Pentobarbital Concentrations Research Articles

Oral self-administration of pentobarbital by rhesus monkeys: relative reinforcing effects under concurrent signalled differential-reinforcement-of-low-rates schedules

During daily 3-h sessions two separate pentobarbital solutions were concurrently available to rhesus monkeys under signalled differential-reinforcement-of-low-rates (signalled DRL) schedules of mouth contacts with spouts. The schedules were synchronized so that each time the 30-s DRL interval expired, lights above both spouts were illuminated and a liquid delivery could be obtained either from the left or right spout, but not both. First water and then each of four ‘comparison-concentration’ pentobarbital solutions (0.0625, 0.25, 1 and 4 mg/ml) were successively available under one schedule for a block of sessions. Concurrently, deliveries of a ‘standard concentration’ solution were available from the second spout under an identical DRL schedule; the concentration of this standard solution remained constant throughout the testing of the series of comparison solutions. Three pentobarbital concentrations (4, 1 and 0.25 mg/ml) in turn served as the standard concentration. Relative reinforcing effects were directly related to pentobarbital concentration: in general, within pairs of concurrently available pentobarbital solutions more behavior was maintained by the higher of the two drug concentrations. These findings are discussed in the context of previous studies using ratio and interval schedules which have found relative reinforcing effects to be directly related to reinforcer magnitude.

Electrical activation of expiratory muscles increases with time in pentobarbital-anesthetized dogs.

Although the pentobarbital-anesthetized dog is often used as a model in studies of respiratory muscle activity during spontaneous breathing, there is no information regarding the stability of the pattern of breathing of this model over time. The electromyograms of several inspiratory and expiratory muscle groups were measured in six dogs over a 4-h period by use of chronically implanted electrodes. Anesthesia was induced with pentobarbital sodium (25 mg/kg iv), with supplemental doses to maintain constant plasma pentobarbital concentrations. Phasic electrical activity increased over time in the triangularis sterni, transversus abdominis, and external oblique muscles (expiratory muscles). The electrical activity of the costal diaphragm, crural diaphragm, and parasternal intercostal muscles (inspiratory muscles) was unchanged. These changes in electrical activity occurred despite stable plasma levels of pentobarbital and arterial PCO2. They were associated with changes in chest wall motion and an increased tidal volume with unchanged breathing frequency. We conclude that expiratory muscle groups are selectively activated with time in pentobarbital-anesthetized dogs lying supine. Therefore the duration of anesthesia is an important variable in studies using this model.

Electroencephalographic activity and serum and cerebrospinal fluid pentobarbital levels in determining the therapeutic end point during barbiturate coma

Controversy exists regarding the optimal means for monitoring the patient receiving pentobarbital therapy during medical coma. Serum pentobarbital levels have been used traditionally to gauge cerebral penetration and efficacy of the drug. These peripheral levels have been assumed to reflect pentobarbital concentrations in the cerebrospinal fluid (CSF) and, therefore, the physiological effect on the central nervous system. To determine the relative accuracy of serum versus CSF pentobarbital levels, continuous electroencephalographic (EEG) monitoring in 10 consecutive patients was studied prospectively. Each patient received pentobarbital therapy for cerebral protection in the face of a traumatic injury. Simultaneous serum and CSF pentobarbital levels were obtained 1) before and after the initial barbiturate bolus, 2) every 12 hours during constant infusion therapy, and 3) before and after subsequent boluses necessary because of elevated intracranial pressure (ICP) (ICP greater than 15 mm Hg) or loss of burst suppression by continuous EEG monitoring (defined as greater than five bursts per minute). ICP and relevant clinical events were recorded hourly. Serum and CSF levels ranged from 33 to 74 mg/L and 4 to 54 mg/L, respectively. There was poor correlation between serum and CSF pentobarbital levels at any given time, although patients remained in burst suppression 73% of the time during their therapy. The EEG monitoring not only provided dynamic physiological monitoring, but it also permitted the lowest pentobarbital dose to maintain burst suppression for a specific patient's metabolism, reducing the likelihood of toxicity. In conclusion, CSF pentobarbital levels are of no greater accuracy than serum pentobarbital levels in predicting physiological effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Electroencephalographic Activity and Serum and Cerebrospinal Fluid Pentobarbital Levels in Determining the Therapeutic End Point during Barbiturate Coma

