J. Spierdijk

Pharmacokinetics of lignocaine and bupivacaine in surgical patients following epidural administration. Simultaneous investigation of absorption and disposition kinetics using stable isotopes

SummaryThe pharmacokinetics of lignocaine (lidocaine) and bupivacaine following epidural administration were studied in 12 surgical patients using a stable isotope method. Shortly after epidural administration of the agent to be evaluated, a deuterium-labelled analogue was administered intravenously. Plasma concentrations of the unlabelled and the deuterium-labelled local anaesthetics were determined using gas chromatography and mass fragmentography. The pharmacokinetic behaviour of both agents was consistent with a 2- compartment open model and two parallel first-order absorption processes. The mean distribution and elimination half-lives were 12 minutes and 100 minutes for lignocaine, and 22 minutes and 143 minutes for bupivacaine. The mean volumes of the central compartment and the mean steady-state volumes of distribution were: lignocaine, 43L and 99L; bupivacaine, 33L and 68L. Total plasma clearances averaged 0.95 L/min (57 L/h) for lignocaine and 0.52 L/min (31.2 L/h) for bupivacaine. The half-lives, characterising the fast and slow absorption processes, were 9.3 and 82 minutes for lignocaine, and 7.0 minutes and 362 minutes for bupivacaine; the fractions of the doses absorbed in the fast and slow processes were lignocaine 0.38 and 0.58, bupivacaine 0.28 and 0.66, respectively. The results indicate that the local anaesthetics are completely absorbed from the epidural space into the general circulation. The initial absorption rates of both local anaesthetics appear to be similar, but, later, the absorption of bupivacaine proceeds much more slowly than the absorption of lignocaine.

THE EFFECT OF AGE ON SYSTEMIC ABSORPTION AND SYSTEMIC DISPOSITION OF BUPIVACAINE AFTER SUBARACHNOID ADMINISTRATION

In order to evaluate the role of the pharmacokinetics of the age-related changes in the clinical profile of spinal anesthesia with bupivacaine, we studied the influence of age on the systemic absorption and systemic disposition of bupivacaine after subarachnoid administration in 20 male patients (22-81 yr), ASA Physical Status 1 or 2, by a stable isotope method. After subarachnoid administration of 3 ml 0.5% bupivacaine in 8% glucose, a deuterium-labeled analog (13.4 mg) was administered intravenously. Blood samples were collected for 24 h. Plasma concentrations of unlabeled and deuterium-labeled bupivacaine were determined with a combination of gas chromatography and mass fragmentography. Biexponential functions were fitted to the plasma concentration-time data of the deuterium-labeled bupivacaine. The systemic absorption was evaluated by means of deconvolution. Mono- and biexponential functions were fitted to the data of fraction absorbed versus time. The maximal height of analgesia and the duration of analgesia at T12 increased with age (r = 0.715, P less than 0.001; r = 0.640, P less than 0.01, respectively). In 18 patients the systemic absorption of bupivacaine was best described by a biexponential equation. The half-life of the slow systemic absorption process (r = -0.478; P less than 0.05) and the mean absorption time (r = -0.551; P less than 0.02) decreased with age. The total plasma clearance decreased with age (r = -0.650, P less than 0.002), whereas the mean residence time and terminal half-life increased with age (r = 0.597, P less than 0.01; r = 0.503, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic-pharmacodynamic modelling of the interaction between flumazenil and midazolam in volunteers by aperiodic EEG analysis.

SummaryThe CNS effects resulting from the combined administration of midazolam and flumazenil were studied in 8 healthy volunteers to develop a model of the pharmacokinetic-pharmacodynamic interaction. Electroencephalograms (EEG) were recorded between Fp1-M1 and FP2-M2. The EEG parameter total number of waves between 12 and 30Hz (TNW12–30) derived by aperiodic analysis was used to quantify the effect. Following a 15 min baseline EEG recording, infusion of placebo or flumazenil was started. Infusion regimens for flumazenil were designed so that ‘steady-state’ concentrations of 10 and 20 µg/L were obtained. Doses of midazolam 15, 30 and 60mg over 5 min were given 30 min after the start of placebo infusion (session A) or flumazenil infusion to 10 µg/L (session B) or 20 µg/L (session C), respectively. Venous blood samples were taken until 8h after the start of the flumazenil or placebo infusion. A sigmoid maximum effect (Emax) model was used to characterise the relationship between the plasma concentration of midazolam which is in equilibrium with the effect compartment concentration (Cem) [Cem/Kp] and TNW 12–30.Within 2 to 5 min of starting the midazolam infusion all subjects fell asleep, with loss of eyelid reflex. They awoke between 25 and 82 min later in all 3 sessions. The mean (± SD) plasma drug concentrations of midazolam corresponding to half the maximum increase in TNW 12–30 (EC50) were 276 ± 64, 624 ± 187 and 1086 ± 379 µg/L in sessions A, B and C, respectively. The half-lives reflecting equilibration between plasma concentration and effect (t½ke0), estimated by a nonparametric method, were 2.2 ± 1.2, 3.3 ± 3.3 and 2.9 ± 1.2 min for the 3 different sessions. Emax and N were not affected by flumazenil. In each subject the plot of the average measured steady-state plasma flumazenil concentration versus the EC50 of midazolam showed a linear relationship. The plasma concentration of flumazenil that doubled the EC50 of midazolam (Cf,2) was 6.5 ± 1.0 µg/L. The observed interaction is consistent with the competitive nature of the antagonism of midazolam by flumazenil.

