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Benzodiazepines are a group of two-ring heterocyclic compounds consisting of a benzene ring fused to a diazepine ring. The first benzodiazepine, chlordiazepoxide, was introduced in clinical practice as anxiolytic and hypnotic in 1960 under the brand name Librium. Diazepam (Valium) followed in 1963. There are today over 30 benzodiazenines (15 are marketed in the USA) used for anxiety, panic, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal and as a premedication for medical or dental procedures.
In epilepsies:
Sedation (sometimes intolerably severe), drowsiness, fatigue, hypersalivation, behavioural and cognitive impairment, restlessness, aggressiveness and coordination disturbances.
Benzodiazepines are addictive and regulated in schedule IV of the Substance Controlled Act. Long term use is associated with benzodiazepine tolerance, dependence and withdrawal syndrome. Benzodiazepine tolerance manifests with decreasing efficacy over time so that larger doses are required to achieve the same effect as with the original dose. In benzodiazepine dependence a person becomes dependent on benzodiazepines physically, psychologically or both. Benzodiazepine withdrawal is similar to the barbiturate or alcohol withdrawal syndrome. Administration of therapeutic doses of benzodiazepines for 6 weeks or longer can result in physical dependence, characterised by a withdrawal syndrome when the drug is discontinued. With larger doses, the physical dependence develops more rapidly.
GABA is the main inhibitory neurotransmitter in the brain. It is synthesised in the presynaptic terminals of inhibitory neurones and degraded by GABA transaminase (GABA-T). Of the GABA receptors, GABAA and GABAC are ligand-gated ion channels, whereas GABAB receptors are G-proteincoupled receptors.
The action of GABAergic AEDs is mainly through the GABAA (inhibition of most types of epileptic seisure) and GABAB (activation of absence seizures) receptors.
When GABA binds to GABAA receptors, chloride (Cl–) channels open and allow increased entry to Cl– ions, which ultimately cause hyperpolarisation of the neurone or inhibition. There are three basic binding sites to this complex GABAA receptor; the GABA site, the benzodiazepine site and a barbiturate site within the ion channel. Most drugs affecting the GABAA receptor act to modulate it rather than to directly excite or inhibit it. This modulation generally acts to increase the probability of the channel opening for a given concentration of GABA, or to increase the time that the receptor remains open. GABAA receptors are the main binding sites for benzodiazepines and barbiturates. Benzodiazepine derivaties (e.g. clobazam, clonazepam and diazepam) increase the frequency of the Cl– channel openings, whereas barbiturates (e.g. phenobarbital) prolong the opening time of the Cl–channel. Both the benzodiazepines and barbiturates also enhance the affinity of the GABAA receptors for GABA.
The GABAB receptors are metabotrophic transmembrane receptors for GABA that are linked via G-proteins to potassium channels. Thalamic GABAB receptors modulate absence seizures. Baclofen, a GABAB receptor agonist, promotes absence seizures.
Tiagabine and vigabatrin increase GABA and cause nonspecific activation of he GABAA (thus inhibiting seizures) and GABAB (thus aggravating absences) receptors. The antiepileptic effect of most other AEDs with GABA-ergic activity (e.g. gabapentin, pregabalin and valproate) is probably in combination with other anti-epileptic properties.
GABAA-receptor agonists
