New local anesthetics.

Local anesthetics are used for performing various regional anesthesia techniques to provide intraoperative anesthesia and analgesia, as well as for the treatment of acute and chronic pain. Older medications such as lidocaine and bupivacaine as well as newer ones such as mepivacaine and ropivacaine are being used successfully for decades. Routes of administration include neuraxial, perineural, intravenous, various infiltrative approaches, topical, and transdermal. There are new innovations with the use of older local anesthetics in a novel manner, in addition to the development and use of new formulations. This chapter seeks to summarize the pharmacokinetics of local anesthetics and address the role of newer local anesthetics, as well as clinical implications, safety profiles, and the future of local anesthetic research. Finally, some clinical pearls are highlighted.

Influence of protein fermentation and carbohydrate source on in vitro methane production.

Incubations were carried out with batch cultures of ruminal micro-organisms from sheep to analyse the influence of the N source on in vitro CH4 production. The two substrates were mixtures of maize starch and cellulose in proportions of 75:25 and 25:75 (STAR and CEL substrates, respectively), and the three nitrogen (N) sources were ammonia (NH4 Cl), casein (CA) and isolated soya bean protein (SP). Five isonitrogenous treatments were made by replacing non-protein-N (NPN) with CA or SP at levels of 0 (NPN), 50 (CA50 and SP50, respectively) and 100% (CA100 and SP100) of total N. All N treatments were applied at a rate of 35 mg of N/g of substrate organic matter and incubations lasted 16.5 h. With both proteins, N source × substrate interactions (p = 0.065 to 0.002) were detected for CH4 production and CH4 /total VFA ratio. The increases in CH4 production observed by replacing the NPN with protein-N were higher (p < 0.05) for STAR than for CEL substrate, but the opposite was observed for the increases in volatile fatty acid (VFA) production. As a consequence, replacing the NPN by increased levels of CA or SP led to linear increases (p < 0.05) in CH4 /total VFA ratio with STAR, whereas CH4 /total VFA ratio tended (p < 0.10) to be decreased with CEL substrate. Increasing the amount of both proteins decreased linearly (p < 0.05) ammonia-N concentrations, which may indicate an incorporation of amino acids and peptides into microbial protein without being first deaminated into ammonia-N. In incubations with the tested N sources as the only substrate, the fermentation of 1 mg of CA or SP produced 1.24 and 0.60 µmol of CH4 respectively. The results indicate the generation of CH4 from protein fermentation, and that the response of CH4 production to protein-N supply may differ with the basal substrate.

Lipid emulsion reverses Levobupivacaine-induced responses in isolated rat aortic vessels.

BACKGROUND: The goal of this in vitro study was to investigate the effects of lipid emulsion (LE) on local anesthetic levobupivacaine-induced responses in isolated rat aorta and to determine whether the effect of LE is related to the lipid solubility of local anesthetics. METHODS: Isolated rat aortic rings were suspended for isometric tension recording. The effects of LE were determined during levobupivacaine-, ropivacaine-, and mepivacaine-induced responses. Endothelial nitric oxide synthase and caveolin-1 phosphorylation was measured in human umbilical vein endothelial cells treated with levobupivacaine alone and with the addition of LE. RESULTS: Levobupivacaine produced vasoconstriction at lower, and vasodilation at higher, concentrations, and both were significantly reversed by treatment with LE. Levobupivacaine and ropivacaine inhibited the high potassium chloride-mediated contraction, which was restored by LE. The magnitude of LE-mediated reversal was greater with levobupivacaine treatment than with ropivacaine, whereas this reversal was not observed in mepivacaine-induced responses. In LE-pretreated rings, low-dose levobupivacaine- and ropivacaine-induced contraction was attenuated, whereas low-dose mepivacaine-induced contraction was not significantly altered. Treatment with LE also inhibited the phosphorylation of endothelial nitric oxide synthase induced by levobupivacaine in human umbilical vein endothelial cells. CONCLUSIONS: These results indicate that reversal of levobupivacaine-induced vasodilation by LE is mediated mainly through the attenuation of levobupivacaine-mediated inhibition of L-type calcium channel-dependent contraction and, in part, by inhibition of levobupivacaine-induced nitric oxide release. LE-mediated reversal of responses induced by local anesthetics may be related to their lipid solubility.

