Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 17 Drugs Affecting Uterine Motility

MAJOR DRUG CLASSES 

Uterine stimulants

Oxytocin

Prostaglandins

Prostaglandin F

Prostaglandin E2

Ergot alkaloids

Progesterone receptor antagonists

Uterine relaxants

Adrenergic β2 receptor agonists

Nonsteroidal antiinflammatory drugs

Ca++ channel blocking drugs

Progesterones

Therapeutic Overview

Disorders associated with abnormal uterine motility range from relatively minor aggravations to life-threatening emergencies. The principal goals of drug therapy may be to either stimulate or relax the uterine smooth muscle. Because the effects of these drugs are often based on empirical observations rather than on well-designed, controlled studies, their potential benefits must be weighed against possible adverse effects to the woman or her fetus.

Uterine Stimulants

There are three clinical uses for uterine stimulants:

• To induce abortion in the first half of pregnancy

• To induce or augment labor in late gestation

• To prevent or arrest postpartum hemorrhage

Use of drugs to terminate early pregnancy is increasingly replacing surgical procedures and their attendant complications. Development of oxytocic drugs to prevent or treat postpartum hemorrhage represents a major advance that has largely eliminated this important cause of maternal mortality. These drugs have also markedly reduced the dangers associated with the induction of labor.

Although treatment goals are similar for each of these situations, the specific drugs used differ because of subtle differences in uterine environment and physiological status. Uterine contractions are naturally phasic, allowing for resumption of normal utero-fetal-placental hemodynamics between contractions in pregnancy. Thus drugs used to induce or perpetuate labor should mimic the physiological process. However, for postpartum hemorrhage, stimulation of tonic contractions is necessary to avert excessive blood loss. Changes in plasma estrogen and progesterone concentrations through the menstrual cycle or

Abbreviations

COMT

Catechol-O-methyl transferase

COX

Cyclooxygenase

IM

Intramuscular

IV

Intravenous

MLC

Myosin light-chain

MLCK

Myosin light-chain kinase

MLCP

Myosin light-chain phosphatase

NO

Nitric oxide

NSAID

Nonsteroidal antiinflammatory drug

OT

Oxytocin

PG

Prostaglandin

during pregnancy can significantly alter uterine responses. This may occur through alterations in receptor density, coupling to effector mechanisms, or other processes.

In general there are four groups of compounds used clinically to stimulate uterine motility. The most potent and specific is oxytocin (OT), which is commonly used to induce or augment labor in late gestation. It is much less useful in early gestation, however, because the uterus responds poorly to OT. The second group consists of the prostaglandins (PGs) of the E or F families. Because the uterus is always responsive to PGs, they can stimulate contractions at any stage of gestation (see Chapter 15). The PGs are used in combination with mifepristone to induce early abortion. They are also commonly used in late gestation and can ripen the cervix and cause myometrial contraction. The third group is the ergot alkaloids (see Chapter 36). These compounds cause intense tonic myometrial contractions, which are undesirable for stimulating labor but are useful for treating postpartum hemorrhage. They are, however, rapidly being replaced by analogs of OT or PGs. The final group is the progesterone receptor antagonists, of which mifepristone is the most widely used (see Chapter 40). These are particularly useful for termination of early pregnancy, when uterine quiescence is dependent principally on progesterone. They have also recently been used to induce labor in late gestation.

Uterine Relaxants

There are four clinical uses for uterine relaxants:

• To prevent or arrest preterm labor.

• To reverse inadvertent overstimulation.

• To facilitate intrauterine manipulations, such as conversion of a fetus from a breech to a cephalic presentation, surgical procedures, or postpartum replacement of an inverted uterus.

• To relieve painful contractions during menstruation, referred to as dysmenorrhea.

The most important disorder of uterine motility is preterm labor (delivery before 37 weeks of gestation). Although this occurs in only 6% to 10% of births in the United States, it is associated with approximately 75% of deaths and disabilities arising from birthing. In addition to the human loss and emotional costs, health care associated with neonatal intensive care of premature newborns costs billions of dollars each year. Resulting neurodevelopmental problems, or other chronic illnesses, contribute to an even greater loss of human potential.

In contrast to uterine stimulants, the effectiveness of uterine relaxants is controversial. There are several groups of agents used to stop uterine contractions, referred to as tocolytics, during late pregnancy when the fetus may be too premature to thrive outside the uterus. They are most commonly administered between 20 and 35 weeks of gestation. Most tocolytics are nonspecific and also cause relaxation of other smooth muscle beds, including blood vessels. Cardiovascular side effects often limit their clinical usefulness.

