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PubMed1998

Thiopental attenuates relaxation and cyclic GMP production in vascular smooth muscle of endotoxin-treated rat aorta, independent of nitric oxide production.

As thiopental (thiopentone) suppresses cyclic GMP (cGMP) formation produced by nitric oxide donor drugs, we have tested if it suppresses cGMP formation and increases vascular tone after induction of calcium-calmodulin-independent nitric oxide synthase (iNOS). Rat aortic rings were treated with Escherichia coli lipopolysaccharide (LPS) 1 microgram ml-1 for 4 h, and the effects of thiopental on tension, cGMP concentrations and nitrite accumulation were determined. Thiopental 0.3 mmol litre-1 reduced the tension of phenylephrine-precontracted aortic rings before LPS treatment, but caused no significant effects on tension in the presence of L-arginine 10 mumol litre-1 after LPS treatment. L-Arginine 1 mumol litre-1 to 1 mmol litre-1 increased concentrations of cGMP in LPS-treated aorta in a concentration-dependent manner. This was reduced by thiopental 0.3-1 mmol litre-1. Treatment with L-arginine 1 mmol litre-1 increased concentrations of nitrite, the end product of nitric oxide; this was not affected by thiopental 1 mmol litre-1. We conclude that thiopental suppressed cGMP formation in iNOS-induced vascular smooth muscle without affecting nitric oxide production.

Anesthetics, Intravenous↗
PubMed1999

Haemodynamic effects of propofol vs thiopental in infants: an echocardiographic study.

Rapid i.v. induction of general anaesthesia is indicated in infants at risk of vomiting or regurgitation to reduce the risk of aspiration of gastric contents. Propofol is an alternative to thiopental in infants, and we have compared cardiovascular changes when propofol or thiopental was used for induction of anaesthesia in infants. Twenty infants, ASA I or II, aged 1-11 months, undergoing elective surgery were allocated randomly to receive either thiopental or propofol for i.v. induction. Cardiovascular and echocardiographic data were recorded in both groups before, during and for 5 min after induction of anaesthesia. Doses required to induce anaesthesia in each group were mean 10.3 (SD 0.9) mg kg-1 of thiopental and 6.1 (0.6) mg kg-1 of propofol. Thiopental did not alter significantly systolic or mean arterial pressure, afterload indices, rate-corrected velocity of circumferential fibre shortening or cardiac index, but decreased shortening fraction at 1 and 5 min after induction compared with awake values. Propofol did not alter heart rate, shortening fraction, rate-corrected velocity of circumferential fibre shortening or cardiac index at 1 and 5 min after i.v. induction compared with awake values. After induction, systolic and mean arterial pressures and afterload indices decreased more after induction with both agents, but did not become abnormal. Thus propofol decreased arterial pressure more than thiopental because of an effect on afterload. Cardiac output remained unchanged with both agents.

Anesthesia, General↗
PubMed1999

Midazolam premedication and thiopental induction of anaesthesia: interactions at multiple end-points.

We have studied the effects of midazolam premedication on multiple anaesthetic end-points (hypnotic, loss of verbal contact (LVC); motor, dropping an infusion flex or bag (DF); analgesic, loss of reaction to painful stimulation (LRP); and EEG, attainment of burst suppression (BUR)) during induction by slow thiopental infusion at a rate of 55 mg kg-1 h-1. Patients received midazolam 0.05 mg kg-1 i.v. (group TM, n = 12) or no midazolam (group T0, n = 13). ED50 and ED95 values and group medians for times and doses at the end-points were measured. Midazolam premedication reduced significantly thiopental ED50 and ED95 values at all end-points (exception for ED95 for BUR). Potentiation was greatest for the motor end-point (dropping the infusion bag (DF)) (ED95 +52%, ED50 +23%, median +39%), and smallest for painful stimulation (LRP) (median +18%; ED50 +13%). For LRP and DF, premedication was associated with significant, non-parallel increases in the slope of the thiopental dose-response curves, resulting in marked potency ratio changes from ED50 to ED95 (LRP +31%, DF +29%). There were no such increases for LVC or BUR. The interaction between midazolam and thiopental varied with the anaesthetic end-point and may also depend on the dose of thiopental. Our data suggest that the mechanism of interaction between midazolam premedication and thiopental was different for motor effects or analgesia (DF, LRP) compared with hypnotic effects or cortical depression (LVC, BUR), in agreement with the different central nervous system substrates underlying these distinct anaesthetic end-points.

