- Email: [email protected]
Calcium channel blockers as tocolytics
Calcium Channel B l o c k e r s as Tocolytics Katherine E. Economy and Alfred Z. Abuhamad
This artide reviews the clinical and basic science investigations regarding the safety and efficacy o f calcium channel blockers as tocolytic agents. The authors reviewed the English langt~age literatm-e o n the pharmacology and clinical applications o f calcium antagonists in obstetrics. A MEI)LINE (19662000) search was performed with the terms "calcium channel blockers, . . . . randomized controlled trial," "preterm labor," "calcium antagonist," "tocolysis," and "nifedipine." References from these data sources were then used to find additional studies. Animal data and clinical trials in humans were included. The safety o f these agents was researched in published data from the nonobstetric as well as obstetric literature. The calcium channel blockers most commonly used as tocolytics are nifedipine and nicardipine. These agents act to inhibit calcium influx across cell membranes, thereby decreasing tone in the smooth muscle o f the vasculature. They act as profound vasodilatory agents and have minimal effect on the cardiac conduction system. Numerous randomized clinical trials have shown them to be as effective as beta-mimetics and magnesium in achieving tocolysis. When used for tocolysis, calcium antagonists have fewer maternal side effects than other tocolytics and have n o adverse effect o n fetal outcome. Copyrigl~ 9 2001 by W . B . Saunders
Company
alcium channel blockers, also known as calcium inhibitors or calcium antagonists, were first used in clinical medicine in the 1960s, They have since e m e r g e d as frontline agents in the treatment of patients with hypertension and cardiac arrhythmias. 1 In 1972, verapamil was reported in the obstetrical literature as a treatment for preterm labor; however, its use was limited secondary to maternal side effects. 2 Almost a decade later, the first prospective study o f nifedipine as a tocolyfic suggested that these agents may be safe and effective for use in p r e g n a n t women, a Today, calcium channel blockers are widely used in obstetrics as tocolytics and for the treatment o f hypertension. T h e calcium antagonists represent a diverse group of c o m p o u n d s that act both on the cardiac conduction system, primarily causing depression at the sinoatrial and atrioventricular nodes, and on the smooth muscle of the vasculature causing vasodilatafion and lowering of
C
From the Division of Maternal Fetal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and Division of Maternal Fetal Medicine, Eastern Virginia Medical School, Norfork, VA. Address reprint requests to Katherine E. Economy, MD, Harvard Medical School, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. C(/lzyright 9 2001 by W.B. Saunders Company 0146-0005/01/2505-0002535. 00/0 doi:10.10 53/sper. 2001. 2 7165
264
blood pressure. 4 The classification o f calcium channel blockers depends o n their core chemical structure. T h e most important classes for obstetrics and gynecology are the phenylalkyline (verapamil-like), the benzothiazepine (diltiazemlike), and the dihydropyiridine (nifedipine-like) types. 1 The latter group, which includes nifedipine, nicardipine and nitrendipine, are the most potent vasodilators and selectively inhibit myometrial contractions both in vitro and in vivo. They have less effect on the cardiac conduction system than other classes of calcium antagonists and therefore result in minimal depression of sinoatrial and atrioventricular nodal function. O f the calcium antagonists, nifedipine has been the most commonly used in clinical trials of tocolysis. Mechanism of Action Although they differ chemically and pharmacologically, all the calcium antagonists act primarily by blocking the transmembrane influx o f calcium ions through voltage-dependent, slowly inactivating (L-type) calcium channels. 5 These L-type channels have been f o u n d in vascular and nonvascular smooth muscle, cardiac muscle, and in a n u m b e r of noncontractile tissues such as pancreas, gastric mucosa, and the adrenal glands/ T h e regulation of L-type channels differs by tissue-type. In cardiac myocytes they are activated by a variety o f stimuli including cat-
Seminars in Perinatology, Vol 25, No 5 (October), 2001: pp 264-271
Calcium Channd Blockers as Tocolytics
echolamines, endothelin, and the alpha-adrenergic system. 6,7 In the pregnant uterus, calcium channels play a vital role in the normal process o f parturition. During labor, myometrial contractions require an increase in intracellular concentration. This occurs partly t h r o u g h L-type channels. 8 Both L-type and T-type channels have b e e n identified in h u m a n myocytes and nifedipine has b e e n shown to inhibit the L-type, whereas magnesium inhibits the T-type channels. 8 Because L-type channels increase intracellular free calcium by bulk calcium transport, the effect o f I.~type inhibitors may be primarily to decrease the amplitude o f contractions, a It has b e e n shown that h u m a n fetal membranes release an e n d o g e n o u s calcium channel inhibitor. 9 Membranes from women in preterm labor have significantly lower e n d o g e n o u s calcium channel inhibitor activity then those from women at term or women preterm not in labor. I~ This suggests that an abnormally low a m o u n t of this inhibitor may contribute to the pathophysiology of p r e t e r m labor. T h e 1,4-dihydropyridine class o f calcium channel blockers such as nifedipine may function as exogenous inhibitors and thereby achieve tocolysis.
Pharmacology Currendy, 9 calcium antagonists are marketed in the United States for treatment o f hypertension, angina, and supraventricular arrhythmias. O f these, only diltiazem, nicardipine, and verapamil are available in intravenous formulations. T h e bioavailability after oral administration depends o n the first-pass metabolism in the intestinal wall and liver. All calcium channel blockers are metabolized in the liver to a different degree. 1I Nifedipine is available in both an immediateand sustained-release formulation. Immediaterelease nifedipine is over 90% absorbed and approximately 60% to 70% bioavailable after hepatic metabolization. T h e kidney excretes it primarily as 2 biologically inactive metabolites. Nifedipine acts in about 20 minutes and peak plasma concentrations are reached between 30 and 60 minutes. T h e elimination haft-life is approximately 2 to 3 hours. Iz Calcium channel blockade is reversible after cessation of the drug, and repeated dosing does not result in tachyphylaxis. I3
265
Several studies have examined the pharmacokinetics o f nifedipine in p r e g n a n t women. 14,1~ These suggest that m e a n peak and trough serum concentrations are similar for pregnant and n o n p r e g n a n t women, although levels in pregnant women vary considerably. In one study, the maternal peak serum concentration after sublingual therapy ranged from 23.4 to 197.9 n g / mL. 15 The same authors r e p o r t e d a mean elimination half-life o f 81 minutes (range, 49 to 137 minutes). Neonatal nifedipine levels varied depending on when the last dose o f nifedipine was given. Five hours after maternal nifedipine ingestion, neonatal levels were consistently less than 6 n g / m L A 5 T h e dosage o f nifedipine used for treatment o f preterm labor varies widely across clinical triMs. Most regimens use a loading dose of 10 to 40 mg over the first h o u r followed by maintenance doses of 10 to 60 mg every 4 to 12 hours. Although the maximum r e c o m m e n d e d dally dose o f nifedipine is 120 mg/day, some trials showing greater efficacy have used m a x i m u m doses o f up to 160 m g / d a y to achieve tocolysis with no increase in maternal side effects. I6 The most comm o n side effects include transient facial flushing, headache, and nausea. Less c o m m o n side effects include palpitations, dizziness, chest pain, nasal congestion, and heartburn. 17
Fetal Effects In h u m a n studies, there is n o evidence that calcium channel blockers adversely affect the fetus. However, conflicting data from animal studies have p r o m p t e d many investigators to recomm e n d their use with caution. T h e calcium antagonists cross the placenta to varying degrees. Ferguson et allg were the first to describe significant placental transfer o f nifedipine in humans, and others have subsequently identified the drug in fetal serum, amniotic fluid, and breast milk. is The fetal-maternal serum ratio of nifedipine varies widely across studies with a mean of about 66%/3 The calcium channel blockers do not appear to have a teratogenic effect on the fetus.I9,2~A large case control study showed no significant increased risk of congenital anomalies among 586 mothers who had been exposed to calcium channel blockers as compared with 907 controls (2.6% versus 2.4%, respectively).2I Nifedipine is
266
Economy and Abuhamad
excreted into h u m a n breast milk in amounts less than 5% o f a therapeutic dose. 22 This is in contrast to diltiazem, which passes freely into breast milk and appears at concentrations almost equal to peak serum concentrations. 2a N o n e o f the calcium channel blockers are contraindicated in breastfeeding. The major adverse fetal effect r e p o r t e d in animal studies is a decrease in uteroplacental blood flow secondary to maternal hypotension. A significant fall in maternal arterial pressure decreases uterine blood flow and may lead to fetal hypoxemia and acidosis. Parisi et al ~4 reported a reduction in maternal placental blood flow, decrease in fetal pH, fetal bradycardia, and death in 5 o f 15 near-term ewes after nicardipine infusion. A n o t h e r study o f nicardipine infusion in the p r e g n a n t rabbit showed a similar decrease in uteroplacental flow. 25 Richichi et al26 studied the chrpnic effects o f high dose nifedipine in rats as c o m p a r e d with low dose and placebo and d o c u m e n t e d lower weight in rat pups in the high dose group. They postulated that this decrease in fetal weight may be due to an underperfusion o f the uterus and placenta as a secondary effect o f over-dilatation o f the peripheral vasculature. In general, the animal studies that have docu m e n t e d adverse fetal effects reported maternal serum concentrations o f calcium channel blockers that were m u c h higher than those known to be therapeutic in humans. One study in ewes that used low-dose nifedipine to achieve levels comparable to h u m a n doses showed persistent acidosis and hypoxemia in the fetus despite only a transient fall in maternal blood pressure. 18 H u m a n studies have not supported these adverse outcomes. In o n e o f the original studies o f placental transfer o f nifedipine in humans, Doppler studies were p e r f o r m e d and the fetuses were delivered soon after maternal ingestion. The fetal serum level was approximately 74% of the maternal level. T h e m e a n umbilical artery systolic/diastolic ratios were u n c h a n g e d after administration, and all fetuses had 1-minute Apgar scores greater than 7.14 Mari et a127 measured maximum velocity waveforms in the middle cerebral, renal, and umbilical arteries before and 5 hours after nifedipine administration to the mother. T h e y f o u n d n o significant differences between the measurements. 27 In clinical trials of calcium channel blockers
for tocolysis, fetuses in the calcium antagonist arms have outcomes that are similar, and in some cases better, than those for o t h e r tocolytics such as ritodrine and magnesium. 16,z8-sa Papatsonis et al39 c o m p a r e d the neonatal o u t c o m e o f 185 fetuses b o r n to mothers who had b e e n randomized to receive treatment with nifedipine or ritodrine. After controlling for gestational age, newborns in the nifedipine group had a significantly lower risk of respiratory distress syndrome, intracranial bleeding, and neonatal jaundice, a9 In summary, although some animal data have shown adverse effects from calcium channel blockers, the p r e p o n d e r a n c e o f evid e n c e from clinical trials suggests that these agents are safe with respect to fetal outcome.