Because there is no evidence clearly supporting the superiority of any one tocolytic, their use varies markedly. Magnesium sulfate is used most frequently as a tocolytic agent despite the lack of evidence of effectiveness from well-designed trials. Adrenergic β2 receptor agonists (see Chapter 11), usually ritodrine or terbutaline, have often been prescribed, but their use is declining because of maternal side effects. The nonsteroidal antiinflammatory drugs (NSAIDs) and PG synthesis inhibitors (see Chapter 36) have also been used, although there are concerns about potential adverse effects on the fetus. Similarly, calcium channel blockers (principally nifedipine) are used increasingly, but their efficacy has not been proven. The more recently developed OT antagonist, atosiban, has demonstrated efficacy but may be associated with fetal adverse effects and has not been approved for use as a tocolytic in the United States. Limited research supports the use of nitroglycerin as a nitric oxide (NOdonor to enhance uterine quiescence, and there has been a resurgence of interest in the use of progesterone supplementation in early pregnancy to prevent preterm labor in women at high risk.

Dysmenorrhea is caused by uterine spasms secondary to the release of PGs at the time of endometrial breakdown associated with menstruation. Several NSAIDs relieve the discomfort associated with uterine cramps around the time of menstruation (see Chapter 36).

A summary of the therapeutic considerations for the use of drugs that affect uterine motility is presented in the Therapeutic Overview Box.

Mechanisms of Action

Though similar in many ways to other organs containing smooth muscle, the uterus is unique. Its physiological and

Therapeutic Overview

Uterine Stimulation

Uterine Relaxation

Pregnancy termination

Arrest of preterm labor

Cervical ripening

Facilitation of intrauterine manipulation

Induction of labor

Reversal of pharmacological uterine hyperstimulation

Augmentation of labor

Relief of dysmenorrhea

Postpartum uterine atony

 

pharmacological characteristics change constantly in response to changes in estrogen and progesterone throughout the menstrual cycle and more so during pregnancy. Most unique are the massive anatomical and physiological changes that transform it during pregnancy. Not surprisingly, the factors regulating uterine contractility, and the effectiveness of drug therapy, change remarkably during the menstrual cycle, pregnancy, and particularly around parturition.

At first glance, the uterus appears anatomically simple (Fig. 17-1). There is a body (fundus) and an outflow tract (cervix) through which the fetus and placenta must pass during parturition. The fundus is composed principally of smooth muscle (myometrium) surrounding the uterine cavity, which is lined with a specialized endometrium containing stromal cells and glandular epithelium. During pregnancy the myometrium undergoes massive hypertrophy and hyperplasia, predominantly under the influence of estrogen. The endometrium is also a target for estrogen and progesterone, changing dramatically throughout the menstrual cycle. In pregnancy, stromal cells enlarge, whereas glandular epithelial cells become less prominent. The pregnant endometrium is termed the decidua. As pregnancy progresses, the fetus grows in a gestational sac composed of two types of fetal tissue—the inner amnion, a single layer of cuboidal epithelial cells with a loose connective tissue matrix, and the outer chorion, which is a continuation of the placental trophoblast that extends from the edge of the placenta and surrounds the entire developing conceptus. As the fetus grows, the amniochorial layer becomes fused with the maternal decidua. Near the time of parturition, the decidua is invaded by cells of the immune system. The timing of parturition is a complex and coordinated event involving fetal tissues as well as the maternal decidua, myometrium, and immune system. It appears that there are several redundant pathways for initiation of labor.

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FIGURE 17–1 Anatomy of the nonpregnant and pregnant uterus. Uterine contractility in the nonpregnant uterus depends on circulating hormonal factors, particularly estrogen and progesterone, and to a lesser extent on interactions between the endometrium and myometrium. There is growing evidence that in late pregnancy, paracrine interactions involving the fetal membranes (amnion and chorion), endometrium (decidua), and myometrium may be the major regulators of uterine activity.

It is important not to view labor simply as the onset of myometrial contractions. For successful parturition, the cervix must also undergo dramatic changes, called ripening. In this process collagen and glycosaminoglycans of the cervix are broken down, and the content of H2O and hyaluronic acid increases, probably as a consequence of the action of matrix metalloproteinases. As a result, the cervix is transformed from a rigid structure that keeps the products of conception confined to the uterus into a soft and pliable structure. During ripening the cervix becomes thin (effacement) and then begins to open (dilation). Active labor contractions ensue to continue the process of dilating the cervix and pushing the fetus through the maternal pelvis. These processes must be well coordinated to ensure normal progressive labor.

