Uterine Stimulants
62
62
and Relaxants
Leo R. Brancazio and Robert E. Stitzel
DRUG LI ST
GENERIC NAME PAGE GENERIC NAME PAGE
Atosiban 721 Magnesium sulfate 720
Carboprost tromethamine 719 Methylergonovine 718
Dinoprostone 719 Misoprostol 719
Ergonovine 718 Oxytocin 718
Hydroxyprogesterone 721 Nifedipine 721
Indomethacin 721 Terbutaline 720
The physiological processes involved in parturition dissociation; this process may involve the actions of the
(i.e., labor, delivery, and birth) require a complex inter- peptide hormone relaxin, which is produced both in the
play of hormonal action, neuronal activity, and uterine corpus luteum and in the placenta. Relaxin also aids in
smooth muscle contraction. During the first two the dissociation of the connective tissue between the
trimesters of pregnancy, the uterus remains in a rela- pelvic bones, a process that also aids in the facilitation
tively quiescent state, demonstrating little or no con- of birth. At the true onset of labor, coordinated, rhyth-
traction of the myometrium.This inactivity is largely the mic contractions of the uterus begin, and as labor pro-
result of the inhibitory action of high circulating levels gresses, the myometrial contractions increase in inten-
of progesterone on the uterine musculature (see sity and strength. These contractions force the fetus
Chapter 63). During the final trimester, however, uter- against the cervix, further dilating the cervix. Once the
ine smooth muscle becomes increasingly excitable, such cervix has dilated sufficiently, the uterine contractions
that mild muscle contractions are seen (Braxton-Hicks push the fetus through the birth canal.
contractions); these gradually increase in both strength A variety of endocrine hormones play a role in ini-
and frequency, occasionally to the extent that they may tiating the changes in uterine contractility, especially
even be thought to signal the onset of labor, a phenom- during the final trimester. It is probable that the con-
enon termed false labor. Parturition requires in part the centration of receptors responsive to the hypothalamic
integration of processes that involve cervical canal dila- peptide hormone oxytocin (see Chapter 59) increases in
tion and uterine smooth muscle contractions that are the uterine musculature in response to the increasing
strong enough to expel the fetus. levels of estrogen during pregnancy. Although circulat-
Other physiological events must occur at the end of ing blood levels of oxytocin do not change markedly
pregnancy to facilitate birth. The cervix begins to soften throughout pregnancy, it is likely that the augmented
(cervical ripening) as a direct result of connective tissue number of oxytocin receptors in the uterus makes the
716
62 Uterine Stimulants and Relaxants 717
muscle increasingly responsive to plasma oxytocin. prostaglandins. The stretching of the softened cervix in-
There also is speculation that the uterus itself may be duced by increasing fetal pressure results in local recep-
capable of synthesizing oxytocin. If such a synthesis tor stimulation and the initiating of a spinal reflex that
does indeed occur, much higher local concentrations of eventually results in the release of oxytocin from the
the peptide will be found than would be predicted posterior pituitary. This additional oxytocin will further
strictly on the basis of circulating amounts of the hor- promote uterine contractions.
mone. Increases in the number of myometrial -adren- Release of oxytocin at this stage of parturition pro-
ergic and angiotensin receptors also will increase the motes prostaglandin production, particularly of the E
sensitivity of these muscle cells to contractile stimuli. and F series, within the decidua; these prostaglandins
Finally, the possibility of fetal factors playing a role in are powerful myometrial stimulants and thus further
the initiation of parturition should be considered. enhance uterine contractions. The prostaglandin con-
Although, like other smooth muscle, the myo- centration in maternal serum and amniotic fluid in-
metrium is capable of contraction at any time, it is creases with the progression of labor.
