Drugs that affect uterine function

CHAPTER 64


Drugs that affect uterine function


Most of the drugs discussed in this chapter have applications related to labor and delivery. Some are used to delay or prevent preterm labor. Some are used to induce labor. And some are used to control postpartum hemorrhage. In addition to these drugs, we discuss one other group: drugs used to decrease menorrhagia (heavy menstrual bleeding).


Drugs that alter uterine function fall into two major groups: oxytocic drugs and tocolytic drugs. The oxytocic drugs, also known as uterotonic drugs, stimulate uterine contraction. In contrast, the tocolytic drugs cause uterine relaxation. Clinical applications of the oxytocic and tocolytic drugs are summarized in Table 64–1.




Drugs for preterm labor


Preterm birth, defined as birth before 37 weeks’ gestation, is the leading cause of newborn morbidity and mortality. Infants who survive preterm birth are at increased risk of infection, cerebral palsy, intracranial hemorrhage, and, most commonly, neonatal respiratory distress syndrome. In the United States, about 12.5% of all live births (540,000 annually) are premature. These preterm births account for 75% of neonatal mortality and 50% of congenital neurologic deficits. Risk factors for preterm delivery include a previous preterm delivery, multifetal pregnancy, cervical or uterine abnormalities, intrauterine infection and inflammation, and social factors (poverty, limited education, unmarried status, inadequate prenatal care). The annual cost of preterm births is estimated at $26 billion—about $52,000 per infant. Drugs for preterm labor fall into two major groups: drugs used to suppress preterm labor that has already started, and drugs used to prevent preterm labor from ever occurring. The first group is larger and used more widely.



Drugs used to suppress preterm labor


All of the drugs employed to suppress preterm labor are tocolytics. That is, they all promote uterine relaxation, and thereby delay delivery. Be aware, however, that benefits are limited: These drugs can only suppress labor briefly, not long term. On average, delivery is postponed by only 48 hours. Hence, birth still takes place prior to term. If tocolytics don’t permit pregnancy to reach term, what are they good for? The answer: Almost nothing—if they are used alone. However, when tocolytics are combined with glucocorticoids, which accelerate fetal lung development (see Chapter 107), the outcome can be improved: Infants experience less respiratory distress syndrome, intraventricular hemorrhage, and mortality. Tocolytics also buy time to treat infection, if present. Unfortunately, tocolytic drugs can pose a risk to the fetus. Accordingly, the ultimate goal of treatment is to extend fetal time in the womb, but without causing significant fetal or neonatal harm.



Control of myometrial contraction and mechanisms of tocolytic drug action


Contraction of the myometrium (uterine smooth muscle) is regulated by multiple mediators, including beta-adrenergic agonists, oxytocin, and prostaglandins (Fig. 64–1). As a result, there are multiple ways in which drugs can suppress uterine activity. However, although these drugs work through different mechanisms, they all have one thing in common: Ultimately, they all decrease the availability of phosphorylated light-chain (LC) myosin, the form of myosin that interacts with actin to cause contraction. As indicated in Figure 64–1, four classes of tocolytic drugs—beta-adrenergic agonists, calcium channel blockers, cyclooxygenase (COX) inhibitors, and oxytocin receptor antagonists—work to reduce the activity of myosin LC kinase, the enzyme that converts myosin to its phosphorylated form. A fifth group—the nitric oxide donors—work to increase the activity of myosin LC phosphatase, the enzyme that removes phosphate from myosin, thereby converting it to its inactive form. Note also that three drug groups—COX inhibitors, oxytocin receptor antagonists, and calcium channel blockers—decrease the release of calcium from the sarcoplasmic reticulum (SR). As indicated in the figure, calcium combines with calmodulin to form a complex that increases myosin light-chain kinase activity. Hence, in the absence of sufficient free calcium, myosin LC kinase activity declines, causing the phosphorylation of myosin to decline as well.


