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.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0404.2008.01004.x

Benzodiazepines in epilepsy: pharmacology and pharmacokinetics.

1 The Classification of Epileptic Seizures and Epileptic Syndromes.- 2 Neonatal Seizures.- 3 Infantile Spasms (West Syndrome).- 4 Lennox-Gastaut Syndrome.- 5 Febrile Seizures.- 6 Absence Seizures.- 7 Juvenile Myoclonic Epilepsy.- 8 Generalized Tonic-Clonic Epilepsies.- 9 Progressive Myoclonic Epilepsy.- 10 Generalized Status Epilepticus.- 11 Simple Partial Seizures.- 12 Complex Partial Seizures.- 13 Benign Focal Epilepsy of Childhood.- 14 Focal Status Epilepticus: Modern Concepts.

Epilepsy : electroclinical syndromes

Controlled induction of paired helical filaments of the Alzheimer type in cultured human neurons, by glutamate and aspartate.

Excitatory amino acid glutamate has several important functions in the mammalian central nervous system (CNS). This review focuses on the transmitter role of glutamate and discusses anatomical and pharmacological data of clinical neurological relevance. Experimental and clinical conditions which have been associated with altered content, uptake, membrane binding or release of glutamate in the CNS are discussed. Such conditions include, epilepsy, disorders of the basal ganglia, cerebral ischemia, hypoxia, hypoglycemia, metabolic encephalopathies, olivopontocerebellar atrophy and cerebellar ataxias, amino acidopathies, mental and other neurological disorders. With the exception of a few fibre systems, it is very difficult to differentiate between glutamate and aspartate as CNS transmitters. The term glutamate is, thus, used in the sense glutamate and/or aspartate unless specifically stated.

Neurotransmitter glutamate: its clinical importance

All benzodiazepines enter cerebral tissue rapidly. However, the duration of action is short for diazepam (<2 hours) and midazolam (3 to 4 hours) and longer for clonazepam (24 hours) and lorazepam (up to 72 hours), and is not correlated with the plasma concentration-time profiles of these drugs. Although a relationship between the plasma concentration of diazepam, lorazepam and midazolam and their pharmacodynamic effect has been demonstrated in healthy individuals, some caution is warranted as the clinical relevance of these data has not been clearly established. The physicochemical properties of benzodiazepines (lipid solubility and protein binding) regulate their rate and extent of entry into the brain and cerebrospinal fluid. However, the duration of the pharmacological activity of benzodiazepines may be in part related to the affinity of these compounds for the benzodiazepine receptors in the brain: midazolam, clonazepam and lorazepam have higher affinities than diazepam. In the emergency setting, the intravenous route is the most suitable, delivering adequate quantities of benzodiazepines as fast as possible. However, when intravenous administration is not available, rectal administration of a solution is a convenient method for diazepam, midazolam being the only one of these drugs that should be given intramuscularly. The assessment of the efficacy of benzodiazepines in the management of acute seizures and status epilepticus is mainly based on nonrandomised uncontrolled trials. According to the route of administration, the efficacy was 28.6 to 100% (intrarectal) and 54 to 100% (intravenous) for diazepam, 82 to 100% (intravenous) for lorazepam, and 79% (intranasal), 93 to 100% (intramuscular) and 100% (intravenous) for midazolam. Although diazepam was initially chosen for the management of refractory status epilepticus, the longer duration of action of lorazepam and clonazepam may favour the use of these 2 drugs. However, double-blind evaluations are necessary to determine which drug is best.

Pharmacokinetic optimization of benzodiazepine therapy for acute seizures. Focus on delivery routes.

Glutamate, GABA, and CNS disease: A review

Lorazepam was studied in a double-blind, placebo-controlled, crossover trial in eight patients with frequent partial complex seizures refractory to therapy with a combination of standard anticonvulsant drugs. Concomitant antiepileptic drugs were maintained at therapeutic serum levels throughout the study, and concentrations of lorazepam were monitored. Following an 8-week baseline observation, patients were randomly assigned to placebo or lorazepam (1 mg BID). The dose was increased biweekly until seizures stopped or unacceptable side effects occurred. Eight weeks later, patients were crossed over, and the same escalating dose paradigm was followed. When seizure frequency during the last 2 weeks of each treatment was compared, seven of eight patients had fewer seizures on lorazepam, and the eighth had decreased seizure duration (a significant difference: p less than 0.01, two-tailed sign test). Blood level data suggest a narrow therapeutic window, with seizure improvement occurring at concentrations of 20-30 ng/ml and side effects at greater than 33 ng/ml. Lorazepam appears to be a useful adjunct in refractory partial complex seizure therapy. It should not be stopped abruptly, as an increase in seizure frequency may result.

Lorazepam: A Controlled Trial in Patients with Intractable Partial Complex Seizures

Stress cardiomyopathy: an under recognized mystery

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Glutamate, GABA, and CNS disease: A review

Lorazepam: A Controlled Trial in Patients with Intractable Partial Complex Seizures

Stress cardiomyopathy: an under recognized mystery