Adult↗
PubMed2004

Thiopental and isoflurane attenuate the decrease in hippocampal phosphorylated Focal Adhesion Kinase (pp125FAK) content induced by oxygen-glucose deprivation.

BACKGROUND: Thiopental and isoflurane exhibit neuroprotective effects against cerebral ischaemia. Here, we hypothesized that oxygen-glucose deprivation decreases the ATP-dependent phosphorylation process of Focal Adhesion Kinase (pp125FAK, a functionally important non-receptor tyrosine kinase), and that this phenomenon is attenuated by thiopental and isoflurane. METHODS: Rathippocampal slices were subjected to an anoxic-aglycaemic (or physiologic, control) challenge followed by 3-h reperfusion, and treated with various concentrations of thiopental and isoflurane. PP125FAK phosphorylation was measured by immunoblotting. Neuronal death was assessed by immunostaining with bis-benzimide. RESULTS: Significant neuronal death was detected after 30 min (but not 10) of anoxia-aglycaemia (40 (4) vs 14 (5)% of control, P<0.05). At 30 min, phosphorylated pp125FAK content was significantly decreased by anoxic glucose-free conditions (55 (27)% of control, P<0.05). This effect was markedly attenuated by thiopental (10 and 100 microM) and isoflurane (1 and 2%). Under control conditions, thiopental (1, 10, and 100 microM) and isoflurane (0.5, 1, and 2%) increased pp125FAK phosphorylation in a concentration-related fashion. This effect was blocked by chelerythrin and bisindolylmaleimide I and IX (10 microM, three structurally distinct inhibitors of protein kinase C, PKC) but not the N-methyl-D-aspartate (NMDA) receptor antagonist MK801 (10 microM). CONCLUSION: Phosphorylated pp125FAK content was markedly decreased in hippocampal slices subjected to oxygen-glucose deprivation. Thiopental and isoflurane significantly attenuated this phenomenon, possibly via PKC activation.

Adenosine Triphosphate↗
PubMed1996

Motor and sensory disability has a strong relationship to induction dose of thiopental in patients with the hypertropic variety of Charcot-Marie-Tooth syndrome.

In a prospective study, we determined the anesthetic induction dose of thiopental and the clinical variables influencing the appropriate induction dose of thiopental in 20 patients with the hypertrophic variety of Charcot-Marie-Tooth syndrome (CMT). As controls we chose 50 patients without CMT. Motor disturbance was evaluated in terms of muscle weakness of the distal lower and upper extremities. We examined sensory disturbance by evaluating loss of sensation in the index finger and great toe. The preinduction cardiac output was measured by echocardiography. Anesthesia was induced with repeated injections of 50 mg thiopental. The minimum induction dose of thiopental (MID) was confirmed when the eyelash reflex ceased. We maintained anesthesia with enflurane and nitrous oxide. The 95% confidence interval of the MID in patients used as the controls was 2.5-4.9 mg/kg. The MID in 11 patients with CMT was less than 2.5 mg/kg. MIDs in the patients with CMT were significantly smaller than those of the control patients (P < 0.0001). Also we found a strong relationship between the MID and the severity of both motor and sensory disturbances (P = 0.003 and 0.002, respectively). There was no relationship between the MID and other clinical variables, such as age, gender, inherited type, body weight, and preinduction cardiac output. Because delay in the recovery from anesthesia can be caused by an inappropriate dose of thiopental in CMT patients in whom motor and sensory function is seriously impaired, the dose of thiopental probably should be reduced and based on the individual patient's response.

Adolescent↗
PubMed2002

The effects of thiopental and propofol on cell swelling induced by oxygen/glucose deprivation in the CA1 pyramidal cell layer of rat hippocampal slices.

