lunes, 23 de abril de 2018

Benzodiazepinas / Benzodiazepines

Abril 22, 2018. No. 3059

Toxicidad de benzodizepinas
Toxicity, Benzodiazepine
Michael Kang; Sassan Ghassemzadeh.
HTLM
Uso racional de benzodiacepinas: hacia una mejor prescripción
Viviana Domínguez , Martín Collares,Gustavo Tamosiunas
Rev. Urug. Med. Interna Diciembre 2016 N°3: 14-24
Resumen
Las benzodiacepinas constituyen un grupo de fármacos de amplia prescripción en la práctica clínica. Sus efectos farmacológicos son compartidos pero su perfil farmacocinética modifica su utilidad en los diferentes escenarios clínicos. Su prescripción irracional es un problema de salud pública mundial, siendo el uso crónico y los riesgos asociados al mismo un claro ejemplo de este patrón de uso no apropiado. Están sujetas a interacciones farmacológicas frecuentes y existen poblaciones más vulnerables a sus efectos adversos, como los ancianos. Algunos de sus efectos adversos más notorios son las caídas y la aparición de dependencia y tolerancia asociado a un incorrecto uso crónico, con la aparición de síndromes de discontinuación si estese interrumpe en forma brusca. Existen pautas de uso racional que deben conocerse al realizar su prescripción. Palabras claves: benzodiacepinas. Prescripción.
Prescripción de benzodiazepinas y riesgo de suicidio: una revisión de la literatura.
Prescribed Benzodiazepines and Suicide Risk: A Review of the Literature.
Prim Care Companion CNS Disord. 2017 Mar 2;19(2). doi: 10.4088/PCC.16r02037.
Abstract
OBJECTIVE: To evaluate whether prescribed benzodiazepines affect one's risk of suicide. DATA SOURCES: A PubMed search of English-language publications from database inception until October 11, 2016, was conducted using the terms benzodiazepine and suicide. References and related articles were also searched to yield additional publications. STUDY SELECTION/DATA EXTRACTION: Studies were included if they addressed the relationship between suicidal behavior and the prescribed use of either specific benzodiazepines or benzodiazepines as a class. A total of 17 studies were included in this review. RESULTS: The majority of studies found that benzodiazepines were associated with increased suicide risk. This finding was consistent across various populations and different types of research, including a placebo-controlled crossover trial, a laboratory model of suicidal behavior, case-control studies regarding completed suicides on inpatient units, and large naturalistic studies. CONCLUSIONS: Benzodiazepines appear to cause an overall increase in the risk of attempting or completing suicide. Possible mechanisms of prosuicidal effects may include increases in impulsivity or aggression, rebound or withdrawal symptoms, and toxicity in overdose.
Una interacción electrostática entre subunidades en el receptor GABAA facilita sus respuestas a las benzodiazepinas.
An inter-subunit electrostatic interaction in the GABAA receptor facilitates its responses to benzodiazepines.
J Biol Chem. 2018 Apr 5. pii: jbc.RA118.002128. doi: 10.1074/jbc.RA118.002128. [Epub ahead of print]
Abstract
Benzodiazepines are positive allosteric modulators of the GABAA receptor (GABAAR), acting at the α-γ subunit interface to enhance GABAAR function. GABA or benzodiazepine binding induces distinct conformational changes in the GABAAR. The molecular rearrangements in the GABAAR following benzodiazepine binding remain to be fully elucidated. Using two molecular models of the GABAAR, we identified electrostatic interactions between specific amino acids at the α-γ subunit interface which were broken by, or formed after, benzodiazepinebinding. Using two-electrode voltage clamp electrophysiology in Xenopus laevis oocytes, we investigated these interactions by substituting one or both amino acids of each potential pair. We found that Lys-104 in the α1 subunit forms an electrostatic bond with Asp-75 of the γ2subunit after benzodiazepine binding, and that this bond stabilizes the positively-modified state of the receptor. Substitution of these two residues to cysteine and subsequent covalent linkage between them increased the receptor's sensitivity to low GABA concentrations and decreased its response to benzodiazepines, producing a GABAAR that resembles a benzodiazepine-bound wildtype GABAAR. Breaking this bond restored sensitivity to GABA to wildtype levels and increased the receptor's response to benzodiazepines. The α1 Lys-104 and γ2 Asp-75 interaction did not play a role in ethanol or neurosteroid modulation of GABAAR, suggesting that different modulators induce different conformational changes in the receptor. These findings may help explain the additive or synergistic effects of modulators acting at the GABAAR.
KEYWORDS: Cys-loop receptor; GABA receptor; Xenopus; allosteric regulation; benzodiazepines; cysteine-mediated cross-linking; electrophysiology; electrostatics

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