4.   Route of administration/dose

a.   Terbutaline can be administered intravenously (IV) or subcutaneously (SC). However, it is most commonly administered by intermittent injection in doses of 0.25 mg every 20 to 30 minutes up to 4 doses until uterine quiescence is achieved. Terbutaline (0.25 mg) can then be administered subcutaneously every 3 to 4 hours. For acute tocolysis, terbutaline can be administered IV at a rate of 2.5–5 mcg/min. The dose is increased by 2.5–5 mcg/min up to a maximum of 25 mcg/min. The infusion rate should be titrated based on uterine quiescence or maternal side effects. One or two doses of 0.25 μg IV or SC are often effective in relieving uterine hypertonus.

b.   Salbutamol 100 μg IV or terbutaline 250 μg IV over 1 to 2 minutes can be useful for uterine hyperstimulation.

c.   Ritodrine 50 μg per minute IV is increased by 50 μg per minute every 10 minutes until response is achieved, usually at 150 μg per minute, with a maximum dose 350 μg per minute. Alternatively, 10 mg IM can be given every 3 to 8 hours for 12 to 48 hours. Once contractions have stopped after IV or IM treatment, 10 mg can be given orally every 2 hours for 24 hours, followed by 10 to 20 mg every 4 to 6 hours to a maximum of 120 mg daily.

5.   Toxicity/side effects (see Table 4.1)

a.   Maternal cardiopulmonary side effects are mainly related to the stimulation of β₁ receptors leading to tachycardia, dysrhythmias, and myocardial ischemia due to increased oxygen demand. Careful consideration should be given to their use in parturients with significant cardiac disease.

b.   β₂ receptor stimulation can cause hyperglycemia and hypokalemia. Their use is contraindicated in women with uncontrolled diabetes.

c.   Pulmonary edema is a rare but serious complication of β-agonist use in pregnancy. The etiology is multifactorial and includes physiologic plasma volume expansion in pregnancy, exacerbated by β₂–mediated increased pulmonary capillary permeability and β₁-mediated left ventricular failure, particularly in women with preexisting cardiac disease.⁵

d.   The central nervous system symptoms associated with the use of β-mimetic therapy include tremors, headache, and nervousness.

e.   Fetal tachycardia and hypoglycemia can occur as these drugs readily cross the placenta.

6.   Anesthetic considerations

a.   Cardiovascular side effects, typically tachycardia and hypotension, can occur even after discontinuation of the drug due to prolonged half-lives of these medications in pregnant women (up to 90 minutes). Therefore, anesthetic drugs that cause tachycardia should be avoided and profound tachycardia should be treated with β-blockers. Treatment of hypotension with either ephedrine or phenylephrine, depending on the heart rate, is acceptable.

b.   One should avoid aggressive hydration prior to neuraxial block because these patients are at risk for the development of pulmonary edema. The amount of fluids should be carefully titrated, and vasopressors should be used to maintain normal blood pressure.

c.   Hyperventilation should be avoided because it can lead to respiratory alkalosis and worsen hypokalemia due to intracellular movement of potassium.

d.   These drugs should be used with caution in women at risk for massive hemorrhage due to the increased risk of hypotension and tachycardia. The presence of these signs may interfere with the ability of the mother to compensate for the hemorrhagic response and also confuse the clinical presentation.

e.   These drugs are relatively contraindicated in patients with tachycardia-sensitive heart disease, poorly controlled hyperthyroidism, or diabetes mellitus due to the potential for worsening metabolic effects.

f.   Prolonged use of these drugs can result in desensitization of the β receptors and tachyphylaxis.

B. Calcium channel blockers

1.   Nifedipine is the most commonly administered calcium channel blocker.

Calcium channel blockers are divided into two major categories based on their predominant physiologic effects: dihydropyridines, which are predominantly vasodilators, and the nondihydropyridines, which reduce vascular permeability. Nifedipine is a short-acting dihydropyridine and is the main calcium channel blocker used in pregnant women.

2.   Uses

a.   Tocolysis to prolong pregnancy in threatened preterm labor. In a systematic review and meta-analysis of Cochrane Collaboration, the use of a calcium channel blocker reduced the risk of delivery within 48 hours of trial entry compared with placebo/no treatment (RR 0.30; 95% CI, 0.21 to 0.43), but there was no statistically significant reduction in this outcome compared with other classes of tocolytics such as β-agonists, glyceryl trinitrate patch, nonsteroidal anti-inflammatory drugs (NSAIDs), magnesium sulphate, and oxytocin receptor antagonists. However, calcium channel blockers showed significant benefits over β-agonists with respect to prolongation of pregnancy, serious neonatal morbidity, and maternal adverse effects.⁶ The relative safety, maternal tolerance, ease of administration, and reduction in adverse neonatal outcomes support the use of nifedipine over other tocolytic drugs for inhibition of acute preterm labor.⁶

b.   Antihypertensive therapy in acute hypertensive situations. Nifedipine is most commonly used over other calcium channel blockers because of its minimal effects on the cardiac conducting system.⁷ Nifedipine causes vasodilation of the systemic and pulmonary vasculature, which is reversed on stopping the drug and it exhibits a lack of tachyphylaxis.⁷