generally quiescent throughout most of pregnancy. As Many of the biochemical and molecular events that
pregnancy progresses, spontaneous repetitive action po- are responsible for uterine smooth muscle contraction
tentials can be seen, but muscle tension will develop are the same as those that control other smooth muscle
only once these action potentials become synchronized tissues (Fig. 62.1). Once uterine smooth muscle sensitiv-
electrical discharges. Contractions do become evident, ity has been augmented, actin and myosin must interact
however, several weeks before labor begins. The con- for contraction to occur. This interaction depends on the
tractions of the myometrium progressively increase phosphorylation of the contractile proteins by the en-
during the onset of labor, in part through the action of zyme myosin light chain kinase (MLCK). This enzyme
a positive neuroendocrine feedback system that in- requires Ca and is active only when associated with
volves both synthesis and release of oxytocin and calmodulin. Activation of the entire muscle contraction
Ca2
-receptor,
Calcium channel
other
receptors
-receptor
Ca2 PIP2
ATP
Adenylyl cyclase
calmodulin
IP3 DAG
PDE
Inactive
Ca2 Sarcoplasmic
cAMP
kinase
product
Reticulum
MLCKi MLCKi-P
MLCKa
MLCi MLCa-P
RELAXATION
actin
CONTRACTION
Smooth muscle cell
FI GURE 62. 1
Major biochemical events of smooth (uterine) muscle contraction and relaxation. Calcium (Ca )
binds to calmodulin and initiates a series of biochemical reactions that ultimately lead to
muscle contraction. MLCKi, myosin light chain kinase (inactivated); MLCKa, myosin light chain
kinase (activated); MLCi, inactive myosin light chain; MLCa-P phosphorylated active myosin light
,
chain; MLCKi-P phosphorylated MLCK; PDE, phosphodiesterase; PIP2, phosphatidylinositol; IP3,
,
inositol triphosphate; DAG, diacylglycerol.
718 VII DRUGS AFFECTING THE ENDOCRINE SYSTEM
process involves the receptor binding of estrogen, oxy- ders progress into labor and deliver vaginally. It has also
tocin, 1-adrenergic agonists, and prostaglandins (PGE1 been used following incomplete abortion after 20 weeks
and PGE2). A decrease in the progesterone estrogen ra- of gestation (although use of prostaglandins may be
tio in the myometrium is also an important factor in the preferred in this instance), and it may be used after full-
timing and initiation of labor; this altered ratio may in- term delivery to prevent or control uterine hemorrhage.
volve increased fetal estrogen production, particularly in Oxytocin in high doses is used to induce abortion. An
the latter weeks of pregnancy. Cytokines produced by the oxytocin challenge test (an assessment of the fetal heart
fetus are also thought to be responsible for stimulating rate in response to oxytocin-induced contractions) can
uterine contraction. be performed in certain high-risk (e.g., those with hy-
Uterine relaxation is mediated in part through inhi- pertension, diabetes, preeclampsia) obstetrical patients
bition of MLCK. This inhibition results from the phos- as a measure of fetal well-being.
phorylation of MLCK that follows the stimulation of Inappropriate use of oxytocin can lead to uterine
myometrial -adrenoceptors; relaxation involves the rupture, anaphylactoid and other allergic reactions, and
activity of a cyclic adenosine monophosphate (cAMP) possibly maternal death. Prolonged stimulation of uter-
mediated protein kinase, accumulation of Ca in the ine contractions can result in the following fetal adverse
sarcoplasmic reticulum, and a decrease in cytoplasmic reactions: persistent uteroplacental insufficiency, sinus
Ca . Other circulating substances that favor quies- bradycardia, premature ventricular contractions, other
cence of uterine smooth muscle include progesterone, arrhythmias, and fetal death. Prolonged use of oxytocin
which increases throughout pregnancy, and possibly can lead to water intoxication secondary to the antidi-
prostacyclin. Progesterone s action probably involves uretic hormone like effects of oxytocin. Maternal and
hyperpolarization of the muscle cell membrane, reduc- fetal cardiovascular parameters should be monitored
tion of impulse conduction in muscle cells, and in- during oxytocin administration.
creased calcium binding to the sarcoplasmic reticulum. Oxytocin may be given by intravenous infusion (e.g.,
Drugs and hormones used clinically to enhance uter- labor induction), intramuscular injection (e.g., control
ine contractions are primarily employed either to induce of postpartum bleeding), or as a nasal spray (e.g., to pro-
or to augment contractions during labor and delivery. mote milk ejection).