Estabilidad temporal de mepivacaína al 1.5% alcalinizada / Alkalinized 1.5% mepivacaine stability over time

Objetivos: Estudiar la estabilidad en el tiempo de la mepivacaína alcalinizada en cuanto a valores de pH y formación de precipitados, ya que apenas existe información en la literatura acerca de la estabilidad temporal de este anestésico, y la información disponible aconseja alcalinizarla justo antes de su empleo. Material y métodos: Fueron preparadas tres jeringas (A, B y C) de 20 mL conteniendo mepivacaína al 1.5%. La jeringa A fue utilizada como control de pH, y las jeringas B y C fueron alcalinizadas adicionando 2 mL de bicarbonato al 8.4%. Fue medido el pH y calculado el porcentaje de base libre asociado en cada jeringa previamente a la alcalinización y posteriormente cada 10 minutos hasta completar una hora, salvo para la jeringa C en los últimos 30 minutos, que permaneció cerrada como control de fuga de CO2. Las soluciones fueron inspeccionadas visualmente durante todo el procedimiento para identificar eventuales precipitados macroscópicos y, tras la hora de estudio, fueron filtradas para indagar sobre la formación de precipitados microscópicos. Tras el filtrado, el pH de cada solución anestésica fue medido de nuevo. Resultados: Tras la alcalinización de la mepivacaína al 1.5% se produjo un aumento inmediato y significativo de los valores de pH y del porcentaje calculado de base libre en las jeringas alcalinizadas B y C con respecto a la de control A, y en todas las jeringas el pH permaneció muy estable durante una hora. Además, a los 60 minutos apenas existieron diferencias entre los valores de pH de las jeringas B y C, lo que indica que no se produjo fuga significativa de CO2. En este tiempo no hubo sospecha de formación de precipitados por inspección visual, y las mínimas diferencias encontradas entre los pesos secos de los filtros indican que no hubo formación de precipitados significativa (…) (AU)

PurposeIt is recommended to alkalinize mepivacaine just before employing it. However, data regarding alkalinized mepivacain estability over time are very scarce. The aim of this work was to investigate for pH stability and precipitation of alkalinized mepivacaine. Materials and Methods: Three syringes (A, B, C) containing 20mL of 1.5% mepivacaine each one were prepared. Syringe A served as pH control, and syringes B and C were alkalinized by adding 2mL of8.4% sodium bicarbonate solution. pH was measured into each syringe before alkalinization and every ten minutes lasting for one hour after. Associated free base percentage was calculated, except for the last 30 minutes for syringe C, which remained closed to serve as CO2 leakage control. Solutions were examinated by naked eyes looking for macroscopic precipitates, filtered after the procedure and the filters were weighed in order to looking for microscopic precipitates. After filtration pH was again measured. Results: Alkalinization resulted in immediate and significant increases in pH values and associated free base percentage of syringes B and C compared to syringe A. After that and for one hour pH values remained very stable. Besides, pH values between syringes B and C were very similar at 60 minutes, indicating no-significative leakage of CO2. The procedure was completed without evidence of precipitation by visual inspection, and differences between dry filters weights were minimalindicating no significative formation of microprecipitates. Conclusions: 1.5% mepivacaine solutions can be alkalinized and stored at room temperature in closed syringes for at least one hour before administration. In our opinion previous alkalinizationis much more convenient to daily clinical practice that actual recommendation of alkalinization just before use (AU)

Blood concentrations of tetracaine and its metabolite following spinal anesthesia.

Blood concentrations of tetracaine and its metabolite, p-butylaminobenzoic acid, were measured after spinal anesthesia with tetracaine which had been administered to patients under going orthopedic surgery. Tetracaine, an ester anesthetic, was given to 10 patients, the dose was 8-14mg, and blood samples were collected 1, 2 and 6h after the injection of tetracaine. We used gas chromatography/mass spectrometry for purposes of analysis. Tetracaine was not detected in any blood sample, but the metabolite was detected in each sample with the mean concentrations of 126.5, 97.9 and 43.3ng/ml at 1, 2 and 6h, respectively. This data will be useful in determination of the cause of death after spinal anesthesia with tetracaine.

Recognition of local anesthetics by alphabeta+ T cells.

