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At least 19 recordsLinked to original sources
PubMed1999

Meperidine and lidocaine block of recombinant voltage-dependent Na+ channels: evidence that meperidine is a local anesthetic.

BACKGROUND: The opioid meperidine induces spinal anesthesia and blocks nerve action potentials, suggesting it is a local anesthetic. However, whether it produces effective clinical local anesthesia in peripheral nerves remains unclear. Classification as a local anesthetic requires clinical local anesthesia but also blockade of voltage-dependent Na+ channels with characteristic features (tonic and phasic blockade and a negative shift in the voltage-dependence of steady-state inactivation) involving an intrapore receptor. The authors tested for these molecular pharmacologic features to explore whether meperidine is a local anesthetic. METHODS: The authors studied rat skeletal muscle mu1 (RSkM1) voltage-dependent Na+ channels or a mutant form heterologously coexpressed with rat brain Na+ channel accessory beta1, subunit in Xenopus oocytes. Polymerase chain reaction was used for mutagenesis, and mutations were confirmed by sequencing. Na+ currents were measured using a two-microelectrode voltage clamp. Meperidine and the commonly used local anesthetic lidocaine were applied to oocytes in saline solution at room temperature. RESULTS: Meperidine and lidocaine produced tonic current inhibition with comparable concentration dependence. Meperidine caused phasic current inhibition in which the concentration-response relationship was shifted to fivefold greater concentration relative to lidocaine. Meperidine and lidocaine negatively shifted the voltage dependence of steady-state inactivation. Mutation of a putative local anesthetic receptor reduced phasic inhibition by meperidine and lidocaine and tonic inhibition by lidocaine, but not meperidine tonic inhibition. CONCLUSIONS: Meperidine blocks Na+ channels with molecular pharmacologic features of a local anesthetic. The findings support classification of meperidine as a local anesthetic but with less overall potency than lidocaine.

Algorithms↗
PubMed1996

A comparison of the haemodynamic effects of intrathecal meperidine, meperidine-bupivacaine mixture and hyperbaric bupivacaine.

PURPOSE: To study the haemodynamic effects of intrathecal meperidine, administered either alone or mixed with bupivacaine. METHODS: We studied 42 Chinese patients, aged 59-87 yr, scheduled for transurethral bladder or prostate surgery, randomized into three equals groups, that received either meperidine 0.8 mg.kg-1, meperidine 0.4 mg.kg-1 plus 1.5 ml of 0.5% heavy bupivacaine or 3 ml of heavy bupivacaine 0.5%. Non-invasive systolic (SAP) and mean (MAP) arterial pressures, central venous pressure and cardiac index, stroke index and heart rate (HR) measured by the BoMed NCCOM3-R7S bioimpedance device, were recorded over the first 25 min. Systemic vascular resistance index (SVRI) was derived. Onset of sensory and motor block was also measured. Decreases in MAP of 25% were treated with colloid and metaraminol. RESULTS: The onset of block was slower in the meperidine group (P < 0.05). Decreases in SAP, MAP and SVRI (all; P < 0.001) occurred within five minutes in all three groups. The HR was increased in the bupivacaine group (P = 0.03), but bradycardias treated with atropine occurred in six patients receiving meperidine and four patients receiving the mixture. Six patients receiving meperidine and two patients receiving the mixture required general anaesthesia for inadequate block. The incidence of nausea and vomiting was higher in the patients receiving meperidine (P < 0.05). No other complications were encountered. CONCLUSIONS: Intrathecal meperidine used alone or mixed with bupivacaine has no intra-operative advantage over heavy bupivacaine 0.5%.

Aged↗
PubMed1979

Meperidine and normeperidine levels following meperidine administration during labor. I. Mother.

Because of the unavailability of sensitive analytic techniques, the pharmacokinetics of meperidine have not been clearly delineated in obstetric patients during labor. Moreover, the production of the active meperidine metabolite--normeperidine--has not been investigated. By means of gas chromatographic and mass spectrometric techniques, these characteristics of meperidine metabolism were evaluated in 23 pregnant patients in the present study. The data show that the disappearance curve and pharmacokinetic constants for meperidine are similar to those previously reported for nonpregnant subjects. In regard to normeperidine, the data indicate that it is produced within ten minutes after meperidine injection, increases rapidly for the next 20 minutes, and then slowly increases throughout labor. The results enumerate the pharmacokinetic constants of meperidine in obstetric patients and describe the appearance of normeperidine, the active meperidine metabolite, following meperidine administration during labor.

