51. Antiepileptic drugs

Page created on June 10, 2019. Last updated on January 7, 2022 at 22:25

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. Drugs are not used acutely in case of an epileptic seizure, except in the case of status epilepticus.

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 as it is life-threatening. It must be treated emergently with effective broad-spectrum antiepileptics.

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, 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 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 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.

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

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.

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®)
  • Oxcarbamazepine
  • Phenytoin
  • 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, gabapentin, pregabalin)
  • Anxiety disorder (gabapentin, pregabalin)

Mechanism of action

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

Gabapentin and pregabalin block calcium channels, attenuating neurotransmitter release.

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.

This is something certain examiners like to ask on the exam.

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

  • 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

  • Absence seizures

Mechanism of action

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

Side effects

  • GI symptoms

Broad spectrum antiepileptics

Compounds

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

Valproate is generally the first line drug in treating generalized seizures, except in pregnant women. Lamotrigine is generally the first choice for focal seizures.

Indications

  • Partial seizures (both types)
  • Generalized tonic-clonic seizures
  • Generalized absence seizures
  • Bipolar disorder (valproate, lamotrigine
  • Migraine prophylaxis (valproate)
  • Status epilepticus (lorazepam, midazolam, valproate, levetiracetam)

These antiepileptics are useful for treating almost all types of 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

Previous page:
50. Antidepressants

Next page:
52. General anesthetics

Parent page:
Pharmacology 2

Leave a Reply

Your email address will not be published.