They have particular value in limiting an extended preg-
nancy, preventing the early rupture of membranes, or
Ergonovine Maleate and
aiding placental insufficiency. Many of these com-
Methylergonovine Maleate
pounds also are useful in limiting postpartum hemor-
Ergonovine (Ergotrate) and methylergonovine (Meth-
rhage. The primary use of uterine relaxants (tocolytic
ergine) are compounds obtained either directly or semi-
agents) is in the prevention of premature labor. These
synthetically from ergot, a fungus that grows on rye and
drugs act either directly to suppress myometrial smooth
other grains. These compounds stimulate uterine
muscle contraction or indirectly to inhibit synthesis or
smooth muscle directly, thereby increasing muscular
release of the prostaglandins and/or other endogenous
tone and enhancing the rate and force of rhythmical
uterine stimulants.
contractions. Ergonovine also stimulates cervical con-
tractions. These drugs are capable of inducing a sus-
tained tetanic contraction, which can shorten the final
UTERINE STIMULANTS
stage of labor and aid in the reduction of postpartum
blood loss. Both are commonly used for the routine ex-
Oxytocin
pulsion of the placenta after delivery and in postpartum
Oxytocin (Pitocin, Syntocinon) is a cyclic 8 amino acid and postabortal atony and hemorrhage.
peptide that is synthesized in the paraventricular nu- Both drugs are partial agonists at -adrenergic re-
cleus of the hypothalamus and transported within hy- ceptors and at some serotonin and dopamine receptors;
pothalamic neurons (in association with neurophysin) they also can inhibit the release of endothelial-derived
to the posterior pituitary for storage. Its mechanism of relaxation factor. They may induce arterial vasocon-
action involves the direct stimulation of oxytocin recep- striction and have minor actions on the central nervous
tors found on the myometrial cells. Oxytocin circulates system. Their -adrenergic blocking activity is relatively
unbound in the plasma, where it has a half-life of ap- weak compared with those of other ergot alkaloids.
proximately 15 minutes. It is primarily inactivated in the Absorption is rapid and largely complete after oral
kidneys and liver. administration, and onset of action occurs in 5 to 15
Oxytocin is generally considered to be the drug of minutes and lasts about 3 hours. Both ergonovine and
choice for inducing labor at term. In combination with methylergonovine can be given intramuscularly or in-
amniotomy, oxytocin is highly successful in inducing travenously, although intravenous administration can
and augmenting labor. When given oxytocin, approxi- be associated with transient but severe hypertension.
mately 80% of patients with documented labor disor- These compounds undergo hepatic metabolism, with
62 Uterine Stimulants and Relaxants 719
elimination primarily by renal excretion of metabolites. Carboprost has been used successfully to control
They also can be found in breast milk, and therefore, postpartum bleeding that was secondary to loss of uter-
neither drug should be administered longer than neces- ine tone and where the myometrium was unresponsive
sary, since prolonged use can lead to ergot poisoning to oxytocin, ergonovine, or methylergonovine. Given in-
(ergotism), including gangrene, in the nursing infant. tramuscularly, carboprost causes an almost immediate
Adverse reactions associated with their administra- and sustained uterine contraction. Clinical experience
tion include hypertension, headache, and possible has shown that the use of this agent has saved many
seizures. Nausea, vomiting, chest pains, difficulties in women from operative interventions (including hys-
breathing, and leg cramps also have been reported. terectomy) to control postpartum hemorrhage.
These alkaloids should not be used in cases of threat- Misoprostol (Cytotec) is a prostaglandin E1 analogue
ened spontaneous abortion or in patients with known that is being evaluated as a cervical ripening agent. It
allergies to the drugs. Contraindications generally in- also is used in the treatment and prevention of peptic
clude angina pectoris, myocardial infarction, pregnancy, ulcer disease (see Chapter 40). Clinical trials show that
and a history of a cerebrovascular accident, transient misoprostol is an effective agent for both cervical ripen-
ischemic attack, or hypertension. ing and labor induction. It appears to be as effective as
dinoprostone and is much less expensive.
