Benzodiazepines: Anticonvulsant and other clinical uses
Adam Doble, Ian L Martin, David Nutt in Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
Benzodiazepines are among the most potent and best-tolerated anticonvulsant agents known. However, their use as antiepileptic agents has been limited by the rapid development of tolerance to their prophylactic effect and to rebound seizures upon treatment interruption. The deleterious effects of benzodiazepines on vigilance and cognitive function are also evidently a drawback in the use of benzodiazepines as antiepileptic agents over long time periods. The principal therapeutic uses of flumazenil are to reverse the effects of benzodiazepines when used in anaesthesia and in the treatment of coma resulting from benzodiazepine overdose. Many of the psychotropic effects of benzodiazepines make them appropriate for use as anaesthetic agents, or as adjuncts to anaesthesia. The introduction of flumazenil has been of considerable importance in the use of midazolam and other benzodiazepines in anaesthesia. A further use of benzodiazepines is in the treatment of alcohol withdrawal.
Structures of benzodiazepine recognition site ligands
Adam Doble, Ian L Martin, David Nutt in Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
The development of radioligand binding assays proved invaluable for later studies of structure-activity relationships at the benzodiazepine recognition site. The methylene group at the 3-position of a 1,4-benzodiazepine ring is known to be either above or below the plane of the fused benzene ring, imparting conformational chirality to the molecule. The 1,2-annelation of triazolo- or imidazorings to classical 1,4-benzodiazepines generally results in an increase in affinity only for those compounds with a relatively low affinity in the classical series; little increase in affinity is found for the high affinity 1,4-benzodiazepines. Abecarnil has a high affinity for the benzodiazepine receptor and possesses anxiolytic and anticonvulsant properties; it is more potent than diazepam in most rodent tests of anxiolytic activity and in reducing locomotor activity in mice and rats. The pyrazoloquinolinones, CGS 8216, CGS 9895 and CGS 9896 all exhibit high affinity for the benzodiazepine recognition site in vitro.
Behavioural pharmacology
Adam Doble, Ian L Martin, David Nutt in Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
The behavioural pharmacology of inverse ago-nists at the benzodiazepine binding site is the mirror image of that of full agonists. The behavioural arousal seen following administration of inverse agonists may be considered the counterpart to the sedative effects of classical full agonist benzodiazepines. Reversal of behavioural effects by flumazenil is regarded as an essential criterion in attributing a role for the benzodiazepine receptor in behavioural pharmacological properties of novel drugs. Art interesting aspect of tolerance is that the time-course of its apparition appears to depend on the behavioural parameter measured. The first of these so-called ‘ethological models’ was the social interaction model, in which the behavioural interaction between two rats, strangers to one another, was recorded upon their first meeting. Central nervous system depression is an important behavioural consequence of the administration of benzodiazepines, although this effect is not nearly as pronounced as with other minor tranquillisers such as meprobamate, barbiturates or even alcohol.
Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia or bipolar disorder: A randomised, placebo-controlled, blinded trial
Published in The World Journal of Biological Psychiatry, 2016
Lone Baandrup, Jane Lindschou, Per Winkel, Christian Gluud, Birte Y. Glenthoj
Objectives. We assessed if prolonged-release melatonin can facilitate withdrawal of long-term benzodiazepine usage in patients with schizophrenia or bipolar disorder. Methods. Randomised, placebo-controlled, blinded, parallel superiority trial of 24 weeks duration. Participants were randomised to prolonged-release melatonin 2 mg daily versus matching placebo and were continuously guided to gradually reduce their usual benzodiazepine dosage. The primary outcome was mean benzodiazepine daily dosage at 24 weeks. Secondary outcomes included pattern of benzodiazepine dosage over time, benzodiazepine cessation proportion, and benzodiazepine withdrawal symptoms. Results. In total, 86 patients (21–74 years) were enrolled: 42 were randomised to melatonin versus 44 to placebo. We found no significant effect of melatonin on mean benzodiazepine dosage at 24 weeks (melatonin group 8.01 mg versus placebo group 5.72 mg diazepam equivalents; difference between means –2.29; 95% CI –5.78 to 1.21; P = 0.20). Benzodiazepine cessation proportion was 38.1% (16/42) in the melatonin group versus 47.7% (21/44) in the placebo group (OR 0.64; 95% CI 0.26 to 1.56; P = 0.32). Prolonged-release melatonin had no effect on benzodiazepine withdrawal symptoms. Conclusions. Benzodiazepine dosage was comparably low between the groups after 24 weeks of guided gradual dose reduction. In this context, prolonged-release melatonin did not seem to further facilitate benzodiazepine discontinuation.
