RESUMO
Bupivacaine, a drug used in obstetric anesthesia and analgesia, is commercially available as a racemic mixture of the R-bupivacaine and S-bupivacaine enantiomers, which show differences in pharmacokinetics, efficacy and toxicity. Changes in bupivacaine plasma protein binding is of clinical relevance considering its high protein binding (approximately 95%) and its classification as an intermediate hepatic extraction ratio drug (E = 0.38). Furthermore, the plasma protein binding of bupivacaine is also of clinical relevance considering that pregnancy is a physiological condition associated with reduced plasma albumin concentration. Also, different pathological conditions, such as pre-eclampsia, can reduce the maternal plasma protein concentrations and consequently increase the bupivacaine placental transfer. This report describes the development and validation of analytical methods for the sequential analysis of the total and unbound concentrations of bupivacaine enantiomers in human plasma using liquid chromatography coupled to mass spectrometry (LC-MS/MS) with a sensitivity compatible with application in pharmacokinetic studies including placental transfer. Aliquots of 200 µL of plasma or plasma ultra-filtrate were extracted with n-hexane in alkaline medium after the deproteinization of the matrix with acetonitrile and water. The separation of bupivacaine enantiomers was obtained on a Chirex® 3020 chiral stationary phase column using as a mobile phase a mixture of 95% n-hexane:ethanol (80:20, v/v) at a flow rate of 0.8 mL/min. The lower limit of quantification was 0.25 ng of each enantiomer/mL of plasma as the total concentration and 0.125 ng of each enantiomer/mL of plasma as the unbound concentration. The methods were applied to study the pharmacokinetics of bupivacaine enantiomers after the administration of 2.5 mg of 0.5% racemic bupivacaine hydrochloride with 1:200,000 epinephrine via the epidural route to an HIV-positive parturient woman undergoing antiretroviral treatment. The parturient showed lower AUC0-∞ (25.42 vs. 30.57 ng.h/mL) and higher volume of distribution (841.96 vs 655.05 L) and total clearance (98.34 vs 81.79 L/h) for the R-bupivacaine enantiomer. The pharmacokinetics of bupivacaine were enantioselective displaying a lower plasma proportion of the enantiomer R-bupivacaine (AUC(R)/(S) ratio equal to 0.83). The placental transfer was approximately 60% for both bupivacaine enantiomers. The unbound fraction (Fu) for the R-bupivacaine enantiomer was higher (10.84%) than the eutomer S-bupivacaine (6.29%).
Assuntos
Anestésicos Locais/sangue , Proteínas Sanguíneas/metabolismo , Bupivacaína/sangue , Troca Materno-Fetal , Equilíbrio Ácido-Base/efeitos dos fármacos , Anestesia Epidural/efeitos adversos , Anestesia Epidural/métodos , Anestesia Obstétrica/efeitos adversos , Anestesia Obstétrica/métodos , Anestésicos Locais/química , Anestésicos Locais/farmacocinética , Bupivacaína/química , Bupivacaína/farmacocinética , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Feto/efeitos dos fármacos , Feto/metabolismo , Voluntários Saudáveis , Humanos , Gravidez , Ligação Proteica , Estereoisomerismo , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodosRESUMO
BACKGROUND AND OBJECTIVES: The pharmacokinetics for levobupivacaine in transversus abdominis plane (TAP) blocks has not been previously reported. We aimed to determine the extent of the block and the effect on plasma concentrations of levobupivacaine with the addition of epinephrine. METHODS: We enrolled 11 healthy volunteers in this double-blind, 2-intervention, 2-period crossover study. The intervention periods were defined as a unilateral left TAP block with 20 mL of 0.25% levobupivacaine with (E) or without (no E) 5 µg/mL epinephrine. Subjects were randomized to E, followed by no E or no E followed by E, with 2-week washout period. Sensory dermatomal anesthesia was recorded. Blood samples were obtained for the measurement of plasma levobupivacaine levels. RESULTS: The median cranial-to-caudal spread of sensory blockade for sharp touch was T9 (interquartile range [IQR], T7-T10) to L1 (IQR, T12-L1) with epinephrine and T9 (IQR, T8-T10) to T12 (IQR, T11-L1) without epinephrine (P > 0.05). The mean maximum arterial levobupivacaine concentrations with epinephrine were 0.36 (95% bootstrap confidence interval [95% CI], 0.30-0.42) µg/mL and 0.63 (95% CI, 0.49-0.85) µg/mL without epinephrine (P = 0.014, difference in means of 0.27 [95% CI, 0.12-0.46]). The mean maximal venous levobupivacaine concentration was 0.32 (95% CI, 0.28-0.39) µg/mL and 0.49 (95% CI, 0.37-0.68) µg/mL, with and without epinephrine, respectively (P = 0.006, difference in means of 0.17 [95% CI, 0.08-0.33]). The mean duration of the blockade was 10.2 hours (95% CI, 8.5-12.5 hours) with epinephrine and 10.3 hours (95% CI, 8.7-12.4 hours) without epinephrine (P = 1.000). CONCLUSIONS: Adding epinephrine to levobupivacaine reduces its peak plasma concentration after unilateral TAP blocks, with no remarkable effects on block characteristics or duration.