Abstract Controversy exists regarding the optimal means for monitoring the patient receiving pentobarbital therapy during medical coma. Serum pentobarbital levels have been used traditionally to gauge cerebral penetration and efficacy of the drug. These peripheral levels have been assumed to reflect pentobarbital concentrations in the cerebrospinal fluid (CSF) and, therefore, the physiological effect on the central nervous system. To determine the relative accuracy of serum versus CSF pento-barbital levels, continuous electroencephalographic (EEG) monitoring in 10 consecutive patients was studied prospectively. Each patient received pentobarbital therapy for cerebral protection in the face of a traumatic injury. Simultaneous serum and CSF pentobarbital levels were obtained 1) before and after the initial barbiturate bolus, 2) every 12 hours during constant infusion therapy, and 3) before and after subsequent boluses necessary because of elevated intracranial pressure (ICP) (ICP > 15 mm Hg) or loss of burst suppression by continuous EEG monitoring (defined as greater than five bursts per minute). ICP and relevant clinical events were recorded hourly. Serum and CSF levels ranged from 33 to 74 mg/L and 4 to 54 mg/L, respectively. There was poor correlation between serum and CSF pentobarbital levels at any given time, although patients remained in burst suppression 73% of the time during their therapy. The EEG monitoring not only provided dynamic physiological monitoring, but it also permitted the lowest pentobarbital dose to maintain burst suppression for a specific patient's metabolism, reducing the likelihood of toxicity. In conclusion, CSF pentobarbital levels are of no greater accuracy than serum pentobarbital levels in predicting physiological effect. Constant EEG monitoring remains the best modality by showing the presence of burst suppression moment-to-moment and thus establishing the minimal necessary dose.

Interaction of Doxapram and Pentobarbital in Mice

We found a statistically significant increase in duration of pentobarbital-induced narcosis in doxapram-treated mice. The influence of doxapram (a respiratory stimulant) pretreatment on pentobarbital metabolism in mice was assessed by measurements of sleeping times, hypothermia, LD50 values, hepatic microsomal metabolism and relative plasma and brain levels of pentobarbital. When doxapram was given intraperitoneally 60 min. prior to administration of pentobarbital, doxapram potentiated pentobarbital-induced narcosis in a dose- and time-dependent manner, but had no effect on onset time. Doxapram potentiated hypothermia, increased acute toxicity, and prolonged the pentobarbital half-life in brain and plasma, but measurement of the concentration of pentobarbital in the brain and plasma immediately upon recovery from narcosis showed that there were no differences in any of the groups examined. Also, brain-to-plasma ratios of pentobarbital did not differ between the control and doxapram-treated groups. Doxapram competitively inhibited the hepatic metabolism of pentobarbital in 9000 x g supernatant incubation mixtures. The results obtained from these experiments indicate that inhibition of drug-metabolizing enzymes by doxapram may account for its enhancement of the duration of pentobarbital-induced narcosis.

The Influence of Cryogenic Brain Injury on the Pharmacodynamics of Pentobarbital Evidence for a Serotonergic Mechanism

To study of the influence of brain injury on the pharmacodynamics of pentobarbital, the authors examined the effect of a focal cortical freezing lesion in rats on the brain concentration of pentobarbital associated with lack of response to tail clamp. The freezing lesion was made with a probe (-50 degrees C) applied through a craniotomy to the intact dura over the left parietal cortex. Three days after injury the rats were anesthetized with a continuous intravenous infusion of pentobarbital until they first did not respond to tail clamp stimulation. The brains were then removed for determination of pentobarbital by high-performance liquid chromatography. The brain pentobarbital concentration required to prevent response to tail clamp (EC50) was reduced from 209 +/- 39 nmol/g (mean +/- standard deviation) in rats without brain injury to 149 +/- 28 nmol/g in the injured animals (P = 0.005). The cortical serotonin (5-HT) concentration was increased from 1904 +/- 358 pmol/g in uninjured rats to 2513 +/- 598 pmol/g (P less than 0.01) in injured animals ipsilateral to the lesion. Pretreatment of the rats with p-chlorophenylalanine (PCPA, 200 mg/kg by intraperitoneal injection) to inhibit 5-HT synthesis abolished both the increase in 5-HT concentration associated with the injury (left cortex, 708 +/- 389 pmol/g; right cortex, 911 +/- 979 pmol/g) and the effect of the lesion on EC50 (uninjured, EC50 = 186 +/- 24 nmol/g; injured, EC50 = 179 +/- 47 nmol/g). Prevention of the decrease in EC50 by inhibition of 5-HT synthesis provides support for a functional role for 5-HT in the influence of cold injury on the pharmacodynamics of pentobarbital.

