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Anti-epileptic drugs (part 2)
For most people with epilepsy, the treatment for their seizures includes anti-epileptic drugs (AEDs). But how do AEDs stop seizures from happening?
Anti-epileptic drugs (AEDs) work on the brain to make it less likely to have seizures. But how exactly do they do this? In AEDs part two we look at how AEDs work on the brain to stop seizures.
To understand this topic we will be referring back to the topics from other Back2Basics articles on how neurones work.
What do AEDs do?
AEDs make the brain less likely to have seizures by altering and reducing the excessive electrical activity (or excitability) of the neurones that normally cause a seizure. Different AEDs work in different ways and have different effects on the brain. The way AEDs work is not fully understood. How AEDs have been developed is somewhat ‘random’ either by luck (finding that an existing drug used for something else happens to work on seizures), or by huge numbers of different drugs being tried in an effort to find one that works.
Ways of acting
There are several different ways in which AEDs stop seizures from happening, by working on particular ‘targets’ in the brain. AEDs may affect the neurotransmitters responsible for sending messages, or attach themselves to the surface of neurones and alter the activity of the cell by changing how ions flow into and out of the neurones.
In this article we will look at four targets (although there are others too): sodium ion channels, calcium ion channels, the GABA system and receptor agonists, and glutamate receptor antagonists.
Sodium ion channels
Sodium channels are the parts of the neurone that affect how electrical signals or messages are passed along the length of a neurone. “Action potentials are events that cause the cell membrane of the neurone to depolarize and repolarize. This is because they change the amount of ions inside and outside the cell, which then changes the electrical charge of the cell. This is how messages travel along a neurone”. Sodium channels affect how ‘excitable’ neurones are and how easily messages are sent from one brain cell to another.
Some AEDs (such as phenytoin, lamotrigine and carbamazepine) work by affecting the sodium channels of neurones. AEDs that bind or attach themselves to the sodium channels, affect how ions flow through the channels and stop the channel becoming activated or creating an action potential. This slows down how fast and how well the sodium channels work, which effectively stops the neurone from sending repeated messages.
Calcium ion channels
Calcium ions, like sodium ions, are involved in sending electric messages through the brain. Calcium channel are particularly involved with sending a message from one neurone to another, by affecting the release of neurotransmitters across the synapse, and the movement of calcium ions in the receiving neurone.
AEDs that target calcium channels (such as lamotrigine and topiramate) work by blocking the calcium channels. This prevents messages being sent across the synapse from one neurone to another either by stopping the release of neurotransmitters or by preventing calcium entering the second neurone.
One particular type of calcium channel, called the T-type channel, is involved in keeping the normal rhythm of brain activity. This channel is also involved in the specific brain activity that happens in absence seizures. AEDs that specifically target, and block, the T-type calcium channel (such as ethosuximide), work specifically on reducing absence seizures.
GABA system and receptor agonists
GABA (gamma amino butyric acid) is a type of inhibitory neurotransmitter in the brain, which effectively stops brain messages from continuing to be sent (‘switches messages off’). GABA helps chloride ions pass into neurones, which affects the resting membrane potential of the cell and makes it difficult for the neurone to send messages.
AEDs that work on the GABA system and its receptors are agonists, and effectively increase the movement of chloride into cells, and increase the switching off of messages.
AEDs such as gabapentin work by increasing the production of GABA, and sodium valproate and vigabatrin work by decreasing the breakdown of GABA, both of which result in an increased amount of GABA.
AEDs such as benzodiazepines (including clonazepam and clobazam) increase how often GABA receptors open, and barbiturates (such as phenobarbitone) increase how long the receptors are open for, again affecting the release and movement of GABA.
Increasing the making of GABA, reducing its breakdown, and increasing its movement, all results in increases its inhibitory effect (more GABA means more prevention of messages being sent).
Glutamate receptor antagonists
Glutamate is a type of amino acid, and is a major excitatory neurotransmitter in the brain. Messages are sent from one neurone to another in excitation, due to the movement of sodium and calcium ions into cells, and potassium out of cells. This movement of ions through the cell membranes is helped by glutamate, which binds to different receptors on the cell membrane.
Drugs that effect and prevent glutamate uptake (antagonists) prevent glutamate from helping the movement of ions through the cell membrane and so prevent the spread of the messages from one neurone to another.
None of the AEDs work only on glutamate receptors, but some (such as topiramate) have this effect as well as working on other targets as well.
Different AEDs use different targets, or a combination of targets. For some it is known which targets they use, but for others it is not yet known.
Glossary
Agonist – a substance that helps another substance to work better.
Antagonist – a substance that prevents, or gets in the way of, another substance working.
Amino acid – a substance that is the building blocks of proteins.
Action potential - the messages sent and received by neurones.
Cell membrane - the outside wall or coating of neurones, which contains ion channels.
Ion channels - the 'gateways' in the cell membrane which ions pass through when messages are sent from one cell to another.
Ions - chemicals found in the body that have an electrical charge. Important ions for neurone communication are Sodium, Potassium, Calcium and Chloride.
Messages - signals that send information around the body.
Neurotransmitters - chemicals that help to send messages from one neurone to another.
Neurotransmitters can be excitatory - causing an action potential to be set up in a receiving cell so that the message continues to be sent, or inhibitory- so an action potential cannot be set up and the message is stopped.
Synapse - the point at which two neurones connect. The neurones may be separated by a small space called a synaptic gap.
Neurones (or neurons) - the individual cells that make up the nervous system. Also called nerve cells.
© Epilepsy Society
December 2007
