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

1848 Although incompletely understood, risk factors for
preterm labor include multifetal gestation, premature
rupture of the membranes, intrauterine infection, and
placental insufficiency. The more premature the baby,
the greater the risk of complications, prompting efforts
to prevent or interrupt preterm labor.
The therapeutic objective in preterm labor is to
delay delivery so that the mother can be transported
to a regional facility specializing in the care of premature
babies and supportive agents can be administered;
such supportive treatments include glucocorticoids to
stimulate fetal lung maturation (see Chapter 42) and
antibiotics (e.g., erythromycin, ampicillin) to diminish
the frequency of neonatal infection with group B
β-hemolytic Streptococcus. Based on concerns over
deleterious effects of antibiotic therapy, it is essential
that antibiotics not be administered indiscriminately
to all women thought to have preterm labor, but rather
be reserved for those with premature rupture of the
membranes and evidence of infection.
SECTION IX
SPECIAL SYSTEMS PHARMACOLOGY
Prevention of Preterm Labor: Progesterone Therapy.
Progesterone levels in some species diminish considerably
in association with labor, whereas administration of
progesterone inhibits the secretion of pro-inflammatory
cytokines and delays cervical ripening. Thus, progesterone
and its derivatives have long been advocated to
diminish the onset of preterm labor in women at increased
risk due to previous preterm delivery. Despite considerable
controversy, recent randomized trials have revived
interest in this approach. One drug used in this setting is
17α-hydroxyprogesterone at a dose of 250 mg administered
weekly by intramuscular injection (Meis et al.,
2003). Vaginal administration of progesterone (200 mg
each night) also was used in one clinical trial with apparent
efficacy (Fonseca et al., 2007). One clinical trial suggested
that progesterone administration in this setting was
associated with an increased incidence of gestational diabetes
(Rebarber et al., 2007), and the role of progesterone
prophylaxis during pregnancy remains to be established.
Tocolytic Therapy for Established Preterm Labor.
Because preterm birth typically is heralded by the
uterine contractions of labor, the inhibition of these
contractions, or tocolysis, has been a focus of therapy
(Simhan and Caritis, 2007). Although tocolytic agents
delay delivery in ~80% of women, they neither prevent
premature births nor improve adverse fetal outcomes
such as respiratory distress syndrome. Thus,
while widely employed, they should be viewed as
temporizing agents, as described in “Prevention of
Preterm Labor: Progesterone Therapy.”
Specific tocolytic agents include β adrenergic
receptor agonists, MgSO 4
, Ca 2+ channel blockers, COX
inhibitors, oxytocin-receptor antagonists, and nitric
oxide donors. The mechanisms of action of these agents
are illustrated in Figure 66–2.
The β adrenergic receptor agonists relax the myometrium by
activating the cyclic AMP-PKA signaling cascade that phosphorylates
and inactivates myosin light-chain kinase, a key enzyme in uterine
contraction. Ritodrine, a selective β 2
agonist, was specifically
developed as a uterine relaxant and remains the only tocolytic drug
to have gained FDA approval; it was voluntarily withdrawn from the
U.S. market. Terbutaline (BRETHINE), which is FDA-approved for
asthma, has been used off label for this purpose and can be administered
orally, subcutaneously, or intravenously. Terbutaline may
delay births, but only during the first 48 hours of treatment, and is
associated with a number of adverse maternal effects, including
tachycardia, hypotension, and pulmonary edema.
Similarly, Ca 2+ channel blockers inhibit the influx of Ca 2+
through depolarization-activated, voltage-sensitive Ca 2+ channels in
the plasma membrane, thereby preventing the activation of myosin
light-chain kinase and the stimulation of uterine contraction.
Nifedipine (PROCARDIA, ADALAT), the Ca 2+ channel blocker used most
commonly for this purpose, can be administered parenterally or
orally. Relative to β 2
adrenergic agonists, nifedipine is more likely
to improve fetal outcomes and less likely to cause maternal side
effects.
Based on the role of prostaglandins in uterine contraction,
cyclooxygenase inhibitors (e.g., indomethacin) have been used to
inhibit preterm labor, and some data suggest that they may reduce the
number of preterm births. Because they also can inhibit platelet function
and induce closure in utero of the ductus arteriosus, these
inhibitors should not be employed in term pregnancies (or in pregnancies
beyond 32 weeks of gestation, when the risk of severe complications
of prematurity is relatively lower). Short courses of treatment
(<72 hours) pose less risk for impaired circulation in the fetus.
Atosiban (TRACTOCILE), a nonapeptide analog of oxytocin,
competitively inhibits the interaction of oxytocin with its membrane
receptor on uterine cells and thereby decreases the frequency of uterine
contractions. Although atosiban increased the number of women
who remained undelivered for 48 hours and is widely used in
Europe, it is not FDA-approved in the U.S.
Nitric oxide is a potent vasodilator and smooth muscle relaxant,
and drugs such as nitroglycerin and other nitrates that increase
its levels are used to treat myocardial ischemia (see Chapter 28).
Both intravenous nitroglycerin and transdermal nitrate preparations
have been evaluated in clinical trials to inhibit preterm labor. The
major adverse effect is maternal hypotension.
Despite numerous clinical trials, the superiority of any one
therapy has not been established, and none of the drugs has been
shown definitively to improve fetal outcome. Thus, despite widespread
and enthusiastic use by some centers, many experts do not
endorse the routine use of tocolytic agents. Recent meta-analyses of
published reports concluded that Ca 2+ channel blockers and atosiban
(not available in the U.S.) provided the best balance of successfully
delayed delivery with lesser risks to the mother and baby
(reviewed by Iams et al., 2008).