Female & Male Pharmacology PDF

AQULOGO Pharmacology Of The Female Reproductive System Hussein Hallak, Ph.D. Al-Quds University Hypothalamic-pituitary-ovarian Axis CG: Chorionic Gonadotropin Hormonal Changes During The Menstrual Cycle Actions Of Progesterone ◼ Promotes endometrial devel...

AQULOGO Pharmacology Of The Female Reproductive System Hussein Hallak, Ph.D. Al-Quds University Hypothalamic-pituitary-ovarian Axis CG: Chorionic Gonadotropin Hormonal Changes During The Menstrual Cycle Actions Of Progesterone ◼ Promotes endometrial development during the luteal phase of the menstrual cycle ◼ Is the main determinant of the onset of menstruation ◼ It stimulates the growth and development of the mammary gland during pregnancy ◼ It decreases the amount of cervical mucus and increases its viscosity Actions Of Progesterone ◼ It increases basal body temperature ◼ It is essential for the maintenance of pregnancy Actions Of ESTRADIOL ◼ It stimulates the growth and development of the mammary gland during puberty ◼ It promotes endometrial proliferation during follicular phase of menstrual cycle ◼ It promotes proliferation of the vaginal epithelium Actions Of ESTRADIOL ◼ It is weakly anabolic ◼ It blocks resorption of bone ◼ It increases the levels of HDL and it decreases the levels of LDL ◼ It is carcinogenic. It increases the incidence of endometrial and breast cancer General Pharmacological Properties Of Estrogens And PROGESTINS ◼ Progesterone and estradiol are rapidly inactivated when given orally ◼ Synthetic analogs are more useful ◼ Many routes of administration are possible  Some Synthetic PROGESTINS Norethisterone, Norethindrone, norethynodrel, ethynodiol diacetate, levonorgestrel were derived from testosterone and have androgenic activity Norgestimate, desogestrel, cyproterone and gestodene: new generation progestin designed to minimize androgenic side effects such as acne, hirsutism, nausea and lipid changes Gestodene & Cyproterone: no pro-androgenic effect instead anti-androgenics activity Some Synthetic Estrogens mestranol is a prodrug of ethinyl estradiol Hormonal Contraception In Females PROGESTINS only ◼ Types (continuous administration) ◼ Oral: Minipill (norethindrone, norgestrel) ◼ Transdermal (norethindrone, norgestrel) ◼ Vaginal rings (norethindrone, norgestrel) ◼ IM injections: Depoprovera (medroxyprogesterone acetate)  Contraception: PROGESTINS Only ◼ Effectiveness: 96-98%. ◼ Mechanism of action. ◼ Prevent ovulation by inhibiting the hypothalamus and the pituitary. ◼ Decrease the amount and increase the viscosity of cervical mucus (i.e., Prevent fertilization). ◼ Changes in “receptiveness” of endometrium. ◼ Adverse effects. ◼ Abnormal menstrual bleeding.  PROGESTINS + Estrogens ◼ Oral (21 days on, 7 days off), usually containing norethindrone and ethynil estradiol ◼ Monophasic preparations ◼ Biphasic preparations ◼ Triphasic preparations ◼ Other forms of delivery such as IM injections, transdermal patches and vaginal rings are also available ◼ Effectiveness 97-98 %, but high compliance rate is needed  PROGESTINS + Estrogens Mechanisms of action. ◼ Prevent ovulation by inhibiting the pituitary and the hypothalamus. ◼ Decrease the amount and increase the viscosity of cervical mucus (i.e., Prevent fertilization). Adverse effects. ◼ Nausea, headaches, acne, hirsutism. ◼ Cardiovascular effects: mostly in smokers 35 years or older. ◼ Metabolic and endocrine effects  PROGESTINS + Estrogens Health benefits ◼ Decreased incidence of ovarian cysts and benign fibrocystic breast disease ◼ Decreased incidence of endometrial and ovarian cancer ◼ Increased HDL and decreased LDL levels  Example ◼ Ethinylestradiol 0.02 mg + Gestodene 0.075 mg GYNERA ◼ Low estrogen for women weighing less than 70 kg ◼ May be useful in Acne treatment ◼ Ethinylestradiol 0.03 mg + Gestodene 0.075 mg ◼ For women weighing more than 70 kg cyproterone and ethinyl estradiol. Contraceptive & androgen-dependent conditions (acne & excessive body hair) Example ◼ 21 active film coated tablets each containing 3 mg of drospirenone and 0.03 mg of ethinyl estradiol and 7 inert film coated tablets ◼ Drospirenone: had anti-mineralocorticoid properties, counteracts the estrogen-stimulated activity of the renin-angiotensin-aldosterone system, and is not androgenic. Yasmin® Example ◼ Microgynon 30: ethinylestradiol and levonorgestrel; monophasic pill, one tablet