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PubMed1998

Barbiturate coma may promote reversible bone marrow suppression in patients with severe isolated traumatic brain injury.

OBJECTIVES: Barbiturate coma is employed in brain-injured patients whenever increases in intracranial pressure remain unresponsive to less aggressive therapeutic regimens. Barbiturate-mediated neuroprotection, however, is weakened by an increased infection rate related to barbiturate-induced immunosuppression. Co-administration of barbiturates with antibiotics known to induce bone marrow suppression could, in turn, potentiate barbiturate-mediated immunosuppression. Adverse drug reactions and interactions of thiopental with antibiotics in terms of leukopenia, infection rate, and bone marrow suppression were investigated. METHODS: White blood cells were measured daily, tracheobronchial secretion and urine were examined for bacterial growth twice a week or if an infection was suspected. RESULTS: A total of 52 patients with severe isolated head injury were consecutively investigated. Due to increased intracranial pressure (ICP), which did not respond to analgosedation, barbiturate coma was performed in 23 cases. The other 29 patients remained analgosedated. Leukocytes and neutrophils were reversibly and significantly decreased in all patients, mostly sustained under thiopental. The pulmonary infection rate due to gram-negative organisms was nearly doubled during barbiturate coma. Reversible agranulocytosis and bone marrow suppression attributed to antibiotics developed in six patients after thiopental administration. Mortality rate, however, was not increased by these adverse effects. CONCLUSIONS: Barbiturate coma may cause reversible leukopenia and an increased infection rate. Long-term administration of thiopental may also promote reversible antibiotic-induced bone marrow suppression. The mechanisms and site of interaction between thiopental and antibiotics cannot be assessed by the present study and remain to be clarified. However, during and after barbiturate coma, close monitoring of leukocytes and infections and careful selection of antibiotics is required.

Adult↗
PubMed1998

Rapid tolerance and crosstolerance to motor impairment effects of benzodiazepines, barbiturates, and ethanol.

Motor impairment (tilt-plane test) test was used to assess the phenomenon of rapid tolerance and crosstolerance to benzodiazepines, barbiturates, and ethanol. The motor impairment responses to benzodiazepines (chlordiazepoxide and diazepam) and to various barbiturates (pentobarbital, phenobarbital, and barbital) were significantly reduced on day 2 in rats that had been treated on day 1 with benzodiazepines and barbiturates, respectively, compared to the control group treated with saline on day 1. Benzodiazepine treatment on day 1 resulted in rapid crosstolerance to the motor impairment effects of ethanol on day 2. Benzodiazepine treatment, however, did not result in rapid crosstolerance to the three barbiturates (pentobarbital, barbital, and phenobarbital) tested. In contrast to the lack of rapid crosstolerance to barbiturates after treatment with benzodiazepines, barbiturate treatment clearly conferred rapid crosstolerance to benzodiazepines and to ethanol. This asymmetry of rapid crosstolerance raises the possibility that benzodiazepines and barbiturates invoke tolerance by mechanisms that are not wholly identical. Therefore, tolerance to the broad range of actions of barbiturates would include crosstolerance to the effects of benzodiazepines, whereas tolerance to benzodiazepines would include only a weak or partial crosstolerance to some of the effects of barbiturates.

Animals↗
PubMed2005

Supramolecular assemblies and molecular recognition of amphiphilic schiff bases with barbituric acid in organized molecular films.