Maternal Effects W h e n used for tocolysis, calcium channel blockers have 2 primary effects, those on uterine contractility and those on uterine perfusion. In vitro and in vivo data show that the 1,4-dihydropyridine agents are p o t e n t selective inhibitors o f myometrial contractions. In one of the original studies o f tocolytic effects, Csapo et al40 measured uterine electrical response to nicardipine in the rabbit uterus and showed a decrease in activity. This same group studied tocolytic effect in the p r e g n a n t rat and were able to arrest labor and delay delivery of subsequent rat pups after spontaneous delivery o f the first fetus. 4~ Additional studies in the ewe d o c u m e n t e d similar inhibition of uterine contractions in active labor at doses that did not produce major hemodynamic changes in the mother. In vitro studies o f h u m a n myometrial strips obtained from w o m e n u n d e r g o i n g cesarean delivery in the third trimester showed that nifedipine produces a doserelated decrease in oxytocin-induced contraction strength. 41 Nifedipine has also b e e n shown to inhibit contractions induced by potassium, prostaglandins, and vasopressin. 42-44 Calcium channel blockers act directly on uterine artery smooth muscle to increase perfusion, particularly in hypertensive subjects in whom the vessels may be constricted. However, these agents can also decrease perfusion indirectly by causing a fall in mean arterial pressure (MAP) and cardiac output. Animal data conflict regarding which effect predominates. Histologic analysis of uterine and placental tissue o f rats treated
Calcium Channel Blockers as Tocolytics
with nifedipine showed an increase in the vascularization and dilation of sinusoids over untreated rats suggesting that the overall effect is o n e of increased perfusion. 26 Ducsay et al45 investigated the effects of nifedipine administration in pregnant rhesus monkeys and r e p o r t e d decreases in maternal MAP and uterine blood flow with associated fetal hypoxemia. A similar study o f nifedipine infusion in sheep showed that when the blood pressure of the m o t h e r fell by approximately 15%, uterine blood flow decreased by 21%. 46 Veille et al47 studied the effects o f bolus infusion of nifedipine o n maternal m e a n arterial pressure and uterine blood flow in goats and n o t e d that an immediate and transient fall in MAP p r o d u c e d no significant change in uterine blood flow. Most recently, Blea et al~s c o m p a r e d low-dose and high dose nifedipine infusion with placebo in sheep and f o u n d that the low-dose nifedipine caused a transient 25% decrease in blood flow to the uterus with a corresponding significant increase in vascular resistance. O f note, their low-dose group achieved serum levels that were comparable to therapeutic levels in humans. Many studies in humans have used Doppler ultrasound to look for changes in uterine artery blood flow after administration o f calcium channel blockers. Marl et al27 f o u n d n o difference in systolic to diastolic (S/D) ratios before and 5 hours after treatment. Pirhonen et al 4s n o t e d that nifedipine caused a 10% decrease in maternal MAP and a fall in the S / D ratio o f the uterine but not the arcuate arteries. A study o f hypertensive p r e g n a n t women who received b o t h oral and intravenous nicardipine showed n o decrease in uterine artery perfusion by Doppler study. 49 In summary, data from h u m a n studies suggest that calcium channel blockers may cause a clinically insignificant fall in maternal m e a n arterial pressure, but have little to n o effect on uterine perfusion. 5~
Toeolytic Effectiveness Nifedipine is the primary calcium channel blocker used for tocolysis, and several studies have examined its efficacy. T h e majority o f the studies compare the use of nifedipine to ritodrine. A search o f MEDLINE (1966-2000) with the search terms "calcium channel blockers,"
267
"randomized controlled trial," "preterm labor," "calcium antagonist," "tocolysis," and "nifedipine" yielded 15 prospective randomized trials involving the use o f calcium channel blockers. 16, 28-~, 5~-~4Thirteen o f the 15 r e p o r t e d on nifedipine c o m p a r e d with a n o t h e r tocolytic (magnesium, ritodrine, terbutaline or diltiazem). O f the remaining studies one c o m p a r e d nicardipine with magnesium 3s and the o t h e r c o m p a r e d nifedipine with n o treatment for maintenance tocolysis only. 54 In addition, there have b e e n 2 meta-analyses o f r a n d o m i z e d trials comparing nifedipine with ritodrine. 55-~6 T h e r e have b e e n no randomized trials comparing calcium channel blockers to placebo. In 1980, Ulmsten et al3 r e p o r t e d on 10 primigravid women with p r e t e r m labor defined by regular uterine contractions who had b e e n treated with nifedipine for three days. They used a protocol of 30 mg loading dose followed by 20 mg every 5 hours. In all patients, contractions stopped and delivery was postponed for at least 3 days. T h e m e a n interval to delivery was 14.3 days. T h e same authors next r e p o r t e d on 28 women with preterm labor. 57 With a slightly different protocol of 30 mg loading dose and 20 mg every 8 hours, they achieved tocolysis for 72 hours in 23 o f the patients. In the first r a n d o m i z e d prospective study, 60 women with p r e t e r m contractions were allocated to receive either ritodrine, nifedipine or no treatment. Success was defined as delay of delivery for 48 hours. Success rates were 75% for the nifedipine treated patients, 45% in the ritodrine group and 35% in the control group. 28 Subsequently, Ferguson et ala0 published the first study that used a m o r e stringent definition of preterm labor (contractions accompanied by cervical change). They randomized 66 women to either nifedipine or ritodrine and found n o significant difference between the 2 in their ability to delay delivery 48 or 72 hours. They did find a greater incidence and severity o f maternal side effects a m o n g the ritodrine-treated women as c o m p a r e d to the nifedipine-treated women, s~ These results were supported by others who f o u n d that nifedipine was at least as successful as ritodrine in delaying delivery up to 48 hours. In the largest randomized controlled trial to date, Papatsonis et a116 r a n d o m i z e d 185 women with singleton pregnancies to receive nifedipine or ritodrine. The two treatment arms were strati-
268
Economy and Abuhamad
fled for gestational age and state of membranes. Preterm labor was defined as regular uterine contractions a n d / o r rupture of the membranes. Patients in the nifedipine group received loading doses from 10 to 40 mg followed by maintenance doses of 60 to 160 mg of slow-release per day for the first 3 days. They were then weaned to 20 mg 3 times per day until a gestational age of 34 weeks. At 7 days, there was a statistically significant difference among undelivered women between those who had taken nifedipine (62.1%) and those who had taken ritodrine (42.3%, P = .009).a6 The authors postulated that they were able to show a significantly greater tocolytic effect than other studies because they used higher doses of nifedipine. Despite this higher dose, the nifedipine-treated patients still had a lower incidence of side effects. A meta-analysis of randomized studies of nifedipi~e and ritodrine evaluated the data from 10 studies involving 681 patients. 5~ They obtained summary odds ratios for the following end points: delay of delivery for 48 hours, delay of delivery to 36 weeks gestation, prevention of perinatal mortality, and prevention of respiratory distress syndrome and admission to the neonatal intensive care unit (NICU). The pooled odds ratio for delivery within 48 hours was 0.85 (95% CI 0.69-1.0) and for delay of delivery to 36 weeks it was 0.72 (95% CI 0.55, 0.91) both in favor of nifedipine. The nifedipine-treated infants also had a decreased risk of respiratory distress syndrome (OR 0.72, 95% CI 0.54,0.96) and admission to the NICU (OR 0.60,95% CI 0.42,0.86), although only 2 studies reported outcome data on NICU admissions. There was no significant difference in perinatal mortality between the ritodrine and nifedipine groups (OR 1.12, 95% CI 0.69,2.1). The authors had planned to do a formal analysis of maternal side effects, but the data collected from the studies was too heterogeneous to accomplish this. However, in the 5 studies that reported on side effects, the incidence was 16% (23 of 147) in the nifedipine-treated patients and 45% (73 of 132) in the ritodrine-treated group. A second meta-analysis published more recently of trials of nifedipine and beta-adrenergic agents produced similar results. ~6 This analysis excluded two of the studies above because patients received other tocolytics before randomizaton 29,a~ and included another study compar-