UNLABELLED: Cellular swelling has been implicated as an early process after cerebral ischemia. We compared the effects of two commonly used IV anesthetics, thiopental and propofol, on hippocampal CA1 pyramidal cell swelling induced by oxygen/glucose deprivation (OGD) in vitro. Experiments were performed in rat hippocampal slices. Cell swelling in the CA1 pyramidal cell layer was evaluated by determining light transmittance (LT) change through the slices and by histopathological examination. For LT experiments, OGD was induced for 10 min by superfusing slices with glucose-free artificial cerebrospinal fluid equilibrated with 95% nitrogen and 5% CO(2). Thiopental and propofol were present 10 min before and during the period of OGD. The results showed that thiopental (100 and 400 microM), but not propofol (40 and 160 microM), significantly prolonged latency to the peak of LT increase after the onset of OGD. Consistent with the LT experiments, histopathological examination revealed that thiopental, but not propofol, attenuated CA1 pyramidal cell expansion and the gap diminution between CA1 pyramidal cells induced by OGD. These results suggest that thiopental, but not propofol, reduces the neuronal cell swelling caused by OGD. Whether the reduction of cell swelling is related to reduction in cell injury caused by OGD remains to be investigated. IMPLICATIONS: We demonstrated that thiopental, but not propofol, attenuates ischemic neuronal swelling induced by oxygen/glucose deprivation in an in vitro ischemic model.

Animals↗
PubMed1982

Thiopental disposition in lean and obese patients undergoing surgery.

The effect of obesity on the disposition kinetics of thiopental was studied in seven morbidly obese (age 25 to 46 years) and eight age-matched lean patients (age 25 to 43 years), undergoing primarily abdominal surgery. Based upon total (bound + free) thiopental concentrations, the average (+/-SD) volumes of distribution in the terminal disposition phase and at steady-state (V beta and V ss) were significantly larger in the obese (7.94 +/- 4.55 1/kg and 4.72 +/- 2.73 1/kg, respectively) than in the age-matched lean patients (1.95 +/- 0.63 1/kg and 1.40 +/- 0.46 1/kg, respectively). Clearance of total thiopental, normalized for total body weight was not significantly different between the obese (0.18 +/- 0.081 . h-1 . kg-1) and lean patients (0.21 +/- 0.06 1 . h-1 . kg-1). However, total body clearance not normalized for total body weight was significantly larger in the obese (24.98+/- 14.87 1/h) than in the lean patients (11.86 +/- 3.66 1/h). The elimination half-life of thiopental was significantly longer in the obese (27.85 h) than in the lean patients (6.33 h) and this difference was primarily a function of a larger apparent volume of distribution for thiopental. The unbound fraction of thiopental in serum (range, 17.8 per cent to 27.6 per cent) was not correlated with the degree of obesity. The most appropriate means of comparing intrinsic metabolizing capacity (i.e., normalized vs. non-normalized for weight) between lean and obese subjects remains unresolved.

Abdomen↗
PubMed1983

Thiopental pharmacokinetics in patients with cirrhosis.

The effect of cirrhosis on the pharmacokinetics and plasma protein binding of thiopental was studied in eight patients with cirrhosis, aged (mean +/- SD) 42 +/- 11 yr, and nine patients with normal hepatic and renal function, aged 48 +/- 12 yr, undergoing elective abdominal or orthopedic surgery. The total apparent volume of distribution at steady state was of 2.3 +/- 0.5 1 X kg-1 in the controls and of 3.5 +/- 1.9 1 X kg-1 in the patients with cirrhosis. Thiopental plasma clearance based upon total drug concentrations was 3.9 +/- 1.2 ml X min-1 X kg-1 in the normal group and did not differ significantly in the patients with cirrhosis: 4.4 +/- 2.2 ml X min-1 X kg-1. The elimination half-life was of 529 +/- 97 min in the controls and of 714 +/- 252 min in the patients with cirrhosis. The thiopental free fraction was 14.5 +/- 3.4% in the controls and was increased significantly to 25.2 +/- 3.9% in the patients with cirrhosis. Thiopental intrinsic clearance was decreased insignificantly (P = 0.06) from 28.3 +/- 9.0 ml X min-1 X kg-1 in the controls to 18.2 +/- 10.5 ml X min-1 X kg-1 in those with cirrhosis, suggesting that these patients may have a decreased capacity for thiopental metabolism. These results suggest that the risk of a prolonged effect following thiopental administration appears unlikely in patients with cirrhosis.

Adult↗
PubMed1988

Comparison of the effects of isoflurane and thiopental on neurologic outcome and neuropathology after temporary focal cerebral ischemia in primates.

