High-performance liquid chromatographic method for an automated determination of local anaesthetics in human plasma.

A method is described that allows the rapid and precise determination of the local anaesthetics bupivacaine and etidocaine from biological fluids. This method uses a fully automated system with solid-phase extraction in combination with a column-switching technique. Both sample extraction on a LiChrocart pre-column and elution onto the analytical LiChrospher column, were performed automatically and concomitantly using conventional HPLC equipment in conjunction with an OSP-2 on-line sample preparator from Merck combined with UV detection. Recoveries were found to be 96.7 and 96.4% for 2 micrograms/ml bupivacaine and etidocaine, respectively. Lower limits of quantification were found to be 0.05 microgram/ml plasma for both of the compounds.

Circadian phase dependent acute toxicity and pharmacokinetics of etidocaine in serum and brain of mice.

The aim of this study was to investigate the possible influence of the time of administration on etidocaine acute toxicity and kinetics in mice. Different groups of adult male NMRI mice maintained under controlled environmental conditions (lights on 06.00-18.00) were injected at one of the following times: 10.00, 16.00, 19.00, 22.00, 01.00 and 04.00 h with four doses of etidocaine at each time point to establish the acute toxicity (LD 50). To assess chronokinetics, a single 40 mg kg-1 i.p. dose of etidocaine was given to adult male NMRI mice at four fixed times: 10.00, 16.00, 22.00 and 04.00 h. Etidocaine serum levels were determined by GLC. The data showed significant 24 h variations of the Cmax only (highest value = 9.64 +/- 1.31 micrograms mL-1 at 10.00 P less than 0.05; amplitude, (maximum-minimum) mean x 100 = 84%) Vd, (amplitude = 59.7%), alpha and beta phase elimination half-lives (amplitude = 52 and 35%, respectively), clearance (amplitude = 23%) and AUC infinity 0 (amplitude = 22%) were not found to be significantly time dependent. Etidocaine kinetics in brain were determined similarly; a significant temporal variation was found for the elimination half life (amplitude, 161.9%) and AUC (amplitude, 133.2%) but not for Cmax. These data demonstrate a temporal pattern of etidocaine kinetics similar to those reported previously for other local anaesthetic agents, bupivacaine and mepivacaine. The temporal changes in etidocaine induced acute toxicity may result in part from its chronokinetic changes.

Topical bupivacaine and etidocaine analgesia following fallopian tube banding.

The purpose of this study was to compare the effectiveness and safety of etidocaine and bupivacaine for postoperative analgesia after laparoscope sterilization. The study was performed in 22 healthy patients who received either one per cent etidocaine, 2 mg.kg-1, or bupivacaine 1.5 mg.kg-1 in a double-blind, randomized fashion. The local anaesthetic was dropped onto the fallopian tubes from uterus to fimbriae before tubal occlusion. To establish safety, blood concentrations of the parent drug and its metabolites were measured before application and at 1, 3, 6, 10, 15, 30, 60 and 120 min. The mean peak concentrations were 501.8 +/- 71.3 (SEM) for etidocaine with a range of 225 to 905 ng.ml-1. For bupivacaine, the mean peak concentration was 468 +/- 73.8 SEM with a range from 191 to 1005 ng.ml-1. The mean values are one eighth of the toxic convulsive dose for humans. Etidocaine was metabolized at a faster rate than bupivacaine with a rapid appearance of 2-amino-2'-butyroxylidide (ABX). The bupivacaine metabolite 2,6-pipecoloxylidide (PPX) was detected in low concentrations in the 60-minute samples. We conclude that the topical application of either etidocaine or bupivacaine is a safe procedure in the doses and concentrations used during general anaesthesia for laparoscopic tubal banding.

[The quantitative analysis of amide local anesthetics using high pressure liquid chromatography and ultraviolet detection (HPLC/UV)]. / Die quantitative Analyse von Amid-Lokalanaesthetika mittels Hochdruck-Flüssigkeits-Chromatographie und UV-Detektion (HPLC/UV).

