Antiepleptic drugs moa adr
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Antiepileptic Drugs (AEDs) - Mechanisms of Action & Adverse Effects
Sources: Adams and Victor's Principles of Neurology (12th ed.), Lippincott Illustrated Reviews Pharmacology, Morgan & Mikhail's Clinical Anesthesiology (7th ed.)
Overview of MOA Categories
AEDs work through five broad mechanisms:
- Na⁺ channel blockade - reduces rapid repetitive neuronal firing
- Ca²⁺ channel blockade - especially T-type (thalamic), reduces absence seizures
- GABA potentiation - enhances inhibitory neurotransmission
- Glutamate (AMPA/NMDA) inhibition - reduces excitatory transmission
- Synaptic vesicle protein (SV2A) modulation - reduces neurotransmitter release
Drug-by-Drug Summary
CLASSIC / FIRST-GENERATION AEDs
| Drug | Mechanism of Action | Principal Indications | Adverse Effects |
|---|---|---|---|
| Phenytoin | Na⁺ channel inhibitor (blocks rapid repetitive firing) | Focal & generalized tonic-clonic seizures | Rash/SJS, gingival hyperplasia, hirsutism, peripheral neuropathy, osteoporosis, enzyme inducer; nonlinear (zero-order) pharmacokinetics |
| Carbamazepine | Na⁺ channel inhibitor | Focal seizures, trigeminal neuralgia, bipolar disorder | Hyponatremia (SIADH), drowsiness, dizziness, blurred vision, Stevens-Johnson syndrome, blood dyscrasias (neutropenia, leukopenia, aplastic anemia), cardiac conduction abnormalities; strong enzyme inducer |
| Phenobarbital | GABA-A potentiation - increases Cl⁻ channel opening duration | Focal & most generalized seizures | Sedation, cognitive/behavioral impairment, tolerance, dependence; enzyme inducer |
| Valproic acid | Multiple: GABA potentiation (inhibits GABA reuptake + breakdown), Na⁺ channel blockade, T-type Ca²⁺ channel inhibition, NMDA inhibition | Broadest spectrum - focal, generalized, absence, myoclonic; migraine prophylaxis | Hepatotoxicity (potentially fatal), pancreatitis, hyperammonemic encephalopathy, weight gain, tremor, alopecia, thrombocytopenia, teratogen (neural tube defects, postnatal cognitive effects); enzyme inhibitor |
| Ethosuximide | T-type Ca²⁺ channel blockade (thalamic pacemaker) | Absence seizures ONLY | Insomnia, dizziness, headache, ataxia, weight gain, GI upset; rarely aplastic anemia, hepatic failure |
SECOND-GENERATION AEDs
| Drug | Mechanism of Action | Principal Indications | Adverse Effects |
|---|---|---|---|
| Lamotrigine | Na⁺ AND Ca²⁺ channel inhibition | Focal & generalized seizures; bipolar depression | Rash (potentially SJS - especially with rapid titration or co-use with valproate); generally well tolerated; no enzyme-inducing properties |
| Levetiracetam | SV2A (synaptic vesicle glycoprotein 2A) modulation - reduces neurotransmitter release | Focal, myoclonic, generalized tonic-clonic; very few drug interactions | Irritability, mood changes, psychosis; otherwise well tolerated; virtually no pharmacokinetic interactions |
| Topiramate | Multiple: Na⁺ channels, Ca²⁺ channels, GABA-A potentiation, AMPA glutamate receptor inhibition | Focal & generalized; migraine prophylaxis | Nephrolithiasis, cognitive impairment ("dopamax"), weight loss, metabolic acidosis, paresthesias, acute angle-closure glaucoma |
| Oxcarbazepine | Na⁺ channel inhibitor (keto-analog of carbamazepine) | Focal seizures | Hyponatremia (more than carbamazepine), dizziness, headache, rash; enzyme inducer |
| Gabapentin | Binds α₂δ subunit of voltage-gated Ca²⁺ channels (mechanism not fully understood) | Focal seizures (adjunctive); neuropathic pain | Mild drowsiness, dizziness, ataxia, weight gain, diarrhea; few drug interactions; 100% renal elimination |
| Pregabalin | Same as gabapentin (α₂δ Ca²⁺ channel subunit) | Focal seizures (adjunctive); neuropathic pain, GAD | Similar to gabapentin; weight gain more prominent |