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Figure 64–1  Control of myometrial contraction and the actions of tocolytic drugs.
The figure shows five pathways that regulate availability of myosin LC phosphate (myosin LC PO4), the form of myosin needed for contractile interaction with actin. Note that two enzymes—myosin LC kinase and myosin LC phosphatase—play central roles. Four classes of tocolytic drugs (numbers 1, 2, 3, and 4 in the figure) work to reduce the activity of myosin LC kinase, and thereby reduce production of myosin LC phosphate. A fifth class—the nitric oxide donors—increases the activity of myosin LC phosphatase, and thereby stimulates conversion of myosin LC phosphate to its inactive (dephosphorylated) form. Note also the important role played by calcium in controlling the activity of myosin LC kinase. (AA = arachidonic acid, ATP = adenosine triphosphate, cAMP = cyclic adenosine monophosphate, CCBs = calcium channel blockers, cGMP = cyclic guanosine monophosphate, COX = cyclooxygenase, GTP = guanosine triphosphate, IP3 = inositol triphosphate, LC = light-chain, NO = nitric oxide, PG = prostaglandin, PIP3 = phosphatidylinositol triphosphate, PO4 = phosphate, SR = sarcoplasmic reticulum.)


Specific tocolytic drugs


Multiple drugs can suppress preterm labor. Options include terbutaline (a beta2-adrenergic agonist), nifedipine (a calcium channel blocker), and COX inhibitors (eg, indomethacin). All of these drugs appear equally good at suppressing labor, and hence there is no obvious “first-choice” agent among them. Accordingly, selection is based primarily on side effects, which are summarized in Table 64–2. Interestingly, none of the drugs currently employed to suppress preterm labor has been approved for this use by the Food and Drug Administration (FDA).




Terbutaline, a beta2-adrenergic agonist

Terbutaline, used primarily for asthma (see Chapter 76), is a selective beta2 agonist that can effectively suppress preterm labor. By activating beta2 receptors in the uterus, terbutaline increases production of cyclic AMP (cAMP), a mediator that leads to suppression of myosin light-chain kinase activity. The result is a decrease in both the intensity and frequency of contractions. Unfortunately, although terbutaline is effective, it poses a significant risk to the mother. Adverse effects result from activating beta1 receptors as well as beta2 receptors. (Although terbutaline is classified as beta2 selective, it can activate beta1 receptors too, albeit less readily than beta2 receptors.) Effects of greatest concern are pulmonary edema, hypotension, and hyperglycemia in the mother, and tachycardia in both the mother and fetus. For suppression of labor, terbutaline is administered subQ, not PO. The initial dosage is 250 mcg every 20 minutes for up to 3 hours. Dosing should stop after 48 hours, and should be interrupted if the maternal heart rate exceeds 120 beats per minute. Although terbutaline can be used to suppress preterm labor, it should not be given to prevent preterm labor.



Nifedipine, a calcium channel blocker

Nifedipine [Adalat, Procardia, others] can suppress preterm labor for at least 48 hours. Efficacy equals that of terbutaline—and safety is superior. How does nifedipine work? It blocks calcium channels, and thereby inhibits entry of calcium into myometrial cells. As a result, release of calcium from the SR is reduced, and hence the activity of myosin light-chain kinase is reduced as well. Maternal side effects, which are rare, include transient tachycardia, facial flushing, headache, dizziness, and nausea. Hypotension may occur in hypovolemic patients. There is some concern that nifedipine may compromise uteroplacental blood flow. In animal studies, calcium channel blockers have caused acidosis, hypoxemia, and hypercapnia in the newborn. To suppress preterm labor, an initial loading dose (30 mg sublingual) is followed by maintenance doses (10 or 20 mg PO) every 4 to 6 hours. The basic pharmacology of calcium channel blockers is discussed in Chapter 45.



Indomethacin, a cyclooxygenase inhibitor

Indomethacin [Indocin] is a second-line tocolytic agent generally reserved for women who go into labor extremely early. The drug is as effective as terbutaline, but carries a higher risk of neonatal complications. Indomethacin suppresses labor by inhibiting synthesis of prostaglandins, local hormones that promote uterine contraction by increasing release of calcium from the SR. Adverse neonatal outcomes include prolonged renal insufficiency, bronchopulmonary dysplasia, necrotizing enterocolitis, and periventricular leukomalacia (white matter injury caused by reduced blood flow in the brain). In addition, indomethacin can cause in utero closure of the ductus arteriosus. Adverse maternal effects include nausea, gastric irritation, interstitial nephritis, and, rarely, increased postpartum bleeding. Tocolytic treatment is initiated with a loading dose (50 or 100 mg, usually rectal) followed by maintenance doses (25 to 50 mg PO) given every 4 to 8 hours for 2 to 3 days.









