Antiprogestin

ANTIPROGESTIN

Mifepristone It is a 19norsteroid with potent competitive anti-progestational and significant anti-glucocorticoid as well as antiandrogenic activity.

Given during the follicular phase, its antiprogestin action results in attenuation of midcycle Gn surge from pituitary → slowing of follicular development and delay/failure of ovulation. During the luteal phase, it prevents secretory changes normally brought about by progesterone.

a)     Later in the cycle, it blocks progesterone support to the endometrium, unrestrains PG release from it—this stimulates uterine contractions. Mifepristone also sensitizes the myometrium to PGs and induces menstruation. If implantation has occurred, it blocks decidualization, conceptus is dislodged, HCG production falls, secondary luteolysis occurs–progesterone secretion decreases and cervix is softened.

b)    Mifepristone is a partial agonist and competitive antagonist at both A and B forms of PR. In the absence of progesterone (anovulatory cycles, after menopause) it exerts weak progestational activity—induces predecidual changes. The weak agonistic action is not manifest in the presence of progesterone.

c)     The antiglucocorticoid action of usual doses is also not manifest in normal individuals because blockade of negative feedback at hypothalamicpituitary level elicits ACTH release → plasma cortisol rises and overcomes the direct antiglucocorticoid action. Amelioration of Cushing’s symptoms has been obtained with large doses (see p. 287).

d)    Pharmacokinetics Mifepristone is active orally, but bioavailability is only 25%. It is largely metabolized in liver by CYP 3A4 and excreted in bile; some enterohepatic circulation occurs; t½ 20–36 hr.

e)     Interaction with CYP 3A4 inhibitors (erythromycin, ketoconazole) and inducers (rifampin, anticonvulsants) has been reported.

Uses

1.  Termination of pregnancy  of up to 7 weeks:

600 mg as single oral dose causes complete abortion in 60–85% cases. To improve the success rate, current recommendation is to follow it up 48 hours later by a single 400 mg oral dose of misoprostol. This achieves >90% success rate and is the accepted nonsurgical method of early first trimester abortion. In place of oral misoprostol, a 1 mg gemeprost pessary can be inserted intravaginally. Mifepristone administered within 10 days of a missed period results in an apparent late heavy period (with dislodged blastocyst) in upto 90% cases.

This procedure is generally safe, but prolonged bleeding and failed abortion are the problems in some cases. Anorexia, nausea, tiredness, abdominal discomfort, uterine cramps, loose motions are the other side effects.

2. Cervical Ripening

24–30 hours before attempting surgical abortion or induction of labour, mifepristone 600 mg results in softening of cervix; the procedure is facilitated.

3. Postcoital Contraceptive

Mifepristone 600 mg given within 72 hr of intercourse interferes with implantation and is a highly effective method of emergency contraception. The menstrual cycle, however, is disturbed.

4. Once-a-month Contraceptive

A single 200 mg dose of mifepristone given 2 days after midcycle each month prevents conception on most occasions. Administering mifepristone in late luteal phase to dislodge the embryo (if present) and to ensure menstruation irrespective of conception, has also been tried. These alternative methods of contraception, though attractive, may prolong/disrupt the next menstrual cycle and thus be difficult to use continuously. There is little experience with these methods and they are not popular.

5. Induction of labour

By blocking the relaxant action of progesterone on uterus of late pregnancy, mifepristone can induce labour. It may be tried in cases with intrauterine foetal death and to deliver abnormal foetuses.

6. Cushing’s Syndrome

Mifepristone has palliative effect due to glucocorticoid receptor blocking property. May be used for inoperable cases.

Other uses under evaluation are—in endometriosis, uterine fibroid, certain breast cancers and meningioma.

MIFEGEST, MIFEPRIN 200 mg tab.

TPILL + MISO: Mifepristone 200 mg (3 tabs) + Misoprostol 200 μg (2 tabs); for medical termination of pregnancy of upto 49 days: take 3 tablets of TPILL on day 1, followed on day 3 by 2 tablets of MISO.

Other recently developed antiprogestins are Onapristone (a pure antagonist) and Gestinone (more efficacious in endometriosis).