A bolaform Schiff base, N,N'-bis(salicylidene)-1,10-decanediamine (BSC10), has been synthesized and its interfacial hydrogen bond formation or molecular recognition with barbituric acid was investigated in comparison with that of a single chain Schiff base, 2-hydroxybenzaldehyde-octadecylamine (HBOA). It has been found that while HBOA formed a monolayer at the air/water interface, the bolaform Schiff base formed a multilayer film with ordered layer structure on water surface. When the Schiff bases were spread on the subphase containing barbituric acid, both of the Schiff bases could form hydrogen bonds with barbituric acid in situ in the spreading films. As a result, an increase of the molecular areas in the isotherms was observed. The in situ H-bonded films could be transferred onto solid substrates, and the transferred multilayer films were characterized by various methods such as UV-vis and FT-IR spectrosopies. Spectral changes were observed for the films deposited from the barbituric acid subphase, which supported the hydrogen bond formation between the Schiff bases and barbituric acid. By measuring the MS-TOF of the deposited films dissolved in CHCl3 solution, it was concluded that a 2:1 complex of HBOA with barbituric acid and a 1:2 complex of BSC10 with barbituric acid were formed. On the other hand, when the multilayer films of both Schiff bases were immersed in an aqueous solution of barbituric acid, a similar molecular recognition through the hydrogen bond occurred. A clear conformational change of the alkyl spacer in the bolaform Schiff base was observed during the complex formation with the barbituric acid.

Journal Article↗
PubMed1993

Effect of barbiturate therapy on phenytoin pharmacokinetics.

OBJECTIVE: To evaluate the effect of high-dose pentobarbital therapy on phenytoin pharmacokinetics. DESIGN: A prospective, clinical study. SETTING: The intensive care unit of a university hospital. PATIENTS: Ten adult patients with cerebral lesions requiring anticonvulsants and control of intracranial pressure. INTERVENTIONS: Each patient received phenytoin sufficient to maintain a plasma concentration at 15 micrograms/mL (60 mumol/L) both before and after barbiturate therapy. Plasma concentrations of total phenytoin, unbound phenytoin, and the major metabolite of phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin, were measured, and pharmacokinetic variables obtained before and after barbiturate therapy were compared. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of total phenytoin remained within the therapeutic range during the 12-hr period preceding barbiturate therapy. After barbiturate therapy, plasma concentrations of both total and unbound phenytoin were significantly less than those concentrations before barbiturate therapy. For total phenytoin, maximum metabolic velocity was increased by 62% (1.09 +/- 0.62 to 1.77 +/- 0.52 mg/L/hr, 1.20 +/- 0.68 to 1.95 +/- 0.57 nmol/L/sec, p < .05), and area under the plasma concentration-time curve (0 to infinity) and mean residence time were each decreased by 73% (32.5 +/- 20.0 to 8.7 +/- 3.1 min.mg/mL, 2.14 +/- 1.25 to 0.57 +/- 0.19 sec.mmol/L, p < .01, and 135,000 +/- 69,000 to 37,000 +/- 11,000 secs, p < .005, respectively) after barbiturate therapy. The plasma concentration of the principal metabolite of phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin, was significantly increased after barbiturate therapy. CONCLUSIONS: Phenytoin metabolism is increased by barbiturate therapy, and supplemental doses of phenytoin and frequent drug monitoring may be required after barbiturate therapy.

Adult↗
PubMed1982

Effect of barbiturates on the GABA receptor of cat primary afferent neurones.