Parturition can be considered as an evolution from the quiescent, relatively unresponsive uterus of pregnancy to a sensitive contractile organ at the onset of labor, involving two distinct phases: activationand stimulation. During activation the myometrium acquires an increased number of receptors for stimulants, particularly OT, an increased number of ion channels, and an increased number of gap junctions. Gap junctions are important in efficient cell-to-cell signal transmission essential for generation of a strong, coordinated contraction characteristic of active labor. The stimulation phase occurs with the arrival of a stimulant to the now-responsive myometrium. Increasing evidence supports an important role for OT or PGs produced locally within an intrauterine paracrine system.

Regulation of Myometrial Contractility

Although the processes regulating the myometrium and other smooth muscles are similar in some respects (see Chapters 919 and 24), there are unique aspects in the control of the myometrium that determine its responsiveness to drugs. Much of our understanding of this process is derived from animal models, particularly sheep. In this species the signal for parturition is mediated through the fetus. In the days preceding the onset of labor, the fetal adrenal increases the secretion of cortisol; the resulting increase in fetal serum cortisol induces the synthesis of placental 17-hydroxylase, which catalyzes conversion of placental progesterone to estrogen. The consequential large increase in the maternal serum estrogen/progesterone ratio stimulates increased uterine contractility and labor onset. In most species this “progesterone withdrawal” is thought to be a critical step in transformation of the uterus from its quiescent state during pregnancy into an active state during parturition.

In humans, however, there appears to be no major increase in fetal serum cortisol concentration and no significant change in the estrogen/progesterone ratio in maternal serum before labor onset. In addition, administration of cortisol does not induce labor. Thus many investigators have concluded that the mechanisms regulating parturition in humans differ from those in animal models.

Recently, however, it has been shown that fetal membranes and decidua synthesize and metabolize estrogen, progesterone, and OT, suggesting the possible existence of a paracrine system within the pregnant human uterus. In addition, evidence suggests an increase in the estrogen/progesterone ratio in these tissues and an increase in the local synthesis of OT at the onset of human labor. Thus the hormonal mechanisms in humans may be similar to those in animals, albeit occurring in a more localized manner. At term, there is also an influx of immune cells into the decidua, including proinflammatory cytokines (tumor necrosis factor, interleukin-1, and interleukin-6). Interactions between the intrauterine paracrine system and the maternal immune system may be an important regulator of human parturition.

The actions of estrogen and progesterone on the uterus are not well understood. As in other tissues (see Chapter 40), expression of some uterine genes may be increased, whereas others are decreased through interactions with nuclear receptors. The reproductive effects of estrogen appear to use estrogen receptor α, whereas effects of progesterone are mediated primarily through the progesterone receptor B isoform (see Chapter 40). In human pregnancy it has been speculated that a progesterone withdrawal may be caused by increased expression of the progesterone receptor A isoform, which may counteract the effects of progesterone receptor B activation.

The molecular mechanism that underlies myometrial contraction is similar in most respects to that of other smooth muscle (see Chapter 24). The final focal point of the contractile response is the interaction of phosphorylated myosin light chains (MLCs) with actin. Phosphorylation of MLCs is regulated by the balance of activity between MLC kinase (MLCK) and MLC phosphatase (MLCP), which is regulated by Ca++-calmodulin (Fig. 17-2). The most important uterine stimulants (OT and PGF) activate specific G-protein coupled membrane receptors that activate Gq and membrane phospholipase C (see Chapter 1), leading to the release of Ca++ from the sarcoplasmic reticulum and the influx of Ca++ through L-type Ca++ channels. The resultant increase in intracellular Ca++ increases MLCK activity and uterine contraction.

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FIGURE 17–2 Regulation of uterine contractility. The major uterine stimulants are OT and PGF, which have specific G-protein coupled receptors on the cell surface linked to membrane phospholipase C (PPLC), which hydrolyzes membrane phosphatidylinositol-4,5-bisphosphate (PIP2) to produce inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 stimulates the release of Ca++ from the sarcoplasmic reticulum, followed by Ca++ influx through L-type Ca++ channels. The increased intracellular Ca++ binds to and activates calmodulin (CaM), which activates myosin light chain kinase (MLCK). This enzyme phosphorylates myosin light chains (MLC), and this stimulates the myosin-actin interaction that results in contraction. DAG stimulates protein kinase C (PKC), which may contribute to the activation of MLCK. Inhibition of uterine contractions may be attempted by pharmacologically inhibiting any of the steps in this pathway. Uterine relaxation may result from stimulation of β2 receptors, which results in the production of cyclic AMP (cAMP). This activates protein kinase A (PKA), which may phosphorylate and inactivate MLCK. The cAMP also increases Ca++ reuptake into the sarcoplasmic reticulum. Nitric oxide (NO) stimulates soluble guanylyl cyclase, which stimulates protein kinase G (PKG), and this may have an effect similar to that of PKA. Stimulation of these pathways may promote uterine quiescence.

