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PubMed2004

Pharmacokinetics of tocolytic agents.

Tocolytic agents are drugs designed to inhibit contractions of myometrial smooth muscle cells. Such an effect has been demonstrated in vitro or in vivo for several pharmacological agents, including beta-adrenergic agonists, calcium channel antagonists, oxytocin antagonists, NSAIDs and magnesium sulfate. However, the aim of tocolysis is not only to stop uterine contractions or to prevent preterm delivery, but to prevent perinatal morbidity and mortality associated with preterm birth. The achievement of this goal has not yet been clearly demonstrated for any of the drugs available, and the use of tocolytic agents may appear controversial. Therefore, it is important to avoid maternal and fetal toxicity when tocolytic agents are used. During pregnancy, all steps of drug pharmacokinetics are altered. Absorption of drugs administered orally is limited because of delayed stomach emptying and reduced intestinal motility. The volume of distribution of drugs is increased. The metabolic activity of the liver is increased, accelerating the metabolism of lipophilic drugs. Renal filtration is increased, leading to enhanced renal elimination of water-soluble drugs. These modifications are generally responsible for reduced plasma concentration and reduced half-life of most drugs. These specific modifications have to be taken into account when using a drug in pregnant women. The aim of this review is to provide the reader with pharmacological data about drugs currently used to treat preterm labour. Such data in pregnant women may affect the choice of optimal drug dosage and route of administration.

Adrenergic beta-Agonists↗
PubMed1982

The use of magnesium sulfate as the primary tocolytic agent to prevent premature delivery.

The efficacy of magnesium sulfate was evaluated as the primary tocolytic agent in the management of patients at risk for premature delivery. One hundred ninety-two patients determined to be 36 weeks' gestation or less were treated. One hundred seven patients (55.7%) received an additional oral beta-mimetic agent once labor was arrested. One hundred nineteen patients had intact membranes and 73 patients had ruptured membranes. Delay of delivery of 48 hours or longer was achieved in 70.6% of the patients with intact membranes and 60.2% of patients with ruptured membranes. Intervening obstetric complications, maternal morbidity, and neonatal septic and respiratory morbidity were increased in patients with ruptured membranes compared to patients with intact membranes. Magnesium sulfate is considered to be effective tocolytic agent having minimal adverse effects in managing patients at risk for premature delivery. Its use in patients with ruptured membranes, as with any tocolytic agent, remains controversial.

Adolescent↗
PubMed1993

Do tocolytic agents stop preterm labor? A critical and comprehensive review of efficacy and safety.

OBJECTIVE: Our aim was to determine the efficacy and safety of tocolytic agents currently used to treat premature labor. STUDY DESIGN: We carried out a comprehensive review of tocolytic agents in the treatment of premature labor. Three hundred twenty-eight studies published between 1933 and 1992 were analyzed. RESULTS: An analysis of randomized, placebo-controlled, clinical trials showed that magnesium sulfate is not better than placebo in the treatment of premature labor. beta-Adrenergic receptor agonists effectively stop premature labor for only 24 to 48 hours. Calcium channel blockers and oxytocin antagonists inhibit uterine contractions, but their role in stopping labor is undefined. Prostaglandin inhibitors appear to be effective in treating premature labor and have few adverse side effects. CONCLUSIONS: The only tocolytic drugs that might be effective are the prostaglandin inhibitors. Tocolytic agents should be used only between 24 and 32 completed weeks of gestation. Magnesium sulfate should not be used to treat premature labor. Oxytocin antagonists should be used only in experimental clinical trials. Calcium channel blockers and beta-adrenergic receptor agonists inhibit uterine contractions but do not prolong gestation for longer than 48 hours.

Adrenergic beta-Agonists↗
PubMed1995

Ritodrine and nifedipine as tocolytic agents: a preliminary comparison.

The effectiveness of the tocolytic agent and other betamimetic drugs in the treatment of preterm labor remains controversial. Effectiveness or efficancy of ritodrine has not yet convincingly been proven. A major concern are the marked side effects of beta-mimetics. The calcium channel blocker nifedipine has been used for tocolysis shortly after its introduction in clinical practice and is considered to be a probable good alternative for ritodrine. The efficacy of nifedipine versus ritodrine in the treatment of preterm labor was assessed in a retrospective study. 32 patients received intravenous ritodrine and 29 oral nifedipine. As endpoints were used: postponement of delivery, maternal side effects and perinatal outcome. The results of this retrospective study suggest that nifedipine is more successful in postponing delivery than ritodrine. Maternal side effects seemed to occur more frequently and be more serious in patients treated with ritodrine as compared to nifedipine. Perinatal outcome seemed better in the nifedipine group than in the ritodrine group. The promising data from small prospective studies and the results of this retrospective study warrant further large prospective studies on the definitive place of nifedipine in the treatment of premature labor. Until the results of such a trial are available we advocate the use of nifedipine in case of preterm labor, especially in a patient with diabetes mellitus, ruptured membranes, cardiac disease or multiple pregnancy, in order to avoid the characteristic side effects of beta-mimetics.