While adverse reactions are common following the
Dinoprostone, Carboprost Tromethamine,
use of abortion-inducing doses of the prostaglandins,
and Misoprostol
most are not serious. Gastrointestinal disturbances in-
Dinoprostone (Prostin E2) is a naturally occurring
clude nausea, vomiting, and diarrhea. Transient fever,
prostaglandin E2 found in mammalian tissues, human
retained placental fragments, excessive bleeding, de-
seminal plasma, and menstrual fluid (see Chapter 36).
creased diastolic blood pressure, and headache also
Carboprost tromethamine (Hemabate, Prostin/15M) is
have been noted. These drugs should be used with cau-
a synthetic analogue of the naturally occurring
tion in patients with asthma, cervicitis, vaginitis, hyper-
prostaglandin PGF2 . Both drugs stimulate uterine
tension or hypotension, anemia, jaundice, diabetes, or
smooth muscle contractions and can be used to induce
epilepsy. They should not be used in patients with acute
abortion during gestation weeks 12 to 20. Abortion was
pelvic inflammatory disease, drug hypersensitivity, or an
successful in 96% of the cases in which these agents
active renal, hepatic, or cardiovascular disorder. Since
were used, with complete passage of fetal products oc-
prostaglandins are potentially carcinogenic, if preg-
curring more than 75% of the time without surgical in-
nancy is not effectively terminated following their use,
tervention. The mean time to abortion after drug ad-
another method should be used. The prostaglandins are
ministration was 16 hours. The prostaglandins are more
not generally used concomitantly with oxytocin because
effective stimulants of uterine contraction through the
of the possibility of uterine rupture.
second trimester of pregnancy than is oxytocin. Inhibi-
tion of endogenous prostaglandin synthesis with a non-
steroidal antiinflammatory agent, such as aspirin or
UTERINE RELAXANTS
ibuprofen, can increase the length of gestation, prolong
spontaneous labor, or interrupt premature labor. Many risk factors are associated with the triggering of
Dinoprostone is slowly absorbed from the amniotic premature labor, that is, labor that begins before the
fluid into the systemic circulation. It and its metabolites end of week 37 of gestation. These include maternal
readily cross the placenta and can concentrate in the fe- smoking or drug abuse, lack of prenatal care, multiple
tal liver. Dinoprostone is primarily metabolized in the gestation, placental abnormalities, infection of the fetal
maternal lungs and liver and has a half-life in plasma membranes, cervical incompetence, and previous
and amniotic fluid of less than 1 minute and 3 to 6 hours, preterm birth. Although most episodes are of unknown
respectively. Carboprost also is metabolized in maternal origin, premature labor can develop spontaneously or
lung and liver but somewhat more slowly than dinopro- may follow early rupture of fetal membranes, perhaps
stone. It is primarily eliminated by renal excretion of its as a result of a genetically associated abnormality.
metabolites, with small amounts appearing in the feces. Uterine relaxants (tocolytic drugs) are administered
Because dinoprostone produces cervical ripening where prolonged intrauterine life would greatly benefit
along with stimulation of the uterus, it has been used as the fetus or would permit additional time to allow treat-
an alternative to oxytocin for the induction of labor. ment with drugs such as corticosteroids, which promote
Preparations of dinoprostone can be placed in either the production of fetal lung surfactant. Tocolytics are
the cervix or the posterior fornix. Prepidil is a formula- also used when temporary uterine relaxation is be de-
tion and delivery system of dinoprostone that delivers a sirable (e.g., intrauterine fetal resuscitation). While hy-
dose of 0.5 mg into the cervix, while Cervidil consists of dration, bed rest, and sedation have been used to inhibit
the drug embedded in a plastic matrix. The matrix is de- uterine contractions, tocolytics are more likely to inhibit
signed to deliver a dose of 0.3 mg per hour for 12 hours. labor early in gestation, especially before labor is far
720 VII DRUGS AFFECTING THE ENDOCRINE SYSTEM
advanced.Agents used in this regard include magnesium
ability to stimulate 2-receptors elsewhere in the body
sulfate, alcohol, prostaglandin inhibitors, calcium chan-
(see Chapter 2). The side effects include palpitations,
nel blockers, hydroxyprogesterone, and 2-adrenergic
tremor, nausea, vomiting, nervousness, anxiety, chest
agonists.