Pharmacokinetics of lidocaine and bupivacaine following subarachnoid administration in surgical patients: simultaneous investigation of absorption and disposition kinetics using stable isotopes

The pharmacokinetics of lidocaine and bupivacaine following subarachnoid administration were studied in 12 surgical patients using a stable isotope method. After subarachnoid administration of the agent to be evaluated, a deuterium-labelled analogue was administered intravenously. Blood samples were

PHARMACOKINETICS AND EEG EFFECTS OF FLUMAZENIL IN VOLUNTEERS

SummaryThe effect of intravenous flumazenil 10mg on the electroencephalogram (EEG) was investigated in 7 volunteers in a placebo-controlled, randomised, double-blind, crossover study. The EEG was recorded between Fp2-M1 and FP2-M2 and analysed using an aperiodic analysis technique. Two volunteers were excluded from the study because of significant asymmetry between baseline EEG recordings of the left and right hemisphere; in the remainder there were no changes in the β-frequency range (12 to 30Hz) or in other ranges of the EEG during or after flumazenil or placebo administration, with regard to the parameters total number of waves per second or total amplitude per second. There were no changes in heart rate, respiratory rate or blood pressure after administration of flumazenil or placebo. Three volunteers reported feelings of ‘pressure to move’ during the initial 2 min of the flumazenil infusion.The pharmacokinetics of flumazenil were investigated in the same volunteers. Flumazenil 10mg was administered intravenously over 10 min; the data from 1 volunteer were excluded from this analysis because of blood sampling problems. The plasma concentration-time data of the remaining 6 volunteers were characterised by a biexponential function. The pharmacokinetic parameters were (mean ± SD): initial volume of distribution, 16 ± 5.7L; volume of distribution at steady-state, 64.8 ± 12.5L; total body clearance, 53.8 ± 1.2 L/h; distribution half-life, 4.1 ± 1.3 min; and elimination half-life, 70.2 ± 9.9 min.The authors conclude that flumazenil has no significant EEG effects. The rapid distribution and elimination of flumazenil may explain its previously reported short duration of action after intravenous anaesthesia with high doses of midazolam.

Pharmacokinetics of Lidocaine and Bupivacaine Following Subarachnoid Administration in Surgical Patients: Simultaneous Investigation of Absorption and Disposition Kinetics Using Stable Isotopes

The pharmacokinetics of lidocaine and bupivacaine following subarachnoid administration were studied in 12 surgical patients using a stable isotope method. After subarachnoid administration of the agent to be evaluated, a deuterium-labelled analogue was administered intravenously. Blood samples were collected for 24 h. Plasma concentrations of the unlabelled and the deuterium-labelled local anesthetics were determined using a combination of capillary gas chromatography and mass fragmentography. Bi-exponential functions were fitted to the plasma concentration-time data of the deuterium-labelled local anesthetics. The progression of the absorption was evaluated using deconvolution. Mono- and bi-exponential functions were then fitted to the fraction absorbed versus time data. The distribution and elimination half-lives of the deuterium-labelled analogues were 25 ± 13 min (mean ± SD) and 121 ± 31 min for lidocaine and 19 ± 10 min and 131 ± 33 min for bupivacaine. The volumes of the central compartment and steady-state volumes of distribution were: lidocaine 57 ± 10 1 and 105 ± 25 1, bupivacaine 25 ± 6 1 and 63 ± 22 1. Total plasma clearance values averaged 0.97 ± 0.211/min for lidocaine and 0.56 ± 0.14 1/min for bupivacaine. The absorption of lidocaine could be described by a single first order absorption process, characterized by a half-life of 71 ± 17 min in five out of six patients. The absorption of bupivacaine could be described adequately assuming two parallel first order absorption processes in all six patients. The half-lives, characterizing the fast and slow absorption processes of bupivacaine, were 50 ± 27 min and 408 ± 275 min, respectively. The fractions of the dose, absorbed in the fast and slow processes, were 0.35 ± 0.17 and 0.61 ±0.16, respectively. The results indicate that both local anesthetics arc completely absorbed intact from the subarachnoid space into the general circulation.

Spinal Anesthesia with Hyperbaric Lidocaine and Bupivacaine: Effects of Epinephrine on the Plasma Concentration Profiles

The effects of epinephrine on the plasma concentration profiles and some derived pharmacokinetic parameters were studied after subarachnoid injection of hyperbaric lidocaine and bupivacaine solutions. Addition of epinephrine to the local anesthetic solution reduced the mean peak plasma concentration of lidocaine from 526 to 376 ng/ml, but did not significantly reduce the mean peak plasma concentration of bupivacaine (70 vs 56 ng/ml). Epinephrine did not affect the times at which the peak concentrations were reached, the terminal half-lives, or the total plasma clearances. The observed effects of epinephrine on the peak plasma concentrations are consistent with the vascular activity of lidocaine and bupivacaine, respectively.