Magnesium sulfate


Opinion on the role of magnesium sulfate in preterm labor is changing. Although the drug has been popular in the United States (but not in Europe), there seems to be little to recommend its use. Why? First and foremost, the drug doesn’t work: high-dose magnesium sulfate does not prevent or even delay preterm birth. Second, high-dose treatment has been associated with increased infant mortality. However, recent data indicate that, when used in low doses, magnesium may protect against cerebral palsy, without increasing the risk of mortality. The bottom line? High-dose magnesium is both ineffective and dangerous, and therefore should not be used. In contrast, low-dose magnesium may offer the benefit of neuroprotection, even though it won’t delay delivery.


How does magnesium sulfate suppress contractions? It inhibits release of acetylcholine at neuromuscular junctions (NMJs), both in the uterus and in skeletal muscle. At high doses, the drug can cause profound muscle weakness and respiratory arrest.


Magnesium sulfate can cause a variety of maternal adverse effects. Initial reactions include transient hypotension, flushing, headache, dizziness, lethargy, dry mouth, and a feeling of warmth. High doses may cause hypothermia and paralytic ileus. Pulmonary edema, which can be fatal, is seen in 2% of patients. This complication is managed by discontinuing magnesium and giving a diuretic to accelerate magnesium excretion. Magnesium sulfate is contraindicated in patients with myasthenia gravis (because the disease causes muscle weakness), renal failure (because magnesium is eliminated entirely by the kidneys), and hypocalcemia (because hypocalcemia intensifies magnesium-induced suppression of neurotransmitter release).


Magnesium readily crosses the placenta and is associated with increased infant mortality. The drug may also cause hypotonia (muscle weakness) and sleepiness in the newborn. Because elimination of magnesium by neonatal kidneys is slow, hypotonia may persist 3 to 4 days. During this time, mechanical assistance of ventilation may be required.


The risk of adverse effects can be reduced by monitoring (1) magnesium levels; (2) renal function (because renal impairment will cause magnesium levels to rise); (3) fluid balance (because fluid retention increases the risk of pulmonary edema); and (4) deep tendon reflexes (because loss of deep tendon reflexes is an early sign that magnesium levels are rising dangerously high).


In clinical trials testing magnesium sulfate for neuroprotection, two low-dose protocols have been used. In one, dosing consisted of a 4-g IV loading bolus infused over 20 minutes, followed by a maintenance infusion of 1 gm/hr lasting for 24 hours or until delivery, whichever came first. In the other protocol, dosing was limited to a single IV bolus. By way of comparison, high-dose therapy consists of an initial IV bolus (4 to 6 gm), followed by infusion of 2 to 3 gm/hr for 48 to 72 hours.


In addition to its use for preterm neuroprotection, magnesium sulfate is the preferred drug for prevention and treatment of seizures associated with eclampsia and severe preeclampsia (see Chapter 47).




Drugs used to prevent preterm labor


As discussed above, we can arrest preterm labor (albeit briefly) with tocolytics, but is there any way we can prevent it? Yes—at least for some women. Two drug interventions may help: hydroxyprogesterone and antibiotics.



Hydroxyprogesterone caproate




Therapeutic use.

In 2011, the FDA approved hydroxyprogesterone caproate [Makena] for reducing the risk of preterm labor, making it the first and only drug approved for this use. The drug is indicated only for women with a singleton pregnancy and a history of at least one preterm birth. It is not approved for women with multiple pregnancy or other risk factors for preterm birth. Hydroxyprogesterone is a weakly active, naturally occurring progesterone derivative. The mechanism underlying prevention of preterm birth is unknown.


Efficacy of hydroxyprogesterone was demonstrated in a randomized, controlled trial that enrolled 463 pregnant women at high risk of preterm delivery (because of a spontaneous preterm delivery in the past). After random assignment to placebo or treatment groups, one-third of the women were given weekly IM injections of placebo, and two-thirds were given weekly IM injections of hydroxyprogesterone. Injections began at 16 to 20 weeks of gestation and continued until delivery or until 36 weeks of gestation. The result? The rate of preterm delivery was 54.9% in the placebo group, but only 36.3% in the progesterone group—a highly significant reduction. In addition, progesterone reduced the risk of low birth weight and several other complications. Progesterone-induced birth defects were not observed. Although these results are impressive, important questions remain:


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Jul 24, 2016 | Posted by in NURSING | Comments Off on Drugs that affect uterine function

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