Detection of barbiturate-induced surface changes in cerebrocortical synaptosomes by phase partitioning in an aqueous two-phase system

The barbiturates tested in this work (barbital, phenobarbital, thiopental and pentobarbital) modify the partition of synaptosomes in a Dextran T500-poly(ethylene glycol) 4000 two-phase system. Under adequate experimental conditions, the drugs increase the partition into the upper phase and this effect appears to be due to an action on the biological material and not on the interface potential of the system. This conclusion can be drawn from the fact that synaptosomes preincubated with low concentrations (0.1 mM) of barbital and pentobarbital maintained an increased partition into the upper phase. The extent of the effect observed appeared to be inversely proportional to the hydrophobicity of the drugs since phenobarbital and barbital showed a higher effect than thiopental and pentobarbital. Dithionite-induced anoxia, rotenone and ouabain also induced a similar increase of partition of synaptosomes into the upper phase, suggesting that the surface changes detected by phase partitioning modification of synaptosomes could be somehow related to the bioenergetic maintenance of the membrane ATPase.

Cellular and learned tolerances for pentobarbital hypothermia

The development of behavioral tolerance to pentobarbital-induced hypothermia, as separable from cellular and metabolic tolerance, was established. Pentobarbital (PB) was administered to 4 groups of rats, 2 groups of which received intermittent (INT) IP PB treatment. One of these groups, INT/EXP, experienced the hypothermic (measured as rectal body temperature) drug effect after PB injection. The other group, INT/NONEXP, was monitored for body temperature functions (room temperature) before receiving PB (vehicle administration) and then prevented from experiencing PB-induced hypothermia by maintenance of body temperature with a towel wrap restraint and a heating lamp. The INT/EXP group also received equivalent exposure to this towel wrap after vehicle administration. Two other groups received chronic PB treatment (IP and in ground chow), one with experience for hypothermia after injections (CHR/EXP) and one prevented from experiencing the hypothermia (CHR/NONEXP). These groups also received equivalent exposure to the body temperature (at room temperature) testing and towel wrap restraint, EXP rats after vehicle injections and NONEXP after drug injections. A postchronic test of all groups compared the extent of PB hypothermia to prechronic test effects to assess the degree of tolerance. The INT/EXP group demonstrated behavioral tolerance for PB-induced hypothermia, as contrasted with the INT/NONEXP group which demonstrated little or no tolerance. Prominent tolerance was noted in both chronic groups for PB hypothermia, without a significant difference between them. After the postchronic test, chronic treatment was discontinued for 9 days (withdrawal) followed by 9 days of extinction training (vehicle behavioral testing). The two intermittent groups demonstrated no change in the hypothermic drug response during the postwithdrawal and postextinction drug test. However, in CHR/EXP rats tolerance to hypothermia was decreased at the postwithdrawal test, with a greater loss at the postextinction test. CHR/NONEXP animals showed a prominent loss of tolerance at the postwithdrawal test only. Brain concentrations of PB in identically treated rats (up to the postchronic test) yielded evidence of metabolic tolerance in the two chronic treatment groups. Evidence for cellular tolerance was also produced in these two groups when the brain concentrations were correlated with the extent of drug-induced hypothermia. Behavioral tolerance to drug effects was expressed in EXP groups after both chronic and intermittent pentobarbital treatment, compared to effects in the NONEXP groups, and existed separate from cellular and metabolic tolerance.

