GABA antiepileptics

Antiepileptics Na+, Ca2+ channels GABA receptors l Na+currents l Ca2+ currents GABA receptor activity l Excitability of peripheral and central neurons l Release of excitatory neurotransmitters Sedation, dizziness, cognitive impairment, ataxia, hepatotoxicity, thrombocytopenia... 

GABA transporter GAT1 (SLC6A1) GABAergic neurons in CNS <10 Clearance of interstitial neurotransmitter, reuptake into neurons Tiagabine, an antiepileptic drug... 

Figure 16.7 The structure of some established antiepileptic drugs (AEDs) and some newer ones. Note that while the structures of phenytoin and ethosuximide are similar and also close to that of phenobarbitone, they are effective in different forms of epilepsy. Vigabatrin, progabide and gabapentin are clearly related to GABA. Muscimol is a GABAa agonist but is not an effective antiepileptic drug...

The major inhibitory neurotransmitter in the cerebral cortex is y-aminobutyric acid (GABA). It attaches to neuronal membranes and opens chloride channels. When chloride flows into the neuron, it becomes hyperpolarized and less excitable. This mechanism is probably critical for shutting off seizure activity by controlling the excessive neuronal firing. Some antiepileptic drugs, primarily barbiturates and benzodiazepines, work by enhancing the action of GABA. 

Krogsgaard-Larsen, P., Falch, E., Larsson, O. M., and Schousboe, A. (1987) GABA uptake inhibitors relevance to antiepileptic drug research. Epilepsy Res. 1,77-93. 

The efficacy of barbiturates as antiepileptic drugs can be attributed to their effect on the stimulation of epileptogenic neurons, and also on the GABA-ergic channel in the CNS by elevating of the inhibitory action of GABA. Furthermore, barbiturates can reduce the excitatory effects of glutamate at synapses. It is not presently known which of these proposed mechanisms is more important for the development of antiepileptic activity. 

Valproic acid and its salts are a new group of antiepileptic drugs that differs from the known drugs both structurally and in terms of its mechanism of action. It is believed that it acts on the metabolism of the GABA system. Valproic acid has been shown to elevate the level of GABA in the brain by means of competitive inhibition of GABA transaminase and the dehydrogenase of succinic semialdehyde. 

Pregabaline is primarily an antiepileptic. Although it is an analogue of the neurotransmitter GABA it is not a GABA-agonist. It is mentioned here because it is also approved for use in generalized anxiety states. 

Vigabatrin is a new antiepileptic for use in epilepsy unresponsive to other therapy. It is an irreversible inhibitor of GABA-transaminase, the enzyme responsible for inactivation of the neurotransmitter GABA and it has shown efficacy against partial and secondarily generalized seizures. The principal unwanted effects are psychiatric disorders, including depression and psychosis, in a small number of patients. 

Its antiepileptic activity results from its binding to one or more specific GABA receptors increasing GABA mediated inhibition. 

Mechanism of Action. These drugs are known to potentiate the inhibitory effects of GABA in the brain (see Chapter 6), and their antiepileptic properties are probably exerted through this mechanism. 

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