Patients with drug allergy show a specific immune response to drugs. Chemically nonreactive drugs like, for example, local anesthetics are directly recognized by alphabeta+ T cells in an HLA-DR restricted way, as neither drug metabolism nor protein processing is required for T cell stimulation. In this study we identified some of the structural requirements that determine cross-reactivity of T cells to local anesthetics, with the aim to improve the molecular basis for the selection of alternatives in individuals sensitized to a certain local anesthetic and to better understand presentation and T cell recognition of these drugs. Fifty-five clones (52 lidocaine specific, three mepivacaine specific from two allergic donors) were analyzed. Stimulatory compounds induced a down-regulation of the T cell receptor, demonstrating that these non-peptide antigens are recognized by the T cell receptor itself. A consistent cross-reactivity between lidocaine and mepivacaine was found, as all except one lidocaine specific clone proliferated to both drugs tested. Sixteen chemically related local anesthetics (including ester local anesthetics, OH- and desalkylated metabolites) were used to identify structural requirements for T cell recognition. Each of the four clones examined in detail was uniquely sensitive to changes in the structures of the local anesthetic: clone SFT24, i.e., did not recognize any of the tested OH- or desalkylated metabolites, while the clone OFB2 proliferated to all OH-metabolites and other differently modified molecules. The broadly reactive clone OFB2 allowed us to propose a model, suggesting that the structure of the amine side chain of local anesthetics is essential for recognition by the T cell receptor.

Valoración cinética y dinámica de la lidocaína y mepivacaína en odontopediatría / Kinetic and dynamic evaluation of lidocaine and mepivacaine in pediatric dentistry

En una población pediátrica de 20 niños se evalúa el comportamiento cinético y dinámico dela lidocaína y mepivacaína asociados con adrenalina, con referencia específica al período de latencia, profundidad y duración del efecto anestésico

Circadian phase-dependent protein and tissular binding of three local anesthetics (bupivacaine, etidocaine, and mepivacaine) in mice: a possible mechanism of their chronotoxicokinetics?

The aim of this study was to investigate the possible influence of the time of administration on bupivacaine (B), etidocaine (E), and mepivacaine (M) protein and tissue (brain and heart) binding. For each anesthetic agent, a single dose of B (20 mg/kg), E (40 mg/kg), or M (60 mg/kg) was administered intraperitoneally at 10:00, 16:00, 22:00, and 04:00 h. Blood and tissue samples were collected 15 min after drug administration. This study documents significant circadian variations in protein and tissue binding of the three local anesthetic agents. We did not demonstrate a temporal relationship between the respective free and tissue levels. Thus, the temporal variations of free plasma, brain, and heart levels do not seem to be involved in the temporal changes of induced mortality.

Clinical pharmacokinetics in pregnancy and perinatology. I. Placental transfer and fetal side effects of local anaesthetic agents.

Local anaesthetic agents, both of the amide type (e.g., lidocaine, bupivacaine, etidocaine) and of the ester type (e.g., 2-chloroprocaine) are widely used to relieve pain in obstetric and gynaecological practice. The pharmacokinetics of these compounds are discussed in this review, with particular emphasis on the fetal exposure and its relationship to adverse effects on the fetus. 2-Chloroprocaine is rapidly hydrolyzed by esterases, and only traces of this compound reach the fetus, even following multiple injections, suggesting safety for the fetus. The main disadvantage of this compound is the short duration of action (0.5-1 h). The amide-type agents are active for longer time periods (up to several hours). The fetal/maternal total concentration ratios were approximately 0.3 for bupivacaine and etidocaine, 0.5 for lidocaine, 0.7 for mepivacaine, and 1 for prilocaine. The low ratios of bupivacaine and etidocaine result from extensive binding (90%) of these drugs to maternal alpha1-acid glycoprotein which exceeds corresponding fetal protein binding (50%). These low fetal/maternal total concentration ratios cannot be equated with fetal safety, because fetal side effects are better related to the free drug levels. Since the amide-type anaesthetics are weak bases, fetal acidosis will increase the maternal/fetal pH gradient and will result in accumulation of free drug in the fetus and possible fetal side effects. Addition of epinephrine to the injection solution reduces the maternal blood levels of the amide-type compounds, but apparently not the fetal levels to the same extent. Because of possible unwanted effects of epinephrine (decreased uterine blood flow), the addition of this compound is not generally accepted to be of advantage. Paracervical blockade may result in elevated fetal blood levels (possibly by transarterial diffusion into uterine arteries) and possibly fetal bradycardia.

Influence of bupivacaine on mepivacaine protein binding.