1. The effects of the barbiturate anaesthetics, pentobarbitone and thiopentone, on the membrane properties and the gamma-aminobutyric acid (GABA)-induced responses of cat primary afferent neurones were studied with intracellular recording and voltageclamp techniques.2. At low concentrations (10(-7)-10(-5) M) both barbiturates slightly enhanced and prolonged GABA-induced depolarizations or currents without affecting the membrane properties. At these concentrations, barbiturates have no effect on the apparent dissociation constant of the GABA-GABA receptor interaction or the reversal potential for GABA-induced depolarizations or currents.3. At high concentrations (10(-4)-10(-3) M) barbiturates produced a few millivolts reduction in the resting membrane potential. Voltage-clamp analysis revealed that the depolarization was associated with one of the three types of conductance change, i.e., an initial increase followed by a decrease (40% of neurones examined), only an increase (40%) and only a decrease (20%).4. Analysis in different ionic media indicated that the depolarization with a reduced membrane resistance is associated with an increased chloride conductance and that the one with an increased membrane resistance is accompanied by a reduction in potassium conductance. Bath-application of GABA (10(-3) M) or picrotoxin (10(-5) M) inhibited the increase in chloride conductance but not the reduction in potassium conductance.5. Barbiturates at these high concentrations initially caused a marked augmentation and prolongation of GABA responses; this was followed by a depression. The depressant action did not appear to be voltage-dependent. These actions of barbiturates were not accompanied by changes in the apparent dissociation constant of the GABA-current dose-response curve or the reversal potential for GABA currents. In addition, the single exponential decay of GABA current was not changed despite a marked prolongation of its decay time.6. Picrotoxin (10(-5) M) antagonized the depressant effect of barbiturates at high concentrations on GABA currents, and barbiturates (5 x 10(-6) M) reduced the inhibitory action of picrotoxin (5 x 10(-6) M) on the GABA-currents.7. From all these results, it is suggested that the site of barbiturate actions on GABA-responses is mainly the allosteric site (the ionic conductance regulatory subunit) but not the agonist recognition site or the chloride channels linked with GABA receptors.

Action Potentials↗
PubMed1999

Effects of barbiturates on facilitative glucose transporters are pharmacologically specific and isoform selective.

Barbiturates inhibit GLUT-1-mediated glucose transport across the blood-brain barrier, in cultured mammalian cells, and in human erythrocytes. Barbiturates also interact directly with GLUT-1. The hypotheses that this inhibition of glucose transport is (i) selective, preferring barbiturates over halogenated hydrocarbon inhalation anesthetics, and (ii) specific, favoring some GLUT-# isoforms over others were tested. Several oxy- and thio-barbiturates inhibited [3H]-2-deoxyglucose uptake by GLUT-1 expressing murine fibroblasts with IC50s of 0.2-2.9 mm. Inhibition of GLUT-1 by barbiturates correlates with their overall lipid solubility and pharmacology, and requires hydrophobic side chains on the core barbiturate structure. In contrast, several halogenated hydrocarbons and ethanol (all </=10 mm) do not significantly inhibit glucose transport. The interaction of these three classes of anesthetics with purified GLUT-1 was evaluated by quenching of intrinsic protein fluorescence and displayed similar specificities and characteristics. The ability of barbiturates to inhibit other facilitative glucose transporters was determined in cell types expressing predominantly one isoform. Pentobarbital inhibits [3H]-2-deoxyglucose and [14C]-3-O-methyl-glucose uptake in cells expressing GLUT-1, GLUT-2, and GLUT-3 with IC50s of approximately 1 mm. In contrast, GLUT-4 expressed in insulin-stimulated rat adipocytes was much less sensitive than the other isoforms to inhibition by pentobarbital (IC50 of >10 mm). Thus, barbiturates selectively inhibit glucose transport by some, but not all, facilitative glucose transporter isoforms.

3T3 Cells↗
PubMed2004

Barbiturates directly inhibit the calmodulin/calcineurin complex: a novel mechanism of inhibition of nuclear factor of activated T cells.

Barbiturates are frequently used for the treatment of intracranial hypertension after brain injury but their application is associated with a profound increase in the infection rate. The mechanism of barbiturate-induced failure of protective immunity is still unknown. We provide evidence that nuclear factor of activated T cells (NFAT), an essential transcription factor in T cell activation, is a target of barbiturate-mediated immunosuppression in human T lymphocytes. Treatment of primary CD3+ lymphocytes with barbiturates inhibited the PMA and ionomycin induced increase in DNA binding of NFAT, whereas the activity of other transcription factors, such as Oct-1, SP-1, or the cAMP response element-binding protein, remained unaffected. Moreover, barbiturates suppressed the expression of a luciferase reporter gene under control of NFAT (stably transfected Jurkat T cells), and of the cytokine genes interleukin-2 and interferon-gamma that contain functional binding motifs for NFAT within their regulatory promotor domains (human peripheral blood CD3+ lymphocytes). Neither GABA receptor-initiated signaling nor direct interactions of barbiturates with nuclear proteins affected the activity of NFAT. In contrast, barbiturates suppressed the calcineurin-dependent dephosphorylation of NFAT in intact T cells and also inhibited the enzymatic activity of calcineurin in a cell-free system, excluding upstream regulation. Thus, our results demonstrate a novel mechanism of direct inhibition of the calcineurin/calmodulin complex that may explain some of the known immunosuppressive effects associated with barbiturate treatment.

