Concentrations of lidocaine and monoethylglycine xylidide in brain, cerebrospinal fluid, and plasma during lidocaine-induced epileptiform electroencephalogram activity in rabbits: the effects of epinephrine and hypocapnia.

UNLABELLED: When injecting lidocaine into tissues, the mean toxic dose of lidocaine may be increased by adding epinephrine to lidocaine and by decreasing the PaCO(2). In contrast, when lidocaine is introduced directly into an artery or vein, adding epinephrine to lidocaine may decrease the mean toxic dose of lidocaine. Less is known about the effects of decreased PaCO(2) on intravascular lidocaine toxicity. We infused lidocaine in 24 rabbits at 4 mg. kg(-1). min(-1) with/without epinephrine and with/without hypocapnia. We measured the time to onset of lidocaine-induced seizures, total dose of lidocaine at the time of seizures, and concentrations of lidocaine and monoethylglycine xylidide (MEGX), a metabolite of lidocaine, in plasma, brain, and cerebrospinal fluid. Epinephrine decreased onset time by 11% with hypocapnia and by 21% with normocapnia, and it increased plasma MEGX by 1 microg/mL with hypocapnia and 2 microg/mL with normocapnia. Hypocapnia increased onset time by 18% without epinephrine and by 33% with epinephrine, and it increased whole-brain MEGX by 10 microg/mL without epinephrine and by 14 microg/mL with epinephrine. We conclude that, when lidocaine is given intravascularly, hypocapnia increases onset time and lidocaine dose required for seizures. These effects occur with no change in the concentration of lidocaine in plasma or the brain. IMPLICATIONS: Hypocapnia increases the toxic dose of lidocaine given IV without altering lidocaine concentrations in blood, brain, or cerebrospinal fluid. Whole-brain monoethylglycine xylidide concentration is greater during hypocapnia than during normocapnia, and the addition of epinephrine to lidocaine increases the concentration of monoethylglycine xylidide in plasma.

Endotracheal lidocaine administration via an esophageal combitube.

The purpose of this study was to test the hypothesis that lidocaine is systemically absorbed after administration via a Combitube placed in the esophagus, and that therapeutically significant plasma lidocaine concentrations can be attained using this route with standard endotracheal doses (2.0 mg/kg). During general anesthesia, 27 elective surgical patients received 2.0 mg/kg lidocaine (diluted as necessary with 0.9% saline to a minimum total volume of 10 mL) via a Combitube (study group, n = 13) or an endotracheal tube (control group, n = 14). Venous blood samples were drawn for 3 h after lidocaine administration and plasma concentrations determined by gas chromatography using a nitrogen-phosphorus detector (NPD). Overall, average lidocaine concentrations were maximal after 5 min, reaching 0.8+/-0.7 and 1.7+/-0.7 microg/mL in the Combitube and endotracheal tube groups, respectively. Individual patient peak concentrations averaged 1.0+/-0.7 and 2.2+/-1.1 microg/mL in the same two groups, 19+/-16 and 10+/-15 min after lidocaine administration, respectively. No patients reported chest discomfort or dyspnea upon awakening, and no other side effects were noted. In support of the hypothesis, administration of lidocaine via an esophageal Combitube results in systemic drug uptake; however, at conventional endotracheal doses, plasma concentrations are subtherapeutic. It remains to be determined whether higher doses of lidocaine administered via an esophageal Combitube will result in therapeutic plasma concentrations.

Posttreatment with propofol terminates lidocaine-induced epileptiform electroencephalogram activity in rabbits: effects on cerebrospinal fluid dynamics.

UNLABELLED: There are no controlled studies to determine whether propofol given after the onset of lidocaine-induced seizures (posttreatment) stops lidocaine-induced seizures. In this study, we determined whether posttreatment with propofol abolishes lidocaine-induced epileptiform electroencephalogram (EEG) activity as effectively as does midazolam, and cerebrospinal fluid (CSF) dynamics during lidocaine-induced epileptiform EEG activity and its treatment. EEG activity and CSF dynamics were determined in two groups of anesthetized rabbits at each of four experimental conditions: baseline, lidocaine-induced epileptiform activity, treatment with midazolam (n = 6) or propofol (n = 6), and return to baseline. The analog EEG signal was converted into a set of digital parameters using aperiodic analysis, and CSF dynamics were determined using ventriculocistemal perfusion. Propofol (3.8 +/- 1.3 mg/kg) stopped epileptiform activity, as did midazolam (2.0 +/- 1.7 mg/kg). The rates of CSF formation or reabsorption and resistances to CSF reabsorption or flow at the arachnoid villi did not differ among conditions or between groups. Our results indicate that propofol and midazolam both terminate epileptiform activity without changing CSF dynamics. IMPLICATIONS: Propofol may be an alternative to benzodiazepines for treating lidocaine-induced epileptiform electroencephalogram activity in patients.

