22. Antiepileptic drugs

Last updated on June 24, 2019 at 17:59

Introduction to epilepsy

An epileptic seizure occurs when there is abnormal electrical activity in the brain. This electric activity is often comprised of synchronous high frequency discharges in groups of neurons in the brain.

Epilepsy is an umbrella term for multiple conditions that cause recurring, unprovoked epileptic seizures. When an epileptic seizure is provoked by a stroke, brain injury, metabolic or electrolyte disturbances etc., the condition is not called epilepsy.

If a one or more seizures last for more than five minutes, without the affected person recovering their consciousness between the seizures, the condition is called status epilepticus. Unlike most other seizures, status epilepticus is a medical emergency.

There are two types of epileptic seizures; partial (or focal) seizures and generalized seizures.

Partial seizures:

In a partial seizure there is abnormal activity in only one hemisphere. These seizures can be simple or complex.

In simple partial seizures there is no impairment of consciousness. The patient can experience jerking of a single limb or localized sensory disturbances like paraesthesia.

In complex partial seizures the consciousness is impaired, but the person can still stand upright or walk around. An affected person can appear drunk or confused. These seizures most commonly arise from the temporal lobe and move to other areas of the brain. An affected person can suddenly stop moving and just stare into space, they can begin smacking their lips, chewing or swallowing. The person usually doesn’t remember the seizure afterwards.

Generalized seizures:

In a generalized seizure there is abnormal activity in both hemispheres. A partial seizure can progress into a generalized seizure.

The most common type of generalized seizure is the tonic-clonic seizure (“grand mal” seizure), which is the where the affected person experiences convulsions while being unconscious. The extensor muscles in the body spasm, and muscles contract and relax alternately. During this seizure the affected person may bite their tongue or lose bladder control.

Another type is the absence seizure (“petite mal” seizure). In this type the affected person briefly loses consciousness and stops talking or doing whatever they’re doing, but still standing or sitting upright.

The most common cause of epilepsy in adults is alcohol withdrawal.

Pathomechanism:

The mechanism behind epileptic seizures is poorly understood. Facilitation of excitatory neurotransmission, diminishment of inhibitory neurotransmission or enhanced neuronal excitability are potential mechanisms.

Special considerations:

Withdrawal from antiepileptics may trigger seizures. This must be kept in mind when switching between drugs.

These drugs have narrow therapeutic windows, so their plasma level must be routinely monitored to prevent toxicity.

Antiepileptics

We can distinguish three types of antiepileptic drugs, according to which types of seizures they’re useful against:

Seizure type Treated by narrow spectrum drugs Treated by ethosuximide Treated by broad spectrum drugs
Simple partial seizure Yes No Yes
Complex partial seizure Yes No Yes
Generalized tonic-clonic seizure Yes No Yes
Generalized absence seizure No Yes Yes

Mechanism of action:

Many antiepileptics work by stabilizing voltage-gated Na+ channels in their “inactive” or closed state. This prolongs the refractory period of neurons, causing them to fire less frequently.

This effect is use-dependent, meaning that the more overactive a Na+ channel is, the more strongly these drugs bind to the channel. During a seizure the Na+ channels at the area of the seizure are overactive, so the drugs target overactive neurons during a seizure. Na+ channels are mostly unaffected when a seizure is not currently happening.

Some antiepileptics work by other mechanisms as well:

  • By blocking T-type voltage-gated Ca2+ channels
  • By potentiating endogenous GABA activity
  • By potentiating voltage-gated K+ channels
Narrow spectrum antiepileptics

These antiepileptics are useful for treating partial and tonic-clonic generalized seizures, but not absence seizures.

The important drugs here are phenytoin, carbamazepine, gabapentin, vigabatrin and tiagabine.

Indications:

  • Partial seizures (both types)
  • Tonic-clonic generalized seizures

Carbamazepine can also be used to treat trigeminal neuralgia.

Mechanism of action:

Phenytoin and carbamazepine inhibit voltage-gated Na+ channels by the mechanism outlined above.

Gabapentin blocks calcium channels, attenuating neurotransmitter release.

Vigabatrin irreversibly inhibits GABA transaminase, the enzyme that inactivates GABA. This increases levels of GABA in the CNS.

Tiagabine inhibits GABA uptake, allowing GABA to be present in the synaptic cleft for longer.

Pharmacokinetics:

Elimination of phenytoin follows a special pattern called non-linear pharmacokinetics. Elimination is unsaturated (follows first-order kinetics) when the dose is less than 300 mg/day. When the daily dose exceeds 300 mg the enzymes metabolising phenytoin become saturated, causing it to switch to zero-order kinetics above this daily dose.

Interactions:

Phenytoin and carbamazepine induce CYP450 enzymes. Phenytoin has significant plasma protein binding and therefore interacts with other drugs with the same property.

Side effects:

Phenytoin

  • Diplopia
  • Ataxia
  • Gingival hyperplasia
  • Decreased bone density
  • Hirsutism
  • Teratogenic

Carbamazepine

  • Diplopia
  • Ataxia
  • Syndrome of inappropriate ADH
  • Aplastic anaemia
  • Agranulocytosis
  • Teratogenic
Ethosuximide

Ethosuximide can only treat generalized absence seizures, but it’s the preferred drug for these seizures.

Indications:

  • Generalized absence seizures

Mechanism of action:

Ethosuximide blocks T-type Ca2+ channels in neurons in the thalamus.

Side effects:

  • GI symptoms
    • Pain
    • Nausea
Broad spectrum antiepileptics

These antiepileptics are useful for treating almost all types of seizures.

The important drugs here are valproate, topiramate, lamotrigine, levetiracetam. Valproate is a first-line drug in treating generalized seizures, except in pregnant women. Lamotrigine is a newer broad spectrum antiepileptic which has fewer side effects.

Benzodiazepines like diazepam and lorazepam can be used for treating acute episodes of epilepsy and are considered broad spectrum antiepileptics. Barbiturates can also be used.

Indications:

  • Partial seizures (both types)
  • Generalized tonic-clonic seizures
  • Generalized absence seizures

Mechanism of action:

Valproate, topiramate and lamotrigine inhibit voltage-gated Na+ channels by the mechanism outlined above. Valproate also increases levels of GABA in the CNS.

Topiramate binds to an allosteric site on the GABAA receptor, increasing its activity.

Valproate and lamotrigine also block T-type Ca2+ channels.

Pharmacokinetics:

These drugs are metabolized by CYP450 enzymes in the liver.

Valproate is highly plasma protein bound.

Side effects:

Valproate

  • Sedation
  • Nausea
  • Hepatotoxicity
  • Teratogenicity

Levetiracetam

  • Somnolence

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