Glutamate anticonvulsants

Another class of therapeutic agents is used for the treatment of certain genetic diseases or other enzymatic disorders caused by the dysfunction or absence of one particular enzyme. This often leads to an unwanted accumulation or imbalance of metaboUtes in the organism. Eor example, some anticonvulsive agents are inhibitors for y-aminobutyric acid aminotransferase [9037-67-6]. An imbalance of two neurotransmitters, glutamate and y-aminobutyric acid, is responsible for the symptoms. Inhibition of the enzyme leads to an increase of its substrate y-aminobutyric acid, decreasing the imbalance and subsequently relieving the symptoms of the disease. 

Drugs acting on GABA/glutamate - hypnotics/anxiolytics barbiturates, benzodiazepines, chlormethiazole, chloral derivatives, baclofen - anticonvulsants phenobarbitone, primidone, phe-nytoin, sodium, valproate, carbamazepine - alcohol, phencyclidine, ketamine... 

For much of the second half of the twentieth century the benzodiazepines were the mainstay of the treatment of anxiety. Despite well-publicised concerns about their long-term safety, they remain an important therapeutic option. The anticonvulsants contain a number of drugs that act via GABA or glutamate neurotransmission and have a limited but interesting role in the treatment of particular anxiety disorders. 

This anticonvulsant drug blocks voltage-gated sodium channels and inhibits release of glutamate. A controlled study found efficacy in PTSD (Hertzberg et al. 1999). Important side-effects include fever and skin reactions. 

Excitatory neurotransmitters also may be involved in the appearance of epilepsy, since the bursting activity typically seen during epileptic discharges may be due in part to the action of glutamate acting on A-methyl-o-aspartate (NMDA) receptor channels to produce depolarization. It is likely that a major part of the anticonvulsant activity of felbamate involves blockade of the NMDA receptor. Table 32.2 summarizes the most likely mechanism of action associated with available anticonvulsant drugs. 

Lamotrigine is an anticonvulsant drug that attenuates some forms of cortical glutamate release via inhibition of sodium, calcium, and potassium channels. An open-label case series (Uvebrant and Bauziene, 1994) and a case report (Davanzo and King, 1996) described improvement in autistic symptoms and self-injurious behavior, irritability, disturbed sleep, and social impairment in autistic children and an 18-year-old female with profound mental retardation, respectively, who were treated for epilepsy. 

Lamotrigine is an anticonvulsant medication that decreases sustained high-frequency repetitive firing of the voltage-dependent sodium channel, which may then decrease glutamate release (Leach... 

Anticonvulsants may also interfere with neurotransmission by the excitatory neurotransmitter glutamate, in particular by reducing its release. Simply put, inhibitory neurotransmission with GABA may be enhanced and excitatory neurotransmission with glutamate may be reduced by anticonvulsants. 

FIGURE 7-27. Shown here is an icon of topiramate s pharmacologic actions. By interfering with calcium channels and sodium channels, topiramate is thought both to enhance the inhibitory actions of gamma aminobutyric acid (GABA) and to reduce the excitatory actions of glutamate. Topiramate is also a carbonic anhydrase inhibitor (CAI) and as such has independent anticonvulsant actions. 

Lapin I. P., Mirzaev S. M., Ryzov I. V., and Oxenkrug G. F. (1998). Anticonvulsant activity of melatonin against seizures induced by quinolinate, kainate, glutamate, NMDA, and pentylenete-trazole in mice. J. Pineal Res. 24 215-218. 

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