Carol D. Syracuse

Disposition of meperidine and normeperidine following multiple doses during labor: II. Fetus and neonate

It has been suggested that continued diffusion gradients from mother to fetus would exist and that both meperidine and normeperidine would accumulate in the fetus following multiple doses of meperidine to the mother during labor. However, no pharmacokinetic data are available. Therefore, the purpose of this study was to document the disposition of meperidine and normeperidine in the fetus and neonate following multiple doses of meperidine to the mother over long time periods. Twelve infants were studied. The results show surprisingly high concentrations of both meperidine and normeperidine in fetal blood at delivery. In addition, the amount of normeperidine increased with time in umbilical cord blood, the ratio of normeperidine to meperidine increased with time, and the umbilical artery-to-vein ratio of meperidine (but not normeperidine) was greater than one following long drug-to-delivery intervals. The data also suggest that with long drug-to-delivery intervals the levels of normeperidine may become clinically important and that the elimination of both compounds by the neonate is prolonged. The study suggests that multiple doses to the mother over long time periods result in maximum accumulation of both meperidine and normeperidine in fetal tissues.

The half-life of 2-chloroprocaine.

: The purpose of this study was to examine the discrepancy between the reported in vitro half-life of chloroprocaine and the slower observed disappearance of the drug in maternal plasma. The study had two aims. The first was to redetermine the in vitro half-life of 2-chloroprocaine in maternal and fetal plasma. The second was to determine the apparent half-life of 2-chloroprocaine in vivo after intrapartum epidural anesthesia in obstetric patients. Gas chromatography or gas chromatography/mass spectrometry techniques were used to measure 2-chloroprocaine in maternal or fetal plasma. Mean in vitro half-lives of 11.2 +/- 2.8 and 15.4 +/- 5.2 sec were found for maternal and fetal plasma from nine patients, respectively. The maternal half-life was significantly shorter than the fetal half-life (P less than 0.05). The mean apparent in vivo half-life in maternal plasma was found to be 3.1 +/- 1.6 min. The results of this study show that the half-life in vitro is correctly measured in seconds. However, the apparent half-life in vivo after epidural anesthesia is 3.1 +/- 1.6 min and ranges from 1.5 to 6.4 min. The differences in the magnitude of the two findings is probably due to continuous uptake of the drug from the epidural space.

Disposition of meperidine and normeperidine following multiple doses during labor

Normeperidine, the active meperidine metabolite, has been implicated in adverse neonatal effects that may occur following administration of meperidine to parturients. However, recent studies have suggested that normeperidine levels are not high enough to have adverse effects following single low doses of meperidine. It is not clear what occurs following multiple injections. Therefore the purpose of this study was to quantitate plasma levels of meperidine and normeperidine in the mother following multiple doses of meperidine over long time periods and to determine the half-life of normeperidine. Twelve mothers who received multiple intravenous doses of meperidine were studied. The results show that both meperidine and normeperidine accumulate in maternal plasma following multiple injections and that the half-life of normeperidine averages 20.6 hours. The data suggest that maximum exposure of the fetus to both meperidine and normeperidine would result from multiple doses to the mother because of a continued diffusion gradient from mother to fetus.

Maternal, fetal, and neonatal lidocaine levels following local perineal infiltration

Local infiltration of the perineum is a simple and commonly used technique for providing pain relief for episiotomy. It has always been considered safe and effective because a small amount of local anesthetic agent could be administered quickly and accurately to the perineum just prior to vaginal delivery and cord clamping. Because of the short time interval between local infiltration and delivery, very little anesthetic was thought to reach the fetus. However, the maternal and neonatal disposition of lidocaine following local perineal infiltration has not been well studied. The purpose of this study was to document placental transfer or nontransfer of lidocaine following local perineal infiltration. Fifteen normal parturient women at term and their infants were studied. After local perineal infiltration, the concentrations of lidocaine and two metabolites--monoethyl glycine xylidide and glycine xylidide --were determined in maternal plasma, in the umbilical cord vein at delivery, and in maternal and neonatal plasma or urine for 2 days post partum. Lidocaine and its metabolites were quantitated by gas chromatography-mass spectrometry. The pharmacologic results indicated the following: First, lidocaine is detected in maternal plasma as early as 1 minute after injection, and peak plasma concentrations occur within 3 to 15 minutes. Second, there is rapid placental transfer of lidocaine; the mean fetal/maternal ratio of 1.32 was significantly higher than that found following epidural anesthesia. Third, lidocaine and its active metabolites persisted in neonatal urine for at least 48 hours after delivery. This study suggests that local perineal infiltration with lidocaine for episiotomy should be considered similar to any other anesthetic technique in that it may result in significant neonatal drug exposure.

