Midazolam and Other Benzodiazepines

Abstract

The actions of benzodiazepines are due to the potentiation of the neural inhibition that is mediated by gamma-aminobutyric acid (GABA). Practically all effects of the benzodiazepines result from their actions on the ionotropic GABA(A) receptors in the central nervous system. Benzodiazepines do not activate GABA(A) receptors directly but they require GABA. The main effects of benzodiazepines are sedation, hypnosis, decreased anxiety, anterograde amnesia, centrally mediated muscle relaxation and anti-convulsant activity. In addition to their action on the central nervous system, benzodiazepines have a dose-dependent ventilatory depressant effect and they also cause a modest reduction in arterial blood pressure and an increase in heart rate as a result of a decrease of systemic vascular resistance. The four benzodiazepines, widely used in clinical anaesthesia, are the agonists midazolam, diazepam and lorazepam and the antagonist flumazenil. Midazolam, diazepam and flumazenil are metabolized by cytochrome P450 (CYP) enzymes and by glucuronide conjugation whereas lorazepam directly undergoes glucuronide conjugation. CYP3A4 is important in the biotransformation of both midazolam and diazepam. CYP2C19 is important in the biotransformation of diazepam. Liver and renal dysfunction have only a minor effect on the pharmacokinetics of lorazepam but they slow down the elimination of the other benzodiazepines used in clinical anaesthesia. The duration of action of all benzodiazepines is strongly dependent on the duration of their administration. Based on clinical studies and computer simulations, midazolam has the shortest recovery profile followed by lorazepam and diazepam. Being metabolized by CYP enzymes, midazolam and diazepam have many clinically significant interactions with inhibitors and inducers of CYP3A4 and 2C19. In addition to pharmacokinetic interactions, benzodiazepines have synergistic interactions with other hypnotics and opioids. Midazolam, diazepam and lorazepam are widely used for sedation and to some extent also for induction and maintenance of anaesthesia. Flumazenil is very useful in reversing benzodiazepine-induced sedation as well as to diagnose or treat benzodiazepine overdose.

Midazolam Induces Cellular Apoptosis in Human Cancer Cells and Inhibits Tumor Growth in Xenograft Mice

“…The pro-apoptotic effects of midazolam in neuronal cells largely depend on signaling though GABA A receptor and peripheral-type benzodiazepine receptors (PBRs) (Sinner et al, 2011;So et al, 2010;Stevens et al, 2011). PBRs have been reported to regulate various functions including cellular proliferation, oxidative processes, and programmed cell death (Casellas et al, 2002;Olkkola and Ahonen, 2008). Recently midazolam has been shown to induce apoptosis in human Jurkat T-lymphoma cells that lack GABA A receptor (Stevens et al, 2011).…”

Diazepam or midazolam for orotracheal intubation in the ICU?

“…These wide variations in response are typical of benzodiazepines and may be partly explained by high plasma protein binding. 25,26 Obese patients have an increased volume of distribution due to enhanced distribution in peripheral adipose tissues and interactions with other drugs that are metabolized through the cytochrome p450 system can influence the clinical response. 27 Benzodiazepines have synergistic interactions with other drugs like opioids that were simultaneously used in most patients.…”

Effects of Oral Diazepam on Visual Functions of Healthy Nigerian Volunteers

“…Members of the group increase REM latency that is, time from onset of spindle sleep to the first REM burst. The frequency of eyeball movement during REM is decreased and the time spent on REM sleep is shortened [10]. However, nothing has been said about IJBR (2015) 6 (06) www.ssjournals.com the resultant visual effects (defects) following their therapeutic use.…”