Benzodiazepine drug-drug interactions commonly occurring in clinical practice
Published in Current Medical Research and Opinion, 1984
Darrell R. Abernethy, David J. Greenblatt, Hermann R. Ochs, Richard I. Shader
Pharmacokinetic drug-drug interactions which involve currently available benzodiazepines may be classified into two major categories: interactions which affect benzodiazepine rate of absorption, and interactions which affect clearance and, therefore, elimination half-life. Ethanol is the prototype for absorptive interactions. Concurrent ethanol use and oral ingestion of benzodiazepine derivatives uniformly slows the rate but does not change the extent of benzodiazepine absorption. Interactions which affect benzodiazepine clearance affect only those derivatives which are oxidatively metabolized or cleared as a function of hepatic blood flow (high first-pass clearance). Conjugated benzodiazepines are not implicated in such interactions. Rifampin and chronic ethanol use induce benzodiazepine oxidation, while cimetidine, oral contraceptives, ethanol (acute ingestion), disulfiram, isoniazid, and propranolol inhibit benzodiazepine oxidation. In addition, ethanol, cimetidine and isoniazid decrease first-pass hepatic extraction of triazolam, enhancing its systemic availability and decreasing oral clearance. The pharmacokinetic consequence of induction of benzodiazepine oxidation is higher clearance and decreased steady-state concentrations during chronic dosing. Conversely, inhibition of benzodiazepine oxidation decreases clearance and increases steady-state benzodiazepine concentrations during chronic dosing. Because a correlation of benzodiazepine plasma concentration and pharmacological effect is not established, the pharmacodynamic consequences of these interactions are not currently well characterized.
Predictors of Benzodiazepine Discontinuation in Subjects Manifesting Complicated Dependence
Published in Substance Use & Misuse, 2005
HELENA VORMA, HANNU H. NAUKKARINEN, SEPPO J. SARNA, KIMMO I. KUOPPASALMI
We described characteristics of subjects with benzodiazepine dependence that was typically complicated by harmful and hazardous alcohol use or high benzodiazepine doses, and assessed predictors of successful discontinuation of benzodiazepines for this group. Seventy-six patients who participated in a randomized clinical trial of two different gradual withdrawal treatment approaches were assessed. The trial was conducted between February 1995 and July 1999. The mean age ±SD of subjects was 40.0±9.6 years, 55% were male, 38% were married or cohabiting, and 70% had received more than nine years of education. The median benzodiazepine dose was 35 mg /day (range 2.5–180) in diazepam equivalents. The median duration of benzodiazepine use was 84 (range 8–360) months. Subjects with lower benzodiazepine doses and no previous withdrawal attempts were more successful at benzodiazepine discontinuation. Cluster B personality/borderline personality disorder was associated with an inability to stop benzodiazepine use and with “dropping out” of treatment. Alcohol use–related disorders or other psychiatric diagnoses were not associated with outcome. Further studies on predictors of successful benzodiazepine discontinuation in different populations are required. Patients manifesting cluster B personality/borderline personality disorder and benzodiazepine dependence may need concomitant treatment for their personality disorders to benefit from benzodiazepine discontinuation treatment.