Anti-Epileptic Drugs

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Phenolbarbital

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Use: Effective for all seizure types except absence. Can be given PO or IV. IV form very useful in status epilepticus
Mechanism: GABA analog. Opens chloride channel. Produces hyperpolarization
Metabolism: Long half life (100 hours). Needs to be loaded. Hepatic metabolism. Enzyme inducer
Toxicity: Hyperactivity in children. Sedation in adults. Joint and connective tissue problems
History: 1912, sedative hypnotic found to be useful in epilepsy

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Phenytoin

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Use: Effective against all seizure types except absence. Better for focal and secondarily generalized seizures than for the primary generalized ones.
Mechanism: Blocks voltage-gated Na+ channels, which are the final common pathway for seizures.
Metabolism: Can be given PO or IV. Poorly absorbed PO in children. Has zero-order kinetics at high doses because of enzyme saturation. Hepatic metabolism. Variable ½ life (6-24 hours) Strong enzyme inducer.
Toxicity: Gingival hyperplasia, osteomalacia, ataxia. Need to supplement calcium, vitamin D, vitamin K, and folic acid.
History: 1938, Found by systemic search using molecules resembling phenobarbital. Tested in cat model of electroshock seizures.

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Carbamazepine

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Use: Excellent for focal and secondarily generalized seizures. Less effective for primary generalized seizures. Also a mood stabilizer for bipolar disorder. Works well also for neuropathic pain and trigeminal neuralgia.
Mechanism: Na+ channel blockade.
Metabolism: Only has oral preparation. ½ life 12 hours. Hepatic metabolism. Enzyme inducer. Levels increased by Calcium channel blockers, and macrolide antibiotics.
Toxicity: Blurred vision, sedation, neutropenia, hyponatremia, weight gain (most people).
History: 1974, Developed as a congener of the tricyclic antidepressants. Not a benzodiazepine in spite of its name.

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Ethosuximide

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Use: only for absence seizures
Mechanism: Blocks T-type Calcium Channels
Metabolism: Good oral absorption. ½ life 24-48 hours. Mild enzyme inducer. Hepatic metabolism
Toxicity: Sedation, GI distress, occasional behavioral changes
History: 1960, found by systematic search for anti-absence seizure drugs

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Benzodiazepines
(Diazepam, lorazepam)

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Use: Useful as sedatives. Also effective against all seizure types. Tolerance develops rapidly (months). Drugs of choice for status epilepticus, alcohol withdrawal symptoms and alcohol withdrawal seizures.
Mechanism: Agonist at the GABA receptor.
Metabolism: PO or IV administration. Hepatic metabolism, but not major enzyme inducers.
Toxicity: Excessive sedation, depression, withdrawal seizures.
History: c.1960, deliberate synthesis of compounds thought to be sedating.

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Valproate

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Use: Very wide spectrum of efficacy. Works for all seizure types (even absence). Also used for migraine and bipolar disorder.
Mechanism: Not well understood but probably involves several mechanisms. May block Na+ channels. Probably also affects GABA levels, Ca++, and K+ conductances.
Metabolism: Oral and IV preparation. Half Life ~15 hours. Hepatic metabolism. Not a major enzyme inducer.
Toxicity: GI upset, weight gain, menstrual problems, hair loss, low platelet count, hepatic encephalopathy sometimes but not always associated with elevated ammonia levels and carnitine deficiency.
History: 1978, Discovered by chance. Was being used as a solvent to test other anti-seizure drugs.

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Gabapentin

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Use: effective against partial and secondarily generalized seizures. Not good for primary generalized seizures. Also a good anxiolytic, sedative, and mood stabilizer. Works well for peripheral neuropathy and other painful states.
Mechanism: Increases GABA levels in the brain. May have other mechanisms.
Metabolism: PO preparation only. Short ½ life (6 hours). Well absorbed. Is not metabolized. Excreted unchanged in the urine. Very few drug interaction. Not an enzyme inducer.
Toxicity: sedation, particularly in the elderly. Occasional GI distress, and pedal edema.
History: 1993. Developed as a GABA agonist but is not.

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Lamotrigine

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Use: Broad spectrum efficacy against all seizure types. Also works for bi-polar disorder, and neuropathic pain.
Mechanism: Blocks Na+ channels. Blocks release of glutamate.
Metabolism: Only an oral preparation Renally excreted after glucoronidation. Not a major enzyme inducer. ½ life of 24 hours.
Toxicity: Allergic rash 5-10%. Other problems minor. Not sedating. May cause insomnia.
Tolerated better than carbamazepine by elderly
History: 1995, Tested because folate antagonists were thought (wrongly) to be anti-convulsants.

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Topiramate

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Efficacy higher than other drugs but side-effects are worse.
Use: Broad spectrum of efficacy, but not particularly good for absence. Good for migraine prevention. Some use in neuropathic pain. Causes weight loss.
Mechanism: Multiple mechanisms. Na+ channel blockade, GABA agonist, glutamate antagonist.
Metabolism: Some hepatic metabolism, but mainly renal clearance without change. ½ life of 24 hours. Only an oral preparation. Not an enzyme inducer.
Toxicity: Sedation, aphasia, parasthesias, kidney stones.
History: Initially developed as a drug for diabetes. Incidentally found to be an anticonvulsant.

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Levetiracetam

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Use: Broad spectrum of use for focal and generalized seizures. Equivalent IV or PO dosing. Favorite of oncologists.
Mechanism: Controversial, blocks Ca++ channels, but probably has other effects as well.
Metabolism: 2/3 excreted renally unchanged. Some enzymatic hydrolysis by liver and RBCs to inactive metabolites. Not protein-bound. Not an enzyme inducer.
Toxicity: Cognitive and behavioral problems.