Modulation of the sarcoplasmic reticulum [formula omitted] by pentobarbital

The dependence of the (Ca 2+ + Mg 2+)-ATPase activity of sarcoplasmic reticulum vesicles upon the concentration of pentobarbital shows a biphasic pattern. Concentration of pentobarbital ranging from 2 to 8 mM produce a slight stimulation, approximately 20–30%, of the ATPase activity of sarcoplasmic reticulum vesicles made leaky to CA 2+, whereas pentobarbital concentrations above 10 mM strongly inhibit the activity. The purified ATPase shows a higher sensitivity to pentobarbital namely 3–4-fold shift towards lower values of the K 0.5 value of inhibition by this drug. These effects of pentobarbital are observed over a wide range of ATP concentrations. In addition, this drug shifts the Ca 2+ dependence of the (Ca 2+ + Mg 2+)-ATPase activity towards higher values of free Ca 2+ concentrations and increase several-fold the passive permeability to Ca 2+ of the sarcoplasmic reticulum membranes. At the concentration of pentobarbital that inhibit this enzyme in the sarcoplasmic reticulum membrane, pentobarbital does not significantly alter the order parameter of these membranes as monitored with diphenylhexatriene, whereas the temperature of denaturation of the (Ca 2+ + Mg 2+)-ATPase is decreased by 4–5 C°, thus, indicating that the conformation of the ATPase is altered. The effects of pentobarbital on the intensity of the fluorescence of fluorescein-labeled (Ca 2+ + Mg 2+)-ATPase in sarcoplasmic reticulum also support the hypothesis of a conformational change in the enzyme induced by millimolar concentrations of this drug. It is concluded that the inhibition of the sarcoplasmic reticulum ATPase by pentobarbital is a consequence of its binding to hydrophobic binding sites in this enzyme.

Interaction between pentobarbital and GABA-activated ionic channels in rat cerebellar neurons

Using techniques of voltage clamping at the membrane, intracellular perfusion, and concentration clamping, GABA- and barbiturate-activated currents were investigated in single neurons isolated from the rat cerebellum. The dissociation constant for interaction between GABA and GABA receptors was measured at 3±0.8 × 10−5 M. The presence of pentobarbital in the bathing solution exerts a potentiating effect on GABA-induced conductance in isolated neurons, shifting the dose-response curve for GABA towards lower concentration values without increasing peak chloride conductance. The concentrations at which GABA effects are potentiated range between 10−6–10−4 M. High concentrations of pentobarbital inhibit GABA-activated conductance; at concentrations in excess of 5 × 10−4 M, it also brings about activation of chloride conductance, depressed by bicuculline and picrotoxin, in the absence of GABA. A short-term increase in membrane conductance is produced by rapid pentobarbital washout.

Treatment of refractory generalized tonic-clonic status epilepticus with pentobarbital anesthesia after high-dose phenytoin.

We report the results of treatment of refractory generalized tonic-clonic status epilepticus in 17 adults. Of 13 patients who received high-dose phenytoin (PHT, mean dose 23.8 mg/kg), seizure control was sustained in five patients. In 12 cases, anesthetic doses of pentobarbital rapidly suppressed convulsions, but sustained control required prolonged treatment. Break-through seizures were, in most cases, explained by inadequate serum pentobarbital concentrations, although we could not establish a therapeutic range of serum concentrations. EEG monitoring is necessary to assess the therapeutic response but is not a reliable index of depth of anesthesia. Some cases developed pharmacodynamic tolerance to pentobarbital. The most serious treatment complications were cardiorespiratory, but the most common and disabling side effects, although reversible, were neurologic. Fifteen patients were discharged from the hospital in stable condition; two patients died, but not as a direct consequence of treatment. Our results suggest a very good outcome of pentobarbital anesthesia for patients in refractory status epilepticus who are a reasonable medical risk and who receive optimal medical management.

Pentobarbital quantitation using immunoassays in Reye's syndrome patient serum.

Analysis of serum pentobarbital concentrations in 28 specimens from Reye's syndrome patients was conducted with modifications of three nonspecific immunoassay procedures originally designed to detect barbiturates in serum or urine. An adaptation of the urine enzyme-multiplied immunoassay technique (EMIT) Dupont aca barbiturate screen to the quantitation of serum pentobarbital is described. Replicate analysis of control specimens containing pentobarbital across a wide spectrum of concentrations revealed a between-day precision of less than 6%. Regression analysis revealed excellent agreement with a high-performance liquid chromatography (HPLC) method: (HPLC) = 0.98 (aca) - 0.07 (r = 0.97). Multiple linear regression analysis with a serum EMIT barbiturate screen and a urine fluorescence polarization immunoassay screen modified to quantitate pentobarbital in serum revealed excellent agreement among all methods, demonstrating that immunoassays offer a reliable approach to pentobarbital quantitation.

