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

Postcoital Contraception
Postcoital (or emergency) contraception is indicated for
use in cases of mechanical failure of barrier devices or in
circumstances of unprotected intercourse (Cheng et al.,
2008). Because it is less effective than standard oral contraceptive
regimens, it is not intended as a regular
method of contraception. The mechanisms of action of
the postcoital contraceptives are not fully understood,
but their efficacy clearly cannot be accounted for solely
by the inhibition of ovulation. Other potential mechanisms
of action include effects on gamete function and
survival and on implantation. These agents do not affect
established pregnancies.
PLAN-B, which contains two tablets of the progestin levonorgestrel
(0.75 mg each), is marketed specifically for postcoital contraception
and may be obtained in the U.S. without a prescription by
women ≥18 years of age. Treatment is most effective if the first dose is
taken within 72 hours of intercourse, followed by a second dose
12 hours later; a single dose of 1.5 mg within 72 hours of intercourse
appears to be equally effective. The levonorgestrel regimen has largely
replaced the Yuzpe regimen (previously marketed in the U.S. as PRE-
VEN), which combined an estrogen and a progestin and was associated
with a lower efficacy and a higher incidence of nausea and vomiting.
Other options for postcoital contraception include mifepristone
(MIFEPREX), which is not FDA-approved for this indication but is
highly effective in oral doses ranging from 10-50 mg when taken
within 5 days after unprotected intercourse (Cheng et al., 2008) and
copper intrauterine devices when inserted within 4 days of unprotected
intercourse. Mifepristone also has abortifacient activity when used in
a different treatment regimen (see “Pregnancy Termination”). The
selective progesterone receptor modulator ulipristal (ella, ellaOne),
was recently approved as an emergency contraceptive, effective up to
120 hours after unprotected intercourse; see Chapter 40 for details.
Pregnancy Termination
If contraception is not used or fails, either mifepristone
(RU-486, MIFEPREX) or methotrexate (50 mg/m 2 intramuscularly
or orally) can be used to terminate an
unwanted pregnancy in settings outside surgical centers.
A prostaglandin then is administered to stimulate
uterine contractions and expel the detached conceptus;
in the U.S., prostaglandins used include dinoprostone
(PGE 2
; PROSTIN E2) administered vaginally or the PGE 1
analog misoprostol (CYTOTEC) given orally or vaginally,
both of which are used off label for this purpose.
Prostaglandins used in other countries include the PGE 2
analog sulprostone (NALADOR) and the PGE 1
analog
gemeprost (CERVAGEM).
As approved by the FDA, mifepristone (600 mg) is taken for
pregnancy termination within 49 days after the start of a woman’s last
menstrual period. The synthetic PGE 1
analog misoprostol (400 μg)
is administered orally 48 hours later; vaginal administration is at
least as effective but is not FDA approved. Complete abortion using
this procedure exceeds 90%; when termination of pregnancy fails or
is incomplete, surgical intervention is required. Other published regimens
include lower doses of mifepristone (200 or 400 mg) and different
time intervals between the mifepristone and misoprostol. Finally,
repeated doses of misoprostol alone (e.g., 800 μg vaginally or sublingually
every 3 hours or every 12 hours for three doses) also have been
effective in settings where mifepristone is unavailable. Vaginal bleeding
follows pregnancy termination and typically lasts from 1-2 weeks
but rarely (in 0.1% of patients) is severe enough to require blood transfusion.
A high percentage of women also experience abdominal pain
and uterine cramps, nausea and vomiting, and diarrhea secondary to
the prostaglandin. Myocardial ischemia and infarction have been
reported in association with sulprostone and gemeprost.
Mifepristone is a 17α-alkyl-19-nortestosterone derivative that
acts as a competitive antagonist at the progesterone receptor. The biological
mechanisms involved in the abortifacient actions of mifepristone
are unclear. Its actions are associated with focal hemorrhage
and breakdown of the stromal extracellular matrix that ultimately
leads to the breakdown of the uterine endometrium. Inhibition of
expression of stromal cell “tissue factor,” the primary initiator of
hemostasis, and activation of extracellular matrix proteases are thought
to contribute to these effects. In addition, mifepristone increases the
sensitivity of the uterus to the uterotonic effects of prostaglandins.
Mifepristone is metabolized through a series of reactions initiated by
hepatic CYP3A4, and interactions can occur with other drugs that are
substrates for this enzyme (see Chapters 6 and 40). Women receiving
chronic glucocorticoid therapy should not be given mifepristone
because of its anti-glucocorticoid activity, and the drug should be used
very cautiously in women who are anemic or receiving anticoagulants.
Methotrexate is a potent abortifacient, probably as a result of
the ability of the placenta to concentrate FH 2
Glu n
(dihydrofolate
polyglutamate) and its analogs (see Chapter 61).
Because mifepristone carries a risk of serious, and
sometimes fatal, infections and bleeding following its use
for medical abortion, a black box warning has been added
to the product labeling. Women receiving mifepristone
should be informed of these risks and cautioned to seek
immediate medical attention if symptoms or signs of
these conditions occur. Fulminant septic shock associated
with Clostridium sordellii infections may result and is
attributable to the combined effects of uterine infection
and inhibition of glucocorticoid action by mifepristone
(Cohen et al., 2007). Patients who develop symptoms
and signs of infection, especially a marked leukocytosis
even without fever, should be treated aggressively with
antibiotics effective against anaerobic organisms such as
C. sordellii (e.g., penicillin, ampicillin, a macrolide, clindamycin,
a tetracycline, or metronidazole).
DRUG THERAPY IN GYNECOLOGY
Drugs used in the treatment of nonmalignant gynecological
disorders include those that induce sexual differentiation
in females with impaired biosynthesis of the
1837
CHAPTER 66
CONTRACEPTION AND PHARMACOTHERAPY OF OBSTETRICAL