Uterine Stimulants

The most potent and specific uterine stimulant is OT (Fig. 17-3). This nonapeptide hormone is synthesized in the hypothalamus and stored in the posterior pituitary. It has been used for many decades to stimulate uterine contractions, which are indistinguishable from normal labor. However, its role in the physiological regulation of parturition is not yet completely clear. There is a marked increase in the concentration of OT receptors in the uterus at the time of parturition, suggesting that OT plays an important functional role in mediating this event.

image

FIGURE 17–3 Structure of oxytocin.

The other major uterine stimulants are the PGs, principally PGE2 and PGF (see Chapter 15). The rate of intrauterine synthesis of PGs increases several-fold at parturition; however, the role of this process in normal labor is controversial. Because PGs are known to stimulate uterine activity at any time during gestation, they are effective abortifacients (see Chapter 15). PGE2 also appears to be important in stimulating processes that result in ripening of the cervix.

The mechanism of action of the ergot alkaloids in the uterus is unclear. Most evidence suggests their contractile effects are mediated by interaction with α1 adrenergic receptors (see Chapter 11), but they also bind to serotonin and dopamine receptors. The use of these drugs is rapidly being replaced by OT or PG agonists.

The finding that administration of progesterone receptor antagonists during pregnancy caused cervical ripening and uterine contractions supports a role for progesterone in the maintenance of uterine quiescence. The molecular mechanisms are poorly understood but may involve remodeling of the cervical extracellular matrix. For example, mifepristone decreases cervical tensile strength through a mechanism that involves up regulation of matrix metalloproteinase type 2.

Uterine Relaxants

As in many other smooth muscles, β2 receptor stimulation causes relaxation (see Chapters 11Chapter 16 and Chapter 24), an effect mediated by activation of adenylyl cyclase and inhibition of MLCK activity (see Fig. 17-2). NSAIDs inhibit PG synthesis by inhibiting cyclooxygenase (COX, see Chapter 15 and Chapter 36). Both COX-1 and COX-2 catalyze PG generation in the pregnant uterus, but the increased PG generation noted at parturition appears to result predominantly from increased COX-2. However, selective inhibition of COX-2 is associated with an increased incidence of unwanted side effects (see Chapter 36). Although magnesium sulfate is a commonly used tocolytic drug in North America, its mechanism of action is unclear but may be related to its actions as a divalent cation to compete with Ca++ in myometrial cells. In addition, recent studies indicate that magnesium sulfate may act as an antiinflammatory agent during preterm labor.

Calcium channel blockers (nifedipine and nicardipine) inhibit uterine contractions because of their ability to suppress intracellular Ca++ levels by limiting Ca++ influx through L-type Ca++ channels in smooth muscle cells, promoting Ca++ efflux from cells and inhibiting the release of Ca++ from sarcoplasmic reticulum (see Chapters 20 and 22). A meta-analysis of nine randomized trials (679 patients) specifically comparing treatment of premature labor with nifedipine versus β2 receptor agonists (terbutaline or ritodrine) demonstrated that nifedipine was more effective than the β2 receptor agonists in delaying delivery for at least 48 hours. Although early animal studies showed that Ca++ channel blockers produce metabolic acidosis in the fetus, they are increasingly used as tocolytic agents.

Pharmacokinetics

Regardless of whether these compounds are given to stimulate or relax the pregnant uterus, most will cross the placenta and may have adverse effects on the fetus. Many agents affect fetal cardiovascular function, which renders fetal heart rate-based monitoring methods invalid, subsequently requiring special vigilance to avoid detrimental outcomes for either the mother or the fetus. Pharmacokinetic parameters of selected drugs are summarized in Table 17-1.

TABLE 17–1 Selected Pharmacokinetic Parameters

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During pregnancy, there are five important maternal adaptations that can influence drug pharmacokinetics:

• Absorption may be increased as a result of increased blood flow or more efficient mucosal absorption.

• The initial volume of distribution may be increased as a result of the 40% to 50% increase in maternal blood volume.

• There is increased blood flow to maternal liver and kidney that may increase drug metabolism, excretion, or both.

• There is an increased concentration of plasma-binding proteins that may decrease metabolism and excretion.

• The placenta may be a site of drug metabolism or maternal drug disposal secondary to fetal transfer, which can be later transferred back into the maternal compartment.

Uterine Stimulants

OT is a peptide and must be administered parenterally. It is given IV by infusion pump to induce or augment labor and has a short (minutes) t1/2. In concentrations used to induce or augment labor, OT produces clonic uterine activity. The infusion rate is increased at intervals until the frequency and amplitude of contractions are satisfactory. For prophylaxis or treatment of postpartum hemorrhage, OT can be given IM or IV in large doses, which result in tonic, sustained contractions.