To elucidate the mechanism of any drug displacement interaction, we examined the protein binding of mixtures of mepivacaine and bupivacaine in serum and solutions of albumin or alpha 1-acid glycoprotein. Protein binding data with mepivacaine alone were best described by a model with one class of binding site and a partitioning constant in serum and by a model with one class of binding site in both isolated protein solutions. Binding affinity of mepivacaine in serum was reduced in the presence of bupivacaine. Displacement of mepivacaine by bupivacaine was observed when an alpha 1-acid glycoprotein solution was studied. Classic competitive inhibition was demonstrated. Bupivacaine reduced mepivacaine binding to albumin, but the degree of displacement was not significant. When administered simultaneously, these two amino-amide local anesthetics interact synergistically to produce a higher than expected free concentration of mepivacaine. This interaction increases the risk of toxicity.

Lung uptake of lidocaine in man as influenced by anaesthesia, mepivacaine infusion or lung insufficiency.

Pulmonary uptake of lidocaine was investigated in patients before surgery, and aimed at elucidating the influence of general anaesthesia, the presence of another local anaesthetic agent in the blood, or the possible impact of lung insufficiency. When the lung uptake of lidocaine, injected as a bolus together with indocyanine green dye, was calculated as uptake at 95% pass of the dye, there were no statistically significant differences between the four groups. When the extraction in each of the arterial blood samples was calculated on the basis of the relation between relative concentrations, there were statistically significant differences, with a general tendency towards higher extraction of lidocaine in the awake, healthy volunteers, not given mepivacaine, compared to the other groups. In the group in whom mepivacaine was infused, the arterial concentration of mepivacaine increased transiently after the injection of lidocaine. This probably reflects a displacement of mepivacaine from binding sites for both agents. From this study, it is postulated that the ability of the pulmonary circulation to clear the blood of lidocaine is high, and that it is not affected markedly by those situations studied in the present investigation.

Lidocaine and mepivacaine in cord blood.

The concentrations of lidocaine and mepivacaine were measured in stored cord blood samples from 200 deliveries. Newborn and obstetrical charts were reviewed for 100 deliveries for study of the association between cord blood concentrations, drug and route of recorded administration, Apgar scores at birth, and symptoms of possible toxicity. Detectable concentrations were commonly found (117/200), but toxic (3 micrograms/ml) levels were uncommon (4/200). However, recovery studies indicate these levels underestimate maximal exposure because both lidocaine and mepivacaine levels were shown to decrease in refrigerated stored blood. Although toxicity was seldom suspected, diagnostic accuracy was poor. The diagnosis was missed in the two patients with very high levels (5.0 and 9.0 micrograms/ml) of mepivacaine and levels measured in two suspected cases of toxicity were both low (0.4 microgram/ml). Associations between Apgar scores, cord levels, and route of administration (especially for lidocaine) were examined for 65 full-term uncomplicated deliveries. However, evaluation of these associations is problematic because dosages given, time or route of administration, and/or Apgar scores were often either not given or inconsistent with the clinical history. Detectable and potentially clinically significant local anesthetic drug concentrations were found in cord blood after all methods of administration, including local infiltration. These levels appear to underestimate the level of exposure because of instability of these anesthetics in stored cord blood samples. Local anesthetic toxicity appears to be difficult to detect clinically and may require cord blood level monitoring to detect.

Studies on the duration of local anesthesia: a possible mechanism for the prolonging effect of "vasoconstrictors" on the duration of infiltration anesthesia.

Attempts have been made to correlate the duration of the local anesthetic effect with the amount of the local anesthetic compound remaining at the injection site at different times after an injection. In addition to delaying the absorption of the local anesthetic, adrenaline but not a vasopressin-derivate decreased the minimal anesthetic concentration of the local anesthetic agent. It is assumed that the pH value of the tissues at the injection site was kept down through the metabolic effects of adrenaline, thereby transforming the local anesthetic agent into cations, which is the form in which the amide-type of local anesthetics mainly exerts their nerve blocking activity.

Brain-to-blood and saliva-to-blood mepivacaine ratios in rats.

Mepivacaine hydrochloride, 25 and 50 mg/kg sc (with sacrifice at 15 min) produced higher (p less than 0.005) drug levels in neonate (24--36-hr-old) rat brain and blood than in adult rat brain and blood; however, there was no significant difference in the brain-to-blood ratio of the drug between neonates and adults at either dose level. Intraarterial infusion of mepivacaine hydrochloride (20 micrograms/min) in adult rats resulted in measurable (GLC) mepivacaine base levels in pilocarpine-induced parotid salivary secretions collected throughout 30- and 45-min infusion periods. The saliva-to-blood ratios (+/- SEM) of mepivacaine base were 0.64 +/- 0.13 after a 30-min infusion and 2.13 +/- 0.48 after a 45-min infusion.