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PubMed2000

Barbiturates for acute traumatic brain injury.

BACKGROUND: Raised intracranial pressure (ICP) is an important complication of severe brain injury, and is associated with a high mortality rate. Barbiturates are believed to reduce intracranial pressure by suppressing cerebral metabolism, thus reducing cerebral metabolic demands and cerebral blood volume. However, barbiturates also reduce blood pressure and therefore may adversely effect cerebral perfusion pressure. OBJECTIVES: To assess the effects of barbiturates in reducing raised intracranial pressure, mortality and morbidity in people with acute traumatic brain injury. To quantify any side effects resulting from the use of barbiturates. SEARCH STRATEGY: The review draws largely on the search strategy developed for the Cochrane Injuries Group as a whole. However, in addition the Cochrane Library was searched in December 1996 using the text terms "barbiturate*," "pentobarb*," "phenobarb*," "head," and "brain." An updated search was done in April 1999. SELECTION CRITERIA: Randomised or quasi randomised trials of any one or more of the barbiturate class of drugs (amobarbital, barbital, hexobarbital, mephobarbital, methohexital, murexide, pentobarbital, phenobarbital, secobarbital, thiobarbiturate) where study participants had a clinically diagnosed acute traumatic brain injury of any severity. DATA COLLECTION AND ANALYSIS: The reviewer extracted the data and assessed the quality of allocation concealment in the trials. MAIN RESULTS: The pooled relative risk for death (barbiturate vs no barbiturate) was 1.09 (95%CI 0.81 to 1.47). The pooled effect of barbiturates on adverse neurological outcome, measured using the Glasgow Outcome Scale (death, persistent vegetative state or severe disability) was 1.15 (95% 0.81 to 1.64). Two studies examined the effect of barbiturate therapy on intracranial pressure. In the study by Eisenberger et al, a smaller proportion of patients in the barbiturate group had uncontrolled ICP (68% vs 83%). The relative risk for uncontrolled ICP was 0.81 (95%CI 0.62 to 1.06). Similarly, in the study by Ward et al, mean ICP was lower in the barbiturate treated group. Barbiturate therapy results in an increase in the occurrence of hypotension (RR=1.80 95%CI 1.19 to 2.70). For every four patients treated one will develop clinically significant hypotension. Mean body temperature was significantly lower in the barbiturate treated group. Schwartz et al compared pentobarbital with mannitol in the control of intracranial pressure. Pentobarbital was less effective than mannitol for control of raised ICP. 68% of patients in the pentobarbital treated group required a second drug for the treatment of raised intracranial pressure compared to 39% in the mannitol treated group (RR=1.75 95%CI 1.05 to 2.92). There was no substantial difference in mortality between the two study groups (RR=1.18 95%CI 0.73 to 1.92). REVIEWER'S CONCLUSIONS: There is no evidence that barbiturate therapy in patients with acute severe head injury improves outcome. Barbiturate therapy results in a fall in blood pressure in 1 in 4 treated patients. The hypotensive effect of barbiturate therapy will offset any ICP lowering effect on cerebral perfusion pressure.

Barbiturates↗
PubMed2002

Barbiturates induce mitochondrial depolarization and potentiate excitotoxic neuronal death.

