D. Henzel

Pharmacokinetics and pharmacodynamics of vecuronium (ORG NC 45) in patients with cirrhosis.

To evaluate the effect of liver cirrhosis on the pharmacokinetics and the pharmacodynamics of vecuronium, 12 patients with cirrhosis, aged (mean ± SD) 52 ± 12 yr, and 14 control patients, 42 ± 15 yr, undergoing elective surgery under general anesthesia were studied. The simultaneous time courses of the plasma concentration of vecuronium and of the neuromuscular blockade were studied after the administration of a bolus dose of 0.2 mg · kg−1. Vecuronium plasma concentration declined biexponentially in both groups. Vecuronium plasma clearance was reduced significantly (P < 0.01) from 4.26 ± 1.38 ml · min−1 · kg−1 in the controls to 2.73 ± 1.19 ml · min−1 · kg−1 in the patients with cirrhosis. The elimination half-life was 58 ± 19 min in the controls and was prolonged significantly to 84 ± 23 min (P < 0.01) in the patients with cirrhosis. The total apparent volume of distribution was unchanged in patients with cirrhosis (0.253 ± 0.086 1 · kg−1 vs. 0.246 ± 0.092 1 · kg−1 in the controls). Cirrhosis caused a prolongation of the neuromuscular blockade induced by vecuronium: the duration of effect from injection to 50% recovery of the twitch height was prolonged by 100% (P < 0.01) from 62 ± 16 min in the controls to 130 ± 52 min in patients with cirrhosis. The recovery rate (TH 25–75) also was prolonged (P < 0.05) from 21 ± 7 min in the controls to 44 ± 18 min in patients with cirrhosis. Vecuronium plasma concentration measured during recovery from paralysis indicates that cirrhosis did not alter the sensitivity to the relaxant, the plasma concentration corresponding to 50% of recovery (Cp 50) being unchanged between the two groups: 247 ± 60 ng · ml−1 in the controls versus 281 ± 129 ng · ml−1 in the cirrhotic patients. Thus, vecuronium seems to exert a prolonged neuromuscular blockade in patients with cirrhosis, and this change is mediated through its delayed elimination.

Anesthetics Affect the Uptake but Not the Depolarization-evoked Release of GABA in Rat Striatal Synaptosomes

Background Numerous classes of anesthetic agents have been shown to enhance the effects mediated by the postsynaptic gamma‐aminobutyric acid A (GABAA) receptor‐coupled chloride channel in the mammalian central nervous system. However, presynaptic actions of anesthetics potentially relevant to clinical anesthesia remain to be clarified. Therefore, in this study, the effects of intravenous and volatile anesthetics on both the uptake and the depolarization‐evoked release of GABA in the rat stratum were investigated. Methods Assay for specific GABA uptake was performed by measuring the radioactivity incorporated in purified striatal synaptosomes incubated with3 H‐GABA (20 nM, 5 min, 37 degrees Celsius) and increasing concentrations of anesthetics in either the presence or the absence of nipecotic acid (1 mM, a specific GABA uptake inhibitor). Assay for GABA release consisted of superfusing3 H‐GABA preloaded synaptosomes with artificial cerebrospinal fluid (0.5 ml *symbol* min sup 1, 37 degrees Celsius) and measuring the radioactivity obtained from 0.5 ml fractions over 18 min, first in the absence of any treatment (spontaneous release, 8 min), then in the presence of either KCl alone (9 mM, 15 mM) or with various concentrations of anesthetics (5 min), and finally, with no pharmacologic stimulation (5 min). The following anesthetic agents were tested: propofol, etomidate, thiopental, ketamine, halothane, enflurane, isoflurane, and clonidine. Results More than 95% of3 H‐GABA uptake was blocked by a 10 sup 3 ‐M concentration of nipecotic acid. Propofol, etomidate, thiopental, and ketamine induced a dose‐related, reversible, noncompetitive, inhibition of3 H‐GABA uptake: IC50 = 4.6 plus/minus 0.3 x 105 M, 5.8 plus/minus 0.3 x 10 sup ‐5 M, 2.1 plus/minus 0.4 x 10 sup ‐3 M, and 4.9 plus/minus 0.5 x 10 sup ‐4 M for propofol, etomidate, thiopental, and ketamine, respectively. Volatile agents and clonidine had no significant effect, even when used at concentrations greater than those used clinically. KCl application induced a significant, calcium‐dependent, concentration‐related, increase from basal3 H‐GABA release, +34 + 10% (P < 0.01) and +61 plus/minus 13% (P < 0.001), respectively, for 9 mM and 15 mM KCl. The release of3 H‐GABA elicited by KCl was not affected by any of the anesthetic agents tested. Conclusions These results indicate that most of the intravenous but not the volatile anesthetics inhibit the specific high‐affinity3 H‐GABA uptake process in vitro in striatal nerve terminals. However, this action was observed at clinically relevant concentrations only for propofol and etomidate. In contrast, the depolarization‐evoked3 H‐GABA release was not affected by anesthetics. Together, these data suggest that inhibition of GABA uptake, which results in synaptic GABA accumulation, might contribute to propofol and etomidate anesthesia.

