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GABA agonists: drugs for epilepsy

Last updated on September 12, 2021

GABA agonists: drugs for epilepsyEpilepsy is a chronic neurologic disorder that may result from brain injury, developmental malformation, or a genetic abnormality. It is characterized by recurrent seizures caused by sudden, excessive electrical activity in the brain.

Seizures are classified as generalized, in which the electrical discharge occurs throughout the brain, and partial onset, wherein the electrical activity is localized (in simple partial-onset seizures, consciousness is maintained; in complex partial, consciousness is altered). Epilepsy affects up to 1% of the population in industrialized countries, with the highest rates occurring in children and adolescents. Most seizures (60%) are complex partial or secondarily generalized, and 25 to 30% of these seizures are refractory to available therapy. But for every refractory patient, there is another patient who goes into remission on antiepileptic drug (AED) therapy and then, after a seizure-free period, remains in remission when antiepileptic drugs are withdrawn. This shows that epilepsy is not always a lifelong condition.

The most frequently prescribed antiepileptic drugs are phenytoin, carbamazepine, and valproate, although in the past few years a number of new antiepileptic drugs have been approved. These new drugs were developed following major advances in the understanding of neurotransmitters and their receptors, and most enhance the activity of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain. Some also inhibit glutamate, the major excitatory neurotransmitter. Blocking glutamate has not been very successful, but augmenting GABA activity has been quite effective.

Gamma-aminobutyric acid is present in an estimated 60 to 70% of all synapses in the brain. It is formed from glutamate by the enzyme glutamic acid decarboxylase. After synaptic release, GABA is taken up into nerve cells or glial cells. In the neuron, gamma-aminobutyric acid either is re-released or is broken down by GABA transaminase into succinic semialdehyde; in the glial cell, it is metabolized, along with glutamate, by glutamine synthetase to form the amino acid glutamine, which is then transported back to the neuron and used to synthesize more glutamate and gamma-aminobutyric acid.

When released into the synapse, GABA can bind to two different receptor complexes, designated A and B. GABA-A binds gamma-aminobutyric acid, benzodiazepines, barbiturates, and neurosteroids. When GABA-A is activated, it increases the inward flow of chloride through the nerve cell membrane, which hyperpolarizes the membrane and inhibits neuronal firing. Compounds that increase GABAergic activity via the GABA-A receptor are anticonvulsants, and those that antagonize GABA-A are convulsants.

Neuropharmacologists have discovered several ways to enhance GABA-A receptor activity: direct stimulation, inhibition of gamma-aminobutyric acid metabolism, and reduction of neuronal and/or glial GABA reuptake. Blocking gamma-aminobutyric acid reuptake is an especially fruitful area for drug discovery, because there are at least four different GABA transport mechanisms that mediate gamma-aminobutyric acid reuptake in neurons and glial cells. These transporters show different distributions within the central nervous system (CNS); for example, one is prominent in the substantia nigra, an area that plays a crucial role in the development of seizures.

Antiepileptic Drugs and Their Primary Mechanisms of Action

Drug Name Primary Mechanism
Clobazam Enhances GABA-BZ receptors
Dezinamide Blocks sodium channels
Felbamate Blocks sodium channels
Flunarizine Blocks calcium channels
Fosphenytoin Phenytoin prodrug
Gabapentin Increases GABA synthesis (?)
Oxcarbazepine Tricyclic effects as per carbamazepine (?)
Lamotrigine Decreases glutamate release
Levetiracetam Not yet defined
Midazolam Decreases cGMP (?)
Milacemide Enhances glycine
MK-801 Blocks NMDA-linked channels
Progabide Enhances GABA content
Tiagabine Decreases GABA uptake
Topiramate Blocks sodium channels
Stiripentol Unconfirmed
Vigabatrin Decreases GABA catabolism
Zonisamide Blocks sodium channels
GABA: Gamma-aminobutyric acid;
BZ: Benzodiazepine;
NMDA: N-methyl-D-aspartate;
cGMP: cyclic guanosine monophosphate