pain, shortness of breath, hyperglycemia, hypokalemia,
All tocolytic agents are powerful drugs that must be
and hypotension. Serious complications of drug therapy
used with extreme care, since pulmonary edema, myo-
are pulmonary edema, cardiac insufficiency, arrhyth-
cardial infarction, respiratory arrest, cardiac arrest, and
mias, myocardial ischemia, and maternal death.
death can occur during tocolytic therapy. Newborns of
mothers given tocolytics have had respiratory depres-
Terbutaline
sion, intraventricular hemorrhage, and necrotizing ente-
Terbutaline (Brethine, Bricanyl) is a relatively specific
rocolitis.Absolute contraindications to tocolysis include
acute fetal distress (except during intrauterine resusci- 2-adrenoceptor agonist (see Chapters 10 and 39).
tation), chorioamnionitis, eclampsia or severe pre- Terbutaline can prevent premature labor, especially in
individuals who are more than 20 weeks into gestation
eclampsia, fetal demise (of a singleton pregnancy), fetal
and have no indication of ruptured fetal membranes or
maturity, and maternal hemodynamic instability.
in whom labor is not far advanced. Its effectiveness in
premature labor after 33 weeks of gestation is much less
Ethanol
clear. Terbutaline can decrease the frequency, intensity,
and duration of uterine contractions through its ability
Intravenous use of ethanol, while once widely employed
to directly stimulate 2-adrenoceptors. While it appears
to inhibit premature labor, is now of historical interest
to be especially selective for 2-receptor activation,
only. Ethanol inhibits oxytocin release from the pituitary
terbutaline does have some 1 activity as well.
and thus indirectly decreases myometrial contractility.
Terbutaline should be initially used only in an
Today, 2-adrenomimetics and magnesium sulfate have
appropriate hospital setting where any obstetric com-
replaced ethanol for parenteral tocolysis.
plications can be readily addressed. After initial admin-
istration, it can be used in the outpatient setting.
2-Adrenoceptor Agonists
Concomitant use of 2-adrenergic agonists and corti-
costeroids have additional diabetic effects and may
Although 2-adrenoceptor agonists (see Chapter 10)
rarely lead to pulmonary edema.The combination of 2-
are the most commonly used tocolytic agents in the
adrenergic agonists and magnesium sulfate can cause
United States, they are not completely successful in
cardiac disturbances, while coadministration of terbu-
treating preterm labor. Prophylactic administration of
taline with other sympathomimetics can lead to the po-
these agents to patients at high risk for preterm labor is
tentiation of the actions of the latter drugs.
not always effective. There is, however, clear evidence
Terbutaline is frequently used in the management of
that 2-agonists can arrest preterm labor for at least 48
premature labor, although it has not been marketed for
to 72 hours. The efficacy of these drugs beyond this time
such use. Its effectiveness, side effects, precautions, and
frame is in dispute. Even a short delay in delivery can be
desirable, however, in that at very early preterm gesta- contraindications are similar to those of all 2-adrener-
gic agonists. Terbutaline can cause tachycardia, hy-
tions (24 28 weeks) a 2-day delay in delivery may mean
potension, hyperglycemia, and hypokalemia. It can be
a 10 to 15% increase in probability of survival for the
newborn. Furthermore, such a delay allows for cortico- given orally in addition to subcutaneous or intravenous
administration.
steroid administration to the mother, which has been
shown to decrease the incidence and severity of respi-
ratory distress syndrome of the newborn, decrease the
Magnesium Sulfate
incidence of neonatal intraventricular hemorrhage, and
improve survival in the premature newborn. Tocolysis Magnesium sulfate prevents convulsions in preeclamp-
also allows for the transport of the mother to a tertiary sia and directly uncouples excitation contraction in
center where delivery of the preterm infant often re- myometrial cells through inhibition of cellular action
sults in its improved survival. potentials. Furthermore, magnesium sulfate decreases
These drugs act by binding to 2-adrenoceptors on calcium uptake by competing for its binding sites, acti-
myometrial cell membranes and activating adenylyl cy- vating adenylyl cyclase (thereby reducing intracellular
clase. This in turn increases levels of cAMP in the cell calcium), and stimulating calcium-dependent adenosine
(Fig. 62.1), activating cAMP-dependent protein kinase, triphosphatase (ATPase), which promotes calcium up-
hence decreasing intracellular calcium concentrations take by the sarcoplasmic reticulum. Magnesium is fil-
and reducing the effect of calcium on muscle contraction. tered by the glomerulus, so patients with low glomeru-
2-Adrenergic drugs have many side effects. These lar filtration will have low magnesium clearance.