Effects of Volatile Anesthetics, Thiopental, and Ketamine on Spontaneous and Depolarizationevoked Dopamine Release from Striatal Synaptosomes in the Rat

BackgroundRecent experimental data indicate that anesthesia is often associated with significant changes in brain concentrations of dopamine (DA), an inhibitory neurotransmitter located in restricted, but functionally important, areas such as the striatum. Whether the presynaptic DA nerve endings represent potential targets for anesthetics remains unknown. Therefore, the current study was designed to investigate the effects of volatile anesthetics, thiopental, and ketamine on both spontaneous and depolarization-evoked DA release from striatal synaptosomes in the rat. MethodsPurified striatal synaptosomes preloaded with 3H-DA were superfused with artificial cerebrospinal fluid (1 ml/min). Radioactivity obtained from 1-ml fractions was measured over 15 min; first, in the absence of any treatment (spontaneous release), then in either the absence (time-dependent control) or presence (evoked-release) of anesthetic and pharmacologic agents, and finally, again, without any pharmacologic stimulation. The compounds tested were: potassium chloride (15 and 50 mM), glutamate, N-methyl-D-aspartate (NMDA) and kainate (10-4 M and 10-3 M), MK-801 (10-4 M, an antagonist of NMDA receptors) and 6-cyano-7-nitro-quinoxaline-2,3-dione (10-4 M, an antagonist of D,L-α-amino-3-hydroxy-5-methyl-4-isoxazole propionate [AMPA] receptors), halothane, enflurane, isoflurane (1, 1.5, and 2 minimum alveolar concentrations), ketamine (10-5 and 10-4 M), and thiopental (10-5 and 10-4 M). ResultsVolatile anesthetics induced a significant, concentration-related increase in spontaneous 3H-DA release, but thiopental and ketamine were ineffective. The effect of 2 minimum alveolar concentration enflurane (but not halothane or isoflurane) was significantly enhanced when a Mg2+-free cerebrospinal fluid was used, and was reduced by MK-801 application. Nomifensine (10-5 M, a blocker of monoamine transporter) did not affect the 3H-DA release evoked by volatile anesthetics. Glutamate, kainate, NMDA, and potassium chloride induced a significant, dose-related, Ca2+-dependent 3H-DA release. Halothane and isoflurane produced a significant and concentration-related decrease in the 3H-DA peaks evoked by glutamate, kainate, and NMDA; however, enflurane significantly attenuated the glutamate- and kainate-mediated release, but enhanced that evoked by NMDA. Thiopental and ketamine (10-4, but not 10-5 M) significantly reduced the glutamate- and NMDA-stimulated release, but only thiopental decreased the kainate-induced effect. Furthermore, the effect of potassium chloride (15 mM) was significantly reduced by all anesthetics examined, whereas that of potassium chloride (50 mM) was unaffected. ConclusionThe authors conclude that: (1) volatile anesthetics, thiopental, and ketamine exert significant changes in both spontaneous and depolarization-evoked 3H-DA release in the rat striatum; (2) enflurane uniquely enhances NMDA-receptor mediated dopamine release; and (3) the results obtained from these receptor-mediated effects (AMPA and NMDA) may apply to postsynaptic, as well as presynaptic, glutamate receptors.