Barbiturates are widely used as anesthetics, anticonvulsants, and neuroprotective agents. However, barbiturates may also inhibit mitochondrial respiration, and mitochondrial inhibitors are known to potentiate NMDA receptor-mediated neurotoxicity. Here we used rat cortical cultures to examine the effect of barbiturates on neuronal mitochondria and responses to NMDA receptor stimulation. The barbiturates tested, secobarbital, amobarbital, and thiamylal, each potentiated NMDA-induced neuron death at barbiturate concentrations relevant to clinical and experimental use (100-300 microm). By using rhodamine-123 under quenching conditions, barbiturates in this concentration range were shown to depolarize neuronal mitochondria and greatly amplify NMDA-induced mitochondrial depolarization. Barbiturate-induced mitochondrial depolarization was increased by the ATP synthase inhibitor oligomycin, indicating that barbiturates act by inhibiting electron transport sufficiently to cause ATP synthase reversal. Barbiturates similarly amplified the effects of NMDA on cytoplasmic free calcium concentrations. The cell-impermeant barbiturate N-glucoside amobarbital did not influence mitochondrial potential or potentiate NMDA neurotoxicity or calcium responses. However, all of the barbiturates attenuated NMDA-induced calcium elevations and cell death when present at millimolar concentrations. Whole-cell patch-clamp studies showed that these effects may be attributable to actions at the cell membrane, resulting in a block of NMDA-induced current flux at millimolar barbiturate concentrations. Together, these findings reconcile previous reports of opposing effects on barbiturates on NMDA neurotoxicity and show that barbiturate effects on neuronal mitochondria can be functionally significant. Effects of barbiturates on neuronal mitochondria should be considered in experimental and clinical application of these drugs.

Amobarbital↗
PubMed1999

Depressant and convulsant barbiturates both inhibit neuronal nicotinic acetylcholine receptors.

UNLABELLED: Neuronal nicotinic acetylcholine receptors (neuronal nAchRs) are sensitive to many anesthetics, including barbiturates, which suggests that these receptors are potential sites for anesthetic action. Subtle changes in molecular structures of the anesthetic barbiturates can produce compounds with potent convulsant activity. Whereas R(-) isomer of 1-methyl-5-phenyl-5-propyl barbituric acid (MPPB) exerts anesthetic action, S(+)MPPB exhibits pure excitatory effects, including convulsion. 5-(2-cyclohexilidene-ethyl)-5-ethyl barbituric acid is another example of a convulsant barbiturate. We compared the effects of depressant and convulsant barbiturates on the neuronal nAchR-mediated current to determine whether inhibition of neuronal nAchRs contributes to the anesthetic action of barbiturates. Whole cell nicotine-induced currents were recorded in PC12 derived from rat pheochromocytoma, using the conventional whole cell patch clamp technique in the presence and absence of barbiturates. Both depressant and convulsant barbiturates inhibited the nicotine-induced inward current reversibly and in a dose-dependent manner when co-applied with nicotine. All barbiturates accelerated the current decay. There was no significant difference between the concentrations for 50% inhibition for MPPB isomers. There was no correlation between inhibition of ganglionic nAchRs and anesthetic effects of the barbiturates. These results strongly oppose the idea that inhibition of neuronal nAchRs contributes to the anesthetic action of barbiturates. IMPLICATIONS: We found that both convulsant and depressant barbiturates inhibit the current mediated through ganglionic nicotinic acetylcholine receptors in PC12 cells. This finding suggests that the inhibition of neuronal nicotinic acetylcholine receptors does not contribute to the anesthetic action of barbiturates.

Animals↗
PubMed1982

Interaction of barbiturates with benzodiazepine receptors in the central nervous system.

