Pharmacology

How do antiepileptic medications work and what is their mechanism of action?

Answer: Antiepileptic medications are drugs with different mechanisms of action that all lead to decreased electrical activity of neurons in the brain.

Antiepileptic drugs (AEDs) are widely prescribed to help treat patients with epilepsy or other difficult to diagnose seizure disorders. They are sometimes called anticonvulsants. Since epilepsy leads to uncontrolled activity of the brain’s neurons, decreasing the activity of these neurons can help patients keep their symptoms under control, allowing them to live a normal life. Many antiepileptic drugs therefore act to decrease cellular excitation. 

Antiepileptic drugs can be taken in several forms, including pills and tablets. These types of medications are most effective when taken regularly. It may be difficult to predict which dosage is most effective, so the doses may be adjusted on a trial-and-error basis. Some drugs can also be injected, but these are not very common and reserved for use in a hospital. 

There are several different mechanisms that these drugs may use to treat patients. 

Antiepileptic GABA drugs

One neurotransmitter system that is targeted by anticonvulsants is GABA. GABA is widely used across many synapses in the brain. This neurotransmitter is responsible for inhibiting neuronal activity, and the activity of many neurons is regulated by release of GABA. When a molecule of GABA binds to its receptors, called GABAA and GABAB, it decreases the likelihood that the neuron will fire an action potential. By increasing the activity of GABA, antiepileptic drugs decrease overall action potential activity of the brain, which can decrease the severity and the likelihood of seizures. 

One of these drugs is valproate (also called valproic acid), although its effect on GABA signaling is just one of many mechanisms that result in dampened brain activity. Topiramate, a different antiepileptic drug, targets the GABAA receptors as a way to decrease seizures.

Some benzodiazepine drugs help decrease seizure frequency through modifying GABA pathways. These influence neurons by acting as positive allosteric modulators, which increase the intensity of the GABA signal whenever GABA is bound to the receptors. Midazolam and lorazepam are two example benzodiazepine drugs that are prescribed as anticonvulsants.

Antiepileptic voltage-gated sodium channel blockers

It is believed that excess firing of action potentials across neurons leads to seizure activity. For an action potential to take place, neurons need to receive strong excitatory input. When that excitation reaches a threshold, a population of receptors in the cell membrane, called voltage-gated sodium channels, open. These channels cause the cell to depolarize, causing the release of neurotransmitters. 

Therefore, some classes of antiepileptic drugs can target these voltage-gated sodium channels, changing their properties so that fewer action potentials are fired. Some examples of these drugs include carbamazepine and lamotrigine.

Antiepileptic glutamate antagonists

Glutamate is the main excitatory neurotransmitter, meaning that it increases the activity of nerve cells in the brain. By blocking glutamate signaling, antagonist drugs reduce the likelihood of seizures. The most common molecular targets for glutamate antagonists are the AMPA and NMDA types of receptors.

An example of a glutamate antagonist drug used for treating epilepsy is perampanel. 

Side effects of antiepileptic drugs

Since AEDs decrease overall brain activity as a means to control seizure activity, many AEDs have side effects. Common side effects include drowsiness, dizziness, and nausea. Some of them may impair memory, since strong neuronal activity can promote the strengthening of synapses (long-term potentiation), which is the cellular foundation of learning. More serious side effects may include allergic reaction, liver damage, or psychiatric changes. Before being put on AEDs, it is a good idea to ask your healthcare provider about the side effects of the drugs. In all cases, patients should be carefully monitored once starting treatment with AEDs.

What if the antiepileptic drugs don't work for me?

AEDs may not work for everyone. It is estimated that antiepileptic medications are effective for around 70% of patients. But for the remaining 30% of patients, the medications, even when properly dosed and titrated, do not treat the symptoms.

In severe cases of epilepsy that is not responsive to medications, more radical approaches like surgery may be suggested. The purpose of these surgeries is to remove the neurons that are responsible for starting the unusual electrical activity. Alternatively, surgery may be done to destroy the tissue that allows for a “feedback echo” of electrical firing. Usually, this is done by cutting the corpus callosum, the large white matter tract that connects the left and right hemispheres.