Antiepileptics

Introduction

Antiepileptic drugs (AEDs) are used to prevent or reduce the frequency and severity of epileptic seizures. Their primary mechanism involves the suppression of excessive or abnormal neuronal activity in the brain. Different classes of AEDs act through distinct molecular targets

Mechanism of action

1. Inhibition of Voltage-Gated Sodium Channels

Mechanism:

• These drugs bind preferentially to the inactivated state of voltage-gated sodium channels on neuronal membranes.

• By prolonging the refractory period, they prevent the neuron from firing again immediately after an action potential.

• This reduces neuronal excitability, especially in rapidly firing neurons seen in epileptic discharges.

Result:

• Stabilizes the neuronal membrane

• Limits repetitive firing of action potentials

• Prevents seizure propagation

2.Inhibition of Voltage-Gated Calcium Channels

Mechanism:

• Particularly, T-type calcium channels (low-threshold) are important in the rhythmic firing of thalamic neurons.

• By inhibiting these channels, the oscillatory thalamocortical activity responsible for absence seizures is suppressed.

• Some AEDs may also affect high-voltage-activated (HVA) calcium channels, reducing neurotransmitter release.

Result:

• Prevents abnormal burst firing in thalamic circuits

• Decreases neurotransmitter release

• Interrupts epileptogenic circuits, especially in absence seizures

3.Enhancement of GABAergic Activity

Mechanism: Antiepileptics in this category boost GABA, the main inhibitory neurotransmitter, by:

Activating GABA-A receptors → more Cl⁻ influx → hyperpolarization

Inhibiting GABA-transaminase → less GABA breakdown

Blocking GABA reuptake → more GABA in synapse

Result:

Increases neuronal inhibition

Decreases neural excitability

Suppresses seizures

4.Inhibition of Glutamatergic Activity

Mechanism:

Glutamate is the main excitatory neurotransmitter. Some AEDs:

• Block glutamate receptors, such as NMDA (N-methyl-D-aspartate) and AMPA/kainate receptors.

• Inhibit presynaptic glutamate release by blocking voltage-gated ion channels or modulating intracellular calcium.

Result:

• Reduces excitatory transmission

• Protects against excitotoxicity

• Prevents seizure initiation and spread

5. Modulation of Synaptic Vesicle Protein 2A (SV2A)

Mechanism:

• SV2A is a protein found on synaptic vesicles, essential for neurotransmitter release.

• AEDs targeting SV2A modulate vesicle fusion and neurotransmitter exocytosis, reducing excessive neurotransmission.

Result:

• Stabilizes synaptic activity

• Limits synchronous firing of neurons

• Decreases excitatory neurotransmitter release

6. Inhibition of Carbonic Anhydrase

Mechanism:

• Carbonic anhydrase catalyzes the conversion of CO₂ and H₂O to carbonic acid and vice versa.

• Inhibition leads to increased CO₂ levels and mild acidosis in the brain.

• This alters ionic conductance and reduces neuronal excitability, possibly by affecting potassium and chloride transport.

Result:

• Changes in intracellular and extracellular pH

• Stabilization of neuronal firing thresholds

• Anticonvulsant effect through ionic modulation

Examples of Medication Brand Names

IPANTEN(Phenytoin Soduim)

Oxigrex(Oxcarbazepine)

NERVATIN(Pregabalin)

ANDOGABLIN(Pregabalin)

Pregaba(Pregabalin)

Zonivan(Zonisamide)

Convagran(Zonisamide)

LYRICA(Pregabalin)

Indication

• Epilepsy – focal, generalized, status epilepticus

• Neuropathic pain – trigeminal neuralgia (carbamazepine), diabetic neuropathy, postherpetic neuralgia (gabapentin, pregabalin)

• Mood stabilizer – bipolar disorder (valproate, lamotrigine, carbamazepine)

• Migraine prophylaxis – topiramate, valproate

• Alcohol withdrawal – benzos, sometimes carbamazepine

• Fibromyalgia – pregabalin

• Restless legs syndrome – gabapentin, pregabalin

Side Effects

May occur with many AEDs)

• Drowsiness / Fatigue

• Dizziness or lightheadedness

• Nausea / Vomiting

• Weight gain or loss

• Tremor

• Ataxia (loss of coordination)

• Blurred or double vision

• Cognitive impairment (memory issues, slowed thinking)

• Mood changes (irritability, depression, anxiety)

Precautions and Contraindications

1. Do not stop suddenly – can cause seizures or status epilepticus.

2. Monitor drug levels – for drugs like phenytoin and valproate.

3. Use effective contraception – some AEDs reduce contraceptive effectiveness.

4. Watch liver and blood effects – especially with valproate and carbamazepine.

5. Caution in pregnancy – risk of birth defects; folic acid is recommended.

Monographs

Mono1

Gabapentin

Mono2

Phenobarbital

Mono3

Eslicarbazepine

Mono4

Levetira cetam

Mono5

Fosphenytoin

Mono6

Topiramate

Mono7

Zonisamide

Mono8

Pregabalin

Mono9

Phenytoin

Mono10

Oxcarbazepine

Mono11

Lacosamide

Reference

https://aubmc.org.lb/Documents/publications/patient_info/drugs-seizure.pdf

https://emedicine.medscape.com/article/1187334-overview

https://www.sciencedirect.com/science/article/pii/S0885392411004659

https://www.pharmacytimes.com/view/understanding-common-adverse-events-associated-with-antiepileptic-medications

https://www.sciencedirect.com/science/article/pii/S0028390820300320

https://www.osmosis.org/learn/Antiepileptics:_Nursing_Pharmacology

https://www.tga.gov.au/news/safety-updates/antiepileptic-medicines-updated-precautions-pregnancy-and-women-childbearing-potential

https://www.rch.org.au/neurology/patient_information/antiepileptic_medications/

https://nurseslabs.com/antiseizure-drugs/

https://healthinfo.healthengine.com.au/antiepileptics

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