Beta-adrenergic receptor function is acutely altered in surgical patients.

Catecholamine-induced desensitization of β-adrenergic receptors resulting in hyporesponsivness to further stimulation has been frequently reported after an increase in endogenous catecholamines. To examine the possibility of β-adrenoceptor desensitization due to intraoperative adrenergic activation (surgical stress), the alterations of human lymphocyte β-adrenergic receptor density and affinity observed after anesthesia and surgery Were studied using (−)251I-iodocyanopilldolol binding in 19 Patients Undergoing noncardiac surgical procedures with general anesthesia (thiopental, fentanyl, and halothane or isoflurane). In 13 patients, repeated determinations of plasma levels of norepinephrine and epinephrine showed an increase during the surgical procedure (norepinephrine ±60%; epinephrine +60%); this change was not observed in the remaining patients. A significant postoperative increase in receptor density (Bmax +25%) and a significant decrease of receptor affinity for isoproterenol (IC50 +22%) were found in the patients who experienced intraoperative adrenergic activation. By contrast, no significant change in β-receptor density or affinity was found in the patients who had normal intraoperative adrenergic activation. In addition, heart rate responses to the postoperative changes in plasma catecholamines (an index of cardiac sensitivity to agonist) were significantly attenuated in patients who experienced both intraoperative adrenergic activation and a decrease in affinity of β-receptor for agonist, suggesting hyporesponsiveness to β stimulation. We conclude that β-adrenergic receptors and, consequently, β-adrenergic responsiveness might be altered by perioperative adrenergic activation in surgical patients.

Halothane and Isoflurane Differentially Affect the Regulation of Dopamine and Gamma-aminobutyric Acid Release Mediated by Presynaptic Acetylcholine Receptors in the Rat Striatum

Background General anesthetics are thought to produce their hypnotic effects mainly by acting at ligand‐gated ionic channels in the central nervous system (CNS). Although it is well established that volatile anesthetics significantly modify the activity of the acetylcholine nicotinic receptors of the neuromuscular junction, little is known about their actions on the acetylcholine receptors in the CNS. In this study, the effects of halothane and isoflurane on the regulation of dopamine (DA) (gamma‐aminobutyric acid [GABA]) depolarization‐evoked release mediated by nicotinic (muscarinic) presynaptic receptors were studied in the rat striatum. Methods Assay for GABA (dopamine) release consisted of3 H‐GABA (sup 3 H‐DA)‐preloaded synaptosomes with artificial cerebrospinal fluid (0.5 ml/min, 37 degrees Celsius) and measuring the radioactivity obtained from 1‐min fractions for 18 min, first in the absence of any treatment (spontaneous release, 8 min), then in the presence of depolarizing agents combined with vaporized halothane and isoflurane (0.5–5%, 5 min), and finally with no pharmacologic stimulation (5 min). The depolarizing agents were potassium chloride (KCl; 9 mM) alone or with acetylcholine (10 sup ‐6 ‐ 10 sup ‐4 M) and/or atropine (10 sup ‐5 M) for experiments with3 H‐GABA, and KCl (15 mM) and nicotine (10 sup ‐7 ‐ 5 x 10 sup ‐4 M) alone or with mecamylamine (10 sup ‐5 M) for experiments with3 H‐DA. Results Potassium chloride induced a significant, Ca2+ ‐dependent release of both3 H‐GABA and3 H‐DA. Nicotine produced a concentration‐related, mecamylamine‐sensitive3 H‐DA release that was significantly attenuated by nicotine (10 sup ‐7 M) preincubation. Acetylcholine elicited a dose‐dependent, atropine‐sensitive reduction of the KCl‐evoked3 H‐GABA release. Halothane and isoflurane significantly decreased the nicotine‐evoked3 H‐DA release but had only limited depressant effects on the KCl‐stimulated3 H‐DA and no action on the KCl‐induced3 H‐GABA release. The effects of acetylcholine on3 H‐GABA release were reversed by halothane but not by isoflurane. Conclusion Clinically relevant concentrations of halothane and isoflurane significantly, but differentially, alter the presynaptic cholinergic regulation of the release of inhibitory neurotransmitters in the striatum. These results suggest that the cholinergic transmission may represent an important and specific presynaptic target for volatile anesthetics in the CNS.

