GABA antiepileptic action

Actions Phenobarbital (see p. 94) has antiepileptic activity, limiting the spread of seizure discharges in the brain and elevating the seizure threshold. Its mechanism of action is unknown but may involve potentiation of the inhibitory effects of y-aminobutyric acid (GABA)-mediated neurons. Doses required for antiepileptic action are lower than those that cause pronounced CNS depression. 

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. 

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. 

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. 

Epilepsy is caused by abnormal high-frequency firing of neurons, either in the whole of the cerebral cortex (generalized epilepsy) or in discrete areas of the cerebral cortex (partial epilepsy). The abnormal activity may be due to increased excitatory neuronal transmission, possibly involving abnormal sodium ion channels or decreased inhibitory transmission, possibly due to abnormality at GABA receptors. Certainly, most antiepileptic drugs either block sodium ion channels or enhance the action of GABA or both. 

There are three proposed major mechanisms of action of AEDs (1) sodium channel inactivation, (2) calcium channel blockade, and (3) interaction with GABA-A receptors/ channels. With sodium channel inactivation antiepileptic dmgs have the ability to extend the inactivation of sodium channels which reduces the frequency of the firing of the neurons, which is a feature of the seizures. Dmgs that are associated with this inactivation include phenytoin, carbamazepine and valproate. Calcium channel blockade (T-type) is related to the modulation of neuronal firing associated with absence of seizures and is associated with ethosuximide and zonisamide activity. L-type calcium channel blockade is reportedly associated... 

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