Barbiturates↗
PubMed1986

Barbiturate-refractory epilepsy: safe schedule for therapeutic substitution.

Barbiturates are considered first line antiepileptic drugs in third world countries due to traditional and economic reasons. This prospective uncontrolled study of 52 patients aged 15 to 64 years (mean 24) demonstrates that patients who become refractory to barbiturates are mainly those with partial seizures with or without generalization or with a focal EEG abnormality (71%). Seizures tend to become refractory approximately 6 years after barbiturates were started. Progressive barbiturate withdrawal over a period of two to 8 months (mean 5) with institution of treatment with carbamazepine, phenytoin or sodium valproate allowed complete barbiturate withdrawal in 42 of the 52 patients (81%). Furthermore monthly seizure frequency in those in whom barbiturates were withdrawn decreased from 7.1 to 1.7 per patient. An improvement in mental status was observed but not measured. These results show that barbiturates should not be first-choice drugs in patients who have a chronic disease such as epilepsy, and indicate a schedule for barbiturate withdrawal which is safe and independent of hospitalization or monitoring of antiepileptic drug serum concentrations.

Adolescent↗
PubMed1999

Risk of drug dependence and abuse posed by barbiturate-containing analgesics.

Concern has been raised that the barbiturate component of barbiturate-containing analgesics constitutes a public and individual health problem because of information from literature before 1966 concerning preclinical and clinical abuse liability, and the dependence risk of barbiturates. The safety of barbiturates alone and in combination in analgesics was reviewed. In addition, information from manufacturers of combination products were evaluated. A meta-analysis was not possible because of the paucity of formal clinical trials. Even though barbiturates have a narrow margin of safety and substantial abuse potential, there is no evidence that barbiturate-containing analgesics without codeine represent a public health or social problem because of their abuse potential. However, proper studies to confirm this theory have not been performed. In the absence of better data concerning efficacy and lack of dependence potential, barbiturate-containing analgesics are not first-line medications for the initiation of treatment for pain. Codeine-containing combination analgesics have the potential to be a more important public health problem than those with only barbiturate in the combination.

Analgesics↗
PubMed2004

[Efficacy and safety of antiepileptic therapy in children (a comparative analysis of valproates and barbiturates)].

The study aimed at a comparative analysis of safety and efficacy of valproic acid (valproate) and barbiturates in the treatment of epilepsy in children. Two hundred and forty children were treated with valproate, 94% being assigned to depakine and depakine chrono, and 210 children received barbiturates. Therapeutic effect (a decrease of seizures frequency by 2 and more times or remission) was detected in 82 of 127 (65 +/- 8.53%) patients for valproate monotherapy and only in 26 of 89 (30 +/- 9.45%) for barbiturates monotherapy. An efficacy of antiepileptic therapy in children was significantly higher (p<0.05) for valproates as compared to barbiturates. A drug withdrawal due to poor tolerability was recorded in 6 of 127 (5 +/- 3.7%) patients treated with valproate in monotherapy and in 14 of 210 (7 +/- 3.45%)--in polytherapy; in 53 of 89 (59 +/- 10.2%) patients treated with barbiturates in monotherapy and in 78 of 121 (65 +/- 8.53%) patients treated with barbiturates in polytherapy. Therefore, adverse effects occurred more often in barbiturates than in valproate treatment both for mono- and polytherapy (p<0.05). The results of the study confirmed the high efficacy and safety of valproates, specifically depakine chrono, in the treatment of epilepsy in children. depakine chrono in-take is associated with lower frequency of adverse effects; side-effects are mostly of dose-dependent character and do not result in the drug withdrawal. The authors do not recommend using barbiturates in the first-line treatment in children, because of the lower efficacy, high frequency of medical complications that might result in the drug withdrawal and reducing of the efficacy of other antiepileptic medications.