result both from their residual 1 activity and from their Although the compound does have some cardiac side
62 Uterine Stimulants and Relaxants 721
effects, magnesium sulfate may be preferred over - hibit prostaglandin synthesis. The fetal ductus is more
adrenergic agents in patients with heart disease, dia- sensitive to indomethacin beyond 32 weeks of gesta-
betes, hypertension, or hyperthyroidism. tion. Indomethacin use also can decrease amniotic fluid
There is much debate as to the efficacy of magne- volume and cause oligohydramnios through its ability
sium sulfate. For effective inhibition of uterine activity, to decrease fetal urinary output. Long-term use of ma-
enough must be given to maintain a blood plasma level ternal indomethacin is associated with primary pul-
of at least 5.5 mEq/L. Even at this level, tocolysis may monary hypertension and an increased incidence of in-
be hard to achieve. traventricular hemorrhage in the newborn.
Magnesium toxicity can be life threatening. Patients The calcium channel blocking agent nifedipine
given magnesium lose patellar reflexes at plasma levels (Procardia; see Chapter 19), is one of the more recent
greater than 8 to 10 mEq/L. Respiratory depression can drugs examined as a tocolytic agent. It acts by impairing
occur at levels greater than 10 to 12 mEq/L, with respi- the entry of Ca into myometrial cells via voltage-
ratory paralysis and arrest soon after (e.g., at levels dependent channels and thereby inhibits contractility.
greater than 12 15 mEq/L). Higher levels cause cardiac Although preliminary results appear promising, more
arrest. Toxicity can be avoided by following urine out- studies are needed before its usefulness can be fully as-
put and checking patellar reflexes in patients receiving sessed.
magnesium. Other side effects include sweating, Hydroxyprogesterone has been used prophylacti-
warmth, flushing, dry mouth, nausea, vomiting, dizzi- cally for the 12th to 37th week of pregnancy, particularly
ness, nystagmus, headache, palpitations, pulmonary in women who are in the high-risk category for prema-
edema, maternal tetany, profound muscular paralysis, ture delivery (e.g., those with a history of premature de-
profound hypotension, and neonatal depression. livery or spontaneous abortion). A concern relating to
teratogenic potential has limited its use. Hydroxy-
progesterone as a tocolytic agent requires further eval-
Other Agents
uation before its routine prophylactic administration
Since certain prostaglandins are known to play a role in can be recommended.
stimulating uterine contractions during normal labor, it With the increasing evidence that oxytocin is impor-
is logical that inhibitors of prostaglandin synthesis have tant in human labor, investigators are studying oxytocin
been used to delay preterm labor. Indomethacin antagonists for the treatment of preterm labor.
(Indocin) has been the principal agent for this use. Atosiban is an analogue of oxytocin that is modified at
Indomethacin is given orally or rectally for 24 or 48 positions 1, 2, 4, and 8. It is a competitive inhibitor of
hours to delay premature labor. A potential worry con- oxytocin binding. Early studies have demonstrated that
cerning the use of indomethacin is premature closure of this drug does decrease and stop uterine contractions.
the fetal ductus arteriosus induced by its ability to in- Atosiban is not available for use in the United States.