ing nifedipine with terbutaline) 4 These authors found similar results that nifedipine was more effective than ritodrine or terbutaline in delaying delivery at least 48 hours (summary OR 1.52,95% CI 1.03,2.24). However, they also showed significant prolongation of gestation over 34 weeks in the nifedipine treated women (OR 1.87, 95% CI 1.11, 3.15). Both sets of authors concluded that nifidipine should be considered over beta-adrenergic agents as first line treatment for preterm labor. Calcium channel blockers have also been compared to magnesium in prospective trials. Glock et a136 reported the first such study in which they randomized 80 singleton pregnancies from 20 to 34 weeks with documented cervical change to receive either nifedipine or magnesium. There was no statistically significant difference in tocolytic efficacy between the 2 agents. In addition, there were significantly fewer maternal side effects requiring drug discontinuation in the nifedipine group. Forty-one percent of the nifedipine treated patients experienced a transient drop in blood pressure that did n o t produce lasting fetal hemodynamic compromise. In a similar study, Haghighi et al a7 randomized 74 patients to oral nifedipine or parental magnesium sulfate. Their results suggested that although oral nifedipine had the same efficacy as magnesium sulfate it acted significantly more quickly to arrest uterine contractions. In the first trial of nicardipine in humans, Larmon et alas randomized 122 patients between 24 and 34 weeks' gestation with docum e n t e d preterm labor to receive nicardipine or parental magnesium. Preterm labor was defined as regular uterine contractions associated with cervical change. No significant difference in tocolytic efficacy between the 2 regimens was noted; however, there was a statistically significant difference in the time required for each agent to effect cessation of contractions (3.3 hours for nifedipine compared with 5.3 hours for magnesium sulfate). Patients in the magnesium sulfate group were more likely to have recurrence of preterm labor necessitating further tocolytic attempts (P = .048) and more likely to have adverse side effects (P = .004). Lastly, one study has reported on nifedipine used solely for maintenance tocolysis. 54 Carl" et al54 compared nifedipine to no treatment in 74
Calcium Channel Blockers as Tocolytics
patients who had already received intravenously magnesium tocolysis for 24 to 48 hours. Nifedipine therapy was initiated after magnesium was discontinued and patients were discharged h o m e on a regimen of 20 mg every 4 to 6 hours or n o treatment. Nifedipine was discontinued at 37 weeks. Maintenance therapy with nifedipine did not significantly prolong pregnancy or improve neonatal outcome over no treatment. Data comparing the various calcium antagonism to each other are limited. E1-Sayed et alss randomized 69 women to maintenance tocolysis with either diltiazem or nifedipine after intraveneous tocolysis with magnesium sulfate. Significandy fewer patients reached 37 weeks in the diltiazem group (15.1% versus 41.7%, P = .019) and gestational age was significantly lower in the diltiazem group (mean 35.5 weeks versus 33.4 weeks, P = .022). However, given the lack o f data supporting maintenance tocolysis with any tocolytic, these results should be interpreted with some caution. In summary, available data on the use o f calcium channel blockers support their use as tocolytic agents that are at least as effective as ritodrine, magnesium, terbutaline or n o treatment. These medications may be preferable because they decrease the incidence o f maternal side effects. Calcium antagonists offer the advantage of ease of administration, lack o f n e e d for blood level monitoring, and minimal adverse maternal effect profile.
Safety A n u m b e r of studies in nonobstetric populations have suggested that calcium channel blocker use may be linked to increased risk o f myocardial infarction, malignancy, a n d gastrointestinal hemorrhage. Case control studies in older, nonp r e g n a n t patients with coronary artery disease reported that use o f immediate release calcium antagonists may increase the risk for fatal myocardial infarction. 58 O n e meta-analysis incorporating data from 8350 patients f o u n d a small but a statistically significant increased risk o f mortality in patients treated with nifedipine (RR 1.16,95% CI 1.01,1.33). 59,6~Although questions have b e e n raised about the validity o f this data and about the applicability o f this data to pregn a n t women, older gravidas being treated for hypertension a n d / o r diabetes may be at risk as
269
these patients could have occult coronary artery disease. 1,61 In addition, patients with diabetes may represent a special subgroup for whom calcium inhibitors increase the risk of cardiovascular complications. 1 T h e r e has b e e n at least one case report in the literature o f a myocardial infarction in a healthy 29 year old at 29 weeks gestation who received 2 doses of slow-release nifedipine and developed hypotension and a non-Q-wave myocardial infarction. 62 However, this patient had first received ritodrine and the authors postulated that nifedipine may have exacerbated the effects o f the tachycardia by causing hypotension. In the 14 randomized controlled trials comparing nifedipine with o t h e r agents for tocolysis, no serious adverse effects were n o t e d from nifedipine treatment. Observational studies suggesting that calcium channel blockers are carcinogenic show small increased relative risks in patients who received calcium antagonists for any indication. 63 However, this data came from long-term users, and there is n o evidence that short-term use for tocolysis increases the risk o f any type of cancer, either site-specific or overall. Last, there has b e e n c o n c e r n raised about the concomitant use of calcium channel blockers and magnesium sulfate. Neuromuscular blockade has been r e p o r t e d in 2 patients, one receiving nifedipine for tocolysis 64 the other for hypertension. 65 This extremely rare event can be reversed with calcium gluconate and cessation of magnesium therapy. Cardiac depression has been d o c u m e n t e d in vitro when nifedipine was added to magnesium-infused hearts, 66 and there has been a r e p o r t o f severe hypotension in 2 patients who received both magnesium and nifedipine. 67 Although these risks are largely theoretical, patients receiving b o t h agents should have careful h e m o d y n a m i c monitoring while loading doses are administered.
Conclusion In summary, calcium channel blockers have been used as tocolytics for over 20 years. Data from numerous r a n d o m i z e d clinical trials suggest that they are at least as effective and in some cases more effective than magnesium, ritodrine, or terbutaline. In addition, they have the advantage of fewer serious side effects. Although some
270
Economy and Abuhamad
a n i m a l s t u d i e s r a i s e d c o n c e r n a b o u t t h e i r safety, e v i d e n c e f r o m t r i a l s i n h u m a n s h a v e s h o w n calc i u m c h a n n e l b l o c k e r s t o b e safe a n d e f f i c a c i o u s tocolytics.
18.
19. References 1. Abernethy DR, Schwartz JB: Calcium-antagonist drugs. N EnglJ Med 341:1447-1457, 1999 2. Mosler KH, Rosenboom HG: Newer possibilities of tocolytic treatment in obstetrics. Z Geburtshilfe Perinatol 176:85-96, 1972 3. Ulmsten U, Andersson KE, Wingerup L: Treatment of premature labor with the calcium antagonist nifedipine. Arch Gynecol 229:1-5, 1980 4. Singh BN: The mechanism of action of calcium antagonists relative to their cfinical applications. BrJ Clin Pharmacol 21:109S-121S, 1986 5. McDonald TF, Pelzer S, Trautwein W, et al: Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol Rev 74:365-507, 1994 6. An4drawis NS, Gilligan J, Abernethy DR: Endothelin-Imediated vasoconstriction: specific blockade by verapamil. Clin Pharmacol Ther 52:583-589, 1992 7. Nelson MT, Standen NB, Brayden JE, et al: Noradrenaline contracts arteries by activating voltage-dependent calcium channels. Nature 336:382-385, 1988 8. Young RC, Smith LH, McLaren MD: T-type and L-type calcium currents in freshly dispersed human uterine smooth muscle cells. Am J Obstet Gynecol 169:785-792, 1993 9. Emery SP, Idriss E, Richmonds C, et al: Human fetal membranes release a C a + + channel inhibitor. Am J Obstet Gynecol 179:989-993, 1998 10. Carroll EM, GianopoulosJG, Collins PL: Abnormality of calcium channel inhibitor released from fetal membranes in preterm labor. A m J Obstet Gynecol 184:356362, 2001 11. Abernethy DR, Schwartz JB: Pharmacokinetics of calcium antagonists under development. Clin Pharmacokinet 15:1-14, 1988 12. Raemsch KD, SommerJ: Pharmacokinetics and metabolism of nifedipine. Hypertension 5:II18-1124, 1983 13. Childress CH, Katz VL: Nifedipine and its indications in obstetrics and gynecology. Obstet Gynecol 83:616-624, 1994 14. Pirhonen JP, Erkkola RU, Ekblad UU, et al: Single dose of nifedipine in normotensive pregnancy: Nifedlpine concentrations, hemodynamic responses, and uterine and fetal flow velocity waveforms. Obstet Gynecol 76: 807-811, 1990 15. Ferguson JE, 2nd, Schutz T, Pershe R, et al: Nifedipine pharmacokinetics during preterm labor tocolysis. Am J Obstet Gynecol 161:1485-1490, 1989 16. Papatsonis DN, Van Geijn HP, Ader HJ, et al: Nifedipine and ritodrine in the management of preterm labor: A randomized multicenter trial. Obstet Gynecol 90:230234, 1997 17. Higby K, Xenakis EM, Pauerstein CJ: Do tocolytic agents stop preterm labor? A critical and comprehensive review
20.
21.