In an attempt to determine whether one anesthetic might be clearly advantageous over another in clinical situations of temporary focal ischemia, isoflurane or thiopental (in concentrations producing equal suppression of cerebral function as measured by the electroencephalogram) were studied for their effects on neurologic outcome and cerebral infarct size in pigtailed monkeys exposed to temporary focal ischemia produced by 5 h of middle cerebral artery occlusion (MCAo). Burst suppression was produced for 15 min before MCAo and maintained throughout the ischemic period by 2.18 +/- 0.11% (mean +/- SE) end-expired isoflurane or 135 +/- 18 mg.kg-1 thiopental. Mean arterial pressure was supported with phenylephrine and maintained at approximately 90 mmHg in both groups throughout the ischemic period. At the end of the ischemic period, the isoflurane or thiopental was discontinued, allowing the animals to awaken. Intensive care was provided as needed. Neurologic function was scored for 8 days at the end of which surviving animals were killed and the brains were fixed in formalin and then examined for infarct size. There was no significant difference in final neurologic outcome between the animals receiving isoflurane and those receiving thiopental as determined by the Mann-Whitney rank sum test. Neurologic deficit scores ranged from normal (one of eight in the group receiving isoflurane and three of nine in the group receiving thiopental) to death resulting from brain injury (three in the isoflurane group and five in the thiopental-treated group). There also was no significant difference in infarct size between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Time course of ventilatory depression following induction doses of propofol and thiopental.

To improve our understanding of the respiratory pharmacology of intravenous induction agents, the authors compared the acute effects of intravenous (iv) propofol 2.5 mg.kg-1 and iv thiopental 4.0 mg.kg-1 on the ventilatory response to CO2 (VeRCO2) of eight healthy volunteers. The slope of VeRCO2 decreased from 1.75 +/- 0.23 to a minimum of 0.77 +/- 0.14 1.min-1.mmHg-1 (mean +/- standard error) 90 s after propofol; similarly, the slope of VeRCO2 decreased from 1.79 +/- 0.22 to a minimum of 0.78 +/- 0.23 l.min-1.mmHg-1 30 s after thiopental. For both drugs, the slope was less than control in the 0.5-5-min period after injection (P less than 0.05). The slope returned to baseline within 6 min after thiopental; in contrast, after propofol, the slope remained less than control for the entire 20-min follow-up period (P less than 0.05 at 6-10, 11-15, and 16-20 min after injection). Also, from 6-10, 11-15, and 16-20 min after injection, the slope was less after propofol than at corresponding times after thiopental (P less than 0.05). Recovery of consciousness was approximately 4 min slower after propofol than after thiopental; nonetheless, awareness scores returned to baseline within 14 min after both drugs. The authors conclude that propofol 2.5 mg.kg-1 iv produces longer-lasting depression of VeRCO2 than a 4.0 mg.kg-1 iv dose of thiopental; after propofol, ventilatory depression may persist despite apparently complete recovery of consciousness.

Adult↗
PubMed1994

Effects of volatile anesthetics, thiopental, and ketamine on spontaneous and depolarization-evoked dopamine release from striatal synaptosomes in the rat.

BACKGROUND: Recent 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. METHODS: Purified 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-alpha-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). RESULTS: Volatile 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 Mg(2+)-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, Ca(2+)-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. CONCLUSION: The 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.

Anesthesia, Inhalation↗
PubMed1995

In vitro effects of fentanyl, methohexital, and thiopental on brain endothelial permeability.