Variations in Pancuronium Requirement, Plasma Concentration, and Urinary Excretion Induced by Cardiopulmonary Bypass with Hypothermia

To determine the effects of cardiopulmonary bypass (CPB) and hypothermia on the neuromuscular blockade produced by pancuronium, this relaxant was infused intravenously into 10 anesthetized patients to produce and maintain 90% depression of the twitch tension of the adductor pollicis muscle following supramaximal ulnar nerve stimulation. Infusion rates, plasma concentration of pancuronium, and adductor pollicis temperature were measured every 15 min. During the normothermic period preceding the start of CPB, the pancuronium requirement, the pancuronium plasma concentration, and muscle temperature were (mean ± SEM): 238 ± 12 μg·m-2.15 min-1, 0.31 ± 0.01 μg/ml, and 33.9 ± 0.1 ° C, respectively. At the beginning of CPB, the pancuronium infusion rate increased to 362 ± 32 μg·m-2 15 min-1 (P < 0.001) despite a decrease in the muscle temperature to 29.2 ± 0.9° C (P < 0.001) and in pancuronium plasma concentration to 0.22 ± 0.02 μg/ml. During sustained muscle hypothermia to 28.3 ± 0.4° C the pancuronium plasma concentration remained constant at 0.22 ± 0.01 μg/ml (P < 0.001) while the requirement decreased to 94 ± 15 μg·m-2·15 min-1 (P < 0.001). After the muscle temperature was returned to 34 · 0.6° C, the plasma pancuronium concentration and requirements increased to 0.35 · 0.05 μg/ml and 392 · 32 μg·m-215 min-1 (P < 0.001), respectively. After CPB, these values were 0.39 · 0.04 μg/ml and 239 · 25 μg·m-2*15 min-1. These results demonstrate that pancuronium requirements are increased at the beginning of CPB because of circulatory volume changes and again during rewarming of the patient once muscle temperature reaches about 34° C.

The Effects of Halothane on the Human Beta-adrenergic Receptor of Lymphocyte Membranes

The effects of halothane on beta-adrenergic receptor antagonist interaction were studied using the membranes of human lymphocytes as a model. Membrane preparations of lymphocytes were obtained from blood samples withdrawn from seven healthy young volunteers. Beta-receptor studies were performed using (-)125I iodocyanopindolol (125ICP) binding. Non-specific binding was determined in the presence of (-)isoproterenol. Beta-receptor density (Bmax) and the dissociation constant (KD) for 125ICP were determined from saturation curves. Beta-receptor affinity for agonists evaluated by the IC50 (the concentration of isoproterenol required to inhibit 50% of specific 125ICP binding) and the dissociation constant (KL) for isoproterenol was established from competition curves. The effect of halothane 1%, in an air oxygen mixture (oxygen fraction: 0.3) administered by tonometry during ligand membrane incubation, on beta-adrenergic receptor, was compared to that of control experiments not exposed to halothane. Halothane produced a moderate but significant decrease of Bmax (-10%) and a significant increase in non-specific binding (+30%), while KD, IC50, and KL were unchanged. The authors conclude that halothane, in vitro, decreases beta-adrenergic receptor density. This effect could be mediated by an alteration of the receptor in the membrane due to action of halothane on the lipid phase of the membrane.