Ergot alkaloids produce a tonic contraction ideal for controlling postpartum hemorrhage resulting from uterine atony. These compounds have a longer duration of action than OT, but their use is decreasing because of side effects.

For the termination of pregnancy in the second trimester, PGF is administered into the amniotic fluid. Mean time to abortion is 13 hours, which suggests that the mechanism may be indirect. In other protocols, PGF or PGE2 is administered via vaginal suppositories or can be infused through a catheter placed in the cervix.

PG preparations are used extensively in late gestation to ripen the cervix before induction of labor or to induce labor. PGE2 is usually administered as a gel into the cervix or vagina or as a solid vaginal suppository with little systemic absorption and few side effects. For the gel preparations, it may be difficult to remove the drug from the vagina in cases of hyperstimulation, and gels should be used only when cervical ripening is required. Once the cervix is ripe, it is common to switch to IV OT. However, OT should not be given for at least 6 hours after the last administration of a PG to avert hyperstimulation. Misoprostol has been given orally to induce labor at term. It appears to be effective and safe. Methylated PGs are more resistant to metabolism, more efficacious, and have longer actions. There is increasing evidence of efficacy and effectiveness for induction of labor at any stage of pregnancy.

The antiprogestin mifepristone is increasingly used for early (<8 weeks gestation) termination of pregnancy. It is most effective when used in concert with a PG analog (usually misoprostol). This combination treatment actually increases the efficiency of induction of contractions compared with PG analogs used alone.

Uterine Relaxants

Ritodrine was the first β2 receptor agonist approved for use as a tocolytic agent in late pregnancy. To arrest active labor, it is administered by an IV infusion pump, with the dose carefully titrated to uterine activity. The infusion must be increased slowly and maternal and fetal cardiovascular and metabolic parameters monitored carefully to avert the predictable side effects of these agents. Terbutaline and other β2 receptor agonists have also been used as tocolytics (see Chapter 11). These drugs often lose their effectiveness as a result of tachyphylaxis. Although oral forms of these agents have been used for prophylaxis, the best evidence indicates they are not effective when administered by this route.

Results of early studies indicated that birth could be delayed for 48 hours through use of the NSAIDs. However, the prototype drug indomethacin caused constriction of the fetal ductus arteriosus (seeChapter 15) because PGE2 is necessary to maintain ductal patency, thus reducing their use. However, there has been a recent resurgence in the use of indomethacin by rectal suppository, often followed by oral maintenance therapy. Recent trials have evaluated intravenous infusions of selective COX-2 inhibitors such as celecoxib. Celecoxib maintains uterine quiescence without the constriction of the fetal ductus arteriosus.

Magnesium sulfate is administered IV and is excreted by the kidney, so its dose must be closely monitored in patients with impaired renal function. High infusion rates are required to achieve effective tocolysis, and significant side effects are common at these rates.

Relationship of Mechanisms of Action to Clinical Response

Induction/Augmentation of Labor

Induction of labor must include ripening of the cervix, if this has not occurred naturally. Oxytocic drugs stimulate contractions but often must be administered for a prolonged time if the cervix is unripe. Preinduction use of PGE2 preparations, especially as vaginal suppositories, will facilitate labor in such instances. Whereas the uterine contractile effects of OT are immediate, it takes several hours for cervical ripening by PGE2Mechanical devices are also used to ripen the cervix, and their effects may be partially mediated by induction of PGE2 synthesis. The use of progesterone antagonists for cervical ripening has been reported but is not commonly used.

In the presence of a ripe cervix, infusion of OT IV is the best way to stimulate or augment contractions. In general, induction of contractions requires more OT than augmentation. Induction at term usually requires less OT than preterm, which is a result of increased OT receptors at term. Care must be taken to avoid overstimulation, and two types of stimulants should generally not be used together. At least 4 to 6 hours should elapse from the most recent use of PGE2 before beginning OT infusion.

Early Pregnancy Termination

There are few OT receptors in the myometrium in early pregnancy, and OT is of little use in stimulating activity at this time. The antiprogestin mifepristone can disrupt embryonic and placental development. However, given alone, there is a high rate of incomplete abortion that may still require surgical completion. When given in combination with a PG analog, mifepristone is very successful in inducing abortion in pregnancies at less than 8 weeks’ gestation. Surgical abortion is usually preferred beyond 8 weeks’ gestation. However, administration of PGs locally is also efficacious, particularly after 18 weeks of gestation.

Treatment of Preterm Labor

Our lack of understanding of the mechanisms involved in initiation of parturition has hindered development of effective tocolytic drugs. The drugs currently used often result in increased myometrial relaxation at the cost of systemic side effects, because none of them has specific effects on uterine smooth muscle. Vascular relaxation, subsequent decreases in blood pressure, and tachycardia are the most common side effects, as discussed in the following text. Along with the development of tachyphylaxis, these effects limit the duration of successful treatment with many currently available drugs.

