Class progestrogens and antiprogestrogens

PROGESTERONE, ANTIPROGESTINS

1. Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC. Progestrogens and Antiprogestrogens

2. PROGESTERONE DERIVATIVES Medroxyprogesterone acetate Megestrol acetate Dydrogesterone Hydroxy progesterone caproate Newer – Nomegestrol acetate 19-nor testosterone derivatives a) Older Norethindrone Levonorgestrel Lynesternol-Ethinylesternol , Allylesternol b)Newer compounds Gonanes Desogestrel Norgestimate Gestodene

3. OH O H H H 19-NORTESTOSTERONE OH C CH O H H H NORETHINDRONE O C CH O H H H ETHYNODIOL DIACETATE AC AC Progestins 19-NOR Steroids : Progestins Removal of 19-carbon changed major hormonal effect from an androgen to progestin while maintaining oral activity Estranes : have some androgenic activity as well as estrogenic/anti- estrogenic actions. Rapidly absorbed ( Norethindrone )

4. OH CH 2 C CH O H 3 C H H H DESOGESTREL OCOCH 3 CH 2 C CH HON H 3 C H H H NORGESTIMATE OH CH 2 C CH O H 3 C H H H NORGESTREL H 2 C Gonanes : More potent than estranes and less androgenic activity and are now used in the 3rd generation combination oral contraceptives ( Norgestrel , Norgestimate , Desogestrel ) Progestins

5. Progestins Mechanism of Action: Interacts with PR to mimic the stimulatory affects of progesterone Physiological Target: Reproductive Tract Decreases estrogen-driven endometrial proliferation Establishment and maintenance of pregnancy P/K- usually inactive orally T1/2- short-5-7 min High first pass metb

6. Progesterone

7. Progestins Uterus – secretory changes Cervix- viscid scanty secrtn Vagina-leukocyte infiltrtn Breast-cause proliferation of acini CNS-sedative Body temp-increased respiration- stimulation Metabolism-OCPs-prolonged use- glucose tolerance Pituitary-inhibit Gn sectrn  negetive feed back Natural progesterone- micronised oral

8. Progestins -uses Oral contraceptives HRT to limit estrogen’s effects on the endometrium Uterine Bleeding disorders -DUB Premature labor (decrease uterine contractions) Stimulate Appetite in AIDS or cancer patients Endometriosis- danazol (non- progestrogenic , non-estrogenic, but exhibits hypoestrogenic , hyperandrogenic , cause atropy of endometrium) Premenstrual syndrome Threatened abortion Endometrial Carcinoma

9. Progestins –adverse effects Mild-Nausea, mastalgia , breakthrough bleeding, edema, headache Moderate-break through bleeding, weight gain, skin pigmentation, hirsuitism , bacteruria , vaginal infections and amenorrhoea Severe –venous thromboembolism, myocardial infarction, cerebrovascular disease, GI disorders- cholestatic jaundice, depression, cancer

10. Anti- Progesterones Mifepristone (RU 486) PR agonist ,antagonist Used in first trimester to terminate pregnancy (along with prostaglandins to increase uterine contractions) Post-coital contraceptive (prevent implantation) Investigational : induction of labor after fetal death and treatment of endometriosis . Promotes shedding of endometrium , softening of the cervix, and uterine contractions leading to spontaneous abortion Often used in conjunction with misoprostol prostoglandin

11. 12 Mifepristone/misoprostol regimen Side effects Effects of abortion process Cramping- Often described as similar to menstrual cramps Vaginal bleeding- Median bleeding time 9-13 days Often described as similar to a heavy period or spontaneous miscarriage Common side effects Nausea Vomiting Diarrhea Headache Dizziness Fever, chills, hot flashes, warmth

12. 13 Mifepristone / misoprostol regimen Eligibility for use Non-ectopic pregnancy of ≤63 days’ gestation Absence of contraindications Willingness to undergo vacuum aspiration or dilation and curettage (D&C), if indicated

13. 14 Mifepristone / misoprostol regimen Contraindications to use Confirmed or suspected ectopic (extra-uterine) pregnancy Allergy to either mifepristone or misoprostol Presence of an intrauterine device (IUD) Chronic systemic use of corticosteroids Chronic adrenal failure Coagulopathy or current therapy with anticoagulants Inherited porphyria

14. Anti- Progesterones Interactions : Decreases efficacy of anticoagulants. Inhibits hepatic metabolism by CYP3A4 ( eg.anti -retroviral protease inhibitors, calcium-channel blockers, carbamazepine )

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