Mifepristone - Pharmacology

Pharmacology

In the presence of progesterone, mifepristone acts as a competitive progesterone receptor antagonist (in the absence of progesterone, mifepristone acts as a partial agonist). Mifepristone is a 19-nor steroid with a bulky p-(dimethylamino)phenyl substituent above the plane of the molecule at the 11β-position responsible for inducing or stabilizing an inactive receptor conformation and a hydrophobic 1-propynyl substituent below the plane of the molecule at the 17α-position that increases its progesterone receptor binding affinity.

In addition to being an antiprogestogen, mifepristone is also an antiglucocorticoid and a weak antiandrogen. Mifepristone's relative binding affinity at the progesterone receptor is more than twice that of progesterone, its relative binding affinity at the glucocorticoid receptor is more than three times that of dexamethasone and more than ten times that of cortisol; its relative binding affinity at the androgen receptor is less than one third that of testosterone. It does not bind to the estrogen receptor or the mineralocorticoid receptor.

Mifepristone as a regular contraceptive at 2 mg daily prevents ovulation (1 mg daily does not). A single preovulatory 10 mg dose of mifepristone delays ovulation by 3 to 4 days and is as effective an emergency contraceptive as a single 1.5 mg dose of the progestin levonorgestrel.

In women, mifepristone at doses greater or equal to 1 mg/kg antagonizes the endometrial and myometrial effects of progesterone. In humans, an antiglucocorticoid effect of mifepristone is manifested at doses greater or equal to 4.5 mg/kg by a compensatory increase in ACTH and cortisol. In animals, a weak antiandrogenic effect is seen with prolonged administration of very high doses of 10 to 100 mg/kg.

In medical abortion regimens, mifepristone blockade of progesterone receptors directly causes endometrial decidual degeneration, cervical softening and dilatation, release of endogenous prostaglandins and an increase in the sensitivity of the myometrium to the contractile effects of prostaglandins. Mifepristone induced decidual breakdown indirectly leads to trophoblast detachment, resulting in decreased syncytiotrophoblast production of hCG, which in turn causes decreased production of progesterone by the corpus luteum (pregnancy is dependent on progesterone production by the corpus luteum through the first 9 weeks of gestation--until placental progesterone production has increased enough to take the place of corpus luteum progesterone production). When followed sequentially by a prostaglandin, mifepristone 200 mg is (100 mg may be, but 50 mg is not) as effective as 600 mg in producing a medical abortion.

Contragestion is a term promoted by Étienne-Émile Baulieu in the context of his advocacy of mifepristone, defining it as inclusive of some hypothesized mechanisms of action of some contraceptives and those of mifepristone to induce abortion. Baulieu's definition of a contragestive included any birth control method that could possibly act after fertilization and before nine weeks gestational age.