Page created on June 10, 2019. Last updated on April 5, 2022 at 16:27

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.

If a one seizure lasts for more than five minutes or if the patient has two seizures without recovering their consciousness between the seizures, the condition is called status epilepticus. Unlike most other seizures, status epilepticus is a medical emergency as it is life-threatening. It must be treated emergently with effective broad-spectrum antiepileptics.

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

Focal seizures

In a focal 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, and patients appear awake but are unresponsive. They may stare into space or perform automatisms, like chewing, lip smacking, grimacing, etc.

Generalized seizures

In a generalized seizure there is abnormal activity in both hemispheres. A focal 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 a tonic phase followed by a clonic phase (with convulsions).

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.

Special considerations

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

Many of these drugs have narrow therapeutic windows, so their plasma level must be routinely monitored to prevent toxicity. However, there isn’t a strong correlation between plasma concentration and efficacy for many of these drugs.

Antiepileptic drugs

Antiepileptic drugs prevent future epileptic seizures, and in some cases may stop the seizures as well. However, antiepileptics have other uses as well, both in psychiatry (bipolar disorder) and neuropathic pain. Also, there are dozens of antiepileptic drugs. However, research hasn’t shown that there’s a large difference in efficacy between them. This topic will take into account only the most important ones.

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

Antiepileptics have various side effects and drug interactions which must be taken into account. An individual assessment on which antiepileptic is appropriate for the patient must be made based on the side effect profile, interactions, and which seizures the drug is effective against.

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

Compounds

• Carbamazepine (Tegretol®)
• Oxcarbazepine
• Phenytoin
• Fosphenytoin
• Gabapentinoids (α₂δ ligands)
  • Gabapentin (Neurontin®)
  • Pregabalin (Lyrica®)
• Vigabatrin

Phenytoin is rarely used anymore due to an unfavourable side effect profile, and drug interactions.

Indications

• Partial seizures
• Generalized tonic-clonic seizures
• Bipolar disorder
• Neuropathic pain (carbamazepine, oxcarbazepine, gabapentin, pregabalin)
• Anxiety disorder (gabapentin, pregabalin)

Mechanism of action

Phenytoin, carbamazepine, and oxcarbazepine inhibit voltage-gated Na+ channels by the mechanism outlined above. Fosphenytoin is the prodrug of phenytoin.

The gabapentinoids bind to and block α₂δ subunit-containing voltage-dependent calcium channels, which inhibits the channel. Their name comes from their structural similarity to GABA, but they don’t act on GABA receptors or influence GABA neurotransmission.

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

Pharmacokinetics

Elimination of phenytoin follows a special pattern called mixed-order or non-linear pharmacokinetics. Non-linear pharmacokinetics mean that 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.

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Interactions

Phenytoin, carbamazepine, and oxcarbazepine induce CYP450 enzymes, which is important to know. Phenytoin has significant plasma protein binding and therefore interacts with other drugs with the same property.

Side effects

Phenytoin and fosphenytoin have significant side effects:

• Common
  • Gingival hyperplasia
  • Rash
  • Confusion
  • Cerebellar symptoms (ataxia, diplopia, dysarthria)
  • Osteoporosis
  • Hirsutism
  • Teratogenicity
• Rare but serious
  • Haematological disorder (aplastic anaemia, leukopaenia)
  • Teratogenic
  • Stevens-Johnson syndrome/toxic epidermal necrolysis

Carbamazepine and oxcarbazepine:

• Common
  • Nausea/vomiting
  • Hyponatraemia
  • Rash
  • Drowsiness
  • Teratogenic
• Rare but serious
  • Haematological disorder (aplastic anaemia, leukopaenia)
  • Stevens-Johnson syndrome/toxic epidermal necrolysis

Gabapentinoids

• Weight gain
• Drowsiness
• Hypersensitivity reactions
• Euphoria

Gabapentinoids also have potential for abuse due to their euphoric effects and development of physical dependence to this effect.

Ethosuximide

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

Indications

• Absence seizures

Mechanism of action

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

Side effects

• GI symptoms
• Psychosis
• Haematological disorder

Broad spectrum antiepileptics

Compounds

• Antiepileptics
  • Valproate or valproic acid (Orfiril®)
  • Lamotrigine
  • Levetiracetam (Keppra®)
  • Topiramate
• Benzodiazepines
  • Diazepam
  • Clonazepam
  • Lorazepam
  • Midazolam
• Barbiturates
  • Phenobarbital

Valproate is generally the first line drug in treating generalized seizures, except in pregnant women. Benzodiazepines and barbiturates are covered in their topics.

Indications

• Partial seizures (both types)
• Generalized tonic-clonic seizures
• Generalized absence seizures
• Bipolar disorder
• Migraine prophylaxis
• Status epilepticus
  • 1st choice benzodiazepines
  • 2nd choice antiepileptics

These antiepileptics are useful for treating almost all types of seizures. Benzodiazepines and phenobarbital are rarely used for seizures other than status epilepticus.

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 GABA_A 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:

• Common
  • Weight gain
  • Nausea and vomiting
  • Teratogenicity
• Rare but serious
  • Hepatotoxicity
  • Haematological disorder (aplastic anaemia, leukopaenia)
  • Stevens-Johnson syndrome/toxic epidermal necrolysis

Lamotrigine:

• Common
  • Nausea and vomiting
  • Rash
  • Dizziness
  • Double vision
• Rare but serious
  • Arrhythmia
  • Stevens-Johnson syndrome/toxic epidermal necrolysis