This study was undertaken to develop a time- and cost-effective method for the detection of lidocaine, mepivacaine, prilocaine, bupivacaine, and etidocaine by HPLC/UV. The chromatographic system consisted of a C18-column (300 x 3.9 mm) for reversed-phase chromatography and a mobile phase of 30% acetonitrile and 70% 0.05 M sodium phosphate buffer. For the analysis of lidocaine, mepivacaine, and prilocaine, the buffer was adjusted to pH 5.8. The buffer for the analysis of bupivacaine and etidocaine was adjusted to pH 3.5. The flow rate was 1 ml/min. UV detection took place at a wavelength of 210 nm. All blood samples were taken from a central venous line. After plasma separation, 1 microgram (100 microliters) of internal standard was added to 1 ml plasma. The samples were alkalized and extracted with ether, followed by the extraction of the organic phase in 250 microliters 0.05 N sulphuric acid; 50 microliters of this solution was injected into the system. The chromatographic system allowed the separation of bupivacaine and etidocaine (pH 3.5) as well as lidocaine and mepivacaine or prilocaine (pH 5.8). Separation of prilocaine and mepivacaine in one run was not satisfactory. Recovery rates for all local anesthetic substances were about 90%, standard variations below 3%, and coefficients of variation below 2%. The detection limit was about 30 ng/ml. The method is suitable for clinical practice. Only minor methodological modifications are necessary for the detection of the amide local anesthetics in current clinical use.

Recent advances in local anaesthesia.

In general, the cardiovascular system is more resistant to the toxic actions of local anaesthetics than is the central nervous system. However, if sufficient doses and blood levels of local anaesthetics are achieved, signs of profound cardiovascular depression may be observed. Differences exist between local anaesthetics in terms of their relative potential for cardiotoxicity. The CC/CNS ratio for bupivacaine and etiodcaine is less than for lidocaine. In addition, bupivacaine may precipitate ventricular arrhythmias and ventricular fibrillation. Local tissue toxicity can occur following the administration of local anaesthetics. In general, neural tissue appears to be relatively resistant to the irritant effects of local anaesthetic drugs. However, large dosages of chloroprocaine solutions administered intrathecally have been associated with prolonged sensory-motor deficits in a few patients due probably to the low pH and presence of sodium bisulfite in the chloroprocaine solutions. In general, the incidence of toxic reactions to local anaesthetic agents is extremely low. However, as with any class of pharmacological agents, local anaesthetics may cause severe toxic reactions, due usually to the improper use of these drugs.

Simultaneous measurement of bupivacaine, etidocaine, lidocaine, meperidine, mepivacaine, and methadone.

A gas-liquid chromatographic method for the simultaneous measurement of bupivacaine, etidocaine, lidocaine, meperidine, mepivacaine, and methadone in serum is described. The drugs and the internal standard, prilocaine, are extracted from 1 ml of serum. The procedure involves a two-step extraction and injection of the extract into a gas chromatograph equipped with a 10-ft OV-11 glass column and a nitrogen-phosphorus detector. The temperature gradient program results in a run time of 16 min and retention times for meperidine, prilocaine (internal standard), lidocaine, etidocaine, mepivacaine, methadone, and bupivacaine of 3.8, 5.4, 6.0, 8.7, 11.0, 11.7, and 14.8 min, respectively. Standard curves for all drugs were linear over the 80 to 2,000-ng/ml range and recovery of all components averaged 97 +/- 2% with the lowest detection limit of 10 ng/ml for all drugs except meperidine and methadone, which were 20 ng/ml. The within-day coefficients of variation ranged from 12 to 8% at 500 ng/ml. The day-to-day coefficients of variation of the slope and intercept values ranged from 2 to 0% and 130 to 3%, respectively. Response factors of the nitrogen-specific collector varied with the drug analyzed and resulted in peak area variation at constant offset and attenuation of 30%. This method is intended and adequate for therapeutic monitoring of chronically treated pain patients who are being given various combinations of local anesthetic and/or narcotic agents.

Etidocaine toxicity in the adult, newborn, and fetal sheep.