Treatment of Dysmenorrhea

Painful menstruation is very expensive in terms of productivity and quality of life. The most common form of dysmenorrhea is primary dysmenorrhea, consisting of uterine spasm without underlying pathology. The spasm results from the release of PGs from degenerating endometrial cells. NSAIDs have been extremely effective in preventing or ameliorating this condition (see Chapter 15 and Chapter 36). They are generally administered a few hours before expected menstruation or at the first sign of bleeding and are taken 1 to 2 days thereafter. An alternative approach is to use oral contraceptives to inhibit ovulation, reducing the synthesis of PGs in the endometrium; this results in less uterine spasm during menstruation. Because primary dysmenorrhea is caused by excessive uterine muscle contractions, agents that block uterine contractility (i.e., tocolytics) may be effective in its treatment. NO, nitroglycerin, and Ca++ channel blockers all have tocolytic effects and are under investigation as potential therapies of dysmenorrhea.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

Clinical problems are summarized in the Clinical Problems Box.

Uterine Stimulants

The major side effect of uterine stimulants is hyperstimulation. This is usually easy to recognize by the appearance of frequent (<2 minute interval) contractions or of a prolonged tetanic contraction usually accompanied by maternal pain and often fetal bradycardia. Hyperstimulation produced by OT administered IV is easily reversed by reducing the infusion rate or discontinuing the drug. Because OT has a short half-life, normal uterine tone returns within a few minutes. Hyperstimulation resulting from PG gel insertion into the cervix or vagina may be a greater problem, but in severe cases saline can be used to wash out the PG. If there is no reduction in tone or continued fetal bradycardia, it may be necessary to administer β2 receptor agonists IV. In rare instances emergency cesarean section may be necessary. Induction of labor should be performed only when necessary, and always in settings with adequate facilities.

Because of the low density of OT receptors in the myometrium in early pregnancy, very high doses of OT are required to stimulate contractions during this time. Such high concentrations can result in cross-stimulation of vasopressin receptors, which can cause water intoxication with severe hyponatremia. A similar problem can occur when OT is used to treat postpartum hemorrhage.

As discussed, uterine stimulants should never be given in combination during pregnancy, because of the risk of hyperstimulation and adverse maternal and fetal outcomes. At least 6 hours should elapse after insertion of a PG gel before OT or additional PG is administered. If IV OT has been used, at least 2 hours should elapse before PG preparations are given. Conversely, combinations of uterine stimulants are often beneficial in the management of postpartum hemorrhage due to uterine atony that is resistant to single agents.

PGE2 preparations for cervical ripening may be associated with an increased incidence of uterine rupture during labor in women who have had a previous cesarean section. Other side effects of PG preparations include gastrointestinal and pulmonary problems (see Chapter 15). However, these result very infrequently from local application of a PG gel.

In the past, ergot alkaloids were commonly used to control postpartum hemorrhage. However, because they act on all smooth muscle, a serious risk is hypertension. Myocardial ischemia and infarction also have been reported. From the few studies available, it appears that the progesterone receptor antagonist mifepristone has very few systemic side effects.

Uterine Relaxants

Most tocolytic agents lack specificity for the uterus and produce predictable side effects stemming from their actions on other tissues. Selective β2 receptor agonists are available, but they still stimulate all β adrenergic receptors to some degree. As a result, cardiovascular or metabolic complications may occur in the mother or fetus. β2 receptor agonists cause vasodilation, which commonly results in hypotension. Maternal tachycardia arises as a compensatory mechanism and also results from a direct action of the drug on the heart. These effects are a source of significant discomfort in patients. β2receptor agonists also increase hepatic glycogenolysis, resulting in maternal hyperglycemia, stimulating the secretion of insulin. As glucose is driven into cells by insulin, K+ is also accumulated intracellularly, resulting in maternal hypokalemia. The cardiovascular side effects, particularly in the face of hypokalemia, may trigger cardiac dysrhythmias, which can lead to heart failure. Infusion of β2receptor agonists IV, especially in combination with glucocorticoids (which have salt-retaining properties), may cause excessive fluid retention, which can result in a potentially fatal pulmonary edema. Fluid balance should be monitored closely when these drugs are used in pregnant women. Tachycardia, hyperglycemia, and hyperinsulinemia may also develop in the fetus. Neonatal hypoglycemia may result from prolonged hyperinsulinemia.

