The Drugs: Wherefore and Whence?

Anticonvulsant Drugs, Antiseizure Drugs or Antiepileptic Drugs?
I am seldom picky over words, but I really dislike the term "antiepileptic drug". It sounds like a pill you take if you don't like people with epilepsy. Some rogue, pill-popping gang wandering the streets with a score to settle against those who have epilepsy. Whoever coined this term obviously didn't eat their Wheaties.

Two more acceptable terms are "antiseizure drugs" and "anticonvulsant drugs". Strictly speaking, a seizure is an electrographic event. It is the disruption of brain activity that we can measure using an EEG (see "What is a Seizure" below). A seizure may or may not be associated with a convulsion. A convulsion is the movement/behavior caused by a seizure. For example, tonic-clonic* (formerly called grand mal) seizures cause tonic-clonic movements therefore it is a convulsive seizure. Other seizures, however, do not cause convulsions. For example, simple partial seizures that do not affect motor areas of the brain will not cause any movement- therefore they are non-convulsive seizures. I tend to use the terms "anticonvulsant drugs" and "antiseizure drugs" interchangeably.

*Tonus is continuous contraction of the muscles, causing the limbs to straighten and become stiff. Clonus is the repeated contraction and relaxation of the muscles which results in a jerking movement.

The Drugs.
Upon being diagnosed with epilepsy, the first course of treatment is generally the drugs.

Until the mid 1990s, the "traditional" anticonvulsants were the most commonly prescribed (drugs listed by generic name with trade name in parentheses). These include phenobarbital (Luminal®), primidone (Mysoline®), phenytoin (Dilantin®), carbamazepine (Tegretol®), ethosuximide (Zarontin®), clonazepam (Rivotril®) and valproate (Depakene®). These "first-line" anticonvulsant drugs are only effective in 60-70% of patients. They may also be associated with severe side effects.

In the past decade, a number of new drugs have been introduced to the market. These include felbamate (Felbatol®), fosphenytoin sodium (Cerebyx®), oxcarbazepine (Trileptal®), gabapentin (Neurontin®), lamotrigine (Lamictal®), zonisamide (Zonegran®), levetiracetam (Keppra®), tiagabine (Gabitril®), pregabalin (Lyrica®) and topiramate (Topamax®). Although these newer drugs have fewer side effects, they do not appear to be more effective at stopping seizures than the traditional drugs- meaning 20-30% of patients will not gain adequate seizure control on these meds.

How the Drugs Work.
The new anticonvulsant drugs may not be more effective than the old anticonvulsant drugs because they tend to work in very similar ways. Anticonvulsant drugs generally work to decrease excitation or increase inhibition in the brain. This is usually accomplished by one of three mechanisms: enhancing GABA activity, decreasing sodium channel activity, or decreasing T-type calcium channel activity.

GABA Drugs.
GABA (also know by the less cuddly name: gamma-aminobutyric acid) is the major inhibitory chemical in the brain. It works by slamming on the proverbial brakes (see car analogy under "What is a Seizure" below). The GABA drugs elevate levels of GABA in the brain. Slamming on the brakes will make the brain less excitable and less prone to seizures. It will also make it harder to remember things and stay alert/energetic. This is because these drugs raise GABA levels all over the brain, and not just in the area(s) that cause the seizure.

A number of the anticonvulsants enhance the activity of GABA, often indirectly. Examples of such drugs are: phenobarbital (Luminal®), primidone (Mysoline®), topiramate (Topamax®), diazepam (Valium®) and tiagabine (Gabitril®).

Sodium Channel Blockers.
Sodium channels (specifically, voltage-gated sodium channels) are responsible for the firing of neurons in the brain. Think of a neuron as a water hose. The hose is full of little gates, however, that prevent the water from flowing through it. When the gates "sense" that water is coming, they open and allow the water to flow through. This is a rough analogy of how the voltage gated sodium channels work- only instead of water they allow the passage of positively charged ions (like sodium) into the cell which allows the signal to carry on.

Drugs that work on sodium channels in the brain tend to delay these channels, causing neurons to fire a tiny bit slower than normal. Examples of voltage-gated sodium channel drugs are phenytoin (Dilantin®), carbamazepine (Tegretol®), felbamate (Felbatol®), lamotrigine (Lamictal®), oxcarbazepine (Trileptal®), pregabalin (Lyrica®), topiramate (Topamax®) and zonisamide (Zonegran®).

Calcium Channel Blockers.
T-type calcium channels are thought to cause rhythmic neuronal firing associated with absence seizures. Similar to sodium channels, calcium channels open and allow positively charged ions to enter the cell -- only this time it's calcium and not sodium. Calcium channel blockers tend to be most effective in treating absence seizures. Examples of drugs acting on calcium channels are ethosuximide (Zarontin®), felbamate (Felbatol®), lamotrigine (Lamictal®), topiramate (Topamax®) and zonisamide (Zonegran®).

Drugs for the Treatment of Status Epilepticus.
Status epilepticus is a seizure that does not end on its own. Generally, someone is said to be in status if their seizure lasts longer than 5 minutes. This is when it's important to get to a hospital/call 911 as special drugs will be required to stop these seizures (see "Seizure First Aid" below). These include diazepam (Valium®), lorazepam (Ativan®) and sometimes general anesthetics such as propofol (Diprivan®).

Other Treatments for Epilepsy
This post is long enough. Later, I will cover non-drug treatments such as the ketogenic diet, vagal nerve stimulator and neurosurgery.

Onwards and upwards!
Kirk.

References:
Browne TR & Holmes GL. 2001. Epilepsy – Primary Care. New England Journal of Medicine. 344, 1145-1151.
Burnham WM. 1998. Antiseizure drugs. In: Principles of Medical Pharmacology. New York: 250-277.
Catterall WA. 1987. Common modes of drug action on Na+ channels: local anesthetics, antiarrhythmics and anticonvulsants. Trends in Pharmacological Science. 8, 57-65.
LaRoche SM & Helmers SL. 2004. The new antiepileptic drugs. Journal of the American Medical Association. 291, 605-614.