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

1850 cesarean section in labor induction has not been definitively
established.
SECTION IX
SPECIAL SYSTEMS PHARMACOLOGY
Available preparations include dinoprostone (PGE 2
), which is
FDA approved to facilitate cervical ripening. Dinoprostone is formulated
as a gel for intracervical administration via syringe in a dose
of 0.5 mg (PREPIDIL) or as a vaginal insert (pessary) in a dose of
10 mg (CERVIDIL); the latter is designed to release active PGE 2
at a
rate of 0.3 mg/hr for up to 12 hours and should be removed at the
onset of labor or 12 hours after insertion. No more than three doses
should be used in a 24-hour period. Dinoprostone should not be used
in women with a history of asthma, glaucoma, or myocardial infarction.
The major adverse effect is uterine hyperstimulation, which
may be reversed more rapidly using the vaginal insert by removing
it with the attached tape.
Misoprostol (CYTOTEC), a synthetic derivative of PGE 1
, is
FDA-approved for the prevention and treatment of acid peptic disease
in patients who are receiving nonsteroidal anti-inflammatory
agents (see Chapter 34). Its use in medical abortion is discussed
earlier in “Pregnancy Termination.” It also is used off label either
orally or vaginally to induce cervical ripening; typical doses are 100
μg (orally) or 25 μg (vaginally); an advantage of misoprostol in this
setting is its considerably lower cost. The vaginal dose typically is
repeated every 4-6 hours depending on labor progression. Adverse
effects include uterine hyperstimulation and, rarely, uterine rupture.
Most experts therefore do not use misoprostol for cervical ripening
in women who have had previous cesarean section or other uterine
surgery. Misoprostol should be discontinued for at least 3 hours
before initiating oxytocin therapy.
Oxytocin. The structure and physiology of oxytocin are
discussed in Chapter 38. This section presents therapeutic
uses of oxytocin in obstetrics, which include the
induction of labor, the augmentation of labor that is not
progressing, and the prophylaxis and/or treatment of
postpartum hemorrhage. Although widely used, oxytocin
recently was added to a list of drugs “bearing a
heightened risk of harm” (Clark et al., 2009), and its
role and specific application to most deliveries in the
U.S. remain open to debate. Thus, careful review of the
appropriate indications for oxytocin administration and
attention to the dose and progress of labor during induction
are essential.
Labor Induction. Oxytocin (PITOCIN, SYNTOCINON) is the
drug of choice for labor induction; for this purpose, it is
administered by intravenous infusion of a diluted solution
(typically 10 mIU/mL), preferably via an infusion
pump. Current protocols start with an oxytocin dose of
6 mIU/minute, followed by advancement of dose as
needed (in one protocol, increases of 6 mIU/minute can
be made every 40 minutes if labor is not progressing in
a satisfactory manner). Although there are little definitive
data, 40 mIU/minute is a reasonable maximum
dose, although doses of up to 72 mIU/minute have been
used with apparent safety in some studies. Uterine
hyperstimulation should be avoided; however, if it
occurs, as evidenced by too-frequent contractions (more
than five contractions in a 10-minute interval) or the
development of uterine tetany, the oxytocin infusion
should be discontinued immediately. Because the t 1/2
of
intravenous oxytocin is relatively short (12-15 minutes),
the hyperstimulatory effects of oxytocin will dissipate
fairly rapidly after the infusion is discontinued.
Thereafter, the infusion can be reinitiated at a dose of
half that at which hyperstimulation occurred and
increased cautiously as tolerated.
Because of its structural similarity to vasopressin,
oxytocin at higher doses activates the vasopressin V 2
receptor and has antidiuretic effects. Particularly if
hypotonic fluids (e.g., dextrose in water) are infused too
liberally, water intoxication may result in convulsions,
coma, and even death. Vasodilating actions of oxytocin
also have been noted, particularly at high doses, which
may provoke hypotension and reflex tachycardia. Deep
anesthesia may exaggerate the hypotensive effect of
oxytocin by preventing the reflex tachycardia.
Augmentation of Dysfunctional Labor. Oxytocin also is
used when spontaneous labor is not progressing at an
acceptable rate. To augment hypotonic contractions in
dysfunctional labor, an infusion rate of 10 mIU/minute
typically is sufficient; doses in excess of 40 mIU/minute
rarely are effective when lower concentrations fail. As
with labor induction, potential complications of uterine
overstimulation include trauma of the mother or fetus
due to forced passage through an incompletely dilated
cervix, uterine rupture, and compromised fetal oxygenation
due to decreased uterine perfusion. Oxytocin
usually is effective when there is a prolonged latent
phase of cervical dilation or when, in the absence of
cephalo-pelvic disproportion, there is an arrest of dilation
or descent.
Prevention/Treatment of Postpartum
Hemorrhage
Postpartum hemorrhage is a significant problem in developed
nations and is of even greater importance in developing
countries. After delivery of the fetus or after
therapeutic abortion, a firm, contracted uterus greatly
reduces the incidence and extent of hemorrhage.
Oxytocin (10 IU intramuscularly) often is given immediately
after delivery to help maintain uterine contractions
and tone. Alternatively, oxytocin (20 IU) is diluted
in 1 L of intravenous solution and infused at a rate of
10 mL/minute until the uterus is contracted. The infusion