Adolescent↗
PubMed1988

Barbiturates depress currents through human brain calcium channels studied in Xenopus oocytes.

Barbiturates have had wide use as sedatives, anesthetics and anticonvulsants. Among the sites implicated in the membrane action of barbiturates are the gamma-aminobutyric acidA receptor, receptors for excitatory amino acids and Ca and potassium channels. The expression in Xenopus oocytes of various ligand- and voltage-gated channels offers the opportunity for more-detailed studies of such neuroactive substances as the barbiturates. Using RNA from human temporal cortex, we obtained the expression of an omega-conotoxin-sensitive, dihydropyridine-resistant Ca channel in Xenopus oocytes. Under voltage clamp, barbiturates depressed both the peak current and the steady-state current through this Ca channel. Barbiturates had no effect on the shape of the current-voltage relation, nor did they cause a shift in the voltage-dependence of channel activation. However, both the rate of inactivation of open Ca channels, as well as the proportion of channels inactivated at steady state were increased by barbiturates. The IC50 for these effects was about 0.25 mM for the more potent barbiturates tested. These results are consistent with the hypothesis that sedative and anesthetic effects of barbiturates can be mediated in part by an action to depress Ca currents.

Animals↗
PubMed1978

[Differences of behavior of DSCT neurons in decerebrate and barbiturate anesthetized cats (author's transl)].

Responses of dorsal spinocerebellar tract (DSCT) neurons to random electrical stimulation of peripheral nerves of the hindleg in decerebrate cats were studied using cross-correlation analysis of the output spike train. The spontaneous background discharge in barbiturate's cats had longer mean interspike interval than that in decerebrate cats, but there was no difference of the coefficient of variation in the two groups. This suggests that barbiturate has no effect on raising of the electrical threshold of the axon, but prolonging effect on interspike interval. Comparison of the conduction velocity showed to be slower in barbiturate's cats, so barbiturate reduces the conduction rate of the axon. The DSCT responses to the electrical stimulation of peripheral nerve in decerebrate cats were recorded in 60%, while 85% in barbiturate's cats. The reasons for this difference are that the DSCT cells in decerebrate cats are tonically inhibited from the pontine and bulbar reticular formation and the function of brain-stem reticular formation is suppressed by the barbiturate. Type 2 response in decerebrate cats, which represents reduced excitability of the DSCT cells, had inhibition with shorter initial peak latency and duration as compared to that in barbiturate's cats. This confirms the result of Eccles et al. that barbiturate in moderate dosage increases and prolongs the presynaptic inhibition.

Action Potentials↗
PubMed1996

Physiological comparison of alpha-ethyl-alpha-methyl-gamma-thiobutyrolactone with benzodiazepine and barbiturate modulators of GABAA receptors.