Assuntos
Anestésicos Locais/sangue , Epinefrina/administração & dosagem , Bloqueio Nervoso/métodos , Vasoconstritores/administração & dosagem , Adulto , Anestésicos Locais/administração & dosagem , Anestésicos Locais/farmacocinética , Bupivacaína/administração & dosagem , Bupivacaína/análogos & derivados , Bupivacaína/sangue , Bupivacaína/farmacocinética , Temperatura Baixa , Estudos Cross-Over , Método Duplo-Cego , Combinação de Medicamentos , Humanos , Levobupivacaína , Masculino , Estudos Prospectivos , Tato , Ultrassonografia de IntervençãoRESUMO
BACKGROUND AND OBJECTIVES: Local anesthetics (LA) are safe drugs when the proper dose and localization are used. The rate of absorption of the local anesthetic depends on its mass and blood flow at the site of the injection. The objective of this study was to analyze the plasma concentration of 50% enantiomeric excess (S75R25) 0.5% bupivacaine combined with 1:200,000 epinephrine in the parasacral (PS) and infragluteal (IG) sciatic nerve block (SNB). METHODS: Twenty-eight patients scheduled for ankle and foot surgeries were randomly divided into two groups in this prospective study. In Group 1, SNB was performed with IG neurostimulation, while in Group 2 the PS method was used. Both groups received 30 mL of 0.5% bupivacaine (S75/R25) with 1:200,000 epinephrine. Arterial blood samples, 5 mL, were drawn at 0, 15, 30, 60, and 90 minutes after the administration of the LA. High-performance liquid chromatography was used to analyze the serum concentrations. Demographic data of both groups were compared using the Student t test for independent samples and Fisher's Exact test. Bifactorial Analysis of Variance for repeated samples was used for the data concerning the plasma concentrations. RESULTS: Groups 1 and 2 showed no significant demographic differences. The maximal concentration (Cmax) in Group 1 (308 +/- 91 ng.mL(-1)) was obtained in samples number 5 (90 minutes), while in Group 2 (425 +/- 280 ng.mL(-1)) it was obtained in samples number 2 (15 minutes). Cases of systemic toxicity were not observed. CONCLUSIONS: Cmax of 0.5 % bupivacaine (S75/R25) with 1:200,000 in the parasacral approach was higher when compared with the infragluteal SNB.
Assuntos
Bupivacaína/administração & dosagem , Bupivacaína/sangue , Epinefrina/administração & dosagem , Epinefrina/sangue , Bloqueio Nervoso , Nervo Isquiático , Adolescente , Adulto , Idoso , Nádegas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Região Sacrococcígea , Adulto JovemRESUMO
Bupivacaine is available as a racemic mixture of its enantiomers, d-bupivacaine and l-bupivacaine (LB). The aim of this randomized, double-blind study was to investigate the clinical efficacy and safety of S(-)-bupivacaine compared with standard racemic bupivacaine (RB) in horses under caudal epidural analgesia. Two treatments were administered to each horse, with a 2-week interval between subsequent treatments. Treatment 1 consisted of 0.5% LB at a dose of 0.06 mg/kg of body weight, and treatment 2 consisted of 0.5% RB at a dose of 0.06 mg/kg of body weight. Epidural injections were given in all animals between the first and second coccygeal vertebra. Heart rate (HR), arterial pressures, respiratory rate (RR), rectal temperature (RT), analgesia, and motor blocking were determined before drug administration (basal) and 5, 10, 15 and 30 min after drug administration, and at 30 min intervals thereafter. There were no significant differences between the two treatments in the quality of sensory and motor block. The duration of analgesia was 320 +/- 30 min (mean +/- SD) for RB and 360 +/- 42 min for LB. HRs and RRs, arterial pressures and RT did not change (P < 0.05) significantly from basal values after epidural administration of LB or RB. This study supports that 0.5% LB is an effective alternative to RB in caudal epidural analgesia in conscious, standing horses. The use of LB vs. RB warrants further investigation, particularly for long-lasting surgery in the perineal region.