Female↗
PubMed2001

Magnesium sulfate as a tocolytic agent.

Although magnesium sulfate is widely used as a tocolytic agent in the hope of preventing spontaneous preterm birth, there is a paucity of data from large well-designed randomized clinical studies demonstrating the efficacy of magnesium sulfate therapy. Given the potential for untoward side effects and the inherent risks of magnesium sulfate therapy, a thorough understanding of the potential risks and benefits of this agent is needed. To accomplish this understanding we have provided a detailed review the history, pharmacology, physiology, maternal/fetal side effects, and tocolytic efficacy of magnesium sulfate.

Adrenergic beta-Agonists↗
PubMed1985

Comparative study of the effects of two tocolytic agents (magnesium sulfate and alcohol) on the ionic transfer through the isolated human amnion.

The effects of two tocolytic agents (MgSO4 and ethanol) on ionic transfer through the isolated human amnion were observed and compared. The ionic transfer was estimated by conductance and ionic flux measurements. MgSO4 increased the ionic conductance (Gt) on the fetal side; it also increased the ionic fluxes from fetus to mother and from mother to fetus, but it decreased the flux ratio. Ethanol decreased Gt in both directions as well as the ionic fluxes; the flux ratio, however, remained constant. Thus, the two tocolytic agents (MgSO4 and ethanol) show a negative effect on ionic transfer through the human amnion.

Amnion↗
PubMed1985

Prolonged use of tocolytic agents in the expectant management of placenta previa.

The effects of the prolonged use (greater than seven days) of tocolytic agents, along with other established procedures of conservative, expectant management, were studied in 45 patients with either total or marginal-partial placenta previa. Our regimen prolonged pregnancy for seven days or more in 81.2% of total placenta previas and 91.7% of marginal-partial ones. Antepartum hospitalization and shortened neonatal length of stay resulted in a total saving of $18,175 per case. The prolonged use of tocolytic agents, in addition to expectant management, in patients with placenta previa increased the length of pregnancy, decreased neonatal morbidity and was cost effective.

Birth Weight↗
PubMed1983

Magnesium sulfate as a tocolytic agent.

Magnesium sulfate (MgSO4) has been successfully used to inhibit premature labor. A retrospective review was performed on the use of MgSO4 as a tocolytic agent at Memorial Hospital, Long Beach, California, during a 4-year period (1978-1982). Three hundred fifty-five patients with diagnoses of premature labor were treated with MgSO4 after transport from another hospital. Two hundred seventy-four patients (77%) had a singleton pregnancy with intact membranes, 38 (11%) had a singleton pregnancy with ruptured membranes, 35 (10%) had a multiple gestation with intact membranes, and eight (2%) had a multiple gestation with ruptured membranes. Delivery was successfully delayed in the majority of patients, and the incidence of unexplained failure of tocolysis was only 2%. Side effects occurred in 24 patients (7%) and necessitated stopping the drug in only seven (2%). Serum magnesium levels are reported and the use of MgSO4 in patients with significant vaginal bleeding is discussed. MgSO4 was found to be a successful, inexpensive, and relatively nontoxic tocolytic agent that had few side effects.

Female↗
PubMed1986

Affinity of tocolytic agents on human placental and myometrial beta-adrenergic receptors.

The beta-adrenoreceptor antagonist [3H]-dihydroalprenolol (DHA) has been used to label adrenoreceptors in membranes from human pregnant myometrium and placenta. Six tocolytic drugs were tested for their ability to bind to the beta-adrenergic receptor of placental and myometrial membranes. Tocolytic agents competed with [3H]-DHA binding in the following order of potency: clenbuterol greater than fenoterol greater than ritodrine greater than isoxsuprine greater than orciprenaline greater than terbutaline. All drugs competed for [3H]-DHA binding sites with HILL coefficients greater than unity indicating heterogeneity of binding. In general, binding of beta-adrenoreceptor agonists was weaker in myometrium than in placenta homogenates. According to our results it is very likely that the placenta may play an important role in the pharmacological mechanism of tocolytic agents in inhibitory of premature labor.

Adrenergic beta-Agonists↗
PubMed1987

Thermic effects of tocolytic agents: decreased temperature with magnesium sulfate.