Adult↗
PubMed1979

Meperidine and normeperidine levels following meperidine administration during labor. II. Fetus and neonate.

The time interval between the administration of meperidine to laboring patients and delivery may affect neonatal status, but sophisticated analytic techniques have not been used to determine the exposure of the fetus to meperidine at various drug-delivery intervals. By means of gas chromatography and mass spectrometry, the concentrations of meperidine and normeperidine (the principle metabolite of meperidine) were quantitated in the umbilical cord venous and arterial plasma at delivery and in the urine of the neonate for three days postpartum. Following 50 mg. of meperidine administered intravenously during labor, fetal exposure to meperidine was highest two to three hours after maternal medication while fetal exposure to normeperidine was highest four hours or more after medication. We conclude from this study that there is a definite but nonlinear relationship between the drug-delivery interval and the amount of meperidine and normeperidine an infant receives; and that the drug-delivery intervals resulting in maximum fetal exposure reported here correspond with those resulting in maximum neonatal depression reported by others.

Chromatography, Gas↗
PubMed1990

Hemodynamic effects in dogs of nitrous oxide-meperidine and meperidine, respectively, in comparison with nitrous oxide.

The aim of this investigation on dogs, was to examine the hemodynamic effects of nitrous oxide (N2O) plus meperidine and of meperidine with room air ventilation, respectively, compared with those of N2O on its own. When meperidine (bolus dose 3 mg.kg-1 and continued infusion 4 mg.kg-1.h-1) was added to 80% N2O, mean arterial blood pressure fell from about 20 to 10 kPa (150 to 75 mmHg), as a result of a decrease in peripheral vascular resistance, but no compensatory changes in cardiac output were seen. When N2O was withdrawn, during continued meperidine infusion, cardiac output and stroke volume increased, while peripheral resistance remained low. Coronary vasodilation was noted when meperidine was added to N2O, and persisted when N2O was withdrawn. In the pulmonary circulation a different response was found. Here, no effects were observed when meperidine was added to N2O, while pressure and resistance decreased when N2O was withdrawn and meperidine continued.

Animals↗
PubMed1976

Effects of intravenous meperidine and meperidine with promethazine on uterine activity and fetal heart rate during labor.

A prospective study of the effects of the i.v. injection of 75 mg meperidine, alone or combined with 25 mg promethazine, was conducted by continuous and direct monitoring of the fetus and of intrauterine pressure. The study was carried out in 16 primiparas and 24 multiparas in active spontaneous labor with cervical dilatation of 3 to 4 cm. Administration of meperidine and of meperidine with promethazine was associated with an increase in uterine activity of 31 to 45% (Montevideo units), respectively. The most marked effects were on the amplitude of the uterine contractions. There was no significant change in uterine tone. A tetanic response was recorded in two patients who vomited after the administration of meperidine with promethazine and was followed by slowing of the fetal heart rate. In no other cases were there significant changes in fetal heart rate. Except for the latter two patients, no adverse effect of meperidine or of meperidine with promethazine on the fetal heart rate was noted. The condition of the newborns at birth was excellent in all but three cases, in two of which maternal amniotic infection and high fever were present.

Female↗
PubMed1975

The bioavailability of meperidine using urine assays for meperidine and normeperidine.

The results of a two-way crossover trial of two commercial preparations of meperidine hydrochloride in 24 healthy volunteers is reported. The urinary excretion patterns resulting from dosing with the two preparations were followed for 48 hours, and the urine concentrations of meperidine and a major metabolite, normeperidine, were determined by gas liquid chromatography. Statistical analysis of the data showed no significant difference between the urine concentrations of meperidine and normeperidine produced by either preparation, and the preparations are of comparable bioavailability. The use of the urinary excretion pattern and concentrations represents a rapid, accurate, and quantitative method for determining the bioavailability of different preparations of meperidine hydrochloride.

Adult↗
PubMed1982

Gas chromatographic analysis of meperidine and normeperidine: determination in blood after a single dose of meperidine.

