Anaesthetic effects of pregnanolone in combination with allopregnanolone, thiopental, hexobarbital and flurazepam: an EEG study in the rat.

Norberg L, Backstrom T, Wahlstrom G.

Department of Pharmacology, University of Umea, Sweden.

The anaesthetic interactions of the steroid, 3 alpha-hydroxy-5 beta-pregnan-20-one, in male rats were investigated in different fixed binary combinations with the steroid allopregnanolone (3 alpha-hydroxy-5 alpha-pregnan-20-one), two barbiturates (thiopental and hexobarbital) and the benzodiazepine, flurazepam. Anaesthetic effects were determined using an EEG threshold method. Interactions were assessed using an isobolographic method. The interaction between the two steroids, pregnanolone and allopregnanolone, showed an anaesthetic effect significantly less than additive (antagonistic). The interactions between pregnanolone and the two barbiturates and the benzodiazepine showed an anaesthetic effect significantly greater than additive (potentiation) in all tests performed. These results could be explained by a pharmacodynamic interaction at the hypothetical GABA-benzodiazepine-barbiturate-steroid complex in the CNS.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10536552&dopt=Abstract barbiturate Butalbital Fioricet





Cerebral hemodynamic effects of pentobarbital coma in head-injured patients.

Cormio M, Gopinath SP, Valadka A, Robertson CS.

Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA.

The purpose of this study was to examine the changes in cerebral hemodynamics of head-injured patients undergoing barbiturate treatment of refractory intracranial hypertension. Cerebral blood flow (CBF) and metabolism variables were measured in 67 severely head-injured patients at the following times: before the loading dose of pentobarbital; after the loading dose of pentobarbital (average pentobarbital level 28.1+/-8.3 microg/mL); and 3 days later, when the peak pentobarbital level averaged 42.5+/-17.2 microg/mL. Intracranial pressure (ICP) and mean arterial blood pressure (MAP) were decreased by the loading dose of pentobarbital by an average of 12 and 9 mm Hg, respectively. Cerebral perfusion pressure (CPP) was unchanged when the entire group was analyzed together. CBF, cerebral oxygen consumption (CMR(O)2), and arteriovenous oxygen difference (AVD(O)2) were significantly decreased after the loading dose of pentobarbital, by 20%, 31%, and 11%, respectively. The average cerebrovascular resistance (CVR) was increased by 20%. The change in CMR(O)2 with the loading dose of pentobarbital was closely related to the pretreatment value (n = 67, r2 = 0.65, p < .001). Thirty (45%) of the patients had a "good ICP response," with a reduction in ICP from 34+/-9 to 15+/-5 mm Hg after the initial loading dose of pentobarbital. Twenty-seven (40%) of the patients had a "partial ICP response," with ICP decreasing but still remaining above 20 mm Hg after the loading dose of pentobarbital. In the remaining 10 patients, ICP did not change or even increased after pentobarbital. In the 30 patients with a good ICP response, pretreatment CMR(O)2 and AVD(O)2 were greater before administration of pentobarbital, and CMR(O)2 and AVD(O)2 decreased more with the loading dose of pentobarbital, than in the patients with partial or no ICP response. The outcome was significantly better in the patients with a good or partial ICP response to pentobarbital, with 21% of these patients having a good recovery or moderate disability at 3 months after injury, compared with 100% persistent vegetative state or death in the nonresponders. In summary, barbiturate coma can be a useful treatment modality for acutely reducing ICP in selected patients. Patients with overwhelmingly severe injuries are not likely to benefit, partly because their CMR(O)2 is already markedly reduced by the injury and partly because their outcome is already predetermined by the injury. Patients with systemic hypotension are not likely to have a good response because hypotension limits the amount of barbiturates that can be given.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10547101&dopt=Abstract barbiturate Butalbital Fioricet





Blockade of glutamate receptors and barbiturate anesthesia: increased sensitivity to pentobarbital-induced anesthesia despite reduced inhibition of AMPA receptors in GluR2 null mutant mice.