The GABAA receptor/chloride ionophore (GABAR) is allosterically modulated by several classes of anticonvulsant agents, including benzodiazepines and barbiturates, and some alkyl-substituted butyrolactones. To test the hypothesis that the anticonvulsant butyrolactones act at a distinct positive-modulatory site on the GABAR, we examined the physiological effects of a butyrolactone, a benzodiazepine and a barbiturate on GABA-mediated currents in voltage-clamped neurons and cells transfected with various subunit combinations. The butyrolactone, alpha-ethyl-alpha-methyl-gamma-thiobutyrolactone (alpha EMTBL), altered the EC50 for GABA and changed the apparent cooperativity of GABA responses. In contrast, the benzodiazepine chlordiazepoxide altered the EC50 for GABA with no effect on apparent cooperativity. The barbiturate phenobarbital altered both the EC50 and the amplitude of the maximal GABA response without altering apparent cooperativity. The GABA-mediated effect of the barbiturate, but not the benzodiazepine, added to the maximal effect of the butyrolactone, supporting the hypothesis that butyrolactones do not exert their effect at the barbiturate effector site. Both alpha EMTBL and phenobarbital potentiated GABA currents in transfected cells containing the alpha 1 beta 2 and alpha 1 gamma 2 subunit combinations, as well as alpha 1 subunits alone. Chlordiazepoxide had the minimum requirement of an alpha subunit and a gamma subunit. Specific GABARs lacking benzodiazepine or barbiturate modulation were tested for modulation by alpha EMTBL. The alpha 6 beta 2 gamma 2 combination was modulated by the butyrolactone but not chlordiazepoxide. However, GABARs comprising rho1 subunits were sensitive to both phenobarbital and alpha EMTBL. Although the molecular determinants for alpha EMTBL action appear similar to the barbiturates, our data support the conclusion that alpha EMTBL interacts with GABARs in a distinct manner from barbiturates and benzodiazepines.

4-Butyrolactone↗
PubMed1987

Effect of barbiturate coma on glucose utilization in normal brain versus gliomas. Positron emission tomography studies.

Glucose utilization by normal and neoplastic cerebral tissue can be measured in humans using positron emission tomography (PET) with fluorine-18-labeled 2-deoxy-D-glucose (FDG). Malignant gliomas are known to exhibit hypermetabolic glucose consumption compared to normal brain. Barbiturate-sensitive cerebral glucose utilization is coupled to neuronal activity, and lesions lacking neuronal activity should be relatively insensitive to barbiturate suppression of glucose utilization. In a study to examine this phenomenon, three patients with cerebral gliomas underwent FDG-PET while awake and during deep barbiturate coma. Cerebral glucose utilization was measured in normal brain, tumor, and a homologous, non-neoplastic control site in the contralateral hemisphere. A glucose utilization ratio for tumor/control tissue was calculated. The mean reduction of glucose utilization during barbiturate coma was: gray matter 67%, white matter 47%, basal ganglia 66%, thalamus 57%, cerebellar cortex 55%, tumor 32%, and the contralateral control site 64%. The mean tumor glucose utilization ratio was 1.48:1 in the awake state and 2.69:1 during barbiturate coma. The changes in gray matter, basal ganglia, thalamus, cerebellar cortex, and tumor/control tissue ratio were significant (p less than 0.05). In one patient, deep tumor invasion not evident on computerized tomography, magnetic resonance imaging, or baseline FDG-PET was apparent during barbiturate-enhanced FDG-PET scanning. The study findings suggest that gliomas resist suppression of glucose utilization by barbiturates; this supports the hypothesis that barbiturates reduce neuronal metabolism by blocking synaptic activity. This differential effect on normal brain and gliomas enhances the capability to assess the extent of neoplastic tissue in brain and may represent the basis for novel therapeutic strategies.

Adult↗
PubMed1998

Barbiturates impair astrocyte glutamate uptake.

Barbiturates are widely used as neuroprotective agents during status epilepticus and during surgical procedures that cause cerebral ischemia. The efficacy of this practice is unproved, however, and while barbiturates may counter neuronal excitotoxicity, they can also inhibit mitochondrial ATP production. Since glutamate uptake is energetically costly, mitochondrial inhibition could impair glutamate uptake. To examine this possibility, glutamate uptake was measured in primary rat astrocyte cultures in the presence of several barbiturates. Different barbiturates had differing effects on glutamate uptake at normal glucose concentrations, but all potentiated inhibition of glutamate uptake during glucose deprivation. Thiamylal and thiopental were the most potent barbiturates examined, with 0.3 mM causing approximately 40% reduction in glutamate uptake rates. Barbiturates also potentiated ATP depletion during glucose deprivation, supporting mitochondrial inhibition as the mechanism of these effects. These findings suggest that barbiturates can, under some conditions, impair glutamate uptake at concentrations relevant to their clinical use.