A method is described for the determination of meperidine and its pharmacologically active metabolite, normeperidine, in blood, plasma, and urine using gas chromatography with nitrogen-phosphorus detection. Structural analogs of both meperidine and normeperidine were used as internal standards. Unlike previously reported assays, this procedure was sensitive and convenient enough for use in pharmacokinetic studies of both meperidine and normeperidine following single doses of meperidine. The assay was sensitive to 5 ng of meperidine/ml and 2.5 ng of normeperidine/ml extracted from a 1-ml biological sample. The between-assay coefficients of variation at these concentrations were 9.4 and 10.4%, respectively.

Adult↗
PubMed1993

Direct stimulation of urokinase, plasmin, and collagenase by meperidine: a possible mechanism for the ability of meperidine to enhance cervical effacement and dilation.

Current hypotheses suggest that the degradation of cervical collagen and elastin leads to cervical effacement and dilation during labor. The collagenolytic activity is thought to be initiated through the conversion of latent (pro)collagenase to active collagenase by the plasmin formed from plasminogen or by other proteases similarly formed from their inactive zymogens. We presently demonstrate that meperidine stimulates the activity of several enzymes in the proteolytic cascade leading toward proteolysis of connective tissue proteins. Meperidine in its therapeutic concentration range produces a 26% stimulation of urokinase activity on substrate S-2444, a 39% stimulation of plasmin activity on substrate S-2551, and a 33% stimulation of collagenase activity on 14C-labeled globin substrate. These direct effects on the enzyme activities are noted in vitro with the purified enzymes and were confirmed with several small molecular weight chromogenic substrates and with 14C-globin protein substrate. Oxytocin at levels found during active labor fails to stimulate the in vitro activity of purified urokinase, plasmin, collagenase, trypsin, or tissue-type plasminogen activator. The effect of meperidine on the proteolytic enzymes suggests that its ability to promote cervical effacement and distention during labor may be at least partially due to a meperidine-induced stimulation of cervical proteases.

Cervix Uteri↗
PubMed1976

Meperidine metabolites: identification of N-hydroxynormeperidine and a hydroxy-methoxy derivative of meperidine in biological fluids.

Gas chromatographic and gas chromatographic-mass spectrometric techniques were used to identify non-acidic metabolites of meperidine (N-methyl-4-phenyl-4-carbethoxypiperidine) excreted in human, rat, and guinea pig urine. Following enzymic hydrolysis N-hydroxynormeperidine was identified in the urine of all three species in addition to the expected metabolites normeperidine and meperidine N-oxide. In rat urine the p-hydroxyphenyl metabolite of meperidine was present in appreciable amounts. Also present in small quantity was a new phenolic metabolite of meperidine containing both hydroxyl and O-methoxyl substituents in the phenyl ring of the parent drug. The latter two metabolites were excreted as conjugates in the rat.

Adult↗
PubMed2002

Use of meperidine in patient-controlled analgesia and the development of a normeperidine toxic reaction.

HYPOTHESIS: Intravenous patient-controlled analgesia (IV PCA) meperidine hydrochloride can be used with a reasonable margin of safety. DESIGN: A retrospective review was performed of 355 medical records of patients receiving IV PCA meperidine treatment. Four groups of patients were defined, based on daily meperidine dose and the presence or absence of central nervous system excitation adverse effects. Use of more than 600 mg/d of meperidine hydrochloride was considered a high dose. SETTING: University tertiary care hospital. PARTICIPANTS: Postoperative patients from general, orthopedic, neurosurgical, gynecological, and urologic procedures receiving IV PCA. INTERVENTIONS: If patients were judged to have consumed significant amounts of meperidine, the analgesic regimen was modified to (1) discontinue meperidine therapy, (2) substitute hydromorphone hydrochloride, or (3) decrease the use of meperidine by adding oral methadone hydrochloride or transdermal fentanyl citrate to the regimen. MAIN OUTCOME MEASURES: Patients who received less than 10 mg/kg per day of IV PCA meperidine hydrochloride therapy were unlikely to experience central nervous system excitatory adverse effects and maintain adequate analgesia. RESULTS: The mean meperidine hydrochloride consumption for those patients classified as high dose, asymptomatic was 13.3 mg/kg per day (95% confidence interval, 12.1-14.4 mg/kg per day). This differed statistically significantly (P<.05) from the mean meperidine hydrochloride dose in patients classified as high dose, symptomatic, which was 16.9 mg/kg per day (95% confidence interval, 14.7-19.2 mg/kg per day). The duration of meperidine use did not differ among the 4 patient groups. The incidence of a central nervous system toxic reaction associated with IV PCA meperidine therapy was 2%. CONCLUSIONS: We recommend 10 mg/kg per day as a maximum safe meperidine hydrochloride dose by an IV PCA device for no longer than 3 days. Daily patient evaluation is mandatory. Care must also be taken when using this dose to ensure the absence of renal dysfunction or enhanced hepatic metabolism of meperidine.

