFECTS of CLOMIPHENE
• Hot flashes, blurred vision
• Ovarian enlargement/ hyperstimulation/ cysts
• Increased incidence of multiple births
1. CONTRAINDICATIONS of CLOMIPHENE
a. Pregnancy: Teratogenic effects in animals
1. THERAPEUTIC USES of Tamoxifen and Toremifene
a. Treatment of breast cancer
• Used alone for palliative treatment of advanced breast cancer with estrogen receptor positive tumors.
• Used as adjuvant therapy with surgery or chemotherapy in certain types of early stage breast cancer (Tamoxifen only)
b. For breast cancer: typically given orally, 10-20 mg daily for up to 5 years.
c. May decrease the incidence of subsequent tumor development in the contralateral breast.
1. PHARMACOLOGICAL ACTIONS of Tamoxifen and Toremifene
a. Exhibits both antiestrogenic and estrogenic activities
b. Inhibits proliferation of human breast cancer cells through estrogen receptor blockade
c. Promotes production of TGFb
d. May increase bone density
1. Active metabolite of Tamoxifen
a. 4-hydroxy tamoxifen
• More potent antiestrogen than the parent compound
1. ROA for Tamoxifen and Toremifene
a. Well absorbed orally
• Peak plasma levels 4-7 hours
1. Half life of Tamoxifen and Toremifene
a. Two elimination phases (Tamoxifen):
• Phase 1 has a half-life of 7-14 hours
• Phase 2 has a half-life of 4-11 days.
b. 3-4 weeks of treatment to achieve steady state plasma levels!
1. ADVERSE EFFECTS of Tamoxifen and Toremifene
a. Nausea, vomiting
b. Hot flashes
c. Vaginal bleeding, menstrual irregularities
d. Pulmonary embolism/stroke
e. Hyperlipidemia (tamoxifen only)
f. May increase the risk of endometrial cancer
1. Drug Interactions of Tamoxifen and Toremifene
a. Warfarin, NSAIDS
b. Agents that inhibit CP-450 enzymes
• Anti-retroviral protease inhibitors
• Clarithromycin, cyclosporine
c. Agents that induce CP450 enzymes
• Rifampin, phenobarbital
1. Which drugs are aromatase inhibitors
• Anastrozole (nonsteroidal, competitive)
• Exemestane (steroidal, irreversible)
1. MOA of aromatase inhibitors
a. Inhibits final step in estrogen synthesis in postmenopausal women
• Conversion of androstenedione and testosterone in peripheral tissues
1. Therapeutic Use of aromatase inhibitors
a. Advanced breast cancer in postmenopausal women
1. ROA of aromatase inhibitors
a. Oral administration
1. Metabolism of aromatase inhibitors
a. Exemestane 90% plasma protein bound
b. Both extensively metabolized in liver
1. Adverse Reactions of aromatase inhibitors
a. GI disturbances
b. Fatigue, headache, hot flashes
c. Edema, weight gain
1. Contraindications of aromatase inhibitors
a. Pregnancy
b. Hepatic disease
1. GnRH ANALOGS include
• Leuprolide
• Ganirelix (GnRH antagonist)
1. MECHANISM OF ACTION of GnRH ANALOGS
a. Continual administration of GnRH or administration of long-acting GnRH agonists prevent ovarian synthesis of estrogens
• Downregulation of GnRH receptors
1. THERAPEUTIC USES of GnRH ANALOGS
a. Long-acting GnRH agonists/antagonist are used in assisted fertilization techniques to suppress preovulatory surges of LH.
b. Prostate cancer
c. Endometriosis
d. Idiopathic precocious puberty
e. Control of Ovulation
• Subcutaneous injections once daily for 10-14 days (3-7 days for Ganirelix)
• Follicular growth is induced by concurrent treatment with human menopausal gonadotropins
• Timing of ovulation is then controlled by an ovulation-inducing dose of HCG.
1. ADVERSE EFFECTS of GnRH ANALOGS
a. Hot flashes, headaches, insomnia
b. Bone loss
c. Alterations in lipid metabolism
d. Anorexia
e. Vaginal bleeding
f. Androgen-like effects
1. CONTRAINDICATIONS of GnRH ANALOGS
a. Pregnancy
b. Lactation
1. Antiprogestins include
a. Mifepristone (RU 486)
• Potent competitive antagonist of both progesterone and glucocorticoid binding
• -----Competitive receptor antagonist for the progesterone receptor in the presence of progesterone
• -----Partial agonist at the receptor when present alone
• -----Competitive antagonist for glucocorticoid receptor
• Not approved for use in US
1. Major clinical use of Mifepristone
a. Medical abortion in the first trimester of pregnancy
b. Single dose of RU 486 is given followed by a prostaglandin 48 hours later
1. Potential Uses of Mifepristone
a. Labor induction (full term infants)
b. Induction of labor after fetal death
c. Endometriosis
d. Breast cancer
1. MECHANISM OF ACTION of Mifepristone when sed for abortions
a. Given in the early stages of pregnancy:
• Causes a decidua breakdown by blockade of the progesterone receptor
• Receptor blockade leads to detachment of the blastocyst
• Sensitizes the myometrium to prostaglandins
b. Impairs development of the secretory endometrium and produces menses
1. ROA for Mifepristone
a. Orally active with good bioavailability.
1. Plasma half-life of Mifepristone
a. 20-24 hours.
b. Plasma protein bound, may contribute to long half-life.
1. ADVERSE EFFECTS of Mifepristone
a. Heavy bleeding
b. Nausea, vomiting
c. Anorexia
d. Abdominal pain
e. Fatigue