The systemic toxicity of etidocaine was compared in adult, newborn, and fetal sheep during continuous infusion of the drug into the jugular vein at the rate of 0.5 mg X kg-1 X min-1. All recipients exhibited symptoms of toxicity in the following order: convulsions, hypotension, respiratory arrest, and circulatory collapse. The dose of etidocaine required to produce CNS and cardiovascular toxicity was significantly different among the three age groups, being the highest in the fetus and the lowest in the adult. In contrast, no significant difference in etidocaine blood concentrations at the onset of each toxic symptom was observed among the groups except that convulsions and hypotension occurred at lower blood levels in the fetus as compared with the newborn and adult. Comparisons of etidocaine blood concentrations associated with the onset of convulsions and circulatory collapse (CC/CNS ratio) with those of lidocaine reported previously indicate that a narrower margin exists in adults and newborn following administration of etidocaine.

Plasma protein binding of etidocaine during pregnancy and labour.

Preliminary studies of the ultrafiltration method for measuring the extent of plasma protein binding of etidocaine showed that etidocaine binding was both pH and concentration dependent. Etidocaine (1 microgram/ml) was found to bind avidly to a physiological concentration (74 mg/dl) of alpha 1-acid glycoprotein (alpha 1-AGP) (7.23 +/- 0.64%, mean +/- SD, unbound). In vitro investigation of etidocaine binding in plasma obtained from blood bank donors and from 19 pregnant women prior to induction of labour, during early labour, mid-labour and delivery showed no difference in etidocaine binding (10.3 +/- 3.3%, 7.06 +/- 2.66%, 8.15 +/- 2.57%, 7.84 +/- 3.74% and 9.28 +/- 6.06% unbound respectively). There was a significant increase in the mean plasma total free fatty acid (FFA) concentration from pre-labour (0.535 +/- 0.240 mM) to delivery (0.948 +/- 0.28 mM), while plasma albumin and beta-lipoprotein concentrations remained constant. Alpha 1-Acid glycoprotein concentration tended to increase slightly from pre-labour to early labour (p less than 0.1) but was still within the normal physiological range. There was no correlation between etidocaine binding ratio and the concentrations of FFA or plasma proteins except for a poor correlation with the alpha 1-AGP concentration (r = 0.361, p less than 0.05). Storage of plasma and inadequate control of plasma pH during ultrafiltration appeared to give spurious binding values. These studies with the extensively bound basic drug etidocaine suggest that unlike many acidic drugs which are bound predominantly to serum albumin, the binding of alpha 1-AGP - bound basic drugs may be unaffected by pregnancy and labour.

[Plasma level of etidocaine within the first two hours after axillary plexus block in healthy adults and patients with renal insufficiency (author's transl)]. / Plasmakonzentration von Etidocain in den ersten zwei Stunden nach axillärer Blockade bei Gesunden und bei Patienten mit Niereninsuffizienz.

The plasma level of etidocaine was studied within the first two hours of axillary block in 7 patients with renal insufficiency and 7 healthy adults. After 15-20 min the maximum of plasma concentration was found in the group with renal failure and after 30-45 min in the healthy adults. 30 min after the block the plasma level was 1,26 +/- 0,62 mug/ml in the ill patients and only 0,73 +/- 0,31 in the normal group. Using a mathematical model the ratio of permeation into the blood is significantly higher in the group with renal failure than in the healthy adults. The main reason for these results seems to be the acidosis, which is often combined with renal insufficiency. The meaning of these results for regional anaesthesia in patients like these is discussed.

[Plasma concentrations of etidocaine after supraclavicular plexus block (author's transl)]. / Plasmakonzentrationen des Lokalanästhetikums Etidocain nach supraklavikulärer Plexusanästhesie.

10 patients without concomitant hepatic or renal diseases were given brachial plexus block (Winnie) with etidocaine and the plasma concentrations of the drug were measured. The quantity of local anaesthetic was determined solely by the body weight and amounted to 4 mg/kg body weight. The mean peak concentration was 1.39 microgram/ml, the highest single concentration measured was 1.74 microgram/ml. Peak levels were reached within 40 minutes after administration of the local anaesthetic.