Intravenous, deltoid, or gluteus administration of meperidine during labor?

It has been suggested, but not well verified, that drug absorption from traditional intramuscular injection sites is altered during labor. This study tested the hypothesis that absorption of meperidine from the gluteus muscle would be impeded when compared with deltoid or intravenous administration. Five patients in labor were given 50 mg intravenously, 10 were given 50 mg in the gluteus muscle, and five were given 50 mg in the deltoid muscle. Five nonpregnant subjects served as their own controls for all three routes of administration. Blood samples were obtained at intervals after injection, meperidine was determined by gas chromatography/mass spectrometry, and mean plasma levels of meperidine versus time after administration were plotted. Repeated measures analysis of variance was used to determine whether the curves were significantly different from 30 to 150 minutes. Maternal plasma levels after gluteus injection were significantly lower than those after intravenous injection (F[1,8] = 10.53; p less than 0.01). In nonpregnant subjects, drug levels were not significantly different from 30 to 150 minutes after either gluteus or intravenous injection. Plasma levels after deltoid injection were always higher than those after gluteus injection in both pregnant and nonpregnant subjects (F[1,8] = 9.7; p less than 0.02; F[1,8] = 14.5; p less than 0.004). These findings support impaired absorption of drugs from the gluteus muscle and suggest the deltoid muscle as the favored intramuscular site during labor.

Lack of influence of cimetidine on bupivacaine levels during parturition.

: The concurrent use of cimetidine as a prophylactic antacid and bupivacaine as a local anesthetic for epidural anesthesia for cesarean section has been promoted. However, cimetidine is known to inhibit clearance of many drugs by reducing hepatic blood flow and by inhibiting cytochrome P-450 enzymes. The purpose of this study was to determine whether cimetidine during epidural anesthesia alters the metabolism, disposition, protein binding, or placental transfer of bupivacaine. Thirty-six patients undergoing cesarean section with 0.5% bupivacaine for epidural anesthesia were studied. Sixteen patients received cimetidine (300 mg IM) 1-4 hr before cesarean section and 20 control patients received sodium citrate (30 ml PO) 10 min preoperatively. Bupivacaine and its inactive metabolite, 2,6-pipecolylxylidine (PPX) were quantitated by gas chromatography/mass spectrometry. Maternal plasma concentration time curves, fetal/maternal ratios at delivery, cord vein/cord artery ratios. PPX/bupivacaine ratios, and maternal and neonatal urinary excretion were compared between the two groups. No significant differences could be found between the groups in any of the outcome variables. However, in the presence of cimetidine, the percentage of unbound bupivacaine significantly increased from 1.36 +/- 0.63 to 1.66 +/- 0.78%. The results suggest that a single 300-mg IM dose of cimetidine does not significantly affect bupivacaine disposition or metabolism in parturients when given 1-4 hr before anesthesia.

2-Chlororocaine for local perineal infiltration*

Lidocaine was recently found to rapidly cross the placenta and result in considerable fetal exposure after local infiltration of the perineum for episiotomy. For this reason, a more appropriate agent for local perineal infiltration might be a drug with rapid metabolism and inactive metabolites. 2-Chloroprocaine, an ester-linked local anesthetic agent, is available but is not commonly used for this procedure. The purpose of this study was to evaluate the placental transfer of 2-chloroprocaine after local perineal infiltration. The drug was administered to 17 normal term pregnant women for episiotomy. After local perineal infiltration, the levels of 2-chloroprocaine and/or its metabolite, chloroaminobenzoic acid, were quantitated in maternal and neonatal plasma or urine. The pharmacologic data indicated that 2-chloroprocaine was nondetectable at delivery in maternal and umbilical cord vein; one patient had trace levels in the cord. Chloroprocaine was not detectable in neonatal plasma, but chloroaminobenzoic acid was detectable in both maternal and cord vein plasma. Mean levels of chloroaminobenzoic acid in maternal plasma at delivery were 1.04 +/- 0.32 micrograms/ml, and mean levels in cord vein were 0.35 +/- 0.54 micrograms/ml. Clinically, 2-chloroprocaine provided good analgesia. These results indicate that very little, if any pharmacologically active drug, reaches the fetus after local perineal infiltration with 2-chloroprocaine. Therefore 2-chloroprocaine appears to be preferable to lidocaine when used for local perineal infiltration.