DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

If administered for one or several days in the mid- to late
luteal phase, mifepristone impairs the development of a secretory
endometrium and produces menses. Progesterone-receptor blockade
at this time is the pharmacological equivalent of progesterone withdrawal,
and bleeding normally ensues within several days and lasts
for 1-2 weeks after anti-progestin treatment.
Mifepristone also binds to glucocorticoid and androgen
receptors and exerts anti-glucocorticoid and anti-androgenic actions.
A predominant effect in humans is blockade of the feedback inhibition
by cortisol of adenocorticotropic hormone secretion from the
pituitary, thus increasing both corticotropin and adrenal steroid levels
in the plasma.
Absorption, Fate, and Excretion. Mifepristone is orally active with
good bioavailability. Peak plasma levels occur within several hours,
and the drug is slowly cleared with a plasma t 1/2
of 20-40 hours. In
plasma, it is bound by α 1
-acid glycoprotein, which contributes to the
drug’s long t 1/2
. Metabolites are primarily the mono- and di-demethylated
products (thought to have pharmacological activity) formed via
CYP3A4-catalyzed reactions and, to a lesser extent, hydroxylated
compounds. The drug undergoes hepatic metabolism and enterohepatic
circulation; metabolic products are found predominantly in the
feces (Jang and Benet, 1997).
Therapeutic Uses and Prospects. Mifepristone (MIFEPREX),
in combination with misoprostol or other prostaglandins,
is available for the termination of early pregnancy.
When mifepristone is used to produce a medical abortion, a
prostaglandin is given 48 hours after the anti-progestin to further
increase myometrial contractions and ensure expulsion of the
detached blastocyst. Intramuscular sulprostone, intravaginal gemeprost,
and oral misoprostol have been used. The success rate with
such regimens is >90% among women with pregnancies of ≤49
days’ duration. The most severe untoward effect is vaginal bleeding,
which most often lasts 8-17 days but is only rarely (0.1% of patients)
severe enough to require blood transfusions. High percentages of
women also have experienced abdominal pain and uterine cramps,
nausea, vomiting, and diarrhea due to the prostaglandin. Women
receiving chronic glucocorticoid therapy should not be given
mifepristone because of its anti-glucocorticoid activity. In fact, due
to its high affinity for the glucocorticoid receptor, high doses of
mifepristone can result in adrenal insufficiency; thus mifepristone is
being considered as a chemical treatment for diseases of excess adrenal
cortisol secretion.
Ulipristal
Chemistry. Ulipristal, a derivative of 19-norprogesterone, functions
as a selective progesterone receptor modulator (SPRM), acting as a
partial agonist at progesterone receptors. It has a dimethylaminophenol
group at the 11β position, as does mifepristone, with
an additional acetoxy group at the C17. Unlike mifepristone,
ulipristal appears to be a relatively weak glucocorticoid antagonist.
Pharmacological Actions. In high doses, ulipristal has
anti-proliferative effects in the uterus; however, its most
relevant actions to date involve its capacity to inhibit
ovulation. Ulipristal's anti-ovulatory actions likely
occur due to progesterone regulation at many levels,
including inhibition of LH release through the hypothalamus
and pituitary, and inhibition of LH-induced
follicular rupture within the ovary.
A 30-mg dose of ulipristral can inhibit ovulation when taken
up to five days after intercourse. Ulipristal can block ovarian rupture
at or even just after the time of the LH surge, confirming that at
least some of its effects are directly in the ovary. Ulipristal may also
block endometrial implantation of the fertilized egg, although
whether this contributes to its effects as an emergency contraceptive
(see below) is not clear.
Therapeutic Uses. Ulipristal acetate [ella, ellaOne] has
recently been licensed in the E.U. and the U.S. as an
emergency contraceptive. Studies comparing ulipristal
to levonorgestrel (progesterone-only emergency contraception,
or POEC) demonstrate that ulipristal is at least
as effective when taken up to 72 hours after unprotected
sexual intercourse. In addition, ulipristal remains effective
up to 120 hours (5 days) after intercourse, making
ulipristal a more versatile emergency contraceptive than
levonorgestrel, which does not work well beyond 72
hours after unprotected intercourse. The most severe
side effect in clinical trials using ulipristal has been a
self-limited headache and some abdominal pain.
HORMONAL CONTRACEPTIVES
The incredible growth of the earth’s human population
stands out as one of the fundamental events of the last
two centuries. The Old Testament dictum “Be fruitful
and multiply” (Genesis 9:1) has been followed too religiously
by readers and nonreaders of the Bible alike. In
1798, Malthus started a great controversy by opposing
the prevailing view of unlimited progress for humankind
by making two postulates and a conclusion. Malthus
postulated “that food is necessary for the existence of
man” and that sexual attraction between female and
male is necessary and likely to persist, since “toward the
extinction of the passion between the sexes, no progress
whatever has hitherto been made,” barring “individual
exceptions.” Malthus concluded that “the power of populations
is infinitely greater than the power of the earth
to produce subsistence for man,” producing a “natural
inequality” that would someday loom “insurmountable
in the way to perfectibility of society.”
Malthus was right: The passion between the sexes
has persisted, and the power of populations is very great
indeed, so much so that our sheer numbers have
increased to the point that they are straining the earth’s
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CHAPTER 40
ESTROGENS AND PROGESTINS