Endotracheal flumazenil: a new route of administration for benzodiazepine antagonism.

The purpose of this study was to determine if flumazenil is absorbed from broncho-pulmonary tissue after intratracheal administration and whether therapeutically significant plasma concentrations can be obtained. Six elective surgical patients received a dose of 1.0 mg flumazenil in 10 mL saline intratracheally during general anesthesia. Blood samples were drawn for 6 hours after administration and plasma concentrations were determined by gas chromatography-mass spectrometry (GC-MS). An average peak plasma flumazenil concentration of 65.9 +/- 43.1 ng/mL was attained within 1 minute after administration. No patients reported chest discomfort or dyspnea upon awakening and there were no other side effects noted. Administration of flumazenil via an endotracheal tube results in rapid attainment of therapeutic blood levels.

Intravenous lidocaine decreases but cocaine does not alter the rate of cerebrospinal fluid formation in anesthetized rabbits.

Considering that adrenergic stimulation was reported to decrease the rate of cerebrospinal fluid (CSF) formation (Vf), it was hypothesized that cocaine might exert a similar effect. Accordingly, the present study was designed to examine the effects of low, moderate, and high doses of cocaine on Vf and resistance to reabsorption of CSF (Ra). Because cocaine possesses both adrenergic-stimulating and local anesthetic properties, the present study examined the effects of lidocaine, a local anesthetic without adrenergic-stimulating properties, as a comparison treatment to cocaine. New Zealand white rabbits (n = 17) weighing 3.5-4.3 kg were anesthetized with halothane. A needle was inserted into the left lateral cerebral ventricle and a catheter was inserted into the cisterna magna to permit ventriculocisternal perfusion with mock CSF labeled with blue dextran. A1 each of four experimental conditions, control and three doses of cocaine or lidocaine, fluid volumes and concentrations of blue dextran in timed samples of cisternal outflow were used to determine Vf and the rate of reabsorption of CSF (Va). In turn, Va at normal and elevated CSF pressures (+6 cmH2O) were used to determine Ra. For both the cocaine group (n = 9) and the lidocaine group (n = 8) the three drug doses were 0.5 mg.kg-1 followed by 1.0 microgram.kg-1.min-1, 1.5 mg.kg-1 followed by 3.0 micrograms.kg-1.min-1, and 4.5 mg.kg-1 followed by 9.0 micrograms.kg-1.min-1 i.v. Cocaine caused no significant change of Vf or Ra. In the lidocaine group there was a dose/time-related decrease of Vf (although the slope relating Vf to dose/time was not significantly different from that in the cocaine group), but no significant change of Ra. It is concluded that during halothane anesthesia cocaine does not decrease Vf, a finding not consistent with previous reports that adrenergic stimulation decreases Vf. Decrease of Vf with lidocaine is consistent with previous reports of similar dose-related effects of thiopental, etomidate, midazolam, and fentanyl on Vf.

Regioselectivity and enantioselectivity of metoprolol oxidation by two variants of cDNA-expressed P4502D6.

PURPOSE: The oxidative metabolism of metoprolol was investigated in two human lymphoblastoma cell-lines transfected with variants of cDNA for cytochrome P4502D6. METHODS: The regioselective and enantioselective features of the oxidations of deuterium-labeled pseudoracemic metoprolol were characterized by GC/MS analysis of the substrate and products. RESULTS: There were significant differences between the two P4502D6 variants in the formation kinetics of O-demethylmetoprolol and alpha-hydroxymetoprolol. The h2D6-Val microsomes highly favored the formation of the O-demethylmetoprolol regioisomer 6.3:1 and 2.8:1, respectively from (R)-metoprolol-d0 and (S)-metoprolol-d2, while the corresponding ratios for h2D6v2 microsomes were much lower. For both variants, O-demethylmetoprolol formation favored the (R)-substrate 1.5 to 2-fold, while alpha-hydroxymetoprolol formation was non-enantioselective. Similar Km values of metoprolol oxidation, 10-20 microM, were observed for the two microsomal preparations. CONCLUSIONS: The regioselectivity, enantioselectivity, and Km values for the h2D6-Val microsomes resemble those observed for the native P4502D6 in human liver microsomes, whereas the h2D6v2 microsomes deviated remarkably in regioselectivity.

Epinephrine is metabolized by the spinal meninges of monkeys and pigs.