Assuntos
Analgesia Epidural/veterinária , Anestésicos Locais/farmacocinética , Bupivacaína/farmacocinética , Cavalos/fisiologia , Anestésicos Locais/administração & dosagem , Anestésicos Locais/sangue , Anestésicos Locais/química , Animais , Pressão Sanguínea/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Bupivacaína/administração & dosagem , Bupivacaína/sangue , Bupivacaína/química , Método Duplo-Cego , Frequência Cardíaca/efeitos dos fármacos , Cavalos/metabolismo , Injeções Epidurais/veterinária , Medição da Dor/efeitos dos fármacos , Estudos Prospectivos , Respiração/efeitos dos fármacos , Resultado do TratamentoRESUMO
The aim of the present study was to investigate the stereoselectivity in the kinetic disposition and the transplacental distribution of bupivacaine in term parturients during labor. Maternal age ranged from 18-37 years and fetal gestational age from 37.6-41.5 weeks. Healthy parturients (n = 23) received epidural 0.5% racemic bupivacaine alone (group A) or combined with epinephrine (group B). Maternal venous blood was sampled at regular intervals until 8 h after drug administration and umbilical venous blood was obtained at delivery. Bupivacaine enantiomers were determined in plasma samples by HPLC using a Chiralcel(R) OD-R column and a UV detector. One- or two-compartment models were fitted to data and differences between the (+)-(R) and (-)-(S) enantiomers were compared with the paired Wilcoxon test (P< 0.05). The influence of epinephrine was evaluated using the unpaired Mann-Whitney test (P< 0.05). The disposition of bupivacaine in maternal plasma was stereoselective, with higher V(d/f) (140.60 vs. 132.81 L for group A and 197.86 vs. 169.46 L for group B) and C(l/f) (29.00 vs. 25.43 L/h for group A and 33.15 vs. 26.39 L/h for group B) and lower t(1/2)beta (3.24 vs. 3.30 h for group A and 4.36 vs. 4.45 h for group B) being observed for (+)-(R)-bupivacaine. The combined administration of epinephrine resulted in higher V(d/f) (197.86 vs. 140.60 L for (+)-(R) and 169.46 vs. 132.81 L for (-)-(S)) and t(1/2)beta values (4.36 vs. 3.24 h for (+)-(R) and 4.45 vs. 3.30 h for (-)-(S)). The transplacental distribution of bupivacaine was stereoselective only when bupivacaine was administered without epinephrine (group B), with a higher cord blood/maternal blood ratio being observed for (-)-(S)-bupivacaine (0.40 vs. 0.35). Chirality 16:65-71, 2004.