| Zonisamide | Na⁺ channel inhibition + weak T-type Ca²⁺ channel inhibition | Focal & generalized | Nephrolithiasis, cognitive effects, weight loss (similar to topiramate), rash |
| Lacosamide | Enhances slow inactivation of voltage-gated Na⁺ channels (unique mechanism vs. fast inactivation of other Na⁺ blockers) | Focal seizures (adjunctive, ≥16 yrs) | Dizziness, fatigue, nausea, ataxia, prolonged PR interval (cardiac monitoring advised) |
| Vigabatrin | GABA potentiation - irreversible inhibition of GABA transaminase | Infantile spasms (West syndrome); focal seizures | Permanent irreversible visual field defects (retinal toxicity) - requires baseline and serial visual field testing |
THIRD-GENERATION / NEWER AEDs
| Drug | Mechanism of Action | Adverse Effects |
|---|---|---|
| Brivaracetam | SV2A binding (higher affinity than levetiracetam) | Sedation, dizziness, fatigue, irritability; less mood/psychosis risk than levetiracetam |
| Perampanel | Selective AMPA glutamate receptor antagonist | Dizziness, somnolence, aggression, hostility, irritability |
| Cenobamate | Na⁺ channel blockade + GABA-A modulation | Diplopia, dizziness, headache, fatigue; avoid in familial short QT syndrome |
| Cannabidiol | Unknown | Somnolence, decreased appetite, diarrhea, elevated LFTs; obtain AST/ALT/bilirubin at baseline |
| Fenfluramine | Unknown | Decreased appetite, weight loss, somnolence; available only via REMS due to risk of valvular heart disease and pulmonary arterial hypertension |
BENZODIAZEPINES (adjunctive/acute use)
| Drug | Mechanism | Uses | ADR |
|---|---|---|---|
| Clonazepam | GABA-A potentiation (benzodiazepine site) | Absence, myoclonic, Lennox-Gastaut; status epilepticus | Sedation, cognitive impairment, tolerance, withdrawal seizures on abrupt stop |
| Clobazam | GABA-A potentiation (benzodiazepine site) | Lennox-Gastaut (adjunctive, >2 yrs) | Drowsiness, dizziness, depression, aggression; withdrawal seizures on abrupt stop |
| Diazepam / Lorazepam | GABA-A potentiation | Acute seizures / status epilepticus | Sedation, respiratory depression, tolerance |
Key Adverse Effects to Remember (High-Yield)
| ADR | Drug(s) |
|---|---|
| Gingival hyperplasia + hirsutism | Phenytoin |
| Stevens-Johnson Syndrome | Phenytoin, Carbamazepine, Lamotrigine |
| Hyponatremia (SIADH) | Carbamazepine, Oxcarbazepine, Eslicarbazepine |
| Hepatotoxicity | Valproate (also phenytoin, carbamazepine) |
| Teratogenicity (Neural tube defects) | Valproate (highest risk), Carbamazepine, Phenytoin |
| Weight gain | Valproate, Gabapentin, Pregabalin |
| Weight loss | Topiramate, Zonisamide, Felbamate |
| Nephrolithiasis | Topiramate, Zonisamide |
| Cognitive impairment ("dopamax") | Topiramate, Phenobarbital |
| Retinal toxicity / visual field loss | Vigabatrin |
| Mood/psychosis | Levetiracetam |
| Cardiac (PR prolongation) | Lacosamide |
| Blood dyscrasias | Carbamazepine, Ethosuximide, Felbamate |
| Enzyme inducers (↑ P450, reduce other drug levels) | Phenytoin, Carbamazepine, Phenobarbital, Oxcarbazepine |
| Enzyme inhibitor (↑ other drug levels) | Valproate |
Summary: MOA Classification at a Glance
Na⁺ channel blockers: Phenytoin, Carbamazepine, Oxcarbazepine, Lamotrigine,
Lacosamide, Topiramate, Valproate, Zonisamide
Ca²⁺ channel blockers: Ethosuximide (T-type), Gabapentin, Pregabalin (α₂δ),
Lamotrigine, Levetiracetam, Topiramate
GABA potentiators: Phenobarbital, Benzodiazepines, Vigabatrin,
Valproate, Topiramate, Gabapentin (indirect)
Glutamate inhibitors: Topiramate (AMPA), Perampanel (AMPA), Valproate (NMDA)
SV2A modulators: Levetiracetam, Brivaracetam
Adams and Victor's Principles of Neurology, 12th ed., Table 15-5 | Lippincott Illustrated Reviews Pharmacology, Ch. 19 | Morgan & Mikhail's Clinical Anesthesiology, 7th ed., Table 28-3
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