[The interaction of sedativa with etidocaine in patients with brachial plexus block (author's transl)]. / Die Beeinflussung der Plasmaetidocainspiegel durch Sedativa nach supraclaviculärer Plexusanaesthesie.

The influence of diazepam and phenobarbital on plasma etidocaine concentrations is studied. It is shown that there is no statistical relevant interaction. The mean peak levels occurred within 40 min after application of local anaesthetics and amounted to 1,439 micrograms/ml. The mean half times were calculated and are 135 min.

Lidocaine, bupivacaine, etidocaine, and epinephrine-induced arrhythmias during halothane anesthesia in dogs.

Arrhythmogenic doses of epinephrine were determined in six mongrel dogs anesthetized at 1.4 MAC halothane initially in the absence of local anesthetics and then at increasing arterial plasma levels of lidocaine, bupivacaine, and etidocaine. The authors gave epinephrine intravenously at 5 microgram/kg/min and calculated the arrhythmogenic dose as a function of time until two or more premature ventricular contractions occurred within a 10-sec period. The control arrythmogenic dose of epinephrine was 4.66 +/- 0.46 microgram/kg (mean +/- SEM). Arrythmogenic doses of epinephrine were increased significantly after each dose of lidocaine, bupivacaine, and etidocaine. With the largest doses studied, local anesthetic plasma levels were frequently in the toxic range. The data show that lidocaine, bupivacaine, and etidocaine equally protect against epinephrine-induced arrhythmias in dogs anesthetized with halothane.

Epidural anesthesia for cesarean section: a comparison of bupivacaine, chloroprocaine, and etidocaine.

The authors studied three groups of patients undergoing elective cesarean section during lumbar epidural anesthesia with bupivacaine, 0.75 per cent (15 patients), chloroprocaine, 3 per cent (15 patients) or etidocaine, 1 per cent (ten patients). Excellent sensory and motor block were obtained with chloroprocaine and bupivacaine; sensory anesthesia was inadequate with etidocaine in most patients. Onset of anesthesia, induction--delivery interval, and stay in the recovery room were all longer with bupivacaine when compared with chloroprocaine. Fetal outcomes, as determined by Apgar scores, acid--base status and neurobehavioral testing, were equally good in all groups. At delivery, fetal/maternal concentration ratio of bupivacaine was 0.31 and that of etidocaine, 0.25. The umbilical artery--umbilical vein blood concentration difference for etidocaine was significantly higher than that for bupivacaine. Excellent clinical results were obtained using either bupivacaine, 0.75 per cent, alone, or chloroprocaine, 3 per cent- for induction and maintenance of anesthesia, supplemented with bupivacaine, 0.25 per cent, before removal of the catheter.

Cardiovascular and subjective central nervous system effects of long-acting local anaesthetics in man.

Intravenous infusions of etiodocaine 50, 75 and 100 mg and bupivacaine 75 mg were carried out over ten minutes in healthy young adult males. Cardiovascular sequelae were generally trivial at all doses. A collection of subjective central nervous system symptoms were described which may be regarded as early warning of impending local anaesthetic toxicity. Plasma concentrations of etidocaine were proportional to dose and ranged from 2 micrograms/ml to 5 micrograms/ml at the termination of the infusion. Plasma concentrations of bupivacaine were similar to those from the same dose of etidocaine but declined more slowly on cessation of infusion.

Local anesthetics and pulmonary venous admixture in pregnant and nonpregnant sheep.

Pulmonary venous admixture (Qs/Qt) was determined in nine nonpregnant sheep and in seven pregnant sheep during their last trimesters of gestation. Pulmonary venous admixture was greater in the pregnant animals (5.7 +/- 1.6% of the cardiac output; mean +/- SD) than in the nonpregnant ones (4.2 +/- 1.3%; p less than 0.05). On consecutive days, four local anesthetics were infused in random order via a femoral venous catheter into each sheep for 30 minutes. Total doses of 1.8 mg/kg of bupivacaine, 2.7 mg/kg of etidocaine, 6 mg/kg of lidocaine, and 15 mg/kg or chloroprocaine were administered. None of the anesthetics induced a significant change in pulmonary venous admixture.