One of the most promising gamma-aminobutyric acid (GABA) reuptake inhibitors is tiagabine (Gabitril/Abbott), a novel antiepileptic drug that will probably receive final FDA approval during the first quarter of this year. Developed by researchers at the Danish pharmaceutical company NovoNordisk, tiagabine is a nipecotic acid derivative with an attached lipophilic group that enables the drug to cross the blood-brain barrier. This “rationally” designed drug is a potent, selective, and specific inhibitor of GABA reuptake into presynaptic neurons and glial cells, particularly those in the substantia nigra and associated areas. It binds one of the GABA reuptake transporters and shows no significant affinity for dopamine, norepinephrine, histamine, adenosine, serotonin, glutamate, or acetylcholine sites-either receptors or reuptake transporters.

tiagabineTiagabine has shown broad activity against a range of seizure types, including drug- induced, electroshock-induced, light-induced, amygdala-kindled, and audiogenic. It is well tolerated and does not cause withdrawal effects, displace other drugs, or induce hepatic enzymes (although it is a target for enzyme inducers). It is rapidly and completely absorbed, with a half-life of 5 to 8 hours. Because tiagabine is highly effective for partial- onset seizures, it will be approved initially for the adjunctive treatment of partial seizures, with or without secondarily generalized seizures.

Other new antiepileptic drugs on the market or under investigation include valproate (Divalproex/Abbott), topiramate (Topamax/Ortho-McNeil), gabapentin (Neurontin/Warner Lambert), lamotrigine (Lamictal/Glaxo Wellcome), vigabatrin, oxcarbazepine, and levetiracetam. Valproic acid decreases the activity of the enzyme that degrades gamma-aminobutyric acid and increases the activity of the enzyme that generates GABA; topiramate enhances gamma-aminobutyric acid and inhibits glutamate; and gabapentin, which is structurally related to GABA, has a unique (and as yet poorly understood) influence on gamma-aminobutyric acid neurotransmission.

Vigabatrin acts through the selective, irreversible inhibition of GABA transaminase, the enzyme responsible for the metabolism of gamma-aminobutyric acid. Oxcarbazepine was developed by modifying the chemical formula of carbamazepine to improve tolerability; it is at least as effective as its parent, but is better tolerated, has fewer drug interaction problems, induces fewer enzymes, and causes less skin allergy. Levetiracetam is an interesting new compound in clinical trial that appears to bind a specific receptor on nerve cell membranes. It shows a broad spectrum of anticonvulsant activity and has been particularly effective for partial seizures. It has a high therapeutic index and does not appear to interact with other antiepileptic drugs.

Lamotrigine is the first antiepileptic drug that was designed specifically to inhibit glutamate and its close cousin, aspartate. It blocks sodium channels and stabilizes the presynaptic neuronal membrane, inhibiting the release of glutamate and aspartate. It has a wide spectrum of antiepileptic activity, including partial-onset and primary generalized tonic-clonic seizures, and is particularly useful for mentally retarded patients. It is very well tolerated and does not alter concentrations of concomitant antiepileptic drugs or induce hepatic enzymes although it is a target for enzyme induction. It interacts with both valproic acid (which approximately doubles the plasma elimination half-life of lamotrigine) and carbamazepine (concomitant lamotrigine/carbamazepine therapy can cause a potentially dangerous cerebellar toxic syndrome).

The understanding of epilepsy has advanced substantially in the past decade, and new antiepileptic drugs with novel mechanisms of action are continually being developed. Monotherapy is the goal-that is, the admInistration of one drug with a mechanism of action specific for the form of epilepsy being treated-but in clinical practice, polytherapy is often used. Using multiple drugs increases the risis of adverse effects and drug interactions, but the new GABAergics have such good safety profiles that “rational polytherapy” is a workable solution to what is often a very complex neurologic problem.

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