How theories evolved concerning the mechanism of action of barbiturates

doi:10.1111/epi.12025

Paper

How theories evolved concerning the mechanism of action of barbiturates

Published Dec 1, 2012 · W. Löscher, M. Rogawski

Epilepsia

Q1 SJR score

168

Citations

3

Influential Citations

Full textSemantic Scholar

Abstract

The barbiturate phenobarbital has been in use in the treatment of epilepsy for 100 years. It has long been recognized that barbiturates act by prolonging and potentiating the action of γ‐aminobutyric acid (GABA) on GABAA receptors and at higher concentrations directly activating the receptors. A large body of data supports the concept that GABAA receptors are the primary central nervous system target for barbiturates, including the finding that transgenic mice with a point mutation in the β3 GABAA‐receptor subunit exhibit diminished sensitivity to the sedative and immobilizing actions of the anesthetic barbiturate pentobarbital. Although phenobarbital is only modestly less potent as a GABAA‐receptor modulator than pentobarbital, phenobarbital is minimally sedating at effective anticonvulsant doses. Possible explanations for the reduced sedative effect of phenobarbital include more regionally restricted action; partial agonist activity; reduced propensity to directly activate GABAA receptors (possibly including extrasynaptic receptors containing δ subunits); and reduced activity at other ion channel targets, including voltage‐gated calcium channels. In recent years, substantial progress has been made in defining the structural features of GABAA receptors responsible for gating and allosteric modulation by drugs. Although the precise sites of action of barbiturates have not yet been defined, the second and third transmembrane domains of the β subunit appear to be critical; binding may involve a pocket formed by β‐subunit methionine 286 as well as α‐subunit methionine 236. In addition to effects on GABAA receptors, barbiturates block AMPA/kainate receptors, and they inhibit glutamate release through an effect on P/Q‐type high‐voltage activated calcium channels. The combination of these various actions likely accounts for their diverse clinical activities. Despite the remarkable progress of the last century, there is still much to learn about the actions of barbiturates that can be applied to the discovery of new, more therapeutically useful agents.

Highly Cited

Study Snapshot

Barbiturates treat epilepsy by targeting GABAA receptors, with phenobarbital being minimally sedating at effective doses due to reduced sedative effects and reduced activity at other ion channel targets.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Sign up to use Study Snapshot

Consensus is limited without an account. Create an account or sign in to get more searches and use the Study Snapshot.

Create an account

Paper

How theories evolved concerning the mechanism of action of barbiturates

Sign up to use Study Snapshot

References

Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments

Loop diuretics show potential antiepileptic effects through diverse mechanisms, including NKCC1 and KCC2, and a promising strategy for developing novel CCC-blocking antiepileptic drugs.

Agonist-Specific Conformational Changes in the α1-γ2 Subunit Interface of the GABAA Receptor

The GABAA receptor undergoes agonist-specific conformational changes in the 1-2 subunit interface, resulting in faster labeling in the presence of etomidate than pentobarbital or gabazine.

A novel GABAA receptor pharmacology: drugs interacting with the α+β‐ interface

Drugs interacting with the + interface can allosterically modulate GABAA receptors, potentially addressing a spectrum of receptor subtypes different from benzodiazepines.

Characteristics of concatemeric GABAA receptors containing α4/δ subunits expressed in Xenopus oocytes

Concatemeric GABAA receptors containing 4/ subunits show promising properties for studying neuronal excitability and neuroactive agents in Xenopus oocytes.

Mapping general anesthetic binding site(s) in human α1β3 γ-aminobutyric acid type A receptors with [³H]TDBzl-etomidate, a photoreactive etomidate analogue.

The general anesthetic binding site in human 1-3 GABA(A)Rs is at the interface between the and subunits, with a homologous binding site at the 3-3 subunit interface.

Citations

Management of alcohol withdrawal syndromes in general hospital settings.

Alcohol withdrawal in general hospitals can be effectively managed with benzodiazepine drugs, phenobarbital, antiseizure drugs, and -2 adrenergic drugs.

Development and characterization of novel fast-dissolving pentobarbital suppositories for pediatric procedural sedation and comparison with lipophilic formulations.

Hydrophilic pentobarbital suppositories for pediatric radiological procedures release 100% of pentobarbital sodium in under 10 minutes, compared to lipophilic formulations, demonstrating biopharmaceutical suitability.

Evaluating the detection of barbiturates in dried blood spots: A comparative analysis using gas chromatography-mass spectrometry, gas chromatography-tandem mass spectrometry, and liquid chromatography-tandem mass spectrometry with different extraction methods.

The DBS-GC-MS/MS method provides rapid and accurate analysis of blood barbiturates and their combination drugs, offering advantages over traditional liquid-liquid extraction and LC-MS/MS.

Efficacy and safety of intravenous thiamylal in sedation for colonoscopy in children

Intravenous thiamylal provides effective and safe sedation for children requiring colonoscopy, with a higher success rate without mid-awakening compared to midazolam.

Phenobarbital as an adjunctive agent for sedation in pediatric intensive care unit patients: A single-center, retrospective study from Colorado

Phenobarbital effectively increases time spent in goal sedation score range and decreases morphine, benzodiazepine, and concomitant sedative boluses in critically ill, mechanically ventilated pediatric patients.

Rational analysis of data from LC-MS/MS: new insights in acylcarnitines as biomarkers for brain disorders or neurotoxicity

Plasma acetyl-carnitine (C2) and decanoyl-carnitine (C10) may serve as toxicity biomarkers for PHB poisoning disorders, but their changes in plasma may not fully represent brain changes.

Metabolome and transcriptome integration reveals cerebral cortical metabolic profiles in rats with subarachnoid hemorrhage

Subarachnoid hemorrhage in rats leads to alterations in gene and metabolite levels, affecting immune and inflammatory pathways and potentially offering potential therapeutic targets.

Assessment of sedative activity of fraxin: In vivo approach along with receptor binding affinity and molecular interaction with GABAergic system.

Fraxin extends sleep duration and reduces sleep onset time in mice, likely due to its interaction with GABAA receptor pathways.