22. 23. 24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
of efficacy and safety. Am J Obstet Gynecol 168:12471256; discussion 1256-1259, 1993 Blea CW, Barnard JM, Magness RR, et al: Effect of nifedipine on fetal and maternal hemodynamics and blood gases in the pregnant ewe. Am J Obstet Gynecol 176:922-930, 1997 Soreusen HT, Steffensen FH, Olesen C, et al: Pregnancy outcome in women exposed to calcium channel blockers. Reprod Toxicol 12:383-384, 1998 Magee LA, Schick B, Donnenfeld AE, et al: The safety of calcium channel blockers in human pregnancy: A prospective, multicenter cohort study. A m J Obstet Gynecol 174:823-828, 1996 Sorensen HT, Czeizel AE, Rockenbauer M, et al: The risk of limb deficiencies and other congenital abnormalities in children exposed in utero to calcium channel blockers. Acta Ohstet Gynecol Scand 80:397-401, 2001 Ehrenkranz RA, Ackerman BA, Hulse JD: Nifedipine transfer into human milk. J Pediatr 114:478-480, 1989 Briggs G, Freeman R, Yaffe S: Drugs in Pregnancy and Lactation. Baltimore, MD, Wilkins & Wilkins, 1990 Parisi VM, Salinas J, Stockmar EJ: Fetal vascular responses to maternal nicardlpine administration in the hypertensive ewe. Am J Obstet Gynecol 161:1035-1039, 1989 Lirette M, Holbrook RH, Katz M: Cardiovascular and uterine blood flow changes during nicardipine HC1 tocolysis in the rabbit. Obstet Gynecol 69:79-82, 1987 Richichi J, Vasilenko P: The effects of nifedipine on pregnancy outcome and morphology of the placenta, uterus, and cervix during late pregnancy in the rat. A m J Obstet Gynecol 167:797-803, 1992 Marl G, Kirshon B, Moise KJ, Jr, et al: Doppler assessment of the fetal and uteroplacental circulation during nffedipine therapy for preterm labor. Am J Obstet Gynecol 161:1514-1518, 1989 Read MD, Wellby DE: The use of a calcium antagonist (nffedipine) to suppress preterm labour. Br J Obstet Gynaecol 93:933-937, 1986 Meyer WR, Randall HW, Graves WL: Nifedipine versus ritodrine for suppressing preterm labor. J Reprod Med 35:649-653, 1990 Ferguson JE 2nd, Dyson DC, Schutz T, et al: A comparison of tocolysis with nifedipine or ritodrine: Analysis of efficacy and maternal, fetal, and neonatal outcome. AnlJ Obstet Gynecol 163:105-111, 1990 Bracero LA, Leikin E, Kirshenbaum N, et al: Comparison of nifedlpine and ritodrine for the treatment of preterm labor. A m J Perinatol 8:365-369, 1991 Koks CA, Brolmann HA, de Kleine MJ, et al: A randomized comparison of nifedipine and ritodrine for suppression of preterm labor. EurJ Obstet Gynecol Reprod Biol 77:171-176, 1998 Kupferminc M, Lessing JB, Yaron Y, et al: Nifedipine versus ritodrine for suppression of preterm labour. B r J Obstet Gynaecol 100:1090-1094, 1993 Smith CS, Woodland MB: Clinical comparison of oral nifedipine and subcutaneous terbutaline for initial tocolysis. Am J Perinatol 10:280-284, 1993 Garcia-VelascoJA GG: A prospective randomized trial of nffedipine vs. ritrodrine in threatened preterm labor. InflJ Gynaecol Obstet 61:239-244, 1998
Calcium Channel Blockers as Tocolytics
36. Glock JL, Morales wJ: Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: A randomized study. Am J Obstet Gynecol 169:960-964, 1993 37. Haghighi L. Prevention of preterm delivery: Nifedipine or magnesium sulfate. IntJ Gynaecol Obstet 66:297-298, 1999 38. I.annon JE, Ross BS, May WL, et al: Oral nicardipine versus intravenous magnesium sulfate for the treatment of preterm labor. Am J Obstet Gynecol 181:1432-1437, 1999 39. Papatsonis DN, Kok JH, van Geijn HP, et al: Neonatal effects of nifedipine and ritodrine for preterm labor. Obstet Gynecol 95:477-481, 2000 40. Csapo AI, Puri CP, Tarro S, et al: Deactivation of the uterus during normal and premature labor by the calcium antagonist nicardipine. A m J Obstet Gynecol 142: 483-491, 1982 41. Bird LM, Anderson NC, Jr, Chandler ML, et al: The effects of aminophylline and nifedipine on contractility of isolated pregnant human myometrium. Am J Obstet Gynecol 157:171-177, 1987 42. Andersson KE, Ingemarsson I, Ulmsten U, et al: Inhibition of prostaglandin-induced uterine activity by nifedipine. BrJ Obstet Gynaecol 86:175-9, 1979 43. Forman A, Andersson KE, Ulmsten U: Inhibition of myometrial activity by calcium antagonists. Semin Perinatol 5:288-294, 1981 44. Forman A, Gandrup P, Andersson KE, et al: Effects of nifedipine on oxytocin- and prostaglandin F2 alpha-induced activity in the postpartum uterus. Am J Obstet Gynecol 144:665-670, 1982 45. Ducsay CA, Thompson JS, Wu AT, et al: Effects of calcium entry blocker (nicardipine) tocolysis in rhesus macaques: Fetal plasma concentrations and cardiorespiratory changes. A m J Obstet Gynecol 157:1482-1486, 1987 46. Harake B, Gilbert RD, Ashwal S, et al: Nffedipine: Effects on fetal and maternal hemodynamics in pregnant sheep. Am J Obstet Gynecol 157:1003-1008, 1987 47. Veille JC, Bissonnette JM, Hohimer AR: The effect of a calcium channel blocker (nifedipine) on uterine blood flow in the pregnant goat. Am J Obstet Gynecol 154: 1160-1163, 1986 48. PirhonenJP, Erkkola RU, Ekblad UU: Uterine and fetal flow velocity waveforms in hypertensive pregnancy: The effect of a single dose of nlfedipine. Obstet Gynecol 76:37-41, 1990 49. Carbonne B, Jannet D, Touboul C, et al: Nicardipine treatment of hypertension during pregnancy. Obstet Gynecol 81:908-914, 1993 50. Ferguson JE 2nd, Dyson DC, Holbrook RH, Jr, et al: Cardiovascular and metabolic effects associated with nifedipine and ritodrine tocolysis. Am J Obstet Gynecol 161:788-795, 1989 51. Papatsonis DN, van Geijn HP, Dekker GA: Management
9.71
of preterm labour. Nifedipine in management of preterm labour is safe. BMJ 319:257, 1999 (letter) 52. Janky E, LengJJ, Cormier PH, et al: A randomized study of the treatment of threatened premature labor. Nffedipine versus ritodrine. J Gynecol Obstet Biol Reprod 19:478482, 1990 53. EI-Sayed YY, Holbrook RH, Jr, Gibson R, et ai: Diltiazem for maintenance tocolysis of preterm labor: Comparison to nifedipine in a randomized trial. J Matem Fetal Med 7:217-221, 1998 54. Carr DB, Clark AL, Kernek K, et al: Maintenance oral nifedipine for preterm labor: A randomized clinical trial. A m J Obstet Gynecol 181:822-827, 1999 55. Oei SG, Mol BW, de Kleine MJ, et al: Nifedipine versus ritodrine for suppression of preterm labor; A meta-analysis. Acta Obstet Gynecol Scand 78:783-788, 1999 56. Tsatsaris V, Carbonne B, Papatsonis D, et al: Nifedipine versus ritodrine for suppression of preterm labor; A meta-analysis. Acta Obstet Gynecol Scand 79:618-619, 20OO 57. Ulmsten U: Treatment of normotensive and hypertensive patients with preterm labor using oral nifedipine, a calcium antagonist. Arch Gynecol 236:69-72, 1984 58. Psaty BM, Heckbert SR, Koepsell TD, et al: The risk of myocardial infarction associated with anfihypertensive drug therapies. JAMA 274:620-625, 1995 59. Furberg CD, Psaty BM: Corrections to the nifedipine meta-analysis. Circulation 93:1475-1476, 1996 60. Furberg CD, Psaty BM, Meyer JV: Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation 92:1326-1331, 1995 61. Davis WB, Wells SR, KullerJA, et al: Analysis of the risks associated with calcium channel blockade: Implications for the obstetrician~rynecologis. Obstetrical and Gynecologcial Survey 54:179-182, 1999 62. Oei SG, Oei SK, Brolmann HA: Myocardial infarction during nifedipine therapy for preterm labor. N Engl J Med 340:154, 1999 (letter) 63. Jick H, tick S, Derby LE, et al: Calcium-channel blockers and risk of cancer. Lancet 349:525-528, 1997 64. Snyder SW, CardweU MS: Neuromuscular blockade with magnesium sulfate and nifedipine. AmJ Obstet Gynecol 161:35-36, 1989 65. Ben-Ami M, Giladi Y, Shalev E: The combination of magnesium sulphate and nffedipine: A cause of neuromuscular blockade. Br J Obstet Gynaecol 101:262-263, 1994 66. Thorp JM, Jr, Spielman FJ, Valea FA, et al: Nifedipine enhances the cardiac toxicity of magnesium sulfate in the isolated perfused Spragne-Dawley rat heart. Am J Obstet Gynecol 163:655-656, 1990 67. Waisman GD, Mayorga LM, Camera MI, et ai: Magnesium plus nifedipine: potentiation of hypotensive effect in preeclampsia? AmJ Obstet Gyneco1159:308-309, 1988
This artide reviews the clinical and basic science investigations regarding the safety and efficacy o f calcium channel blockers as tocolytic agents. The authors reviewed the English langt~age literatm-e o n the pharmacology and clinical applications o f calcium antagonists in obstetrics. A MEI)LINE (19662000) search was performed with the terms "calcium channel blockers, . . . . randomized controlled trial," "preterm labor," "calcium antagonist," "tocolysis," and "nifedipine." References from these data sources were then used to find additional studies. Animal data and clinical trials in humans were included. The safety o f these agents was researched in published data from the nonobstetric as well as obstetric literature. The calcium channel blockers most commonly used as tocolytics are nifedipine and nicardipine. These agents act to inhibit calcium influx across cell membranes, thereby decreasing tone in the smooth muscle o f the vasculature. They act as profound vasodilatory agents and have minimal effect on the cardiac conduction system. Numerous randomized clinical trials have shown them to be as effective as beta-mimetics and magnesium in achieving tocolysis. When used for tocolysis, calcium antagonists have fewer maternal side effects than other tocolytics and have n o adverse effect o n fetal outcome. Copyrigl~ 9 2001 by W . B . Saunders
Company
alcium channel blockers, also known as calcium inhibitors or calcium antagonists, were first used in clinical medicine in the 1960s, They have since e m e r g e d as frontline agents in the treatment of patients with hypertension and cardiac arrhythmias. 1 In 1972, verapamil was reported in the obstetrical literature as a treatment for preterm labor; however, its use was limited secondary to maternal side effects. 2 Almost a decade later, the first prospective study o f nifedipine as a tocolyfic suggested that these agents may be safe and effective for use in p r e g n a n t women, a Today, calcium channel blockers are widely used in obstetrics as tocolytics and for the treatment o f hypertension. T h e calcium antagonists represent a diverse group of c o m p o u n d s that act both on the cardiac conduction system, primarily causing depression at the sinoatrial and atrioventricular nodes, and on the smooth muscle of the vasculature causing vasodilatafion and lowering of