Joo DT, Xiong Z, MacDonald JF, Jia Z, Roder J, Sonner J, Orser BA.

Department of Anaesthesia, University of Toronto, Ontario, Canada.

BACKGROUND: Barbiturates enhance gamma-aminobutyric acid type A (GABA(A)) receptor function and also inhibit the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of glutamate receptor. The relative contribution of these actions to the behavioral properties of barbiturates is not certain. Because AMPA receptor complexes that lack the GluR2 subunit are relatively insensitive to pentobarbital inhibition, GluR2 null mutant mice provide a novel tool to investigate the importance of AMPA receptor inhibition to the anesthetic effects of barbiturates. METHODS: GluR2 null allele (-/-), heterozygous (+/-), and wild-type (+/+) mice were injected with pentobarbital (30 and 35 mg/kg intraperitoneally). Sensitivity to anesthetics was assessed by measuring the latency to loss of righting reflex, sleep time, and the loss of corneal, pineal, and toe-pinch withdrawal reflexes. In addition, patch-clamp recordings of acutely dissociated CA1 hippocampal pyramidal neurons from (-/-) and (+/+) mice were undertaken to investigate the effects of barbiturates on kainate-activated AMPA receptors and GABA-activated GABA(A) receptors. RESULTS: Behavioral tests indicate that sensitivity to pentobarbital was increased in (-/-) mice. In contrast, AMPA receptors from (-/-) neurons were less sensitive to inhibition by pentobarbital (concentrations that produced 50% of the maximal inhibition [IC50], 301 vs. 51 microM), thiopental (IC50, 153 vs. 34 microM), and phenobarbital (IC50, 930 vs. 205 microM) compared with wild-type controls, respectively. In addition, the potency of kainate was greater in (-/-) neurons, whereas no differences were observed for the potentiation of GABA(A) receptors by pentobarbital. CONCLUSIONS: The GluR2 null mutant mice were more sensitive to pentobarbital anesthesia despite a reduced sensitivity of GluR2-deficient AMPA receptors to barbiturate blockade. Our results indicate that the inhibition of AMPA receptors does not correlate with the anesthetic effects of barbiturates in this animal model. We postulate that the increase in the sensitivity to anesthetics results from a global suppression of excitatory neurotransmission in GluR2-deficient mice.

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Synaptic membrane freezing affects modulatory sites in avian central nervous system GABA(A) receptor.

Viapiano MS, Rodriguez Gil DJ, Mitridate de Novara AM, Fiszer de Plazas S.

Instituto de Biologia Celular y Neurociencias, Facultad de Medicina, Universidad de Buenos Aires, Argentina.

Studies were carried out to determine whether barbiturates and neurosteroids share common recognition sites at the GABA(A) receptor complex in avian CNS. To achieve this, differentially prepared fresh and frozen synaptic membranes were used. Both the barbiturate, pentobarbital, and the neurosteroid, 3alpha-hydroxy-5alpha-pregnan-20-one, were able to stimulate GABA binding in both types of membranes. Stimulation differed markedly when both drugs were added jointly to different treated tissue. In frozen membranes drugs acted synergistically and were differentially displaced by picrotoxinin, while in fresh ones, where both compounds were inhibited by the convulsant, this additivity was absent. Post-freezing wash supernatants were collected and used as a source of putative endogenous factors involved in the above mentioned membrane differences. Addition of a high molecular weight fraction from supernatants to frozen synaptic membranes led to an inhibition of barbiturate and neurosteroid potentiation, as well as a loss of their additive effect. Our results indicate that GABA(A) receptor modulation by barbiturates and neurosteroids is affected by synaptic membrane treatment, with a common modulatory site in fresh membranes and separate recognition sites after a freeze-thawing procedure. There may also be endogenous factors involved in overlapping of modulatory sites, which would thus regulate GABA(A) receptor functionality by direct interaction with the complex.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10555774&dopt=Abstract barbiturate Butalbital Fioricet