3.   Mechanism of action. Calcium channel blockers directly block the influx of calcium ions across L-type channels of cell membranes. They also inhibit the release of intracellular calcium from the sarcoplasmic reticulum and increase calcium efflux from the cell. The resulting decrease in intracellular free calcium leads to inhibition of calcium-dependent myosin light-chain kinase phosphorylation and in smooth muscle relaxation of the blood vessels and uterus (see Fig. 4.1).

4.   Route of administration/dose

a.   Nifedipine 20 to 30 mg oral loading dose is followed by 10 to 20 mg every 4 to 6 hours to a maximum of 180 mg per day. This can be given for up to 72 hours to inhibit preterm labor.

b.   Long-acting nifedipine 30 to 90 mg once daily as a sustained release tablet can be administered for hypertension in pregnancy.

5.   Toxicity/side effects

a.   Peripheral vasodilatation from nifedipine results in decreased systemic vascular resistance and may cause symptoms such as nausea, flushing, headache, dizziness, and palpitations.

b.   A compensatory increase in heart rate and stroke volume results in an increase in cardiac output, which maintains blood pressure in women with no underlying cardiac dysfunction.⁸

c.   There have been case reports of severe hypotension with adverse fetal effects following nifedipine administration.^9,10

6.   Anesthetic considerations

a.   A variable degree of hypotension may occur intraoperatively.

b.   Conduction abnormalities can also be seen when combined with an inhalational agent.

c.   The coadministration of a calcium channel blocker and magnesium sulfate can synergistically suppress muscular contractility and result in maternal respiratory depression due to respiratory muscle weakness.¹¹

d.   Refractory PPH can occur in the setting of uterine atony. Because oxytocin and prostaglandin agonists act through calcium channel mechanisms, their effect in treating uterine atony may also be limited.¹²

C. Magnesium sulfate

1.   Uses

a.   Prevention and treatment of seizures in preeclampsia/eclampsia. Magnesium sulfate is recommended in patients with preeclampsia for whom there is concern about the risk of eclampsia.¹³ The Magpie trial demonstrated that women with preeclampsia who were given magnesium had a 58% lower risk of eclampsia than those allocated to receive placebo.¹⁴ The number needed to treat to prevent one seizure for women with severe preeclampsia was 63 (95% CI, 38 to 181) and for those without severe preeclampsia was 109 (95% CI, 72 to 225). The American College of Obstetricians and Gynecologists (ACOG)¹⁵ recommends administration of magnesium sulfate to women with eclampsia and preeclampsia with severe features but not to those with mild preeclampsia without any symptoms or gestational hypertension. Magnesium sulfate is usually continued for 24 hours postpartum.

b.   Fetal neurodevelopment. Antenatal magnesium sulfate therapy for women at risk for preterm birth is established as being neuroprotective against motor disorders for the preterm fetus.^16,17 Magnesium therapy given to women at risk for preterm birth substantially reduced the risk of cerebral palsy in their children (RR 0.68; 95% CI, 0.54 to 0.87). The number of women needed to treat to prevent one baby from developing cerebral palsy was 63 (95% CI, 43 to 155). Two large randomized controlled trials further support the use of prenatal magnesium for preventing neurodisabilities in preterm infants.^18,19

c.   Tocolysis to prolong pregnancy. Magnesium sulfate inhibits uterine activity and has been used as a tocolytic agent in women with preterm labor to prevent delivery. However, its efficacy in preventing preterm delivery has been shown on numerous occasions to be equivalent to placebo. A recent Cochrane review found that magnesium sulfate is ineffective at delaying birth or preventing preterm birth, has no apparent advantages for a range of neonatal and maternal outcomes as a tocolytic agent, and its use for this indication may be associated with an increased risk of total fetal, neonatal, or infant mortality.²⁰ The ACOG, however, continues to support the short-term use of magnesium for up to 48 hours to allow for the administration of corticosteroids in women between 24 and 34 weeks’ gestation with preterm labor.²¹

2.   Mechanism of action

a.   The anticonvulsant effect of magnesium sulfate is attributed to its antagonistic action on the N-methyl-D-aspartate (NMDA) receptor and direct cerebral vasodilatation.

b.   It competes with calcium for binding sites on the sarcoplasmic reticulum and decreases intracellular calcium levels. It hyperpolarizes the plasma membrane and inhibits myosin light-chain kinase activity reducing myometrial contractility (see Fig. 4.1).

c.   It increases PGI₂ production by vascular endothelium resulting in smooth muscle relaxation and dilation.

