Living Textbook MC 417

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Anticonvulsant Drugs


Epilepsy is a heterogeneous symptom complex – a chronic disorder characterized by recurrent seizures.  Seizures are finite episodes of brain dysfunction resulting from abnormal repetitive discharge of cerebral neurons.  There are multiple and varied causes of seizures, including genetic, traumatic, metabolic, infectious, malignant, autoimmune, pharmacologic

Classes of Epileptic Seizure:

  • Partial (local, focal; drugs), that could be simple, complex or partial evolving to secondarily generalized tonic-clonic convulsions.
  • Absence (petit mal; drugs). 
  • Tonic-Clonic (grand mal; drugs), Myoclonic and Status epilepticus.

Firing Patterns of Neurons in Seizures

A seizure is a brief change in behavior caused by the disordered, synchronous and rhythmic firing of populations of neurons in the CNS.

Antiseizure Drugs:

Ideal antiseizure drug would interfere with rapid, synchronized firing of neurons without affecting normal function

The major classes act through one or more of the following mechanism:

Voltage-Gated Ion Channels have unique structures.  They go through a cycle of open, closed and inactive forms.  Antiepileptic drugs enter Na+ channel at specific site inside the membrane and should be able to selectively block epileptiform discharges without affecting ordinary action potentials and affect highly depolarized neurons.

Toxicity of Antiepileptic Agents:

They also have a number of drug interactions, since they can induce or inhibit P450s

Other Uses of Antiepileptic Agents:

Mania, neuropathic pain and depression.

Individual Agents:

Phenytoin (Dilantin®)

Mainstay treatment for partial and generalized seizures, status epilepticus

A hydantoin, it inactivates Na+ channels and is relatively non-sedating.

It is metabolized by CYP450, and can weakly induce the enzyme resulting in a number of DDIs.  Metabolism varies among individuals, leading to unpredictable pharmacokinetics.

It has a narrow therapeutic window that has limited it use.

Toxicity includes ataxia, nystagmus, GI distress and allergies.  Long term use can result in gingival hyperplasia and hirsutism.  Teratogenic effects have been observed.

Related agents include Fosphenytoin (Cerebyx®), which is a prodrug (more soluble than Phenytoin), that allows for IV injections and is then rapidly metabolized to Phenytoin (half-life conversion 8-15 min).  It is sometimes used as an IV injection after benzodiazepines to treat status epilepticus or when quick action of drug needed

Ethotoin (Peganone®) is a less toxic, but less effective hydantoin than phenytoin and require frequent doses (not widely used).  Mephenytoin (Mesantoin®) is used in USA b/c can cause fatal blood disorder.

Carbamazepine (Tegretol®)

An iminostilbene that inactivation of sodium channels.  It is the drug of choice for partial complex, but also used for trigeminal neuralgia and bipolar disorders.

It is metabolized by CYP450 through epoxidation or hydroxylation and can also induce the enzyme, leading to induction of its own metabolism, mainly through CYP3A4.

Toxicities include cerebellar toxicity and rashes.  It may give rise to aplastic anemia, which is rare but potentially fatal.  It is also teratogenic.

Related agents include Oxcarbazepine (Trileptal®), which is less potent than carbamazepine and is also used to treat bipolar disorders.  It does not show incidences of anemia.  It is metabolized to form mono and dihyroxylated derivatives followed by glucuronidation.

Lamotrigine (Lamictal®)

Mechanism of action: prolongs the inactivation of sodium channels, may also block glutamate release

It is approved for partial and secondarily generalized seizures, but is also effective in Lennox-Gastaut syndrome and a broad spectrum of seizures.

It is metabolized mainly via glucuronidation, and has a long half-life.

Toxicities include dizziness and ataxia, but most seriously rashes, including Stevens Johnson syndrome.

Topiramate (Topamax®)

Mechanism of action: prolongs the inactivation of sodium channels, but may also potentiate the inhibitory effects of GABA.  It inhibits glutamate action at AMPA receptors.

It is well absorbed and mostly excreted unchanged in urine

Toxicities are rare, but may include somnolence, fatigue, weight loss

It is used as monotherapy and adjunctive therapy for seizures, migraine headache prophylaxis and weight loss.

Gabapentin (Neurontin®) and Pregabalin (Lyrica®)

Mechanism of action: Inactivation of high voltage-activated Calcium channel.  Pregabalin is more potent than Gabapentin

Useful as adjunct treatment for partial seizures, bipolar illness and neuropathic pain. It is also approved for use in neuropathic pain (diabetic neuropathy and postherpetic neuralgia).

Toxicities include some dizziness, somnolence and ataxia, generally well tolerated

Ethosuximide (Zarontin®)

A succinimide that inactivates low voltage-activated T-type Calcium channels

Used solely in absence seizures

Modified oxazolidinediones by replacing an oxygen with a methylene, avoiding some of the toxic effect, thus no cerebellar toxicity or blood dyscrasias
Valproic acid (Depakote®, Depakene®)

Mechanism of action: Inactivates Na+ and Ca2+ channels, and GABA metabolism.

It is useful in partial, general and absence seizures.  It is also used in bipolar illness and chronic pain such as trigeminal neuralgia

It is completely metabolized by β-oxidation and glucuronidation.

Toxicities include GI distress, alopecia and weight gain.

Other Agents used include BZDs ad Barbiturates which are discussed under hypnotics and sedatives.