The effect of the tocolytic agents terbutaline and magnesium sulfate on patients' temperatures was examined. Fifty-two women admitted for preterm labor were randomized to a treatment protocol for one of the two agents. Oral temperatures were measured initially and every two hours during treatment. There was no significant difference between the initial temperature and the lowest temperature recorded during treatment in the terbutaline group, but temperature decreased significantly during treatment with magnesium sulfate. This decrease in maternal temperature may have importance in the treatment of preterm labor with magnesium sulfate in patients with an infectious etiology for uterine activity.

Adult↗
PubMed2001

Prostaglandin inhibitors as tocolytic agents.

Indomethacin, a nonspecific prostaglandin synthetase inhibitor, gained popularity several decades ago as a potent tocolytic agent. This popularity, however, was tempered by concerns over fetal and neonatal complications associated with its use. However, with better recognition of the safety limitations, there has been a renewed interest in using indomethacin for acute tocolysis. More recently, the tocolytic potential of cyclooxygenase-2 (COX-2) specific inhibitors has gained much interest as well as the theoretical minimization of side effects associated with these agents. This article reviews the pharmacology and efficacy of indomethacin and some of the newer cyclooxygenase-2 inhibitors, and discusses the potential adverse fetal and neonatal effects associated with their use. Guidelines will be presented that will assist theclinician in using indomethacin as an effective tocolytic while avoiding untoward effects.

Cyclooxygenase 2↗
PubMed1990

Tocolytic agents act on calcium channel current in single smooth muscle cells of pregnant rat uterus.

Effects of Ca2+ channel blockers and clinically important tocolytic agents, Mg2+ and beta-agonists, were examined on the Ca2+ channel current recorded from freshly isolated single pregnant rat myometrial cells using the whole-cell voltage clamp method. Nifedipine inhibited the Ca2+ channel currents (Ba2+ current) dose-dependently. Inhibition by nifedipine was greater at higher (more positive) holding potentials and higher command potentials. According to the modulated receptor hypothesis, Kd values for resting state and inactivated state of channel were calculated to be 150-300 and 1.2-6.8 nM, respectively (at a command potential of -20 mV). Mg2+ applied in the bath dose-dependently inhibited the Ca2+ current recorded with 2 mM Ca2+ (Ki = 12 mM, at a command potential of -10 mV). Inhibition by Mg2+ was weaker at the higher command potentials. Voltage dependency observed for the Mg2+ block may be due to a shift of the activation curve (Mg2+ neutralizes the outer surface charge) and/or due to the location of the binding site for Mg2+ in the Ca2+ channel electric field. In contrast, high dose of isoproterenol (10 microM) did not produce significant change in the Ca2+ current. In summary, nifedipine and Mg2+ inhibited the Ca2+ channel, with opposite voltage dependencies, whereas isoproterenol had no effect on the Ca2+ current. Thus, beta-agonist may relax the uterine muscle by mechanisms other than inhibition of the Ca2+ channels.

Animals↗
PubMed1992

Interval to delivery in high-risk patients: do tocolytic agents really work?

Some question whether tocolytic drugs reduce uterine activity and prolong gestation. The interval from discontinuance of tocolytics until spontaneous labor and delivery in patients (n = 69) with documented preterm labor (PTL) versus subjects receiving prophylactic tocolytic therapy (n = 41) was studied. Women with documented PTL delivered sooner after cessation of tocolytics (6.1 +/- 6.9 days) than control (C) patients (14.7 +/- 10.8 days, P less than 0.001). Also, 28 of the 69 (41%) patients in the PTL group delivered within 24 h of discontinuation of tocolysis compared to 4 (10%) in the C group (P less than 0.0004). We conclude that tocolytic therapy for documented preterm labor suppresses uterine activity and when these agents are discontinued, contractions return and labor ensues.

Adult↗
PubMed1986

Design of oxytocin antagonists with prolonged action: potential tocolytic agents for the treatment of preterm labor.