3.   Route of administration/dose

a.   Magnesium sulfate is given as a bolus 4 to 6 g IV over 20 minutes and then as an infusion of 1 to 2 g per hour for short-term (usually less than 48 hours) use in preterm labor or fetal neuroprotection.

b.   In the prevention and treatment of seizures, it is administered in similar doses and continued for up to 24 hours postpartum.

4.   Toxicity/side effects

a.   Increasing plasma levels of magnesium are associated with adverse effects (see Table 4.2). Because severe adverse effects are seen above the plasma magnesium level at which deep tendon reflexes are lost, patients should be monitored by regularly checking reflexes.

b.   Fetal cardiac or respiratory effects are not of concern unless maternal toxicity is present.

c.   It may prolong labor and increase the risk of PPH due to its tocolytic effect.

d.   Magnesium is renally excreted and hence toxicity is more common in patients with renal impairment.

e.   If magnesium toxicity occurs, the infusion should be discontinued, and either 10 mL of calcium chloride 10% or 30 mL of calcium gluconate 10% administered by slow intravenous infusion.

5.   Anesthetic considerations

a.   Magnesium causes generalized muscle weakness; hence, it is contraindicated in women with myasthenia gravis.

b.   Magnesium increases the sensitivity to muscle relaxants. A defasciculating dose of a nondepolarizing muscle relaxant before succinylcholine administration should be avoided. The intubating dose of succinylcholine does not need to be altered; however, the maintenance dose of nondepolarizing agents should be reduced.

c.   Magnesium use may exacerbate hypotension caused by hemorrhage or neuroaxial block due to a decrease in systemic vascular resistance.

d.   Magnesium has been shown to inhibit platelet function, to decrease the amount of inhaled volatile agents required, and to amplify the analgesic effect of opioids.

e.   Magnesium toxicity can lead to respiratory depression and cardiac arrest (see Table 4.2).

D. Cyclooxygenase (prostaglandin synthase) inhibitors

1.   Drugs

a.   Indomethacin

b.   Sulindac

c.   Ketorolac

2.   Uses. Tocolysis to prolong pregnancy in threatened preterm labor

a.   The enzyme cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase, exists in two isoforms: COX-1 synthesizes protective prostaglandins, which are responsible for preserving the integrity of the stomach lining, renal function, and platelet aggregation; COX-2 is induced during the inflammatory process and prostaglandins made by COX-2 are also important for inducing uterine contractions during labor.²² NSAIDs such as indomethacin can therefore delay premature labor by inhibiting production of these prostaglandins.

b.   Indomethacin is the most commonly used NSAID in cases of threatened preterm labor. A Cochrane review found that compared to placebo, indomethacin resulted in a reduction in birth before 37 weeks’ gestation (RR 0.21; 95% CI, 0.07 to 0.62), an increase in gestational age (weighted mean difference [WMD] 3.53 weeks; 95% CI, 1.13 to 5.92), and birth weight (WMD 716 g; 95% CI, 426 to 1,007). In addition, compared to other tocolytics, COX inhibition resulted in a reduction in maternal drug reactions requiring cessation of treatment. Surprisingly, no differences were detected in neonatal outcomes.²³

c.   There is some data on the use of selective COX-2 inhibitors (nimesulide,²⁴ celecoxib,²⁵ rofecoxib^26,27) for the treatment of preterm labor; however, most of these agents have been withdrawn or issued with black box warnings because of the adverse cardiovascular risk and severe fetal side effects associated with their use.²⁸

3.   Mechanism of action

a.   NSAIDs inhibit COX (prostaglandin synthase) enzyme, which reduces the synthesis of prostaglandins from the precursor arachidonic acid (see Fig. 4.1). The extent of enzyme inhibition varies among different NSAIDs, by either general inhibition or specific inhibition of COX-2. The synthesis of prostaglandins E₂ and F_2α, which are potent uterine smooth muscle stimulants, is decreased.

b.   Indomethacin is a nonspecific COX inhibitor.

4.   Route of administration/dose

a.   Indomethacin 50 to 100 mg oral or rectal loading dose is followed by 25 to 50 mg every 4 to 6 hours.

b.   It is recommended for use only before 32 weeks’ gestation and should only continue for 48 to 72 hours due to the risk of severe fetal side effects.

5.   Toxicity/side effects

a.   The maternal gastrointestinal side effects associated with the use of these medications include nausea, esophageal reflux, gastritis, and emesis.

b.   Platelet dysfunction is seen due to inhibition of thromboxane A_2.

c.   Renal function may worsen in patients with renal insufficiency from decreased renal blood flow. This is due to inhibition of prostaglandin E₂ and I₂ activity.

d.   There is an increased risk of cardiovascular side effects such as myocardial infarction and stroke.

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