Alteration in hypnotic effect of pentobarbital following repeated agonistic confrontations in mice

We investigated how repeated agonistic confrontations affect the hypnotic effect of pentobarbital (PB) in male mice, using a resident-intruder paradigm. PB concentrations in the cortex, midbrain and brainstem were determined. Agonistic confrontations were terminated after 10 or 20 attack bites, and were repeated for 5 consecutive days. Immediately after the last encounter, PB (55 mg/kg, IP) was administered to both resident and intruder mice. Compared to the control group, intruders exposed to 20 daily attack bites showed a significant prolongation of the latency to sleep and a shortening of the duration of sleeping time. At the stage of induction, no significant difference in brain PB levels was found between the "defeated" and control intruders. At the stage of recovery, however, the "defeated" intruders showed a significantly low level of PB in all brain areas. In contrast, attacking resident mice did not show any significant changes in either the hypnotic effect or regional brain concentration of PB. Because pretreatment with naloxone prior to daily agonistic confrontation antagonized the alteration in PB-induced hypnosis, it seems that endogenous opioid mechanisms may participate in this phenomenon. The present study indicates that susceptibility to a hypnotic drug can be altered by chronic social conflict experience.

The effects of perfluorodecanoic acid on hepatic stearoyl-coenzyme A desaturase and mixed function oxidase activities in rats

Perfluorodecanoic acid (PFDA) causes a dioxin-like toxic syndrome and alters the hepatic oleate/stearate ratio in rats. The acute toxic effects of a single ip dose (50 mg/kg) of PFDA on hepatic stearoyl-CoA desaturase and mixed function oxidases were studied in male Fischer-344 rats, 14 days after dosing. PFDA causes a marked decrease in food intake in rats, resulting in severe body weight loss with delayed lethality (2–3 weeks after dosing). To distinguish the effects of hypophagia from those caused by PFDA, pairfed control rats were used in addition to ad libitum-fed controls. Stearoyl-CoA desaturase activity, responsible for the conversion of stearoyl-CoA to oleoyl-CoA, was absent in both PFDA-dosed rats and their pair-fed controls at Day 14. Electron transfer through the desaturase system was significantly reduced in PFDA-treated rats only, and in these rats there was a significant reduction in microsomal cytochrome b 5, an important component of this electron transfer system. Pentobarbital sleeping times were significantly prolonged in both the PFDA-dosed and pair-fed rats, as compared with the ad libitum-fed controls. This effect was more pronounced in PFDA-dosed rats. Waking plasma pentobarbital concentration was similar in all treatment groups. Hepatic microsomal cytochrome P-450 content was unaffected. Aminopyrine N-demethylase activity was greatly reduced in PFDA-dosed rats. Although pair-fed controls also had reduced demethylase activity, it was not as pronounced as in PFDA-dosed rats, and was probably due to the fasted condition of these animals. Although the mechanism of action of PFDA is not known, it is possible that PFDA affects microsomal enzymes by altering the structure and/or function of the membranes in which they are located, through effects on lipid metabolism.

Interaction between phencyclidine and its pyrolysis product, 1-phenylcyclohexene

The interaction between phencyclidine (PCP) and its pyrolysis product, 1-phenylcyclohexene (PC), at metabolic level was evaluated in Swiss male mice (21–24 g). PC (1.1, 2.2 and 4.4 mmol/kg/day for 4 days, IP, in corn oil) treatment to mice induced the in vitro metabolism ( p<0.05) of amidoryrine (17%), aniline (12%), phenacetin (62–100%), pentobarbital (20–26%), PCP (25–80%) and benzo[ a]pyrene (81– 147%) in the 9000 g liver fraction and the hepatic microsomal contents of cytochrome P-450 (18–42%). The induction of the mixed function oxygenase (MFO) system was consistent with the decreases in the concentrations of IP administered pentobarbital (0.27 mmol/kg, in saline) and PCP (16.4, 32.8 and 65.6 μmol/kg, in saline) in the serum, brain, liver and kidneys of PC pretreated mice. At 1 hr after the above doses of PC, the in vitro metabolism of amidopyrine, aniline, or phenacetin was not inhibited. However, the biotransformation of benzo[ a]pyrene was inhibited by 33 to 45%. Though PC after a single dose did not alter the tissue concentrations of PCP, it increased the pentobarbital concentrations of PCP, it increased the the pentobarbital concentrations in the tissues studied ( p<0.05). These results indicate that PC has a potential to induce the MFO system after the 4-day treatment. This property of PC plays an important role in the reduction of the action of PCP by enhancing its metabolism, thereby decreasing its tissue levels.

