Barbiturates for acute neurological and neurosurgical emergencies - do they still have a role?

Cordato DJ, Herkes GK, Mather LE, Morgan MK.

Department of Neurology, Royal North Shore Hospital, NSW 2065, St. Leonards, Australia

A number of clinical studies have reported poor clinical outcomes for patients treated with barbiturate therapy in acute neurological and neurosurgical emergencies. Barbiturate therapy, as currently practised with thiopentone and pentobarbitone at least, is also associated with a prolonged post-infusion period of clinical unresponsiveness. Hence, the popularity of barbiturate therapy for sedation of critically ill neurological and neurosurgical patients has declined over the past decade. A retrospective study of traumatic brain injury patients treated at the Royal North Shore Hospital, Sydney, with high-dose thiopentone therapy between 1987 and 1997 has found disappointing results with a 1-month mortality outcome of 50% (14 of 28 patients). Nevertheless, barbiturate therapy remains a consideration for patients with severe cranial trauma in whom preferred treatments have failed to control intracranial or cerebral perfusion pressures. More favourable results ( approximately 10% 1-month mortality rate) were encountered for patients with refractory vasospasm complicating subarachnoid haemorrhage or intracerebral haemorrhage complicating supratentorial arteriovenous malformation resection. A well designed, prospective and randomised controlled trial may be of value in further determining the role of barbiturate therapy in acute neurovascular emergencies refractory to standard therapy.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12763328&dopt=Abstract barbiturate Butalbital Fioricet





Mechanism of inhibition of the plasma membrane Ca(2+)-ATPase by barbiturates.

Kosk-Kosicka D, Fomitcheva I, Lopez MM.

Department of Anesthesiology/CCM, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

We have demonstrated that sodium pentobarbital inhibited the activation of the human red blood cell plasma membrane Ca(2+)-ATPase produced by dimerization of enzyme monomers or by calmodulin binding to enzyme monomers. The effects of the barbiturate were dose-dependent. Both Vmax and Ca2+ affinity were reduced. The Ca(2+)-ATPase activity of the dimeric enzyme was distinctly less sensitive with respect to the effective inhibitory concentrations of pentobarbital and to the rate of onset of inhibition than was the calmodulin-dependent activation of enzyme monomers. Temperature dependence of the inhibition was in agreement with direct, nonpolar interactions of pentobarbital with a water-exposed nonpolar patch on the surface of this transmembrane protein. The barbiturate prevented the increase of intrinsic tryptophan fluorescence associated with substrate Ca2+ binding to the enzyme dimer. On the basis of the barbiturate effects we propose a model for the action of detergent-like compounds on the enzyme. They inhibit Ca(2+)-ATPase activity by binding to a nonpolar patch on the water-exposed dimerization surface of the enzyme monomer, part of which is also the binding site for calmodulin. The model assumes that their binding to the nonpolar patch on the monomer interferes with dimerization and weakens but does not prohibit calmodulin binding, whose activation of the enzyme is then submaximal. The model should be applicable to other proteins as the two activation pathways studied have been demonstrated for various enzymes.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8547271&dopt=Abstract barbiturate Butalbital Fioricet





Pharmacology of barbiturate tolerance/dependence: GABAA receptors and molecular aspects.

Ito T, Suzuki T, Wellman SE, Ho IK.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505, USA.

Barbiturates are central nervous system depressants that are used as sedatives, hypnotics, anesthetics and anticonvulsants. However, prolonged use of the drugs produces physical dependence, and the drugs have a high abuse liability. The gamma-aminobutyric acidA (GABAA) receptor is one of barbiturates' main sites of action, and therefore it is thought to play a pivotal role in the development of tolerance to and dependence on barbiturates. Recent advances in the study of the GABAA receptor/chloride channel complex allow us to examine possible mechanisms that underlie barbiturate tolerance/dependence in a new light. In this minireview, we mainly focus on molecular and cellular aspects of the action of barbiturates and the possible mechanisms that contribute to development of tolerance to and dependence on barbiturates.

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Prediction of in vivo tissue distribution from in vitro data. 3. Correlation between in vitro and in vivo tissue distribution of a homologous series of nine 5-n-alkyl-5-ethyl barbituric acids.

Ballard P, Leahy DE, Rowland M.

Discovery-DMPK, Mereside, AstraZeneca, Alderley Park, Cheshire, SK10 4TG, United Kingdom. peter.ballard astrazeneca.com

PURPOSE: To evaluate the ability to determine accurate in vivo tissue-to-unbound plasma distribution coefficients (Kpue) from in vitro data. METHODS: Fresh pieces of fifteen rat tissues/organs were incubated at 37 degrees C with a homologous series of nine barbiturates covering a wide range of lipophilicity (Log P 0.02 to 4.13). Steady-state in vivo Kpue values were estimated from the tissue and plasma concentrations following simultaneous dosing by constant rate i.v. infusion of all nine barbiturates. Drug concentrations in the tissues and media were determined by HPLC with UV or mass spectrometric detection. RESULTS: The pharmacokinetics of the barbiturate series following constant rate i.v. infusion indicated a range of clearance (0.49 to 30 ml x min(-1) x kg(-1)) and volume of distribution at steady state (0.51 to 1.9 l x kg(-1)) values. Good agreement was observed between the in vitro and in vivo Kpu values, although for the most lipophilic barbiturates the in vitro data underpredicted the in vivo tissue distribution for all tissues. CONCLUSION: The in vitro system for predicting the extent of in vivo tissue distribution works well for compounds of widely differing lipophilicity, although for the most lipophilic drugs it may result in an underprediction of in vivo values.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12817889&dopt=Abstract barbiturate Butalbital Fioricet