C
From the Division of Maternal Fetal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and Division of Maternal Fetal Medicine, Eastern Virginia Medical School, Norfork, VA. Address reprint requests to Katherine E. Economy, MD, Harvard Medical School, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. C(/lzyright 9 2001 by W.B. Saunders Company 0146-0005/01/2505-0002535. 00/0 doi:10.10 53/sper. 2001. 2 7165
264
blood pressure. 4 The classification o f calcium channel blockers depends o n their core chemical structure. T h e most important classes for obstetrics and gynecology are the phenylalkyline (verapamil-like), the benzothiazepine (diltiazemlike), and the dihydropyiridine (nifedipine-like) types. 1 The latter group, which includes nifedipine, nicardipine and nitrendipine, are the most potent vasodilators and selectively inhibit myometrial contractions both in vitro and in vivo. They have less effect on the cardiac conduction system than other classes of calcium antagonists and therefore result in minimal depression of sinoatrial and atrioventricular nodal function. O f the calcium antagonists, nifedipine has been the most commonly used in clinical trials of tocolysis. Mechanism of Action Although they differ chemically and pharmacologically, all the calcium antagonists act primarily by blocking the transmembrane influx o f calcium ions through voltage-dependent, slowly inactivating (L-type) calcium channels. 5 These L-type channels have been f o u n d in vascular and nonvascular smooth muscle, cardiac muscle, and in a n u m b e r of noncontractile tissues such as pancreas, gastric mucosa, and the adrenal glands/ T h e regulation of L-type channels differs by tissue-type. In cardiac myocytes they are activated by a variety o f stimuli including cat-
Seminars in Perinatology, Vol 25, No 5 (October), 2001: pp 264-271
Calcium Channd Blockers as Tocolytics
echolamines, endothelin, and the alpha-adrenergic system. 6,7 In the pregnant uterus, calcium channels play a vital role in the normal process o f parturition. During labor, myometrial contractions require an increase in intracellular concentration. This occurs partly t h r o u g h L-type channels. 8 Both L-type and T-type channels have b e e n identified in h u m a n myocytes and nifedipine has b e e n shown to inhibit the L-type, whereas magnesium inhibits the T-type channels. 8 Because L-type channels increase intracellular free calcium by bulk calcium transport, the effect o f I.~type inhibitors may be primarily to decrease the amplitude o f contractions, a It has b e e n shown that h u m a n fetal membranes release an e n d o g e n o u s calcium channel inhibitor. 9 Membranes from women in preterm labor have significantly lower e n d o g e n o u s calcium channel inhibitor activity then those from women at term or women preterm not in labor. I~ This suggests that an abnormally low a m o u n t of this inhibitor may contribute to the pathophysiology of p r e t e r m labor. T h e 1,4-dihydropyridine class o f calcium channel blockers such as nifedipine may function as exogenous inhibitors and thereby achieve tocolysis.
Pharmacology Currendy, 9 calcium antagonists are marketed in the United States for treatment o f hypertension, angina, and supraventricular arrhythmias. O f these, only diltiazem, nicardipine, and verapamil are available in intravenous formulations. T h e bioavailability after oral administration depends o n the first-pass metabolism in the intestinal wall and liver. All calcium channel blockers are metabolized in the liver to a different degree. 1I Nifedipine is available in both an immediateand sustained-release formulation. Immediaterelease nifedipine is over 90% absorbed and approximately 60% to 70% bioavailable after hepatic metabolization. T h e kidney excretes it primarily as 2 biologically inactive metabolites. Nifedipine acts in about 20 minutes and peak plasma concentrations are reached between 30 and 60 minutes. T h e elimination haft-life is approximately 2 to 3 hours. Iz Calcium channel blockade is reversible after cessation of the drug, and repeated dosing does not result in tachyphylaxis. I3
265
Several studies have examined the pharmacokinetics o f nifedipine in p r e g n a n t women. 14,1~ These suggest that m e a n peak and trough serum concentrations are similar for pregnant and n o n p r e g n a n t women, although levels in pregnant women vary considerably. In one study, the maternal peak serum concentration after sublingual therapy ranged from 23.4 to 197.9 n g / mL. 15 The same authors r e p o r t e d a mean elimination half-life o f 81 minutes (range, 49 to 137 minutes). Neonatal nifedipine levels varied depending on when the last dose o f nifedipine was given. Five hours after maternal nifedipine ingestion, neonatal levels were consistently less than 6 n g / m L A 5 T h e dosage o f nifedipine used for treatment o f preterm labor varies widely across clinical triMs. Most regimens use a loading dose of 10 to 40 mg over the first h o u r followed by maintenance doses of 10 to 60 mg every 4 to 12 hours. Although the maximum r e c o m m e n d e d dally dose o f nifedipine is 120 mg/day, some trials showing greater efficacy have used m a x i m u m doses o f up to 160 m g / d a y to achieve tocolysis with no increase in maternal side effects. I6 The most comm o n side effects include transient facial flushing, headache, and nausea. Less c o m m o n side effects include palpitations, dizziness, chest pain, nasal congestion, and heartburn. 17
Fetal Effects In h u m a n studies, there is n o evidence that calcium channel blockers adversely affect the fetus. However, conflicting data from animal studies have p r o m p t e d many investigators to recomm e n d their use with caution. T h e calcium antagonists cross the placenta to varying degrees. Ferguson et allg were the first to describe significant placental transfer o f nifedipine in humans, and others have subsequently identified the drug in fetal serum, amniotic fluid, and breast milk. is The fetal-maternal serum ratio of nifedipine varies widely across studies with a mean of about 66%/3 The calcium channel blockers do not appear to have a teratogenic effect on the fetus.I9,2~A large case control study showed no significant increased risk of congenital anomalies among 586 mothers who had been exposed to calcium channel blockers as compared with 907 controls (2.6% versus 2.4%, respectively).2I Nifedipine is
266
Economy and Abuhamad
excreted into h u m a n breast milk in amounts less than 5% o f a therapeutic dose. 22 This is in contrast to diltiazem, which passes freely into breast milk and appears at concentrations almost equal to peak serum concentrations. 2a N o n e o f the calcium channel blockers are contraindicated in breastfeeding. The major adverse fetal effect r e p o r t e d in animal studies is a decrease in uteroplacental blood flow secondary to maternal hypotension. A significant fall in maternal arterial pressure decreases uterine blood flow and may lead to fetal hypoxemia and acidosis. Parisi et al ~4 reported a reduction in maternal placental blood flow, decrease in fetal pH, fetal bradycardia, and death in 5 o f 15 near-term ewes after nicardipine infusion. A n o t h e r study o f nicardipine infusion in the p r e g n a n t rabbit showed a similar decrease in uteroplacental flow. 25 Richichi et al26 studied the chrpnic effects o f high dose nifedipine in rats as c o m p a r e d with low dose and placebo and d o c u m e n t e d lower weight in rat pups in the high dose group. They postulated that this decrease in fetal weight may be due to an underperfusion o f the uterus and placenta as a secondary effect o f over-dilatation o f the peripheral vasculature. In general, the animal studies that have docu m e n t e d adverse fetal effects reported maternal serum concentrations o f calcium channel blockers that were m u c h higher than those known to be therapeutic in humans. One study in ewes that used low-dose nifedipine to achieve levels comparable to h u m a n doses showed persistent acidosis and hypoxemia in the fetus despite only a transient fall in maternal blood pressure. 18 H u m a n studies have not supported these adverse outcomes. In o n e o f the original studies o f placental transfer o f nifedipine in humans, Doppler studies were p e r f o r m e d and the fetuses were delivered soon after maternal ingestion. The fetal serum level was approximately 74% of the maternal level. T h e m e a n umbilical artery systolic/diastolic ratios were u n c h a n g e d after administration, and all fetuses had 1-minute Apgar scores greater than 7.14 Mari et a127 measured maximum velocity waveforms in the middle cerebral, renal, and umbilical arteries before and 5 hours after nifedipine administration to the mother. T h e y f o u n d n o significant differences between the measurements. 27 In clinical trials of calcium channel blockers
for tocolysis, fetuses in the calcium antagonist arms have outcomes that are similar, and in some cases better, than those for o t h e r tocolytics such as ritodrine and magnesium. 16,z8-sa Papatsonis et al39 c o m p a r e d the neonatal o u t c o m e o f 185 fetuses b o r n to mothers who had b e e n randomized to receive treatment with nifedipine or ritodrine. After controlling for gestational age, newborns in the nifedipine group had a significantly lower risk of respiratory distress syndrome, intracranial bleeding, and neonatal jaundice, a9 In summary, although some animal data have shown adverse effects from calcium channel blockers, the p r e p o n d e r a n c e o f evid e n c e from clinical trials suggests that these agents are safe with respect to fetal outcome.