Oral self-administration of pentobarbital by rhesus monkeys: relative reinforcing effects under concurrent fixed-ratio schedules.

During daily 3-hr sessions, orally delivered pentobarbital solutions and water, or two separate pentobarbital solutions, were concurrently available to rhesus monkeys according to fixed-ratio schedules of mouth contacts with a spout. First water, and then each of four "comparison-concentration" pentobarbital solutions (0.0625, 0.25, 1, and 4 mg/mL), was successively available from one spout for a block of sessions under a fixed-ratio-64 (three monkeys) or fixed-ratio-16 (one monkey) schedule. Under an identically sized fixed-ratio schedule, deliveries of a "standard-concentration" pentobarbital solution were concurrently available from a second spout. The concentration of the standard solution remained unchanged throughout testing of the series of comparison solutions. Each of three pentobarbital concentrations (4, 1, and 0.25 mg/mL) in turn served as the standard concentration. Within each pair of concurrently available solutions, the higher drug concentration maintained more behavior than the lower concentration. Thus when monkeys were provided with concurrent access to different pentobarbital concentrations, relative reinforcing effects were directly related to drug concentration. Further, the amount of behavior maintained by a particular drug concentration was dependent on the concentration of the concurrently available drug solution. Thus, the relative effectiveness of a reinforcer in maintaining behavior is a function of both the reinforcer's magnitude and the availability of alternative reinforcers in the environment.

Different effects of pentobarbital on two .gamma.-aminobutyrate receptors from rat brain: channel opening, desensitization, and an additional conformational change

The effect of pentobarbital on the responses of the gamma-aminobutyric acid (GABA) receptor from rat brain was studied in quantitative measurements of GABA-mediated chloride-exchange rates (reflecting channel-opening equilibrium) and receptor desensitization rates by using 36Cl- tracer ion with native membrane vesicles. Pentobarbital effected the two phases of 36Cl- influx in different ways, supporting previous evidence that these are mediated by two different receptors [Cash, D. J., & Subbarao, K. (1987) Biochemistry 26, 7556; Cash, D. J., & Subbarao, K. (1987) Biochemistry 26, 7562]. Both the chloride-exchange rate and the desensitization rate of the faster desensitizing receptor were increased by pentobarbital at concentrations above 20 microM by an allosteric effect shifting the response curve to lower GABA concentrations. A similar enhancement of the responses of the slower desensitizing receptor occurred up to 200 microM pentobarbital. Two pentobarbital effector sites were involved in the allosteric mechanism. Above 500 microM pentobarbital, both the initial chloride-exchange rate and the desensitization rate of the slower desensitizing receptor were decreased. This inhibition, which was immediate, occurred with saturating as well as low GABA concentrations and therefore was not attributed to decreased GABA binding but to inhibitory sites for pentobarbital, different from the allosteric activating sites and the GABA binding sites. The chloride ion exchange activity was seen to recover with time, at concentrations above 1000 microM pentobarbital, in a process with a very steep dependence on pentobarbital concentration. This reactivation was attributed to the conversion of an initial form of the receptor to a final form that was less inhibited by pentobarbital. The similarity of the effects of pentobarbital on the chloride ion exchange with its effects on electrophysiological measurements supports the fact that these different techniques study the same phenomena. Comparisons of the effects of pentobarbital on desensitization and on high-affinity ligand binding measurements suggest that increased GABA binding at equilibrium reflects an increased conversion to the desensitized state.

