Anticonvulsants

Introduction

Anticonvulsants are drugs used to prevent or reduce the frequency and severity of seizures in epilepsy, a chronic neurological disorder characterized by recurrent, unprovoked seizures. Beyond epilepsy, many anticonvulsants are also prescribed for neuropathic pain, migraine prophylaxis, mood stabilization (bipolar disorder), and anxiety disorders.

Their mechanisms generally involve modulating ion channels, enhancing inhibitory GABAergic transmission, or reducing excitatory glutamatergic transmission.

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Classification of Anticonvulsants

1. Sodium Channel Blockers

• Mechanism: Stabilize inactive state of voltage-gated sodium channels, limiting repetitive neuronal firing.

• Generics:

  • Phenytoin

  • Carbamazepine

  • Oxcarbazepine

  • Lamotrigine

  • Lacosamide

  • Rufinamide

• Uses: Focal seizures, generalized tonic–clonic seizures.

• Adverse Effects: Dizziness, diplopia, ataxia, rash (lamotrigine risk of Stevens–Johnson syndrome), hyponatremia (carbamazepine, oxcarbazepine).

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2. Calcium Channel Blockers (T-type Blockade)

• Mechanism: Inhibit low-threshold T-type calcium channels in thalamic neurons.

• Generics:

  • Ethosuximide

  • Zonisamide (also affects sodium channels)

• Uses: Absence seizures (ethosuximide is first-line).

• Adverse Effects: GI upset, fatigue, dizziness, rare Stevens–Johnson syndrome.

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3. GABAergic Enhancers

• Mechanism: Enhance inhibitory neurotransmission via GABA.

• Generics:

  • Benzodiazepines: diazepam, lorazepam, clonazepam, clobazam.

  • Barbiturates: phenobarbital, primidone.

  • Tiagabine (inhibits GABA reuptake).

  • Vigabatrin (irreversible GABA transaminase inhibitor).

• Uses:

  • Benzodiazepines: status epilepticus, acute seizure control.

  • Barbiturates: generalized and focal seizures (less used today due to sedation).

• Adverse Effects: Sedation, dependence (benzodiazepines, barbiturates), visual field defects (vigabatrin).

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4. Glutamate Modulators

• Mechanism: Inhibit excitatory neurotransmission via AMPA or NMDA receptors.

• Generics:

  • Perampanel (AMPA antagonist).

  • Felbamate (NMDA antagonist, limited use due to toxicity).

• Uses: Refractory epilepsy.

• Adverse Effects: Behavioral changes, dizziness, hepatotoxicity (felbamate).

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5. Broad-Spectrum Agents (Multiple Mechanisms)

• Valproic acid / Divalproex sodium

  • Mechanisms: Increases GABA, blocks sodium and calcium channels.

  • Uses: Broad-spectrum – absence, generalized tonic–clonic, myoclonic, focal seizures; also migraine prophylaxis, bipolar disorder.

  • Adverse Effects: Hepatotoxicity, pancreatitis, teratogenicity (neural tube defects), weight gain, tremor.

• Topiramate

  • Mechanisms: Sodium channel blocker, enhances GABA, inhibits AMPA receptors, carbonic anhydrase inhibitor.

  • Uses: Focal and generalized seizures, migraine prophylaxis.

  • Adverse Effects: Cognitive dysfunction, weight loss, kidney stones, paresthesia.

• Levetiracetam

  • Mechanism: Binds synaptic vesicle protein SV2A, modulating neurotransmitter release.

  • Uses: Broad-spectrum – focal, myoclonic, generalized tonic–clonic seizures.

  • Adverse Effects: Irritability, behavioral changes, somnolence.

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6. Other/Novel Agents

• Gabapentin, pregabalin: Bind α2δ subunit of voltage-gated calcium channels → reduce excitatory neurotransmitter release.

  • Uses: Focal seizures (adjunctive), neuropathic pain, fibromyalgia, anxiety.

  • Adverse Effects: Sedation, dizziness, weight gain, edema.

• Brivaracetam: Similar to levetiracetam, SV2A binding with higher affinity.

  • Uses: Focal seizures.

• Cannabidiol (CBD): Approved for Dravet syndrome and Lennox–Gastaut syndrome.

  • Adverse Effects: Somnolence, diarrhea, hepatotoxicity (with valproate).

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Clinical Indications

1. Generalized Tonic–Clonic Seizures: Valproate, lamotrigine, levetiracetam, topiramate.

2. Absence Seizures: Ethosuximide (first-line), valproate, lamotrigine.

3. Focal Seizures: Carbamazepine, lamotrigine, levetiracetam, phenytoin, oxcarbazepine.

4. Status Epilepticus: IV lorazepam/diazepam → fosphenytoin or valproate.

5. Myoclonic Seizures: Valproate, levetiracetam, clonazepam.

6. Atonic/Lennox–Gastaut: Valproate, lamotrigine, topiramate, clobazam, rufinamide.

7. Non-Epileptic Uses:

   • Neuropathic pain: gabapentin, pregabalin, carbamazepine.

   • Bipolar disorder: valproate, carbamazepine, lamotrigine.

   • Migraine prophylaxis: valproate, topiramate.

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Contraindications (Selected)

• Valproate: Pregnancy (teratogenic, neural tube defects).

• Carbamazepine: Bone marrow suppression, HLA-B*1502 positive (risk of SJS in Asian patients).

• Phenytoin: Pregnancy (fetal hydantoin syndrome).

• Vigabatrin: History of visual field defects.

• Felbamate: History of hepatic dysfunction, aplastic anemia.

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Adverse Effects (Summary by Class)

Class/Drug	Key Adverse Effects
Phenytoin	Gingival hyperplasia, hirsutism, ataxia, teratogenicity
Carbamazepine	Hyponatremia, agranulocytosis, aplastic anemia, rash (SJS/TEN)
Lamotrigine	Rash, Stevens–Johnson syndrome
Valproate	Hepatotoxicity, pancreatitis, teratogenicity, weight gain
Topiramate	Cognitive dysfunction, weight loss, nephrolithiasis
Levetiracetam	Behavioral disturbances (irritability, aggression)
Ethosuximide	GI upset, fatigue, Stevens–Johnson syndrome (rare)
Gabapentin/Pregabalin	Sedation, dizziness, weight gain, peripheral edema
Benzodiazepines	Sedation, tolerance, dependence
Barbiturates	Sedation, respiratory depression, abuse potential

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Clinical Considerations

1. Drug interactions:

   • Enzyme-inducing AEDs (phenytoin, carbamazepine, phenobarbital) reduce efficacy of oral contraceptives and other drugs.

   • Valproate inhibits hepatic enzymes → increases lamotrigine toxicity.

2. Pregnancy considerations:

   • Valproate and phenytoin are teratogenic.

   • Safer options: lamotrigine, levetiracetam.

   • Folic acid supplementation is essential.

3. Therapeutic drug monitoring:

   • Required for phenytoin, carbamazepine, valproate, phenobarbital due to narrow therapeutic index.

4. Tapering:

   • AEDs should not be abruptly discontinued due to risk of seizure recurrence or status epilepticus.

5. Comorbid conditions:

• Bipolar disorder: lamotrigine, valproate, carbamazepine.

• Neuropathic pain: gabapentin, pregabalin, carbamazepine.

• Obesity: avoid valproate, prefer topiramate.

• Depression/anxiety: levetiracetam may worsen mood; lamotrigine is often preferred.