Maternal Effects W h e n used for tocolysis, calcium channel blockers have 2 primary effects, those on uterine contractility and those on uterine perfusion. In vitro and in vivo data show that the 1,4-dihydropyridine agents are p o t e n t selective inhibitors o f myometrial contractions. In one of the original studies o f tocolytic effects, Csapo et al40 measured uterine electrical response to nicardipine in the rabbit uterus and showed a decrease in activity. This same group studied tocolytic effect in the p r e g n a n t rat and were able to arrest labor and delay delivery of subsequent rat pups after spontaneous delivery o f the first fetus. 4~ Additional studies in the ewe d o c u m e n t e d similar inhibition of uterine contractions in active labor at doses that did not produce major hemodynamic changes in the mother. In vitro studies o f h u m a n myometrial strips obtained from w o m e n u n d e r g o i n g cesarean delivery in the third trimester showed that nifedipine produces a doserelated decrease in oxytocin-induced contraction strength. 41 Nifedipine has also b e e n shown to inhibit contractions induced by potassium, prostaglandins, and vasopressin. 42-44 Calcium channel blockers act directly on uterine artery smooth muscle to increase perfusion, particularly in hypertensive subjects in whom the vessels may be constricted. However, these agents can also decrease perfusion indirectly by causing a fall in mean arterial pressure (MAP) and cardiac output. Animal data conflict regarding which effect predominates. Histologic analysis of uterine and placental tissue o f rats treated
Calcium Channel Blockers as Tocolytics
with nifedipine showed an increase in the vascularization and dilation of sinusoids over untreated rats suggesting that the overall effect is o n e of increased perfusion. 26 Ducsay et al45 investigated the effects of nifedipine administration in pregnant rhesus monkeys and r e p o r t e d decreases in maternal MAP and uterine blood flow with associated fetal hypoxemia. A similar study o f nifedipine infusion in sheep showed that when the blood pressure of the m o t h e r fell by approximately 15%, uterine blood flow decreased by 21%. 46 Veille et al47 studied the effects o f bolus infusion of nifedipine o n maternal m e a n arterial pressure and uterine blood flow in goats and n o t e d that an immediate and transient fall in MAP p r o d u c e d no significant change in uterine blood flow. Most recently, Blea et al~s c o m p a r e d low-dose and high dose nifedipine infusion with placebo in sheep and f o u n d that the low-dose nifedipine caused a transient 25% decrease in blood flow to the uterus with a corresponding significant increase in vascular resistance. O f note, their low-dose group achieved serum levels that were comparable to therapeutic levels in humans. Many studies in humans have used Doppler ultrasound to look for changes in uterine artery blood flow after administration o f calcium channel blockers. Marl et al27 f o u n d n o difference in systolic to diastolic (S/D) ratios before and 5 hours after treatment. Pirhonen et al 4s n o t e d that nifedipine caused a 10% decrease in maternal MAP and a fall in the S / D ratio o f the uterine but not the arcuate arteries. A study o f hypertensive p r e g n a n t women who received b o t h oral and intravenous nicardipine showed n o decrease in uterine artery perfusion by Doppler study. 49 In summary, data from h u m a n studies suggest that calcium channel blockers may cause a clinically insignificant fall in maternal m e a n arterial pressure, but have little to n o effect on uterine perfusion. 5~
Toeolytic Effectiveness Nifedipine is the primary calcium channel blocker used for tocolysis, and several studies have examined its efficacy. T h e majority o f the studies compare the use of nifedipine to ritodrine. A search o f MEDLINE (1966-2000) with the search terms "calcium channel blockers,"
267
"randomized controlled trial," "preterm labor," "calcium antagonist," "tocolysis," and "nifedipine" yielded 15 prospective randomized trials involving the use o f calcium channel blockers. 16, 28-~, 5~-~4Thirteen o f the 15 r e p o r t e d on nifedipine c o m p a r e d with a n o t h e r tocolytic (magnesium, ritodrine, terbutaline or diltiazem). O f the remaining studies one c o m p a r e d nicardipine with magnesium 3s and the o t h e r c o m p a r e d nifedipine with n o treatment for maintenance tocolysis only. 54 In addition, there have b e e n 2 meta-analyses o f r a n d o m i z e d trials comparing nifedipine with ritodrine. 55-~6 T h e r e have b e e n no randomized trials comparing calcium channel blockers to placebo. In 1980, Ulmsten et al3 r e p o r t e d on 10 primigravid women with p r e t e r m labor defined by regular uterine contractions who had b e e n treated with nifedipine for three days. They used a protocol of 30 mg loading dose followed by 20 mg every 5 hours. In all patients, contractions stopped and delivery was postponed for at least 3 days. T h e m e a n interval to delivery was 14.3 days. T h e same authors next r e p o r t e d on 28 women with preterm labor. 57 With a slightly different protocol of 30 mg loading dose and 20 mg every 8 hours, they achieved tocolysis for 72 hours in 23 o f the patients. In the first r a n d o m i z e d prospective study, 60 women with p r e t e r m contractions were allocated to receive either ritodrine, nifedipine or no treatment. Success was defined as delay of delivery for 48 hours. Success rates were 75% for the nifedipine treated patients, 45% in the ritodrine group and 35% in the control group. 28 Subsequently, Ferguson et ala0 published the first study that used a m o r e stringent definition of preterm labor (contractions accompanied by cervical change). They randomized 66 women to either nifedipine or ritodrine and found n o significant difference between the 2 in their ability to delay delivery 48 or 72 hours. They did find a greater incidence and severity o f maternal side effects a m o n g the ritodrine-treated women as c o m p a r e d to the nifedipine-treated women, s~ These results were supported by others who f o u n d that nifedipine was at least as successful as ritodrine in delaying delivery up to 48 hours. In the largest randomized controlled trial to date, Papatsonis et a116 r a n d o m i z e d 185 women with singleton pregnancies to receive nifedipine or ritodrine. The two treatment arms were strati-
268
Economy and Abuhamad
fled for gestational age and state of membranes. Preterm labor was defined as regular uterine contractions a n d / o r rupture of the membranes. Patients in the nifedipine group received loading doses from 10 to 40 mg followed by maintenance doses of 60 to 160 mg of slow-release per day for the first 3 days. They were then weaned to 20 mg 3 times per day until a gestational age of 34 weeks. At 7 days, there was a statistically significant difference among undelivered women between those who had taken nifedipine (62.1%) and those who had taken ritodrine (42.3%, P = .009).a6 The authors postulated that they were able to show a significantly greater tocolytic effect than other studies because they used higher doses of nifedipine. Despite this higher dose, the nifedipine-treated patients still had a lower incidence of side effects. A meta-analysis of randomized studies of nifedipi~e and ritodrine evaluated the data from 10 studies involving 681 patients. 5~ They obtained summary odds ratios for the following end points: delay of delivery for 48 hours, delay of delivery to 36 weeks gestation, prevention of perinatal mortality, and prevention of respiratory distress syndrome and admission to the neonatal intensive care unit (NICU). The pooled odds ratio for delivery within 48 hours was 0.85 (95% CI 0.69-1.0) and for delay of delivery to 36 weeks it was 0.72 (95% CI 0.55, 0.91) both in favor of nifedipine. The nifedipine-treated infants also had a decreased risk of respiratory distress syndrome (OR 0.72, 95% CI 0.54,0.96) and admission to the NICU (OR 0.60,95% CI 0.42,0.86), although only 2 studies reported outcome data on NICU admissions. There was no significant difference in perinatal mortality between the ritodrine and nifedipine groups (OR 1.12, 95% CI 0.69,2.1). The authors had planned to do a formal analysis of maternal side effects, but the data collected from the studies was too heterogeneous to accomplish this. However, in the 5 studies that reported on side effects, the incidence was 16% (23 of 147) in the nifedipine-treated patients and 45% (73 of 132) in the ritodrine-treated group. A second meta-analysis published more recently of trials of nifedipine and beta-adrenergic agents produced similar results. ~6 This analysis excluded two of the studies above because patients received other tocolytics before randomizaton 29,a~ and included another study compar-