Study Questi ons
1. Which of the following is the drug of choice for in- 3. Carboprost is used primarily to
ducing labor? (A) Induce labor
(A) Oxytocin (B) Control postpartum bleeding
(B) Misoprostol (C) Antagonize effects of dinoprostone
(C) Methyl ergonovine (D) Inhibit premature labor
(D) Dinoprostone (E) Close the fetal ductus arteriosus
(E) Carboprost tromethamine 4. All of the following are properties of magnesium
2. Adverse reactions to the prostaglandin analogue sulfate that may be related to its ability to relax
carboprost tromethamine include all of the follow- uterine smooth muscle EXCEPT
ing EXCEPT (A) Uncoupling excitation contraction in myome-
(A) Diarrhea trial cells through inhibition of cellular action po-
(B) Fever tentials
(C) Water intoxication (B) Decreasing calcium uptake by competing for
(D) Nausea binding sites
(E) Dyspnea (C) Activating adenylate cyclase
722 VII DRUGS AFFECTING THE ENDOCRINE SYSTEM
(D) Stimulating calcium-dependent ATPase rather than inhibit premature labor. A
(E) Antagonizing prostaglandin action prostaglandin antagonist would be useful to pro-
5. Which of the following is a special concern for the duce closure of the fetal ductus arteriosus.
use of indomethacin for inducing labor (tocolysis)? 4. E. Magnesium has no known effect on
(A) Fetal cardiac arrest prostaglandins. The mechanism of action by which
(B) Fetal gastrointestinal bleeding magnesium sulfate causes smooth muscle contrac-
(C) Fetal hematuria tion is complex and poorly understood. Magnesium
(D) Closure of the fetal ductus arteriosis sulfate uncouples excitation contraction in myome-
(E) Fetal muscular paralysis trial cells through inhibition of cellular action po-
tentials. Furthermore, magnesium sulfate decreases
ANSWERS calcium uptake by competing for binding sites, acti-
1. A. Oxytocin is considered the drug of choice for in- vating adenylate cyclase (reducing intracellular cal-
ducing labor. All other methods of labor induction cium), and stimulating calcium-dependent ATPase,
are compared to oxytocin to establish their efficacy. which promotes calcium uptake by sarcoplasmic
Data demonstrate that oxytocin is highly effective in reticulum.
inducing, establishing, and augmenting labor. 5. D. Indomethacin is a potent prostaglandin synthe-
Oxytocin is not as effective for labor induction when sis inhibitor. Patency of the ductus arteriosis de-
a woman has a cervix that is not favorable for labor. pends on the formation of prostaglandins. Closure
Another agent, such as misoprostol or dinoprostone, of the ductus arteriosis can lead to fetal heart fail-
may be better for women with unfavorable cervices. ure and death. Also, fetal closure can lead to neona-
Both misoprostol and dinoprostone are tal pulmonary hypertension. Neonatologists use in-
prostaglandin analogues. They cause changes in the domethacin for the treatment of neonatal patent
substance of the cervix and uterine contraction. ductus arteriosis, thus often obviating neonatal
Although all agents used for labor induction carry heart surgery. Prostaglandin synthesis inhibitors are
the risk of uterine hyperstimulation, prostaglandins associated with bleeding. Although bleeding is well
are more likely to cause hyperstimulation in women documented in children and adults, the use of in-
with favorable cervices. Furthermore, the current for- domethacin has not been shown to cause hematuria
mulations of prostaglandins do not allow for tight or gastrointestinal bleeding in the fetus. There is
control of blood levels and rapid clearance of med- some evidence, however, that maternal use of in-
ication if hyperstimulation occurs. Methyl ergonovine domethacin may increase the risk of neonatal intra-
is an -agonist that causes direct smooth muscle con- ventricular hemorrhage. Neither muscular paralysis
traction. Carboprost tromethamine is a methylated nor cardiac arrest has been demonstrated in the fe-
analogue of prostaglandin F2 . It is highly potent in tus with maternal use of indomethacin.
causing prolonged uterine contraction. Both medica-
tions are used for the control of uterine bleeding af- SUPPLEMENTAL READING
ter delivery by causing tetanic uterine contractions. Challis JR et al. Prostaglandins and mechanisms of
These medications are contraindicated for labor in- preterm birth. Reproduction 2002;81:633 641.
duction in women with live fetuses. Both medications Cox SM, Sherman M, and Leveno KJ. Randomized in-
can be used in facilitating medical abortions. vestigation of magnesium sulfate for prevention of
2. C. Carboprost tromethamine is methylated at the preterm birth. Am J Obstet Gynecol
15 position. This methylation causes the analogue to 1990;163:797 801.
