Anticonvulsants binding site

The primary action of the benzodiazepines as anticonvulsants is to enhance inhibition through their interaction with the GABAa receptor at the benzodiazepine binding site. However, there appears to be an additional action of benzodiazepines blocking voltage-dependent sodium channels. This effect is not seen at usual doses but is likely a factor in their use in the treatment of status epilepticus (discussed later). 

VPA s mechanism of action is unclear but its anticonvulsant efficacy may be related to the ability to increase CNS levels of GABA (Table 10-2). Due to its rapid absorption, blood levels peak in 1 to 4 hours after oral administration, and the half-life ranges from 6 to 16 hours. It is metabolized primarily through the liver and is eliminated in the urine. VPA is highly protein-bound and usually does not saturate binding sites at serum levels below 45 to 50 pg/mL. Thus, this level would be the expected minimal threshold for its psychotropic effects. 

FIGURE 13-33. Acute withdrawal of benzodiazepines in a benzodiazepine-dependent individual. If benzodiazepines are suddenly stopped in a patient who is tolerant to them and dependent on them, benzodiazepine receptors will experience this as an acute deficiency at their binding sites. Thus, the presence of desensitized benzodiazepine receptors actually worsens the impact of benzodiazepine discontinuation. The brain, which is used to too much benzodiazepine at its receptors, is suddenly starved for benzodiazepine. Therefore, the brain experiences the reverse of benzodiazepine intoxication, namely, dysphoria and depression instead of euphoria anxiety and agitation instead of tranquility and lack of anxiety insomnia instead of sedation and sleep muscle tension instead of muscle relaxation and at worst, seizures instead of anticonvulsant effects. These actions continue either until benzodiazepine is replaced or until the receptors readapt to the sensitivity they had prior to excessive benzodiazepine use. Alternatively, one can reinstitute benzodiazepines but taper them slowly, so that the receptors have time to readapt during dosage reduction, and withdrawal symptoms are prevented. 

The binding sites for benzodiazepines are divided into central and peripheral types. The central or neuronal benzodiazepine receptors are influenced by GABA, linked to chloride channel, and responsible for mediating the anxiolytic, sedative, and anticonvulsant properties of the benzodiazepines. The peripheral or nonneuronal benzodiazepine receptors are found in a variety of tissues, including the kidney, heart, lung, liver, adrenal gland, testis, intestinal smooth muscles, mast cells, platelets, several cell lines, and nonneuronal elements in the central nervous system (CNS). 

Zopiclone, a polysubstituted piperazine-pyridine-pyrrolopyrazine structure, a benzodiazepam binding-site antagonist sedative and anticonvulsant [43200-80-2],... 

Salicylic acid Phenytoin Valproate Altered relation between total anticonvulsant concentration and effect Displacement from plasma protein binding sites... 

Diazepam hyperpolarizes neurons and suppresses neuronal activity by binding to a specific GABA-binding site. It may modify the GABA-binding sites and increase the action of GABA on nerve cells. As anticonvulsants, the benzodiazepines act to suppress the presynaptic transmission of seizure activity. 

Clonazepam, U5P. Clonazepam S-(2-chlorophenyl)-3-dihydro-7-nitro-2//-1,4-benzodiazpin-2-one (iCIonopin). partially selective at benzodiazepine allosteric binding sites on GABAa receptors, is useful in ab.sence seizures and in myoclonic seizures. Tolerance to the anticonvulsant effect often develops, a common problem with the benzodiazepines. Metabolism involves hydroxylation of the 3 position, followed by glucuronidation and nitro group reduction, followed by acetylation. 

Cinoiazepam [inn] is one of the [1,41 benzodiazepines, a BENZODIAZEPINE BINDING-SITE AGONIST, with most of its properties similar to diazepam. It has HYPNOTIC, ANTICONVULSANT and ANXIOLYTIC activity. It has been used orally to treat insomnia and anxiety, cinoxacin [ban, inn, jan, usan] (Clnobac ) is an ANTIMICROBIAL, One of a 4-quinolone family related to nalidixic acid, which, though symthetic, are sometimes described as ANTIBIOTICS. It can be used clinically as an ANTIBACTERIAL, mainly used orally for gut infections. Cinoxate [inn, usan] is a cinnamic acid derivative and can be used in topical sunscreen preparations. 

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