ing nifedipine with terbutaline) 4 These authors found similar results that nifedipine was more effective than ritodrine or terbutaline in delaying delivery at least 48 hours (summary OR 1.52,95% CI 1.03,2.24). However, they also showed significant prolongation of gestation over 34 weeks in the nifedipine treated women (OR 1.87, 95% CI 1.11, 3.15). Both sets of authors concluded that nifidipine should be considered over beta-adrenergic agents as first line treatment for preterm labor. Calcium channel blockers have also been compared to magnesium in prospective trials. Glock et a136 reported the first such study in which they randomized 80 singleton pregnancies from 20 to 34 weeks with documented cervical change to receive either nifedipine or magnesium. There was no statistically significant difference in tocolytic efficacy between the 2 agents. In addition, there were significantly fewer maternal side effects requiring drug discontinuation in the nifedipine group. Forty-one percent of the nifedipine treated patients experienced a transient drop in blood pressure that did n o t produce lasting fetal hemodynamic compromise. In a similar study, Haghighi et al a7 randomized 74 patients to oral nifedipine or parental magnesium sulfate. Their results suggested that although oral nifedipine had the same efficacy as magnesium sulfate it acted significantly more quickly to arrest uterine contractions. In the first trial of nicardipine in humans, Larmon et alas randomized 122 patients between 24 and 34 weeks' gestation with docum e n t e d preterm labor to receive nicardipine or parental magnesium. Preterm labor was defined as regular uterine contractions associated with cervical change. No significant difference in tocolytic efficacy between the 2 regimens was noted; however, there was a statistically significant difference in the time required for each agent to effect cessation of contractions (3.3 hours for nifedipine compared with 5.3 hours for magnesium sulfate). Patients in the magnesium sulfate group were more likely to have recurrence of preterm labor necessitating further tocolytic attempts (P = .048) and more likely to have adverse side effects (P = .004). Lastly, one study has reported on nifedipine used solely for maintenance tocolysis. 54 Carl" et al54 compared nifedipine to no treatment in 74
Calcium Channel Blockers as Tocolytics
patients who had already received intravenously magnesium tocolysis for 24 to 48 hours. Nifedipine therapy was initiated after magnesium was discontinued and patients were discharged h o m e on a regimen of 20 mg every 4 to 6 hours or n o treatment. Nifedipine was discontinued at 37 weeks. Maintenance therapy with nifedipine did not significantly prolong pregnancy or improve neonatal outcome over no treatment. Data comparing the various calcium antagonism to each other are limited. E1-Sayed et alss randomized 69 women to maintenance tocolysis with either diltiazem or nifedipine after intraveneous tocolysis with magnesium sulfate. Significandy fewer patients reached 37 weeks in the diltiazem group (15.1% versus 41.7%, P = .019) and gestational age was significantly lower in the diltiazem group (mean 35.5 weeks versus 33.4 weeks, P = .022). However, given the lack o f data supporting maintenance tocolysis with any tocolytic, these results should be interpreted with some caution. In summary, available data on the use o f calcium channel blockers support their use as tocolytic agents that are at least as effective as ritodrine, magnesium, terbutaline or n o treatment. These medications may be preferable because they decrease the incidence o f maternal side effects. Calcium antagonists offer the advantage of ease of administration, lack o f n e e d for blood level monitoring, and minimal adverse maternal effect profile.
Safety A n u m b e r of studies in nonobstetric populations have suggested that calcium channel blocker use may be linked to increased risk o f myocardial infarction, malignancy, a n d gastrointestinal hemorrhage. Case control studies in older, nonp r e g n a n t patients with coronary artery disease reported that use o f immediate release calcium antagonists may increase the risk for fatal myocardial infarction. 58 O n e meta-analysis incorporating data from 8350 patients f o u n d a small but a statistically significant increased risk o f mortality in patients treated with nifedipine (RR 1.16,95% CI 1.01,1.33). 59,6~Although questions have b e e n raised about the validity o f this data and about the applicability o f this data to pregn a n t women, older gravidas being treated for hypertension a n d / o r diabetes may be at risk as
269
these patients could have occult coronary artery disease. 1,61 In addition, patients with diabetes may represent a special subgroup for whom calcium inhibitors increase the risk of cardiovascular complications. 1 T h e r e has b e e n at least one case report in the literature o f a myocardial infarction in a healthy 29 year old at 29 weeks gestation who received 2 doses of slow-release nifedipine and developed hypotension and a non-Q-wave myocardial infarction. 62 However, this patient had first received ritodrine and the authors postulated that nifedipine may have exacerbated the effects o f the tachycardia by causing hypotension. In the 14 randomized controlled trials comparing nifedipine with o t h e r agents for tocolysis, no serious adverse effects were n o t e d from nifedipine treatment. Observational studies suggesting that calcium channel blockers are carcinogenic show small increased relative risks in patients who received calcium antagonists for any indication. 63 However, this data came from long-term users, and there is n o evidence that short-term use for tocolysis increases the risk o f any type of cancer, either site-specific or overall. Last, there has b e e n c o n c e r n raised about the concomitant use of calcium channel blockers and magnesium sulfate. Neuromuscular blockade has been r e p o r t e d in 2 patients, one receiving nifedipine for tocolysis 64 the other for hypertension. 65 This extremely rare event can be reversed with calcium gluconate and cessation of magnesium therapy. Cardiac depression has been d o c u m e n t e d in vitro when nifedipine was added to magnesium-infused hearts, 66 and there has been a r e p o r t o f severe hypotension in 2 patients who received both magnesium and nifedipine. 67 Although these risks are largely theoretical, patients receiving b o t h agents should have careful h e m o d y n a m i c monitoring while loading doses are administered.
Conclusion In summary, calcium channel blockers have been used as tocolytics for over 20 years. Data from numerous r a n d o m i z e d clinical trials suggest that they are at least as effective and in some cases more effective than magnesium, ritodrine, or terbutaline. In addition, they have the advantage of fewer serious side effects. Although some
270
Economy and Abuhamad
a n i m a l s t u d i e s r a i s e d c o n c e r n a b o u t t h e i r safety, e v i d e n c e f r o m t r i a l s i n h u m a n s h a v e s h o w n calc i u m c h a n n e l b l o c k e r s t o b e safe a n d e f f i c a c i o u s tocolytics.
18.
19. References 1. Abernethy DR, Schwartz JB: Calcium-antagonist drugs. N EnglJ Med 341:1447-1457, 1999 2. Mosler KH, Rosenboom HG: Newer possibilities of tocolytic treatment in obstetrics. Z Geburtshilfe Perinatol 176:85-96, 1972 3. Ulmsten U, Andersson KE, Wingerup L: Treatment of premature labor with the calcium antagonist nifedipine. Arch Gynecol 229:1-5, 1980 4. Singh BN: The mechanism of action of calcium antagonists relative to their cfinical applications. BrJ Clin Pharmacol 21:109S-121S, 1986 5. McDonald TF, Pelzer S, Trautwein W, et al: Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol Rev 74:365-507, 1994 6. An4drawis NS, Gilligan J, Abernethy DR: Endothelin-Imediated vasoconstriction: specific blockade by verapamil. Clin Pharmacol Ther 52:583-589, 1992 7. Nelson MT, Standen NB, Brayden JE, et al: Noradrenaline contracts arteries by activating voltage-dependent calcium channels. Nature 336:382-385, 1988 8. Young RC, Smith LH, McLaren MD: T-type and L-type calcium currents in freshly dispersed human uterine smooth muscle cells. Am J Obstet Gynecol 169:785-792, 1993 9. Emery SP, Idriss E, Richmonds C, et al: Human fetal membranes release a C a + + channel inhibitor. Am J Obstet Gynecol 179:989-993, 1998 10. Carroll EM, GianopoulosJG, Collins PL: Abnormality of calcium channel inhibitor released from fetal membranes in preterm labor. A m J Obstet Gynecol 184:356362, 2001 11. Abernethy DR, Schwartz JB: Pharmacokinetics of calcium antagonists under development. Clin Pharmacokinet 15:1-14, 1988 12. Raemsch KD, SommerJ: Pharmacokinetics and metabolism of nifedipine. Hypertension 5:II18-1124, 1983 13. Childress CH, Katz VL: Nifedipine and its indications in obstetrics and gynecology. Obstet Gynecol 83:616-624, 1994 14. Pirhonen JP, Erkkola RU, Ekblad UU, et al: Single dose of nifedipine in normotensive pregnancy: Nifedlpine concentrations, hemodynamic responses, and uterine and fetal flow velocity waveforms. Obstet Gynecol 76: 807-811, 1990 15. Ferguson JE, 2nd, Schutz T, Pershe R, et al: Nifedipine pharmacokinetics during preterm labor tocolysis. Am J Obstet Gynecol 161:1485-1490, 1989 16. Papatsonis DN, Van Geijn HP, Ader HJ, et al: Nifedipine and ritodrine in the management of preterm labor: A randomized multicenter trial. Obstet Gynecol 90:230234, 1997 17. Higby K, Xenakis EM, Pauerstein CJ: Do tocolytic agents stop preterm labor? A critical and comprehensive review
20.
21.