Adenosine Triphosphate↗
PubMed1981

Anion mass spectrometry of barbiturates.

Recent trends towards increasing abuse of the barbiturates has led to a proposal to legally restrict some of them. The implementation of the resulting legislation might require specific identification of the barbiturates. Such identification is not readily available from electron impact mass spectra and, even when these are supplemented with chemical ionization data, barbiturates differing only in isomeric sidechains are not completely characterized. In this study the anion mass spectra of 30 barbiturates, including all of those commonly available, are presented. The spectra are simple; ions arising from hydrogen atom and sidechain elimination from the initially formed [M]- ion are diagnostic of the barbiturate. For all but two of the barbiturates (butalbital and idobutal) relative peak intensities will discriminate between barbiturates differing only in isomeric sidechains.

Anions↗
PubMed1987

Affinities of barbiturates for the GABA-receptor complex and A1 adenosine receptors: a possible explanation of their excitatory effects.

The effects of barbiturates on the GABA-receptor complex and the A1 adenosine receptor were studied. At the GABA-receptor complex the barbiturates inhibited the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPT) and enhanced the binding of [3H]diazepam. Kinetic and saturation experiments showed that both effects were allosteric. Whereas all barbiturates caused complete inhibition of [35S]TBPT binding, they showed varying degrees of maximal enhancement of [3H]diazepam binding; (+/-)methohexital was identified as the most efficacious compound for this enhancement. At the A1 adenosine receptor all barbiturates inhibited the binding of [3H]N6-phenylisopropyladenosine ([3H]PIA) in a competitive manner. The comparison of the effects on [3H]diazepam and [3H]PIA binding showed that excitatory barbiturates interact preferentially with the A1 adenosine receptor, and sedative/anaesthetic barbiturates with the GABA-receptor complex. It is speculated that the interaction with these two receptors might be the basis of the excitatory versus sedative/anaesthetic properties of barbiturates.

Animals↗
PubMed1982

Barbiturate reduction of calcium-dependent action potentials: correlation with anesthetic action.

Calcium-dependent action potentials were recorded from mouse spinal cord neurons in primary dissociated cell culture following addition of the potassium channel blockers tetraethylammonium ion and 3-aminopyridine. The pharmacologically active barbiturates, pentobarbital and phenobarbital, but not the pharmacologically inactive barbiturate, barbituric acid, produced reversible, dose-dependent reduction of action potential duration at sedative-hypnotic and anesthetic concentrations. Pentobarbital reduced action potential duration at concentrations from 25 to 600 microM (50% reduction at 170 microM) while phenobarbital reduced action potential duration at concentrations from 100 to 5000 microM (50% reduction at 900 microM). The barbiturate concentrations which reduced calcium-dependent action potential duration in this study correlate with reduction of neurotransmitter release from other neuronal preparations and with reduction of calcium uptake by synaptosomes. The results suggest that barbiturates may produce anesthesia in part by reduction of presynaptic calcium entry and consequent reduction of neurotransmitter release in addition to postsynaptic increase of membrane chloride ion conductance. Barbiturate anticonvulsant actions are probably due to postsynaptic augmentation of GABA-mediated inhibition and depression of excitatory synaptic transmission. The major difference between anticonvulsant (phenobarbital) and anesthetic (pentobarbital) barbiturates was the dose-dependency of these actions. Phenobarbital produced postsynaptic modulation of neurotransmitter responses at low concentrations and decreased calcium-dependent action potential duration and increased chloride ion conductance at high concentrations. In contrast, pentobarbital produced all actions at low concentrations. Thus for phenobarbital there would be a large therapeutic index for anticonvulsant activity compared to anesthetic activity but for pentobarbital there would be a small therapeutic index.

Animals↗