犬のペントバルビタールナトリウム麻酔の覚醒に対する腹膜潅流の効果

The effect of peritoneal dialysis on the recovery from anesthesia was evaluated using 10 healthy mixed-breed dogs. The animals were given sodium pentobarbital (25 mg/kg) intravenously. After a surgical anesthesia was attained, peritoneal dialysis was performed using a metal catheter and a commercial dialysis fluid. The arousal time, respiratory rate, heart rate, body temperature, blood pressure and ECG were recorded during and after the dialysis. Furthermore, the pentobarbital concentration in the collected fluid was measured.In 6 of the 10 dogs receiving peritoneal dialysis, the arousal time was decreased to 70 % of those in control dogs. Two other dogs showed no significant reduction, and the rest of the dogs showed a longer arousal time. In addition, the mean pentobarbital concentration in the collected dialysate fluid (273 ml/head) was as low as 6.4μg/ml. Between the control and the dialysis group, no significant difference was found in clinical findings and physiological data.

The pharmacodynamic and pharmacokinetic interaction of pentobarbital and chlorpromazine in rats.

The effect of chlorpromazine on the duration of loss of righting reflex (LRR, sleeping time) of pentobarbital and vice versa in a various dosage ranges were studied in rats. The logarithm of the dose versus sleeping time profile of pentobarbital was shifted to the left and the slope of the profile was decreased as the dose of chlorpromazine was increased. The logarithm of chlorpromazine dose versus duration of LRR during pentobarbital coadministration also showed a distinct dose-dependent profile. However, chlorpromazine itself showed ambiguous duration of LRR because the terminal point of the pharmacologic effect, i.e., the recovery of the righting reflex (RRR, the awakening time), was often difficult to determine clearly. The isobolographic method was introduced to describe the drug interaction of pentobarbital and chlorpromazine quantitatively. Assuming that the sites of action of chlorpromazine and pentobarbital were in the brain, the brain concentrations of pentobarbital at RRR were plotted against the brain concentration of chlorpromazine at RRR. The plots showed a hyperbola-like curve, indicating that there was a supra-additive interaction. In order to clarify the relationship between brain concentrations of the two drugs at RRR, a theoretical consideration was made under the following assumptions: (1) chlorpromazine and pentobarbital have a common central depressant effect, (2) the concentration-effect relationship is described by Hill's equation and (3) the mode of interaction of these drugs is simple additive. The results indicated that the isobolographic plot of pentobarbital and chlorpromazine was reasonably described by the theory and that chlorpromazine enhanced the effect of pentobarbital at least in an additive manner.

Effect of chlorpromazine on the pharmacokinetics and pharmacodynamics of pentobarbital in rats.

The effects of chlorpromazine (4 mg/kg i.v.) on the disposition and duration of loss of the righting reflex (LRR, sleeping time) produced by intravenous pentobarbital (5 to 50 mg/kg) were studied in rats. The plasma concentration time profile following i.v. administration of pentobarbital alone was reasonably well described by a three compartment open model with Michaelis-Menten type elimination kinetics. The brain to plasma concentration ratio of pentobarbital was 1.5 and was almost constant during the experiment. Coadministration of chlorpromazine significantly reduced the systemic clearance of pentobarbital. Since pentobarbital is eliminated from the body mainly by hepatic metabolism, reduction of systemic clearance reflects the reduction of hepatic metabolism of pentobarbital. The hepatic intrinsic clearance of pentobarbital was decreased from 0.438 to 0.331 l/h by chlorpromazine coadministration. Hepatic blood flow was also decreased significantly, whereas the plasma protein binding and the distribution to the red blood cell were not appreciably altered. The profile of duration of LRR versus the logarithm of the dose of pentobarbital was linear over a 20 to 70 mg/kg dose range irrespective of chlorpromazine coadministration. The awakening plasma and brain concentrations of pentobarbital without chlorpromazine were estimated as 12.4 micrograms/ml and 17.8 micrograms/g, respectively. The sleeping time versus the logarithm of pentobarbital dose under chlorpromazine coadministration was shifted to the left and the slope of the linear portion was also decreased. There was no single value of awakening plasma or brain concentration. Plasma concentration at the end of the action decreased with decreasing dose. These facts indicated that the sensitivity of the central nervous system to pentobarbital might be increased by chlorpromazine. In conclusion, chlorpromazine inhibited the hepatic metabolism of pentobarbital, resulting in significant increases in plasma and brain concentrations. However, this pharmacokinetic change could not fully explain the pharmacodynamic alternation.