Concern has been raised about the use of indomethacin to arrest preterm labor because of the adverse effect this may have on constriction of the fetal ductus arteriosus (see Chapter 15). Although this effect may be greater in term fetuses, it can be seen throughout the third trimester. Fetal renal toxicity is also frequent and commonly manifests as a reduction in fetal urine output, resulting in reduced amniotic fluid volume (oligohydramnios). It is not clear whether these disturbances are associated with adverse fetal outcomes, but this is a serious concern in light of increasing evidence regarding the fetal origins of adult disease. Also, findings from retrospective studies have shown that there is an increased incidence of intracranial hemorrhage, patent ductus arteriosus, and necrotizing enterocolitis in neonates receiving indomethacin, although some patients were treated with higher doses for longer periods than currently recommended. Prospective randomized trials are clearly required to evaluate the risk-benefit ratios of NSAIDs for arresting preterm labor.

High doses of magnesium sulfate may cause obtundation, a loss of deep tendon reflexes, respiratory depression, and myocardial depression. Despite the lack of evidence for efficacy, magnesium sulfate is often the tocolytic drug of choice because of its low toxicity when given at low infusion rates.

There is much controversy about tocolytic drugs, particularly concerning their effectiveness and cost/benefit ratio. Many clinical studies have not included a placebo control group, limiting their conclusions without knowledge of potential placebo effects. Although most trials measure prolongation of pregnancy as the primary outcome, the important outcome is the eventual health of the newborn and the mother. In addition, there is no consensus as to the criteria used to exclude treatment in clinical trials. In addition, although there is a consensus that administration of glucocorticoids to the mother for 24 to 48 hours before birth will accelerate fetal pulmonary maturation and reduce the incidence of neonatal respiratory distress syndrome, randomized, placebo-controlled studies have not shown that use of tocolytic drugs increases the chance of completing a course of glucocorticoid therapy. Further, the extensive use of artificial surfactant treatment in preterm neonates may reduce the benefit of glucocorticoids administered in utero. Finally, in most regions of the United States and Canada, tocolytic therapy is the standard of care in preterm labor. Thus the medico-legal climate often dictates that some form of tocolytic therapy be attempted, despite the lack of strong supportive evidence.

CLINICAL PROBLEMS

Uterine Stimulants

Maternal

Fetal

Oxytocin

Uterine hypertonus, rupture, hypotension, H2O intoxication

Hypoxia

Prostaglandins

Uterine hypertonus, rupture, vomiting, diarrhea, fever, bronchospasm

Hypoxia

Mifepristone

None

None

Uterine Relaxants

Maternal

Fetal

Adrenergic β2 receptor agonists

Hypotension, tachycardia, palpitations, dysrhythmias, pulmonary edema, hyperglycemia, hypokalemia

Tachycardia

   

Hyperglycemia

NSAIDs

Gastrointestinal bleeding, nausea, headaches, myelosuppression

Constriction of ductus arteriosus, oligohydramnios

Magnesium sulfate

Skin flushing, palpitations, headaches, depressed reflexes, respiratory depression, impaired cardiac conduction

Muscle relaxation, central nervous system depression (rare)

Progesterone

None

None

New Horizons

Development of tocolytics that act as antagonists of OT receptors remains at the forefront of research. Although atosiban was demonstrated to be effective in delaying delivery in clinical trials, concerns about neonatal mortality have prevented approval for use in the United States. The development of other specific OT receptor antagonists with fewer side effects is proceeding.

The search for novel agents to promote uterine quiescence in the treatment of preterm labor continues to focus on PGs, although relaxation of muscle contractions by agents that act through guanylyl cyclase are also being investigated. New PG receptor antagonists with specificity for the PGF receptor are effective in inducing uterine quiescence in animal models, but effects in humans have not yet been examined. The effects of NO in animals include relaxation of the uterus, similar to effects on other smooth muscles (see Chapter 24). Sildenafil has shown promise in reducing uterine contractility in animal models. However, recent studies indicate that contraction of uterine smooth muscle, unlike vascular smooth muscle, may not depend on the guanylyl cyclase system.

Pharmacogenomics may provide the most promising avenue for the development of novel therapeutic regimens in the treatment of problems associated with uterine contractility. Although few pharmacogenomic studies have focused on uterine contractility, genetic polymorphisms in the catechol-O-methyl transferase (COMT) gene, have recently been linked to several estrogen-related medical problems in women, including increased incidence of preterm labor. COMT catalyzes the methylation of catechol estrogens to 2- or 4- methoxyestrogen, thereby influencing the cellular estrogenic milieu, which is important in parturition. β2 receptor polymorphisms important in the treatment of asthma may also affect responsiveness to β2 receptor agonists used to induce labor.