The interaction of barbiturates with benzodiazepine receptors was studied in extensively washed membrane preparations from rat brain. Sedative/hypnotic and anesthetic barbiturates such as pentobarbital, and convulsant barbiturates such as DMBB, enhanced [3H]diazepam binding in a stereospecific fashion. Freeze-thawing of membranes resulted in a decrease in the potency of barbiturates to enhance [3H]diazepam binding, while the maximum response to barbiturates remained unchanged. Significant differences in both the potency and maximum enhancement of [3H]diazepam binding by pentobarbital was observed among brain regions. The rank order potency of pentobarbital in different brain regions was: cerebellum greater than cortex greater than hippocampus, while the rank order efficacy of pentobarbital in these brain regions was reversed. The effects of a combination of anesthetic and/or convulsant barbiturates on [3H]diazepam binding suggested that these compounds function as partial agonists while a combination of anesthetic or convulsant barbiturates with phenobarbital suggested that latter compound antagonized the actions of both anesthetic and convulsant barbiturates. The convulsant benzodiazepine Ro-5-3663 and inosine were more potent as inhibitors of pentobarbital-enhanced than basal (non-pentobarbital enhanced) [3H]diazepam binding. Solubilization of benzodiazepine receptors with Lubrol-PX resulted in a complete loss of barbiturate enhanced [3H]diazepam binding, and greater than a 75% loss in efficacy in the remaining (insoluble receptor) tissue. These data, coupled with recent observations from this and other laboratories, suggests that the site(s) at which barbiturates act to enhance [3H]diazepam binding to benzodiazepine receptors is distinct from the site at which GABA acts to enhance [3H]diazepam binding. The phenomenon of enhanced benzodiazepine binding by barbiturates may be related to the depressant actions of the barbiturates, that is, their direct effects to increase chloride conductance. Although it is premature to assign a pharmacologic correlate to this neurochemical phenomenon, it appears that this action may be related to the anesthetic effects of the barbiturates. However, the definitive assignment of either the electrophysiologic or pharmacologic sequelae to this neurochemical action will require further investigation.

Animals↗
PubMed2001

Multimodal inclusion complexes between barbiturates and 2-hydroxypropyl-beta-cyclodextrin in aqueous solution: isothermal titration microcalorimetry, (13)C NMR spectrometry, and molecular dynamics simulation.

Multiple types (structures) of inclusion complexes between barbiturates and 2-hydroxypropyl-beta-cyclodextrin (HPCD) were evaluated by isothermal titration microcalorimetry and (13)C NMR spectroscopy. The geometries of the inclusion complexes were suggested by molecular dynamics simulation. Barbituric acid (BA), barbital (B), amobarbital (AB), pentobarbital (PB), secobarbital (SB), cyclobarbital (CB), and phenobarbital (PHB) were used as barbiturates with different substituents on the barbituric acid ring and compared for inclusion types in aqueous solution. The association constants (K), stoichiometries, and thermodynamic parameters change in free energy (DeltaG) change in enthalpy (DeltaH), and change in entropy [DeltaS] for each type of complex were determined from the calorimetric data. The inclusion complexation was largely entropy driven because of hydrophobic interactions. The values of K increased in the order BA<B<AB<PB<SB<CB<PHB. Barbiturates, except B and BA, form two types of inclusion complex with a 1:1 stoichiometry in the un-ionized forms. The first type of inclusion complex with high affinity (K(1)) was characterized by small negative values of DeltaH(1) and large positive DeltaS(1), where the substituent R2 of the barbiturate was initially inserted into the cavity of HPCD through hydrophobic interactions. There was a good relationship between DeltaG(1) obtained from the calorimetric data for the first type of inclusion complex and DeltaG(R2) calculated from the changes in (13)C Nuclear Magnetic Resonance (NMR) chemical shifts for the substituent R2 of barbiturates. These types were very stable in aqueous solution at various pHs. The second type of complex, with low affinity (K(2)), was characterized by large negative values of DeltaH(2) and small positive DeltaS(2), reflecting van der Waals' interactions in the un-ionized forms of barbiturates at pH values less than pK(a). The values of K(2) were markedly decreased to <10(3) M(-1) as the barbiturates were ionized over pH 8. Thus, in the second type, the barbituric acid ring contributed to forming the complexes. The geometries were stabilized by hydrogen bond formation between the hetero atoms in the barbituric acid ring and the secondary hydroxyl groups on the rim of the cyclodextrin. The (13)C NMR chemical shifts of C4 and C6 carbons in the barbituric acid ring were moved upfield significantly by the inclusion complexation. On the other hand, B and BA could form only one type of complex, the lid-type supramolecular complex with small association constants.

2-Hydroxypropyl-beta-cyclodextrin↗