BACKGROUND: The use of anesthetics can lead to changes of the permeability of the blood-brain barrier (BBB). To eliminate those factors, such as varying hemodynamic effects that are associated with anesthesia, an in vitro model of the BBB consisting of brain microvascular endothelial cells (BMEC) was used to study the direct effects of the opiate, fentanyl, and the barbiturates methohexital and thiopental, which are widely used in the clinical setting, on the permeability of confluent monolayers. METHODS: BMEC isolated from porcine brains were grown to confluence on collagen-coated polycarbonate membranes, which were placed into 24 well dishes, thus forming a two-compartment chamber. The permeability of the BMEC monolayer to ions--determined by measurements of the transendothelial resistance (TER)--the passage of sucrose, Evans Blue albumin (EBA), and alpha-aminoisobutyric acid (AIB) across the BMEC monolayer were assessed in the presence and absence of fentanyl (25-100 ng/ml), methohexital (10-50 micrograms/ml), and thiopental (25-100 micrograms/ml). RESULTS: The permeability of cultured BMEC to the tracers used increased significantly after exposure of the monolayer to arabinose and after removal of calcium ions. Fentanyl, methohexital, and thiopental did not change the permeability of the cell monolayer to ions, sucrose, albumin, and AIB. Only thiopental at the concentration of 100 micrograms/ml increased the flux of AIB. CONCLUSIONS: At the concentrations tested, there is little evidence of changes in the permeability of the in vitro BBB caused by fentanyl, methohexital, and thiopental regarding the para- and transcellular route of ions, sucrose, and albumin. Only thiopental at a concentration of 100 micrograms/ml increased the passage of AIB across the BMEC monolayer.

Albumins↗
PubMed1996

Quantitation of depth of thiopental anesthesia in the rat.

BACKGROUND: In contrast to that of inhalational anesthetics, quantitation of anesthetic depth for intravenous agents has not been well defined. In this study, using rodents, the relationship between the constant plasma thiopental concentrations and the clinical response to multiple nociceptive stimuli were investigated characterizing the anesthetic state from light sedation to deep anesthesia and correlated to the degree of electroencephalogram (EEG) drug effect. METHODS: Thirty rats were instrumented with chronically implanted EEG electrodes, arterial and venous catheters. A computer-driven infusion pump was used to rapidly attain and then maintain constant, target plasma thiopental concentrations ranging from 7 to 100 micrograms/ml. Three different target plasma thiopental concentrations were achieved in each rat. Electroencephalographic effects were monitored with aperiodic waveform analysis. The following nociceptive stimuli were applied: (1) unprovoked righting reflex, (2) provoked righting reflex, (3) noise stimulus, (4) tail clamping with an alligator clip, (5) constant tail pressure with an analgesiameter, (6) corneal reflex, and (7) tracheal intubation. For tail clamping, tail pressure, and intubation, either purposeful extremity movement or abdominal muscle contraction response was noted to be present or absent. The clinical responses (present or absent) were modeled using logistic regression to estimate the Cp50, the plasma thiopental concentration with a 50% probability of no response. RESULTS: The following mean Cp50 values (95% confidence interval) were obtained: unprovoked righting reflex, 15.9 (15.1-16.6) micrograms/ml; provoked righting reflex, 21.4 (20.2-22.7) micrograms/ml; noise stimuli, 31.3 (29.7-33.0) micrograms/ml; tail clamp and limb movement, 38.3 (36.1-40.4) micrograms/ml; tail pressure and limb movement, 39.2 (37.1-41.3) micrograms/ml; tail pressure and abdominal muscle contraction, 52.5 (50.0- 55) micrograms/ml; tail clamping and abdominal muscle contraction, 56.1 (50.0-56.2) micrograms/ml; corneal reflex, 60.0 (56.6-63.4) micrograms/ml; and limb movement or muscle abdominal contraction response to intubation, 67.7 (59.2-76.1) micrograms/ml. At an EEG-effect of 9.1 and 2.2 waves/s, there was a 50% chance of limb movement response to tail clamping and tracheal intubation, respectively. There was a poor relationship between the plasma thiopental concentration and the percent increase of either heart rate or mean arterial blood pressure after applying either tail pressure or tail clamp stimuli. CONCLUSIONS: A range of nociceptive stimuli and their observed clinical responses can be used to quantitate thiopental anesthetic depth, ranging from light sedation to deep anesthesia (isoelectric EEG and unresponsive to intubation) in the rodent. Clinical response can be mapped to surrogate EEG measures.

Anesthesia, Inhalation↗
PubMed1997

The comparative amnestic effects of midazolam, propofol, thiopental, and fentanyl at equisedative concentrations.