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Uterine Stimulation

Oxytocin (Syntocinon, Pitocin)

Prostaglandin F (Dinoprost)

Prostaglandin E2 (Dinoprostone, Cervidil, Prepidil, Prostin E2)

Ergot alkaloids (Ergotrate, Ergometrine, Methergine)

Mifepristone (RU486, Mifeprex)

Misoprostol (Cytotec)

Uterine Relaxation

Ritodrine (Yutopar)

Terbutaline (Bricanyl, Brethine)

Indomethacin (Indocid, Indocin)

Celecoxib (Celebrex)

Nicardipine (Cardene)

Progesterone (Prometrium)

17-Hydroxyprogesterone (Delalutin)

FURTHER READING

Belfort et al. 2003 Belfort MA, Anthony J, Saade GR, Allen JCJr, Nimodipine Study Group. A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl J Med. 2003;348:304-311.

Cole et al. 2004 Cole S, Smith R, Giles W. Tocolysis: Current controversies, future directions. Curr Opin Investig Drugs. 2004;5:424-429.

Olson DM, Ammann C. Role of the prostaglandins in labour and prostaglandin receptor inhibitors in the prevention of preterm labour. Front Biosci. 2007;12:1329-1343.

Word et al. 2007 Word RA, Li XH, Hnat M, Carrick K. Dynamics of cervical remodeling during pregnancy and parturition: Mechanisms and current concepts. Semin Reprod Med. 2007;25:69-79.

Wray S. Insights into the uterus. Exp Physiol. 2007;92:621-631.

SELF-ASSESSMENT QUESTIONS

1. Which one of the following is characteristic of the use of β2 receptor agonists for promoting uterine relaxation?

A. No risk of cardiovascular side effects

B. Inhibition of COX-1 and COX-2

C. Loss of effectiveness caused by tachyphylaxis

D. Most commonly used treatment for primary dysmenorrhea

E. A risk of hypoglycemia

2. The mechanism of action of indomethacin includes:

A. Stimulation of adenylyl cyclase.

B. Inhibition of cyclooxygenase.

C. Stimulation of β2 receptors.

D. Blockade of PGF receptors.

E. Inhibition of myosin light chain kinase.

3. A pregnant patient at term presents for induction of labor. The best pharmacological approach would be:

A. Administration of PGE2 vaginal gel until the woman is in active labor.

B. Administration of PGE2 vaginal gel with concurrent intravenous OT through an infusion pump.

C. Administration of OT intramuscularly.

D. Administration of PGE2 vaginal gel until the cervix has ripened followed in 6 hours by intravenous OT through an infusion pump if active labor has not occurred.

E. Intravenous administration of ergonovine.

4. Which of the following is a characteristic of OT?

A. It readily crosses the placenta, where it can cause harmful side effects in the fetus.

B. It is the drug of choice for cervical ripening.

C. The plasma t1/2 is a few minutes.

D. In early pregnancy the uterus is more sensitive to this drug than to PGs.

E. The drug can be administered orally.

Questions 5 and 6 refer to the following vignette:

A 30-year-old G2P0 woman presents to the emergency room with severe abdominal cramping and moderate uterine bleeding. The physical exam is unremarkable except for ~8 mL of blood present in the vagina upon examination with a speculum. The uterus indicates pregnancy at approximately 8 weeks of gestation; HCG is 925 mIU/mL. Forty-eight hours later, HCG is 54 mIU/mL and bleeding is severe.

5. After oxytocin administration fails to control uterine bleeding, ergot alkaloids are administered. Which of the following is correct concerning the use of ergot alkaloids in spontaneous abortion?

A. Oral administration of a large dose of ergonovine is the fastest and most efficacious means for providing immediate relief.

B. Ergot alkaloids are used to treat oxytocin toxicity.

C. Ergot alkaloids in conjunction with magnesium sulfate may effectively save the pregnancy.

D. Large doses of ergot alkaloids act to reduce bleeding by causing sustained contraction of the uterus.

E. Prostaglandins are more effective than ergot alkaloids for management of severe uterine bleeding.

6. Administration of magnesium sulfate is the common prevention of premature delivery. Which of the following is correct concerning the use of this tocolytic agent?

A. Magnesium sulfate promotes smooth muscle contraction by activating protein kinase A (PKA), thereby mimicking the mechanism of action of β adrenergic receptor antagonists.

B. Use of magnesium sulfate is contraindicated between 20 and 36 weeks of gestation.

C. Magnesium sulfate promotes smooth muscle relaxation by preventing elevation of intracellular Ca++ by blocking uptake through membrane-bound Ca++ channels and transporters.

D. Because magnesium sulfate generally takes >48 hours to become effective, it is generally used in conjunction with faster acting tocolytics, including the Ca++ channel blocker, indomethacin.

E. Magnesium sulfate activates myosin light chain kinase by blocking its phosphorylation.