Riluzole Blocks Dopamine Release Evoked by N-methyl-D-aspartate, Kainate, and Veratridine in the Rat Striatum

Background: Dopamine (DA) is released in large amounts during cerebral ischemia and may exacerbate tissue damage. Riluzole (54274 RP) is a recently developed agent that depresses glutamate neurotransmission in the central nervous system (CNS) and that may protect against ischemic injury in some animal models. Because glutamate stimulates the release of DA in the striatum, the authors hypothesized that riluzole could antagonize DA release in this structure. Methods: Assay for DA release consisted of superfusing3 H‐DA preloaded synaptosomes with artificial cerebrospinal fluid (1 ml/min, 37 [degree sign] Celsius) and measuring the radioactivity obtained from 1‐min fractions over 22 min, first in the absence of any treatment (spontaneous release, 8 min), then in the presence of depolarizing agents combined with riluzole (0.1–100 micro Meter, 5 min), and finally with no pharmacologic stimulation (9 min). The following depolarizing agents were tested: KCl (9, 15 mM), veratridine (0.01–1 micro Meter), N‐methyl‐D‐aspartate (NMDA, 0.1–1 mM), kainate (0.1–1 mM), and nicotine (0.01–0.5 mM). Assay for DA uptake was performed by measuring the radioactivity incorporated in synaptosomes incubated with3 H‐DA (44 nM; 5 min; 37 [degree sign] Celsius). Results: All depolarizing agents produced a significant, concentration‐related increase from basal3 H‐DA release. Riluzole was found to decrease the release induced by veratridine (1 micro Meter), NMDA (1 mM), and kainate (1 mM) in a significant, concentration‐related manner (IC50 = 9.5 micro Meter, 1.6 micro Meter, and 5.8 micro Meter for veratridine, NMDA, and kainate, respectively). In contrast, it did not affect the release elicited by either KCl or nicotine. Riluzole had no significant effect on the specific3 H‐DA uptake. Conclusions: Riluzole produced a potent blockade of the release of DA mediated by activation of presynaptic sodium channels, NMDA, and kainate receptors. Depression of glutamate transmission together with blockade of DA release may contribute to the actions of this agent in vivo.

PHARHACOKINETICS AND PHARHACODYNAMICS OF VECURONIUM IN PATIENTS WITH CHOLESTASIS

The pharmacokinetics and pharmacodynamics of vecuronium were studied in nine surgical patients with cholestasis, and in 14 patients without hepatic or renal disease. After the administration of vecuronium 0.2 mg kg-1 the plasma concentration of vecuronium and the degree of neuromuscular blockade were measured. The plasma clearance of vecuronium was decreased significantly (P less than 0.01) from 4.30 +/- 1.56 ml min-1 kg-1 (mean +/- SD) in normal patients to 2.36 +/- 0.80 ml min-1 kg-1 in patients with cholestasis. The elimination half-life was of 58 +/- 22 min in normal patients and was prolonged to 98 +/- 57 min (P less than 0.05) in patients with cholestasis. The total apparent volume of distribution was unchanged in patients with cholestasis. A prolonged neuromuscular blockade induced by vecuronium was observed in patients with cholestasis: the duration of effect from injection to 75% recovery of the twitch height was prolonged from 74 +/- 19 min in normal patients to 111 +/- 13 min in patients with cholestasis. The plasma concentration corresponding to 50% recovery from paralysis did not differ significantly between the two groups. Vecuronium has a prolonged effect in patients with cholestasis which is caused by a delay in its elimination.

Analytical model of some pharmacokinetic and pharmacodynamic properties of fazadinium in man

SummaryThe neuromuscular blocking characteristics and plasma concentration decay of fazadinium bromide, a short acting, non-depolarizing muscular relaxant, were simultaneously observed under standardised conditions in 6 healthy, anaesthetized, adult patients. The results were analyzed by a new pharmacodynamic model, which takes into account certain relationships describing the binding of non-depolarizing neuromuscular blocking agents and the postsynaptic receptor occupation ratio. According to the simulations performed, the pharmacodynamic parameters determined: KB-apparent value of equilibrium constant of fazadinium — receptors exchange (mean ± SEM) 0.404+0.045 µmol/l, and the value of postsynaptic occupation ratio for 50% paralysis of 0.89±0.004 were in agreement with values reported in the literature for mammalian neuromuscular junctions in vitro. The apparent validity of the pharmacodynamic model and its value in simulating dose/effect relationships of non-depolarizing neuromuscular blocking agents are discussed and illustrated.