22. 23. 24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
of efficacy and safety. Am J Obstet Gynecol 168:12471256; discussion 1256-1259, 1993 Blea CW, Barnard JM, Magness RR, et al: Effect of nifedipine on fetal and maternal hemodynamics and blood gases in the pregnant ewe. Am J Obstet Gynecol 176:922-930, 1997 Soreusen HT, Steffensen FH, Olesen C, et al: Pregnancy outcome in women exposed to calcium channel blockers. Reprod Toxicol 12:383-384, 1998 Magee LA, Schick B, Donnenfeld AE, et al: The safety of calcium channel blockers in human pregnancy: A prospective, multicenter cohort study. A m J Obstet Gynecol 174:823-828, 1996 Sorensen HT, Czeizel AE, Rockenbauer M, et al: The risk of limb deficiencies and other congenital abnormalities in children exposed in utero to calcium channel blockers. Acta Ohstet Gynecol Scand 80:397-401, 2001 Ehrenkranz RA, Ackerman BA, Hulse JD: Nifedipine transfer into human milk. J Pediatr 114:478-480, 1989 Briggs G, Freeman R, Yaffe S: Drugs in Pregnancy and Lactation. Baltimore, MD, Wilkins & Wilkins, 1990 Parisi VM, Salinas J, Stockmar EJ: Fetal vascular responses to maternal nicardlpine administration in the hypertensive ewe. Am J Obstet Gynecol 161:1035-1039, 1989 Lirette M, Holbrook RH, Katz M: Cardiovascular and uterine blood flow changes during nicardipine HC1 tocolysis in the rabbit. Obstet Gynecol 69:79-82, 1987 Richichi J, Vasilenko P: The effects of nifedipine on pregnancy outcome and morphology of the placenta, uterus, and cervix during late pregnancy in the rat. A m J Obstet Gynecol 167:797-803, 1992 Marl G, Kirshon B, Moise KJ, Jr, et al: Doppler assessment of the fetal and uteroplacental circulation during nffedipine therapy for preterm labor. Am J Obstet Gynecol 161:1514-1518, 1989 Read MD, Wellby DE: The use of a calcium antagonist (nffedipine) to suppress preterm labour. Br J Obstet Gynaecol 93:933-937, 1986 Meyer WR, Randall HW, Graves WL: Nifedipine versus ritodrine for suppressing preterm labor. J Reprod Med 35:649-653, 1990 Ferguson JE 2nd, Dyson DC, Schutz T, et al: A comparison of tocolysis with nifedipine or ritodrine: Analysis of efficacy and maternal, fetal, and neonatal outcome. AnlJ Obstet Gynecol 163:105-111, 1990 Bracero LA, Leikin E, Kirshenbaum N, et al: Comparison of nifedlpine and ritodrine for the treatment of preterm labor. A m J Perinatol 8:365-369, 1991 Koks CA, Brolmann HA, de Kleine MJ, et al: A randomized comparison of nifedipine and ritodrine for suppression of preterm labor. EurJ Obstet Gynecol Reprod Biol 77:171-176, 1998 Kupferminc M, Lessing JB, Yaron Y, et al: Nifedipine versus ritodrine for suppression of preterm labour. B r J Obstet Gynaecol 100:1090-1094, 1993 Smith CS, Woodland MB: Clinical comparison of oral nifedipine and subcutaneous terbutaline for initial tocolysis. Am J Perinatol 10:280-284, 1993 Garcia-VelascoJA GG: A prospective randomized trial of nffedipine vs. ritrodrine in threatened preterm labor. InflJ Gynaecol Obstet 61:239-244, 1998
Calcium Channel Blockers as Tocolytics
36. Glock JL, Morales wJ: Efficacy and safety of nifedipine versus magnesium sulfate in the management of preterm labor: A randomized study. Am J Obstet Gynecol 169:960-964, 1993 37. Haghighi L. Prevention of preterm delivery: Nifedipine or magnesium sulfate. IntJ Gynaecol Obstet 66:297-298, 1999 38. I.annon JE, Ross BS, May WL, et al: Oral nicardipine versus intravenous magnesium sulfate for the treatment of preterm labor. Am J Obstet Gynecol 181:1432-1437, 1999 39. Papatsonis DN, Kok JH, van Geijn HP, et al: Neonatal effects of nifedipine and ritodrine for preterm labor. Obstet Gynecol 95:477-481, 2000 40. Csapo AI, Puri CP, Tarro S, et al: Deactivation of the uterus during normal and premature labor by the calcium antagonist nicardipine. A m J Obstet Gynecol 142: 483-491, 1982 41. Bird LM, Anderson NC, Jr, Chandler ML, et al: The effects of aminophylline and nifedipine on contractility of isolated pregnant human myometrium. Am J Obstet Gynecol 157:171-177, 1987 42. Andersson KE, Ingemarsson I, Ulmsten U, et al: Inhibition of prostaglandin-induced uterine activity by nifedipine. BrJ Obstet Gynaecol 86:175-9, 1979 43. Forman A, Andersson KE, Ulmsten U: Inhibition of myometrial activity by calcium antagonists. Semin Perinatol 5:288-294, 1981 44. Forman A, Gandrup P, Andersson KE, et al: Effects of nifedipine on oxytocin- and prostaglandin F2 alpha-induced activity in the postpartum uterus. Am J Obstet Gynecol 144:665-670, 1982 45. Ducsay CA, Thompson JS, Wu AT, et al: Effects of calcium entry blocker (nicardipine) tocolysis in rhesus macaques: Fetal plasma concentrations and cardiorespiratory changes. A m J Obstet Gynecol 157:1482-1486, 1987 46. Harake B, Gilbert RD, Ashwal S, et al: Nffedipine: Effects on fetal and maternal hemodynamics in pregnant sheep. Am J Obstet Gynecol 157:1003-1008, 1987 47. Veille JC, Bissonnette JM, Hohimer AR: The effect of a calcium channel blocker (nifedipine) on uterine blood flow in the pregnant goat. Am J Obstet Gynecol 154: 1160-1163, 1986 48. PirhonenJP, Erkkola RU, Ekblad UU: Uterine and fetal flow velocity waveforms in hypertensive pregnancy: The effect of a single dose of nlfedipine. Obstet Gynecol 76:37-41, 1990 49. Carbonne B, Jannet D, Touboul C, et al: Nicardipine treatment of hypertension during pregnancy. Obstet Gynecol 81:908-914, 1993 50. Ferguson JE 2nd, Dyson DC, Holbrook RH, Jr, et al: Cardiovascular and metabolic effects associated with nifedipine and ritodrine tocolysis. Am J Obstet Gynecol 161:788-795, 1989 51. Papatsonis DN, van Geijn HP, Dekker GA: Management
9.71
of preterm labour. Nifedipine in management of preterm labour is safe. BMJ 319:257, 1999 (letter) 52. Janky E, LengJJ, Cormier PH, et al: A randomized study of the treatment of threatened premature labor. Nffedipine versus ritodrine. J Gynecol Obstet Biol Reprod 19:478482, 1990 53. EI-Sayed YY, Holbrook RH, Jr, Gibson R, et ai: Diltiazem for maintenance tocolysis of preterm labor: Comparison to nifedipine in a randomized trial. J Matem Fetal Med 7:217-221, 1998 54. Carr DB, Clark AL, Kernek K, et al: Maintenance oral nifedipine for preterm labor: A randomized clinical trial. A m J Obstet Gynecol 181:822-827, 1999 55. Oei SG, Mol BW, de Kleine MJ, et al: Nifedipine versus ritodrine for suppression of preterm labor; A meta-analysis. Acta Obstet Gynecol Scand 78:783-788, 1999 56. Tsatsaris V, Carbonne B, Papatsonis D, et al: Nifedipine versus ritodrine for suppression of preterm labor; A meta-analysis. Acta Obstet Gynecol Scand 79:618-619, 20OO 57. Ulmsten U: Treatment of normotensive and hypertensive patients with preterm labor using oral nifedipine, a calcium antagonist. Arch Gynecol 236:69-72, 1984 58. Psaty BM, Heckbert SR, Koepsell TD, et al: The risk of myocardial infarction associated with anfihypertensive drug therapies. JAMA 274:620-625, 1995 59. Furberg CD, Psaty BM: Corrections to the nifedipine meta-analysis. Circulation 93:1475-1476, 1996 60. Furberg CD, Psaty BM, Meyer JV: Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation 92:1326-1331, 1995 61. Davis WB, Wells SR, KullerJA, et al: Analysis of the risks associated with calcium channel blockade: Implications for the obstetrician~rynecologis. Obstetrical and Gynecologcial Survey 54:179-182, 1999 62. Oei SG, Oei SK, Brolmann HA: Myocardial infarction during nifedipine therapy for preterm labor. N Engl J Med 340:154, 1999 (letter) 63. Jick H, tick S, Derby LE, et al: Calcium-channel blockers and risk of cancer. Lancet 349:525-528, 1997 64. Snyder SW, CardweU MS: Neuromuscular blockade with magnesium sulfate and nifedipine. AmJ Obstet Gynecol 161:35-36, 1989 65. Ben-Ami M, Giladi Y, Shalev E: The combination of magnesium sulphate and nffedipine: A cause of neuromuscular blockade. Br J Obstet Gynaecol 101:262-263, 1994 66. Thorp JM, Jr, Spielman FJ, Valea FA, et al: Nifedipine enhances the cardiac toxicity of magnesium sulfate in the isolated perfused Spragne-Dawley rat heart. Am J Obstet Gynecol 163:655-656, 1990 67. Waisman GD, Mayorga LM, Camera MI, et ai: Magnesium plus nifedipine: potentiation of hypotensive effect in preeclampsia? AmJ Obstet Gyneco1159:308-309, 1988