BACKGROUND: Epinephrine commonly is added to epidural opioids and local anesthetics, however, little is known about the fate of epidurally administered epinephrine. Studies have identified the epinephrine metabolizing enzyme, catechol-O-methyl transferase (COMT), in the cranial meninges of several species. The purpose of this study was to determine whether the spinal meninges also contain COMT and are capable of metabolizing epinephrine. If so, then the spinal meninges may have an important impact in limiting the bioavailability of epinephrine in both the spinal cord and epidural space. METHODS: Spinal meningeal specimens measuring 4 cm2 were obtained from monkeys (M. nemestrina) and farm-bred pigs and were incubated in bicarbonate-buffered mock cerebrospinal fluid. Epinephrine (200 micrograms base) was added at t = 0, and 200 min later, the mock cerebrospinal fluid was collected for metanephrine analysis. In separate experiments, pig meningeal specimens were separated into dura mater, pia-arachnoid mater, and pia mater, and the experiments were repeated to determine which meninx had the greatest COMT activity. RESULTS: Metanephrine was produced by monkey meninges at the rate of 0.47 ng.min-1.cm-2 and by pig meninges at the rate of 0.23 ng.min-1.cm-2 (P > 0.05). The pia-arachnoid meninx produced metanephrine at a greater rate (4.48 +/- 0.46 ng.min-1.mg-1 tissue) than did the pia mater (1.3 +/- 0.15 ng.min-1.mg-1 tissue) or dura mater alone (1.82 +/- 0.23 ng.min-1.mg-1 tissue). CONCLUSIONS: These data demonstrate the functional presence of COMT in the spinal meninges of pigs and monkeys and suggest that the spinal meninges may limit the spinal bioavailability of epidurally or intrathecally administered epinephrine.

Regioselective and stereoselective oxidation of metoprolol and bufuralol catalyzed by microsomes containing cDNA-expressed human P4502D6.

Regioselective and stereoselective oxidations of pseudoracemic metoprolol, (R)-bufuralol, and (S)-bufuralol by microsomes of h2D6v2 cells--a human lymphoblastoma cell line transfected with a cytochrome P4502D6 expression system--were examined. The formation kinetics of O-demethylmetoprolol and alpha-hydroxymetoprolol were characterized in five different lots of the cDNA-expressed P4502D6. Comparison of the Vmax/KM values indicated that formation of the products from (R)-metoprolol was preferred. Although the favored regiomer overall was O-demethylmetoprolol, the regioselectivity for O-demethylation of metoprolol by the cDNA-expressed enzyme was several-fold less than that observed for the P4502D6 enzyme in human liver microsomes at 20 microM pseudoracematic metoprolol concentration. Oxidation of (R)-metoprolol produced more O-demethylmetoprolol than alpha-hydroxymetoprolol; however, for (S)-metoprolol-d2, a slight preference for alpha-hydroxylation was observed. The O-demethylation and alpha-hydroxylation of metoprolol were inhibited at low microM concentrations of (+/-)-verapamil, a known inhibitor of metoprolol oxidation. (R)- and (S)-Bufuralol were oxidized to their respective diastereomeric 1"-hydroxybufuralols by all 4 lots of h2D6v2 microsomal preparations. Diastereomeric (1'R)-hydroxybufuralols were formed in twice the amount as the hydroxylated diastereomers of (1'S)-products. Product stereoselectivity was observed for the (1'R,1"S)- and (1'S,1"R)-isomers. Although the observed enantioselectivity and diastereoselectivity of the bufuralol oxidation seem to be consistent with those previously reported for human liver microsomes, the regioselectivity of the metoprolol oxidations is unexpectedly low.

Determination of alfentanil and noralfentanil in human plasma by gas chromatography-mass spectrometry.

This report describes a simple gas chromatographic-mass spectrometric (GC-MS) assay for the simultaneous analysis of alfentanil and its major metabolite, noralfentanil, in human plasma. The method facilitates the processing of numerous samples for pharmacokinetic analysis. Alfentanil and noralfentanil are extracted from plasma under basic conditions and noralfentanil is converted to the pentafluoropropionyl derivative. The extraction efficiencies for noralfentanil and alfentanil were > 99% and 70%, respectively. Standard curves were linear (r2 = 0.99) over the ranges of 5-500 ng/ml for alfentanil and 0.4-10 ng/ml for noralfentanil. Inter-day coefficients significant improvement over existing HPLC assays which require radiolabelled significant improvement over existing HPLC assays which require radiolabelled alfentanil. The simultaneous disposition of alfentanil and noralfentanil in plasma after intravenous administration in humans is described.