Adult↗
PubMed1995

Postthoracotomy pulmonary function: a comparison of epidural versus intravenous meperidine infusions.

It has remained unclear whether epidural opioid analgesia permits better recovery of postthoracotomy pulmonary function than an optimal method of systemic opioid administration. Lumbar epidural meperidine infusions were compared with intravenous patient-controlled analgesic (PCA) meperidine infusions in a prospective randomized unblinded study for 72 hours postthoracotomy. Before induction of general anesthesia, patients received a bolus of meperidine, 1 mg/kg, and an infusion of meperidine, 0.33 mg/kg/hr, was started via either a lumbar epidural or intravenous catheter. Postoperatively, the meperidine infusion rates were titrated as needed for analgesia. In addition, the intravenous group received meperidine, 10 mg per dose, as required, from a patient-controlled analgesia pump. No other opioid was administered during the study period. Patients were studied for recovery of spirometric tests of pulmonary function, visual analog pain scores, sedation, arterial blood gases, meperidine dose requirements, radiographic pulmonary complications, and neurologic signs and symptoms. A subgroup of 10 patients (5 from each group) had venous blood samples drawn every 24 hours for 96 hours and assayed for serum meperidine and normeperidine concentrations. Epidural meperidine analgesia was associated with improved postthoracotomy pulmonary function, better analgesia scores, and lower meperidine dose requirements than intravenous PCA meperidine. There were no differences between the epidural versus intravenous PCA subgroups with respect to serum meperidine or normeperidine levels. Normeperidine levels greater than 300 ng/mL were associated with an increased incidence of shakiness and/or tremors. Meperidine provides satisfactory postthoracotomy analgesia via a lumbar epidural infusion. This analgesia is associated with improved recovery of postoperative pulmonary function when compared with an intravenous PCA meperidine infusion.

Aged↗
PubMed1999

Meperidine utilization and compliance with Agency for Health Care Policy and Research guidelines in a tertiary care hospital.

The Agency for Health Care Policy and Research (AHCPR) established guidelines for the use of meperidine (demerol), a common inpatient analgesic. These guidelines define standards of care for acute and chronic cancer pain management and address many of the problems with meperidine and its metabolite, normeperidine. The purpose of this study was to determine whether meperidine was prescribed in compliance with AHCPR guidelines, whether patients exhibited any adverse reactions to meperidine, and to determine the analgesic efficacy of meperidine. Three hundred inpatient charts were reviewed and identified meperidine as the primary analgesic in 157 nonobstetric inpatients. Age, sex, weight, dosing interval, route of administration, duration of meperidine use, serum chemistry values, primary diagnosis, associated medical conditions, and medications concurrently being taken with meperidine were the parameters analyzed. An interview was conducted to ascertain medical and drug history, chronicity of pain syndromes, analgesic drug history, and analgesic efficacy. A visual analog scale for pain (range = 0 to 10) and an analgesic satisfaction survey (range = 1 to 5) were used. Of 157 patients, 124 (79.8%) were in conflict with AHCPR guidelines. The most frequent conflict was found to be suboptimal dosing regimen and treatment of chronic pain. Often concurrent analgesics were given with the meperidine to achieve adequate analgesia. Higher analgesic satisfaction scores were noted when meperidine was given with concurrent analgesics. Meperidine also was administered to patients in renal failure or with medications contraindicated with meperidine use. No significant adverse effects were noted with meperidine use in this sample population other than an increased incidence of confusion in the elderly population.

Academic Medical Centers↗
PubMed2002

Meperidine exerts agonist activity at the alpha(2B)-adrenoceptor subtype.

