Seizures and Anti-Epileptic Drugs Overview

Seizures

• Seizures are sudden, excessive, and synchronous neuronal discharges.
• Result in loss of consciousness, abnormal movements, atypical movements, and distorted perceptions.

Types of Seizures

Partial/Focal Seizures

• Simple partial: Partial sensory seizure, often preceded by an aura.
• Complex partial: Temporal lobe seizure.
• Secondarily generalized: Partial seizure that spreads to involve the entire brain.
• Treatment: Most AEDs are effective; ethosuximide is an exception.

Generalized Seizures

• No aura present before the seizure.
• Generalized tonic-clonic: Muscle stiffening (tonic) and jerking (clonic) movements.
• Tonic/atonic: Muscle stiffness followed by loss of muscle tone.
• Absence: Brief loss of awareness.
• Myoclonic: Sudden, brief muscle jerks.
• Treatment: Limited AED options.

Anti-Epileptic Drugs (AEDs) Mechanisms and Interactions

1. Voltage-Gated Sodium Channels

• Phenytoin: Zero-order kinetics, metabolized by P450 enzymes, enzyme inducer.
• Carbamazepine/Oxcarbazepine: Enzyme inducer for their own metabolism, and also induce P450 enzymes.
• Lamotrigine: Major metabolic pathway is glucuronic acid conjugation. Valproic acid decreases glucuronic acid conjugation of lamotrigine; estrogen increases glucuronic acid conjugation of many drugs.
• Phenobarbital: Enzyme inducer.
• Valproic Acid: High protein binding; blocks metabolism; P450 inducers lower levels of Valproic Acid.

2. GABAergic Mechanism Potentiation

• Phenobarbital: Increases the duration of chloride channel opening.
• Benzodiazepines: Increases the frequency of chloride channel opening.
• Felbamate, topiramate, valproate: Similar effects as benzodiazepines, acting on GABAergic mechanisms.
• Vigabatrin: Blocks GABA transaminase (GABA-T), increasing extracellular GABA.
• Tiagabine: Blocks GABA reuptake in neurons and glial cells, increasing extracellular GABA.
• Benzodiazepines: Lorazepam (IV emergency, sublingual at aura), midazolam (IV emergency), rectal diazepam (children). Long-term treatment options include clonazepam and clobazam. Withdrawal can cause seizures in non-epileptic individuals.

3. Calcium Channel Blockade

• Ethosuximide, Valproic Acid: Low-threshold T-type calcium channels in thalamic pacemaker neurons. Ethosuximide, along with Valproic Acid, is an treatment option for absence seizures.
• Gabapentin, Pregabalin: Act on presynaptic voltage-gated calcium channels, reducing calcium influx and subsequent glutamate release. They are not direct GABA agonists, but they affect GABAergic pathways through modulation of calcium influx.

4. Glutamate Antagonism

• Phenobarbital: Antagonizes glutamate effects.
• Felbamate: NMDA receptor antagonist.
• Topiramate: AMPA receptor antagonist.
• Perampanel: AMPA receptor antagonist.

5. Potassium Channel Permeability Enhancement

• Valproic Acid: Enhances potassium channel permeability.
• Ezogabine: Enhances potassium channel permeability.

6. Exocytosis Antagonism

• Levetiracetam: Binds to the SV2A vesicle protein, decreasing neurotransmitter release.

AED Excretion

• Gabapentin, Pregabalin, Vigabatrin, Levetiracetam: Excreted by the kidneys.

Drug Interactions

• Increased potency: Valproic acid increases phenytoin levels.
• Decreased potency: Carbamazepine decreases carbamazepine and other drug levels.
• Vit D & Bone Health: Low vitamin D can lead to osteoporosis, particularly regarding some anticonvulsants. Oral contraceptives may be affected.
• Liver P450 inducers: Phenytoin, phenobarbital, and carbamazepine are P450 inducers.

Pregnancy

• Folate: Folate supplementation (4 mg/day) is crucial during pregnancy.