be 10 to 15 times more potent then the natural Diddy GA 3rd. Postpartum hemorrhage: New manage-
prostaglandin. Smooth muscles that are especially ment options. Clin Obstet Gynecol 2002;45:330 344.
sensitive to prostaglandin F2 are uterine, gastroin- Goldberg AB, Greenberg MB, and Darney PD.
testinal, and bronchial. The uterine sensitivity allows Misoprostol and pregnancy. N Engl J Med
for the therapeutic efficacy. The gastrointestinal sen- 2001;344:38 47.
sitivity causes the diarrhea and nausea. Gyetvai K, Hannah ME, Hodnett ED, and Ohlsson A.
Prostaglandins are involved in the pyretic response, Tocolytics for preterm labor: A systematic review.
and thus a side effect of their use may be fever. Obstet Gynecol 1999;94:869 77.
Oxytocin has antidiuretic hormone qualities, and Rodts-Palenik S and Morrison JC. Tocolysis: An update
with prolonged use may cause water intoxication. for the practitioner. Obstet Gynecol Surv
3. B. Clinical evidence has shown that the use of this 2002:1:127 131.
agent has saved many women from surgery by con- Winkler M and Rath W. A risk-benefit assessment of
trolling postpartum hemorrhage. It can also induce oxytocics in obstetric practice. Drug Safety
labor but is not the drug of choice. It will induce 1999;20:323 345.
62 Uterine Stimulants and Relaxants 723
Case Study Is Labor Induction Justified?
25-year-old woman is 2 weeks beyond her esti- Patients who are pregnant 2 or more weeks beyond
Amated date of delivery. She reports no pain, no their due date are classified as having postterm or
labor contractions, no vaginal bleeding, no leaking postdate pregnancy. These prolonged pregnancies
fluid from her vagina, and no vaginal discharge. She carry the increased risk of fetal death (2 to 6 times
reports that her fetus is moving. On further history, as high as for women who are at 40 weeks gesta-
you find that the patient reports no other com- tion). Women who are postterm have a higher risk
plaints, and her medical, surgical, social, and family of cesarean section, trauma from delivery, prolonged
histories are all negative. The physical examination bleeding after delivery, and prolonged hospitaliza-
you perform produces normal findings. Notably, her tion. Newborns who are born postterm have an in-
uterine fundal size measurement is 40 cm. Her creased risk of being pathologically large (macroso-
pelvic examination reveals that her cervix is 3 cm mia), birth trauma, intolerance to labor, meconium
dilated, 50% effaced, soft in consistency, and midpo- staining, meconium aspiration, and possible subse-
sition in the vagina. The fetal station is presenting at quent hypoxia or anoxia brain injury. With all these
0. You find no evidence of ruptured membranes. concerns, labor induction may be safer than continu-
Uterine monitoring shows no contractions. You and ing the pregnancy.
the patient decide that labor induction would be Oxytocin is the drug of choice for inducing labor.
safe and appropriate. What would be a good course In appropriate patients, it nearly always leads to
of action? safe vaginal delivery. Patients whose cervix is favor-
able for labor are good candidates for oxytocin.
ANSWER: In this case, the decision to induce labor is
Obstetricians traditionally use a scoring system to
appropriate. In caring for patients, physicians must
rate the cervix (Bishop EH. Pelvic Scoring for
decide who are appropriate patients for labor induc-
Elective Induction. Obstet Gynecol 1964;24:
tion. The median length of human pregnancy is 40
266 268). The following table defines the scoring
weeks (when using the woman s menstrual period to
system. Scores of 6 are considered favorable. Our
date the pregnancy). Pregnancy is considered to be
patient has a score of 8.
full-term from the 37 0/7 weeks to 41 6/7 weeks.
Cervical Cervical
Score Dilation (cm) Effacement (%) Station Consistency Position
0 Closed 0 30 3 Firm Posterior
1 1 2 40 50 2 Medium Midposition
2 3 4 60 70 1,0 Soft Anterior
3 5 80 1