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Pharmacokinetic determinants of clinical activity
Published in Adam Doble, Ian L Martin, David Nutt, Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Adam Doble, Ian L Martin, David Nutt
Certain benzodiazepines penetrate the blood-brain barrier poorly, and their plasma concentrations are thus elevated with respect to the concentrations necessary to interact with GABAA receptors in the central nervous system (CNS). A case in point is midazolam, whose plasma concentrations at the active dose are over a hundred times those observed in the cerebrospinal field (Sjövall et al, 1983). An even more extreme case is clorazepate, which does not penetrate the blood–brain barrier at all (presumably due to its negative charge). This benzodiazepine needs first to be converted into the more lipophilic metabolite desmethyldiazepam (Ochs et al, 1984). It is this metabolite that actually enters the CNS and provides the anxiolytic effect. In fact, clorazepate itself has very little affinity for the benzodiazepine binding site. Other benzodiazepines whose plasma concentrations do not correlate with their receptor affinity are all those that are transformed into more active metabolites, such as quazepam (transformed into 2-oxoquazepam and desmethylflurazepam). In this case, plasma levels of the parent drug to obtain a given level of therapeutic activity are lower than what would be expected.
Antiepileptic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Clonazepam is used for the treatment of myoclonic seizures and absence of seizures in children. Intranasal spray of clonazepam is used as an orphan drug for recurrent acute repetitive seizures. Lorazepam and diazepam are efficacious in the treatment of status epilepticus. The latter is more frequently used because of less lipid solubility, more effectively confined to the vascular compartment, and has a longer effective half-life after a single dose (Porter et al., 2018). Clorazepate is effective in the treatment of focal seizures in combination with other antiepileptics. Clorazepate should be avoided in children less than 9 years of age (Porter et al., 2018). Clobazam is used in a variety of seizure phenotypes and is FDA approved for the treatment of Lennox–Gastaut syndrome in patients of age 2 years or more (Misty et al., 2018). Midazolam is used as an orphan drug for intermittent treatment of episodes of increased seizure activity in refractory epilepsy patients who are otherwise stable on other AEDs. More recently, midazolam was granted orphan drug designation in 2009 as a rescue agent for patients with intermittent bouts of increased seizure activity (i.e., acute repetitive seizure clusters), in 2012 for the treatment of nerve agent-induced seizures, and in 2016 for the treatment of status epilepticus and seizures induced by organophosphorus poisoning (Misty et al., 2018).
Overview of the Biotransformation of Antiepileptic Drugs
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
Some other benzodiazepines should be mentioned because of somewhat different aspects of their biotransformation. Clorazepate is a prodrug which is rapidly decarboxylated in the acid milieu of the stomach to form N-desmethyldiazepam.42 This active metabolite is eventually eliminated from the body as described above. Lorazepam is the only anticonvulsant benzodiazepine which is biotransformed almost completely by glucuronidation without undergoing some phase I reactions first.43 This is because the drug has a hydroxyl group attached to carbon 3 whereas other benzodiazepines must add the 3-hydroxyl group in vivo.
Pharmacotherapy of adjustment disorder: A review
Published in The World Journal of Biological Psychiatry, 2018
Razavi et al. (1999) compared trazodone (mean dose 111.5 mg/day) and clorazepate (mean dose 17.5 mg/day) in a small study of DSM-III-R adjustment disorder in patients undergoing treatment for breast cancer. Eighteen patients were enrolled in a 4-week study, with efficacy assessed by the Hospital Anxiety and Depression Scale and a number of other scales. A successful response to treatment was seen in 91% of those receiving trazodone and 57% of those receiving clorazepate, although in this small sample this difference did not reach statistical significance. There were also no group differences in adverse events. The authors concluded that trazodone is not associated with dependence and is therefore a valuable option in the treatment of adjustment disorders in cancer patients.
What are the pharmacotherapeutic options for adjustment disorder?
Published in Expert Opinion on Pharmacotherapy, 2022
Two studies compared trazodone (a sedative with serotonin antagonist and reuptake inhibitor effects) with clorazepate (a benzodiazepine with GABAergic effects) for the treatment of adjustment disorder [13,14]. One study (n = 18) showed potential benefit for trazodone (91% response rate) compared to clorazepate (57% response rate) at 4 weeks, however the difference was not statistically significant [13]. In a similarly small study (n = 21) conducted in patients living with HIV, trazodone showed similar efficacy compared to clorazepate (80% vs 64% response rate respectively), with fewer concerns of adverse effects [14].