every day for 21 days then a seven day break ◼ Primolut-nor: Norethisterone; menstrual cycle disorders, primary and secondary amenorrhea, pre-menstrual syndrome, menstrual cycle regulation and endometritis ◼ CERAZETTE: Desogestrel; progestogen- only-pill (POP) or mini-pill; used if women do not tolerate estrogens and if breast feeding Example ◼ Qlaire: ◼ 2 dark yellow tablets each containing 3 mg estradiol valerate ◼ 5 medium red tablets each containing 2 mg estradiol valerate and 2 mg dienogest ◼ 17 light yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest ◼ 2 dark red tablets each containing 1 mg estradiol valerate ◼ Seasonique: Dosage one blue-green tablet containing levonorgestrel and ethinyl estradiol daily for 84 consecutive days, followed by one yellow ethinyl estradiol tablet for 7 days  POSTCOITAL Contraceptives ◼ Types: estrogen alone, estrogen + progestin or progestin alone. High doses are needed ◼ Effectiveness ◼ 90-98% ◼ Mechanism of action ◼ If fertilization has occurred: ◼ Prevent implantation ◼ Promote menstrual bleeding  POSTCOITAL Contraceptives ◼ If fertilization has not occurred: ◼ Decrease the amount and increase the viscosity of cervical mucus ◼ Suppress the hypothalamic-pituitary-gonadal axis ◼ Impair ovum transport Adverse effects ◼ Nausea and vomiting ◼ Headache ◼ Dizziness ◼ Breast tenderness ◼ Abdominal and leg cramps Progesterone Receptor Antagonists ◼ Ulipristal : a selective progesterone receptor modulator used for the purposes of emergency contraception ◼ Mifepristone (RU486) ◼ Used for abortions (together with a prostaglandin agonist) ◼ Postcoital contraception Mifepristone, RU486, Abortion Pill ◼ In the year 2000, the United States Food and Drug Administration (FDA) approved a Mifepristone (Mifeprex®) and Misoprostol regimen for termination of pregnancies up to 49 days from the first day of the woman's last menstrual period (LMP). ◼ This approved regimen consists of oral administration of 600 mg Mifepristone followed in 48 hours by the oral administration of 400 µg Misoprostol, with both drugs taken at the Doctor’s office and a follow-up visit around Day 14 post-dose.  Menopause: ◼ Osteoporosis risk ◼ Changes in menstrual periods, which may include heavier or lighter periods, shorter or longer periods, or infrequent periods then eventually no menstrual periods at all. ◼ Hot flashes, which is the feeling of heat & sweating usually around the head and chest areas (30 seconds to several minutes) ◼ Vaginal dryness ◼ Changes in urination ◼ Trouble focusing or remembering ◼ Mood swings ◼ Hair loss ◼ Weight changes Consider estradiol & drospirenone if symptoms are severe  SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs) AND ESTROGEN RECEPTOR ANTAGONISTS Bone Breast CV Uterus system Estradiol Ag Ag Ag Ag Clomiphene Antag Antag Antag Antag Tamoxifen Ag Antag Ag Ag Raloxifene Ag Antag Ag Antag Some SERMs, Such As raloxifene Are Useful For: ◼ Relief of postmenopausal symptoms ◼ Treatment of osteoporosis ◼ This compound is less likely to cause the side effects associated with estrogen treatment such as: ◼ Vaginal bleeding ◼ Breast swelling and tenderness ◼ Increased risk of endometrial and breast cancer Other SERMs Such As tamoxifen Are Useful For: ◼ Treatment of breast cancer, but there may be increased risk of endometrial cancer and thromoboembolemic disease. ◼ True estrogen receptor antagonists such as clomiphene are useful for: ◼ Induction of ovulation. AROMATASE Inhibitors ◼ Inhibit the conversion of testosterone to estradiol. ◼ Useful in the treatment of breast cancer. ◼ They can be steroidal ◼ Formestane ◼ Exemestane ◼ or non-steroidal ◼ Anastrozole ◼ Letrozole. 4,000 postmenopausal women at high risk of breast cancer with half being given 1mg of anastrozole daily and half given a placebo. In the five years of follow up 40 women in the anastrozole group developed breast cancer compared to 85 women placebo group Lancet Dec. 2013 Tamoxifen: Used to treat estrogen-positive breast cancer Tamoxifen: Is a Pro-drug Tamoxifen is a Pro-Drug Jin Y et al: J Natl Cancer Inst 97:30, 2005 CP1229323-3  CYP2D6 Has Reduced Function Alleles CYP2D6 Tamoxifen Polymorphisms Endoxifen *4 Allele CYP3A4 CYP2D6 Endoxifen Tamoxifen Tamoxifen Endoxifen CYP2D6 Polymorphisms Tamoxifen *10 Allele In Japanese Endoxifen Inactive Prodrug Active Drug  Individuals with CYP2D6*4 Have Lower Levels of Endoxifen 180 P