how anti-epileptic drugs work
For most people with epilepsy, the treatment for their seizures includes anti-epileptic drugs (AEDs). But what do these drugs do?
What do they do (and what don’t they do)?
AEDs do not cure epilepsy or treat the reason why epilepsy has started. They are taken to try and stop the symptoms of epilepsy – the seizures. They aim to stop seizures from happening. They do not stop a seizure once it has started. They are prophylactic (preventative) and are usually taken either once or twice a day.
From start to finish – how AEDs get to the brain
To work, drugs need to get from where you take them to where they start to work. They need a route to get there and a waste-removal system to get rid of them afterwards.
The route of administration
There are various ways medications are taken, by mouth, by injection (into the vein, muscle, or just under the skin) or by suppository (into the bottom). AEDs are usually taken orally (by mouth), and are tablets, capsules, liquids and syrups.
Absorption in the stomach
Once swallowed, AEDs go into the stomach. Digestive juices in the stomach help to break down food and, in this case, the tablets containing the medication.
The tablets break down, releasing the medication which can then pass through the wall of the gut into the bloodstream (absorption), and be distributed around the body. The quicker the medicine gets into the bloodstream the quicker it can get to work. The AEDs getting from the gut into the bloodstream is like boarding the train.
Once the medication is absorbed it is bioavailable, which means that it is in a state where it can act and do the job it is supposed to.
Getting to the site of action
Once in the bloodstream, AEDs are carried to the site of action: in this case, the brain.
How well and quickly the drugs get to their site of action depends on how well the part of the body is supplied with blood, and how easily the drug gets from the blood stream into the part of the body.
Although the brain has a good supply of blood, there is a barrier between the blood and the brain that helps protect the brain from infections and toxic chemicals. This means that drugs do not pass easily into the brain.
Once drugs have played their active role, they start to break down (metabolise) so that they can be excreted from the body (passed out through the digestive tract, like with food and drink) or in the urine. How long before AEDs start to be metabolised varies from one to another and is referred to as half-life.
To be excreted in the urine, AEDs have to be broken down so that they can dissolve in water, and then the kidneys can get rid of them. Some AEDs become inactive when they are metabolised.
Most AEDs are metabolised in the liver (hepatic metabolism) where they are changed into water-soluble metabolites with the help of different enzymes. Some AEDs – gabapentin, vigabatrin, levetiracetam and pregabalin, are not metabolised, not affected by hepatic enzymes and they are excreted in the same form in the urine.
How do AEDs work on the brain to stop seizures?
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.
‘Targets’ in the brain
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 (chemicals found in the body that have an electrical charge), flow into and out of the neurones.
We will look at four targets (although there are others too):
- sodium ion channels
- calcium ion channels
- the GABA system and receptor agonists
- 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 (when the balance of ions inside and outside the neurone changes, which causes the electrical charge of the neurone to change). 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 (chemicals that help to send messages from one neurone to another) across the synapse, where two neurones meet 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 (a substance that helps another substance to work better), 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.
The AED perampanel works specifically on glutamate receptors, while some other AEDs (such as topiramate) work on glutamate receptors as well as other targets.
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.