In our continuing effort to produce more potent and specific oxytocin (OT) antagonists that may have value as tocolytic agents, we have synthesized a number of new OT antagonists. Our previous studies have shown that rigid conformational structure and restricted dynamic properties are associated with antagonistic activity of the [1-penicillamine]OT [( Pen1]OT) analogs. We therefore synthesized a series of structural analogs of [Pen1,] OT; [Pen1,Thr4]-OT and [Pen1,Phe2,Thr4]OT with greater restricted conformational features. They are [Pen1,delta 3,4-Pro7]OT; [Pen1,Thr4,delta 3,4-Pro7]OT; [Pen1,Phe2,Thr4,delta 3,4-Pro7]OT; [Pen1, Orn8]OT; [Pen1,Phe2,Thr4,delta 3,4,-Pro7,Orn8]OT; [Pen1, Tyr(OMethyl)2,-Thr4,Orn8]OT; [Pen1,Tyr(OEthyl)2,Thr4,Orn8]OT; [Pen1,Phe(Methyl)2,Thr4,Orn8]OT and [Pen1Phe(Ethyl)2,Thr4, Orn8]OT. As expected, all were found to be potent OT antagonists, with in vitro pA2 values ranging from 5.32 to 7.67. They were also effective OT antagonists in vivo in the term pregnant rats. Structural modifications in the above analogs produced various and interesting effects. Dehydroproline substitution for 7-proline in [Pen1]OT increased antagonistic potency, whereas in [Pen1,Thr4]OT and in [Pen1,Phe2,Thr4]OT decreased antagonistic potency. Most significantly, analogs with O-alkyl-Tyr2, Orn8 and p-alkyl-Phe2,Orn8 substitutions were found to have prolonged action both in the isolated rat uterus assays and in the term pregnant rats. Generally, substitution of the alkyl groups resulted in a reduction in anti-OT potency, and increasing the size of the alkyl substituent from a methylene group to an ethyl group diminished antagonistic potencies markedly.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkylation↗
PubMed1985

Fetal and neonatal effects of indomethacin used as a tocolytic agent.

beta-Mimetic agents are currently recommended for tocolysis. Serious adverse reactions including maternal death may complicate their use. Prostaglandin synthetase inhibitors are effective tocolytic agents. Reports of potential adverse effects have limited clinical use in North America. This study reports the perinatal outcome in 167 infants exposed to indomethacin used for tocolysis in gestations of less than 35 weeks. The rate of preterm delivery was 41.3% (69 of 167). No cases of premature closure of the ductus arteriosus or persistent fetal circulation were observed. The overall perinatal mortality was 17 per 1000 (1.7%). The results support the view of other uncontrolled reports that a short course of indomethacin used for tocolysis in gestations of less than 34 weeks is without deleterious effects on fetus or neonate. Its ease of administration and maternal safety offer advantages over beta-mimetic agents, and prospective comparisons of both should be undertaken.

Birth Weight↗
PubMed2002

In vitro study of tocolytic effect of rofecoxib, a specific cyclo-oxygenase 2 inhibitor. Comparison and combination with other tocolytic agents.

OBJECTIVE: The aim of this work was to study and compare the tocolytic effects of rofecoxib with indomethacin, ritodrine, nicardipine and atosiban. We also studied the combination of rofecoxib with each agent. DESIGN: In vitro animal experimental study. SETTING: Non-selective cyclo-oxygenase (COX) inhibitors have potent tocolytic effect. However, they also have major fetal side effects that seem to be due to COX-1 inhibition. A specific COX-2 inhibitor could be a potent tocolytic agent with less fetal toxicity. SAMPLE: Myometrial strips from pregnant Wistar rats at 18 days of gestation. METHODS: Isometric tension was recorded from 112 pregnant rat myometrial strips in vitro. Strips were exposed to increase molar concentration of one drug or combination. MAIN OUTCOME MEASURES: Contractile activity was assessed by calculating the area under the curve, to obtain a dose-response curve of each drug. EC50 and mean maximal inhibiting concentration were compared using ANOVA. Chemical interaction was defined for each combination. RESULTS: The in vitro tocolytic effect of rofecoxib was demonstrated. Contractile activity stopped at a concentration of 1.6 x 10(-7) M. Effective concentrations were 1000 times less than for indomethacin and significantly lower than ritodrine and atosiban. Rofecoxib combined with ritodrine had a synergic effect. Other combinations only had an additive effect. CONCLUSIONS: Rofecoxib has a potent tocolytic effect in vitro. The high specificity and low effective concentrations of COX-2 may result in low fetal toxicity. Animal fetal side effects need to be explored.

Analysis of Variance↗
PubMed1990

The safety and efficacy of tocolytic agents for the treatment of preterm labor.

Pharmacologic inhibition of uterine contractions remains the mainstay of treatment for preterm labor despite the ongoing controversy regarding its effectiveness. A diverse variety of tocolytic medications have been proposed for clinical use, with betamimetics and magnesium sulfate being the common therapeutic agents of choice in the United States today. The clinician using these agents should be aware of the significant maternal and fetal side-effects associated with these particular medications. New classes of pharmacologic agents, including prostaglandin synthetase inhibitors, calcium channel blockers and phosphodiesterase inhibitors, have been proposed as tocolytic agents and are currently undergoing critical clinical evaluation. The purpose of this review is to provide a compilation of the available clinical studies that document the safety and efficacy of these various tocolytic agents.

Female↗