BACKGROUND: The authors evaluated the effects of midazolam, propofol, thiopental, and fentanyl on volunteer participants' memory for words and pictures at equisedative concentrations. METHODS: Sixty-seven healthy volunteers were randomized to receive intravenous infusions of midazolam (n = 11), propofol (n = 11), thiopental (n = 10), fentanyl with ondansetron pretreatment (n = 11), ondansetron alone (n = 8), or placebo (n = 16) in a double-blind design. Three increasing and then two decreasing sedative concentrations were achieved by computer-controlled infusion in each volunteer. Measures of sedation, memory, and drug concentration were obtained at each target concentration. Drug concentrations were normalized to equisedative effects using both Emax and logistic regression methods of pharmacodynamic modeling. The serum concentrations at 50% memory effect (Cp50s) were determined using four different memory end points. The relative potencies compared with midazolam for memory impairment were determined. RESULTS: Equisedative concentrations were midazolam, 64.5 +/- 9.4 ng/ml; propofol, 0.7 +/- 0.2 microg/ml; thiopental, 2.9 /- 1.0 microg/ml; and fentanyl, 0.9 +/- 0.2 ng/ml. The Cp50s for 50% loss of memory for words were midazolam, 56 +/- 4 ng/ml; propofol, 0.62 +/- 0.04 microg/ml; thiopental, 4.5 +/- 0.3 microg/ml; and fentanyl, 3.2 +/- 0.4 ng/ml. Compared with midazolam, relative potencies (with 95% confidence intervals) were propofol, 0.96 (0.44-1.78); thiopental, 0.76 (0.52-0.94); and fentanyl, 0.34 (0.05-0.76). Large effects on memory were only produced by propofol and midazolam. CONCLUSIONS: At equal sedation, propofol produces the same degree of memory impairment as midazolam. Thiopental has mild memory effects whereas fentanyl has none. Ondansetron alone has no sedative or amnesic effects.

Adult↗
PubMed1997

Computer simulation of the effects of alterations in blood flows and body composition on thiopental pharmacokinetics in humans.

BACKGROUND: Understanding the influence of physiological variables on thiopental pharmacokinetics would enhance the scientific basis for the clinical usage of this anesthetic. METHODS: A physiological pharmacokinetic model for thiopental previously developed in rats was scaled to humans by substituting human values for tissue blood flows, tissue masses, and elimination clearance in place of respective rat values. The model was validated with published serum concentration data from 64 subjects. The model was simulated after intravenous thiopental administration, 250 mg, over 1 min, to predict arterial plasma concentrations under conditions of different cardiac outputs, degrees of obesity, gender, or age. RESULTS: The human pharmacokinetic model is characterized by a steady state volume of distribution of 2.2 l/kg, an elimination clearance of 0.22 l/min, and a terminal half-life of 9 h. Measured thiopental concentrations are predicted with an accuracy of 6 +/- 37% (SD). Greater peak arterial concentrations are predicted in subjects with a low versus a high cardiac output (3.1 and 9.4 l/min), and in subjects who are lean versus obese (56 and 135 kg). Acutely, obesity influences concentrations because it affects cardiac output. Prolonged changes are due to differences in fat mass. Changes with gender and age are relatively minor. CONCLUSIONS: The physiological pharmacokinetic model developed in rats predicts thiopental pharmacokinetics in humans. Differences in basal cardiac output may explain much of the variability in early thiopental disposition between subjects.

Adult↗
PubMed1997

The effect of thiopental and propofol on NMDA- and AMPA-mediated glutamate excitotoxicity.

BACKGROUND: Glutamate excitotoxicity has been implicated as an important cause of ischemic, anoxic, epileptic, and traumatic neuronal damage. Glutamate receptor antagonists have been shown to reduce anoxic, ischemic, and epileptic damage. The effects of thiopental and propofol on N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA)-induced neuronal damage were investigated in this study. METHODS: The Schaffer collateral pathway was stimulated, and a postsynaptic-evoked population spike was recorded from the CA1 pyramidal cell layer of rat hippocampal slices. The recovery of the population spike amplitude was an indicator of neuronal viability. The duration of NMDA (25 microM) or AMPA (15 or 10 microM) treatment was 10 min. Thiopental (600 microM), propofol (112 microM), or the vehicle was present 15 min before, during, and 10 min after the NMDA or AMPA treatment. RESULTS: Thiopental prolonged the time required to completely block the population spike after the addition of NMDA or AMPA. Thiopental improved the recovery of the population spike after 25 microM NMDA (79% vs. 44%) and 15 microM AMPA (50% vs. 15%). Propofol worsened the recovery of the population spike from NMDA-induced damage. The recovery was 8% with propofol compared with 40% with NMDA alone. Propofol did not significantly alter the AMPA-induced neuronal damage. CONCLUSIONS: Thiopental attenuates NMDA- and AMPA-mediated glutamate excitotoxicity. This may be one way barbiturates reduce anoxic, ischemic, and epileptic damage. Propofol enhances NMDA-induced neuronal damage. These results demonstrate that thiopental and propofol have different properties with respect to glutamate excitotoxicity.

