Benzodiazepines in epilepsy: pharmacology and pharmacokinetics

Abstract

Benzodiazepines (BZDs) remain important agents in the management of epilepsy. They are drugs of first choice for status epilepticus and seizures associated with post‐anoxic insult and are also frequently used in the treatment of febrile, acute repetitive and alcohol withdrawal seizures. Clinical advantages of these drugs include rapid onset of action, high efficacy rates and minimal toxicity. Benzodiazepines are used in a variety of clinical situations because they have a broad spectrum of clinical activity and can be administered via several routes. Potential shortcomings of BZDs include tolerance, withdrawal symptoms, adverse events, such as cognitive impairment and sedation, and drug interactions. Benzodiazepines differ in their pharmacologic effects and pharmacokinetic profiles, which dictate how the drugs are used. Among the approximately 35 BZDs available, a select few are used for the management of seizures and epilepsy: clobazam, clonazepam, clorazepate, diazepam, lorazepam and midazolam. Among these BZDs, clorazepate has a unique profile that includes a long half‐life of its active metabolite and slow onset of tolerance. Additionally, the pharmacokinetic characteristics of clorazepate (particularly the sustained‐release formulation) could theoretically help minimize adverse events. However, larger, controlled studies of clorazepate are needed to further examine its role in the treatment of patients with epilepsy.

Alcohol withdrawal syndrome: mechanisms, manifestations, and management

“…They rapidly penetrate the blood–brain barrier, although the diffusion rate into the brain and other tissues varies and is largely determined by lipophilicity. All BZDs are metabolized in the liver by oxidation and/or glucuronidation, and some of them form pharmacologically active metabolites that are responsible for the long duration of action, such as diazepam, chlordiazepoxide, and clorazepate 71. Therefore, the BZDs and their active metabolites may be categorized according to the duration of their effect: short acting (<10 h like lorazepam, oxazepam, and midazolam), intermediate acting (10–24 h as clonazepam), or long acting (>24 h; clobazam, clorazepate, and diazepam) 71.…”

“…All BZDs are metabolized in the liver by oxidation and/or glucuronidation, and some of them form pharmacologically active metabolites that are responsible for the long duration of action, such as diazepam, chlordiazepoxide, and clorazepate 71. Therefore, the BZDs and their active metabolites may be categorized according to the duration of their effect: short acting (<10 h like lorazepam, oxazepam, and midazolam), intermediate acting (10–24 h as clonazepam), or long acting (>24 h; clobazam, clorazepate, and diazepam) 71. The metabolism of BZDs is primarily catalyzed by CYP isoenzymes which may be the target of drug–drug interactions, sometimes leading to paradoxical effects or over sedation.…”

“…Within the first 2 d of withdrawal, BZDs reduce the incidence of seizures by up to 84% and prevent the development of DT 74. The current literature does not suggest one BZD to be more efficacious than another, although differences in pharmacokinetic properties can guide selection 71, 73, 74, 75. The following recommendations include agents 75

with rapid onset to control agitation symptoms

with long action to avoid breakthrough symptoms

with less dependence on hepatic metabolism to lower the risk of over sedation

…”

“…Increased age and liver disease significantly impact the CYP‐dependent metabolism of medications with a 50% decline in the clearance and a four‐ to ninefold increase in terminal half‐life of diazepam with accumulation and production of side effects. Therefore, in the elderly and patients with cirrhosis or severe liver dysfunction, lorazepam or oxazepam is preferred 71, 75, 76…”

First line management of prolonged convulsive seizures in children and adults: good practice points

“…Their working mechanism is well known. BZP activate the binding of GABA to the post-synaptic inhibitory ionotropic GABA-A receptor, thereby opening a chloride channel and hyperpolarizing the postsynaptic neuron, leading to a decreased neuronal excitability [11,12]. BZP typically reach the brain within minutes.…”