Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR

DEPT. OF PHARMACOLOGYSSIMS & RC.

Progestrogens and Antiprogestrogens

PROGESTERONE DERIVATIVES

Medroxyprogesterone acetateMegestrol acetateDydrogesterone Hydroxy progesterone caproateNewer –Nomegestrol acetate19-nor testosterone derivativesa) OlderNorethindroneLevonorgestrelLynesternol-Ethinylesternol,

Allylesternol

b)Newer compounds Gonanes Desogestrel Norgestimate Gestodene

OH

O

HH

H

19-NORTESTOSTERONE

OHC CH

O

HH

H

NORETHINDRONE

OC CH

O

HH

H

ETHYNODIOL DIACETATE

AC

AC

Progestins

• 19-NOR Steroids :ProgestinsRemoval 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)

OHCH 2 C CH

O

H 3C

HH

H

DESOGESTREL

OCOCH 3CH 2 C CH

HON

H 3C

HH

H

NORGESTIMATE

OHCH 2 C CH

O

H 3C

HH

H

NORGESTREL

H2C

• Gonanes: More potent than estranes and less androgenic activity and are now used in the 3rd generation combination oral contraceptives(Norgestrel, Norgestimate, Desogestrel)

Progestins

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

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 sectrnnegetive feed back Natural progesterone-micronised oral

Progestins

MOA- PR-limited distributn PREtarget genes

P/K- usually inactive orally T1/2- short-5-7 min High first pass metb

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

Progestins -uses

Endometriosis -danazol -aromatase inhibitorsPremenstrual syndromeThreatened abortionEndometrial Ca

Progesterone

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 abortionOften used in conjunction with misoprostol prostoglandin

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Mifepristone/misoprostol regimenSide 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

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Mifepristone/misoprostol regimenEligibility 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

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Mifepristone/misoprostol regimenContraindications 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

Anti-Progesterones

▪ Interactions: ▪ Decreases efficacy of anticoagulants.▪ Inhibits hepatic metabolism by CYP3A4 (eg.anti-

retroviral protease inhibitors, calcium-channel blockers, carbamazepine)