Assuntos
Bupivacaína/química , Bupivacaína/farmacocinética , Parto/fisiologia , Vasoconstritores/administração & dosagem , Adolescente , Adulto , Bupivacaína/administração & dosagem , Bupivacaína/sangue , Epinefrina/administração & dosagem , Epinefrina/farmacologia , Feminino , Sangue Fetal/efeitos dos fármacos , Sangue Fetal/metabolismo , Humanos , Cinética , Idade Materna , Troca Materno-Fetal/efeitos dos fármacos , Gravidez , Estereoisomerismo , Vasoconstritores/farmacologiaRESUMO
Justificativa e Obejetivos - A ropivacaína é o mais novo anestésico local de uso na prática clínica. Sua estrutura é semelhante a forma levógira da bupivacaína, tendo portanto baixa toxicidade. Os valores das concentrações plasmáticas que podem ser atingidos em crianças, com o uso desta droga e também da bupivacaína (mesmo a forma racêmica) administradas por via peridural lombar, são ainda pouco conhecidos. O objetivo desse estudo foi avaliar as concentrações sangüíneas de ropivacaína e bupivacaína por via peridural lombar em crianças, em bloqueios eficientes, relacionando-as aos valores descritos como níveis plasmáticos seguros. Método - Oitenta e um pacientes de ambos os sexos, submetidos à cirurgia de membros inferiores, receberam aleatoriamente ropivacaína (n = 41) ou bupivacaína (n = 40) por via peridural lombar associado à anestesia geral. Foram coletadas oito amostras de sangue venoso nos intervalos de tempo: zero (controle), 5, 25, 40, 60, 120, 180 e 240 minutos, e através de cromatografia de gás foram dosadas as concentrações plasmáticas da ropivacaína e da bupivacaína. Resultados - Não houve diferança estatisticamente signidicante com relação aos dados antropométricos e variáveis fisiológicas estudadas entre os pacientes que receberam ropivacaína e bupivacaína. As doses médias administradas de ropivacaína e bupivacaína foram 2,35 mg.kgðû e 2,13 mg.kgðû, respectivamente, que geraram as concentrações plasmáticas de 2,334 µg.mlðû e 1.111 µg.mlðû, aos 25 e 40 minutos. Ambas abaixo do nível considerado seguro (3 µg.kgðû). Conclusões - A administração peridural lombar de ropivacaína e bupivacaína em crianças, nas doses abaixo de 3 mg.kgðû, produz bloqueio anestésico eficaz e determinda concentrações plasmáticas que podem ser consideradas seguras
Assuntos
Humanos , Masculino , Feminino , Anestesia Epidural , Anestésicos Locais/administração & dosagem , Anestésicos Locais/sangue , Anestésicos Locais/uso terapêutico , Bupivacaína/administração & dosagem , Bupivacaína/sangue , Relação Dose-Resposta a DrogaRESUMO
We report a high resolution liquid chromatography method for simultaneous determination of lidocaine, mepivacaine and bupivacaine in serum using cyclicine as a standard. Drugs are extracted from serum using dichloromethane in an alkaline medium type columns in a mobile phase with 0.1 M phosphate buffer at pH 7.5, methanol and acetonitrile (33:17:50) were used for separation. Spectrophotometric measurement was performed at 207 nm. In a concentration ranging from 0.5 to 8 micrograms/ml, r values of 0.997, 0.989 and 0.998 were obtained for lidocaine, mepivacaine and bupivacaine, respectively. The coefficient of variation estimated at 2 micrograms/ml was 2, 19, 2.76 and 2.48%, respectively. A maximal error of 4.5%, 3.6% and 2.9% found for "inter day" repeated measurement at the above concentration for each drug. Thus, high sensitivity, reproducibility and relative simpleness of the method are demonstrated for its clinical use in determination of serum levels of local anesthetics.
Assuntos
Anestésicos Locais/sangue , Cromatografia Líquida de Alta Pressão , Bupivacaína/sangue , Feminino , Humanos , Lidocaína/sangue , Mepivacaína/sangue , GravidezAssuntos
Humanos , Feminino , Gravidez , Anestésicos Locais/sangue , Cromatografia Líquida de Alta Pressão/métodos , Espectrofotometria , Sangue Fetal/efeitos dos fármacos , Troca Materno-Fetal/efeitos dos fármacos , Análise Química do Sangue , Anestésicos Locais/metabolismo , Bupivacaína/metabolismo , Bupivacaína/sangue , Lidocaína/análogos & derivados , Lidocaína/metabolismo , Lidocaína/sangue , Mepivacaína/metabolismo , Mepivacaína/sangueRESUMO
Twenty-four patients having undergone thoracotomies and subcostal incisions were treated for 24 hours with intrapleural bupivacaine with epinephrine. Vital signs, pain scores, and serum bupivacaine levels were recorded. No patient required narcotic medications and all patients obtained adequate analgesia. There were no complications of the technique or toxicity of the drug. Further studies need to be performed to extend the duration of use, to determine pharmacokinetics, and to compare with other techniques.