Anesthetics, Intravenous↗
PubMed2000

Differential effects of halothane and thiopental on surfactant protein C messenger RNA in vivo and in vitro in rats.

BACKGROUND: Pulmonary surfactant is a complex mixture of proteins and phospholipids synthetized by alveolar type II cells. Volatile anesthetics have been shown to reduce surfactant phospholipid biosynthesis by rat alveolar type II cells. Surfactant-associated protein C (SP-C) is critical for the alveolar surfactant functions. Our goal was to evaluate the effects of halothane and thiopental on SP-C messenger RNA (mRNA) expression in vitro in rat alveolar type II cells and in vivo in mechanically ventilated rats. METHODS: In vitro, freshly isolated alveolar type II cells were exposed to halothane during 4 h (1, 2, 4%) and 8 h (1%), and to thiopental during 4 h (10, 100 micrometer) and 8 h (100 micrometer). In vivo, rats were anesthetized with intraperitoneal thiopental or inhaled 1% halothane and mechanically ventilated for 4 or 8 h. SP-C mRNA expression was evaluated by ribonuclease protection assay. RESULTS: In vitro, 4-h exposure of alveolar type II cells to thiopental 10 and 100 micrometer increased their SP-C mRNA content to 145 and 197%, respectively, of the control values. In alveolar type II cells exposed for 4 h to halothane 1, 2, and 4%, the SP-C mRNA content increased dose-dependently to 160, 235, and 275%, respectively, of the control values. In vivo, in mechanically ventilated rats, 4 h of halothane anesthesia decreased the lung SP-C mRNA content to 53% of the value obtained in control (nonanesthetized, nonventilated) animals; thiopental anesthesia increased to 150% the lung SP-C mRNA content. CONCLUSIONS: These findings indicate that halothane and thiopental used at clinically relevant concentrations modulate the pulmonary SP-C mRNA content in rats. In vivo, the additive role of mechanical ventilation is suggested.

Actins↗
PubMed2002

Thiopental inhibits the activation of nuclear factor kappaB.

BACKGROUND: Thiopental is frequently used for the treatment of intracranial hypertension after severe head injury. Its long-term administration increases the incidence of nosocomial infections, which contributes to the high mortality rate of these patients. However, the mechanism of its immunosuppressing effect remains unknown. METHODS: The effect of thiopental (200-1000 microg/ml) on the activation of the nuclear transcription factor kappaB (NF-kappaB; electrophoretic mobility shift assays), on NF-kappaB-driven reporter gene activity (transient transfection assays), on the expression of NF-kappaB target genes (enzyme-linked immunoassays), on T-cell activation (flow cytometric analyses of CD69 expression), and on the content of the NF-kappaB inhibitor IkappaB-alpha (Western blotting) was studied in human T lymphocytes in vitro. RESULTS: Thiopental inhibited the activation of the transcription factor NF-kappaB but did not alter the activity of the cyclic adenosine monophosphate response element binding protein. Other barbiturates (methohexital), anesthetics (etomidate, propofol, ketamine), or opioids (fentanyl, morphine) did not affect NF-kappaB activation. Thiopental-mediated suppression of NF-kappaB could be observed in Jurkat cells and in primary CD3+ lymphocytes from healthy volunteers, was time- and concentration-dependent, occurred at concentrations that are clinically achieved, and persisted for hours after the incubation. It was associated with an inhibition of NF-kappaB-driven reporter gene activity, of the expression of interleukin-2, -6, and -8, and interferon gamma, and of the activation of CD3+ lymphocytes. Suppression of NF-kappaB appeared to involve reduced degradation of IkappaB-alpha. CONCLUSION: The results demonstrate that thiopental inhibits the activation of NF-kappaB and may thus provide a molecular mechanism for some of the immunosuppressing effects associated with thiopental therapy.

Biotransformation↗