BACKGROUND: The opioid agonist meperidine has actions, such as antishivering, that are more pronounced than those of other opioid agonists and that are not blocked with nonselective opioid antagonists. Agonists at the alpha(2) adrenoceptors, such as clonidine, are very effective antishivering drugs. Preliminary evidence also indicates that meperidine interacts with alpha(2) adrenoceptors. The authors therefore studied the ability of meperidine to bind and activate each of the alpha(2)-adrenoceptor subtypes in a transfected cell system. METHODS: The ability of meperidine to bind to and inhibit forskolin-stimulated cyclic adenosine monophosphate formation as mediated by the three alpha(2)-adrenoceptor subtypes transiently transfected into COS-7 cells has been tested. The ability of the opioid antagonist naloxone and the alpha(2)-adrenoceptor antagonists yohimbine and RX821002 to block the analgesic action of meperidine in the hot-plate test was also assessed. The ability of meperidine to fit into the alpha(2B) adrenoceptor was assessed using molecular modeling techniques. RESULTS: Meperidine bound to all alpha2-adrenoceptor subtypes, with alpha(2B) having the highest affinity (alpha(2B), 8.6 +/- 0.3 microm; alpha(2C), 13.6 +/- 1.5 microm, P < 0.05; alpha(2A), 38.6 +/- 0.7 microm). Morphine was ineffective at binding to any of the receptor subtypes. Meperidine inhibited the production of forskolin-stimulated cyclic adenosine monophosphate mediated by all receptor subtypes but was most effective at the alpha(2B) adrenoceptor (alpha(2B), 0.6 microm; alpha(2A), 1.3 mm; alpha(2C), 0.3 mm), reaching the same level of inhibition (approximately 70%) as achieved with the alpha2-adrenoceptor agonist dexmedetomidine. The analgesic action of meperidine was blocked by naloxone but not by the alpha 2-adrenoceptor antagonists yohimbine and RX821002. The modeling studies demonstrated that meperidine can fit into the alpha(2B)-adrenoceptor subtype. CONCLUSION: Meperidine is a potent agonist at the alpha2 adrenoceptors at its clinically relevant concentrations, especially at the alpha(2B)-adrenoceptor subtype. Activation of the alpha(2B) receptor does not contribute significantly to the analgesic action of meperidine. This raises the possibility that some of its actions, such as antishivering, are transduced by this mechanism.

Adenylyl Cyclase Inhibitors↗
PubMed1975

Two mechanisms for the meperidine block of action potential production in frog's skeletal muscle; non-specific and opiate drug receptor mediated blockade.

The effects of meperidine and naloxone, and their interaction effects on action potential production in frog's sartorius muscle fibres, were studied with intracellular micro-electrode techniques. 1. Meperidine, a narcotic analgesic drug, depressed the rate of rise, the rate of fall and the amplitude of the action potentials. 2. At a meperidine concentration of 0-35 mM, the depression in the action potential maximum rate of rise followed a diphasic time course. At first there was a rapid reduction in the maximum rate of rise which was levelling off at about 60% of control 60-90 min after drug application. This was followed by the second phase during which there was an initial rapid decrease in the maximum rate of rise and all surface fibres were inexcitable by 180 min. 3. The addition of naloxone, a narcotic antagonist, in low concentrations (3 X 10(-5) to 3 X 10(-4) mM) at 70-90 min blocked the second phase of the meperidine-induced depression. 4. With lower concentrations of meperidine (0-18 and 0-07 mM) the depression usually developed more slowly (up to 6 hr with the latter dose) and the addition of low naloxone concentrations partially antagonized the effects of meperidine. However, under no conditions was it possible to completely antagonize the effects of meperidine by the addition of naloxone. 5. A linear relation was found between action potential amplitude and the action potential maximum rate of fall. 6. Meperidine caused a shift in the relation of rate of fall against amplitude to higher action potential amplitudes, indicating that the drug inhibited the increase in potassium conductivity (gK) associated with the falling phase of the action potential. 7. When low naloxone concentrations antagonized the effects of meperidine on the rate of rise and restored action potential amplitudes to control levels, the effect of meperidine on the maximum rate of fall was not antagonized. 8. Larger naloxone concentrations (1-5 X 10(-2) mM or more) depressed the action potential rate of rise but did not alter the relation between action potential amplitude and the maximum rate of fall. 9. It is proposed that meperidine blocks action potential production by two mechanisms: (i) a non-specific mechanism in which the increases in both gNa and gK ar depressed and (ii) an opiate drug receptor mediated mechanism causing a specific depression of gNa. 10. The impression gained from the results is that there are opiate drug receptors located on the inner surface of the muscle membrane associated with the 'sodium channels' and that drug activation of these receptors by either meperidine or high naloxone concentrations interferes with the opening of the 'sodium channels' normally produced by membrane depolarization.

Action Potentials↗