Phenytoin
Main indications
Focal seizures; established convulsive status epilepticus follow-on therapy
Mechanism
Fast voltage-gated Na⁺ channel inactivation
Wise drug choice
Antiseizure medicine guide
There is no universally “best” antiseizure medicine. The right drug is the one that matches the seizure biology and the person while imposing the least avoidable treatment burden.
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Selection by seizure type comes first
The table below from the ANZGMU teaching framework has been expanded and updated for web use. It is an orientation tool, not a substitute for the Australian product information, PBS/TGA conditions, local protocols or specialist judgement.
| Seizure / epilepsy type | Typical medicine approach | Wise-choice cautions |
|---|---|---|
| Focal seizures | Lamotrigine or levetiracetam are widely guideline-supported initial options; carbamazepine/oxcarbazepine, lacosamide and others may be appropriate depending on the person. | Avoid choosing solely by habit: mood, cognition, pregnancy potential, interactions, cardiac conduction, sodium and comorbidities matter. |
| Generalized tonic-clonic seizures | Lamotrigine, levetiracetam or valproate are common broad-spectrum choices; reproductive safety can materially change the decision. | Check for coexisting absence or myoclonic seizures before using narrow-spectrum sodium-channel agents. |
| Absence seizures | Ethosuximide when pure absence epilepsy; broader-spectrum treatment if other seizure types coexist. | Carbamazepine, oxcarbazepine and phenytoin can worsen absence seizures. |
| Myoclonic seizures / JME | Levetiracetam or valproate are common core options; individual regulatory and reproductive considerations are crucial. | Carbamazepine, oxcarbazepine and phenytoin can worsen myoclonus; lamotrigine can occasionally exacerbate it. |
| Tonic / atonic seizures | Syndrome-based specialist management; lamotrigine or valproate are common options, with adjunctive choices depending on syndrome. | Think Lennox–Gastaut and other developmental epileptic encephalopathies; treatment is rarely a one-drug algorithm. |
| Convulsive status epilepticus | Immediate benzodiazepine followed by protocol-driven second-line therapy. | This is an emergency pathway, not ordinary outpatient medicine selection. |
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Phenobarbital
Main indications
Focal/generalized seizures; neonatal seizures; selected status settings
Mechanism
GABA-A potentiation
Primidone
Main indications
Focal seizures; essential tremor
Mechanism
Converted partly to phenobarbital; GABAergic effects
Carbamazepine
Main indications
Focal epilepsy; trigeminal neuralgia
Mechanism
Use-dependent Na⁺ channel blockade
Oxcarbazepine
Main indications
Focal epilepsy
Mechanism
Na⁺ channel blockade via active monohydroxy metabolite
Eslicarbazepine acetate
Main indications
Focal epilepsy
Mechanism
Slow/inactivated-state Na⁺ channel modulation
Lamotrigine
Main indications
Focal and generalized epilepsies
Mechanism
Na⁺ channel blockade; reduced glutamate release
Lacosamide
Main indications
Focal seizures; add-on in generalized tonic-clonic in some jurisdictions
Mechanism
Enhances slow Na⁺ channel inactivation
Valproate / sodium valproate
Main indications
Broad-spectrum, especially generalized/myoclonic epilepsies
Mechanism
Multimodal: ↑GABA, Na⁺ and T-type Ca²⁺ effects
Ethosuximide
Main indications
Typical absence seizures
Mechanism
T-type Ca²⁺ channel blockade
Levetiracetam
Main indications
Focal and generalized epilepsies, including myoclonic seizures
Mechanism
SV2A synaptic vesicle binding
Brivaracetam
Main indications
Focal seizures; broader use varies by jurisdiction
Mechanism
High-affinity SV2A binding
Topiramate
Main indications
Focal/generalized seizures; Lennox–Gastaut; migraine prevention
Mechanism
Na⁺ block, AMPA antagonism, GABA effects, carbonic anhydrase inhibition
Zonisamide
Main indications
Focal seizures; broader-spectrum use
Mechanism
Na⁺ and T-type Ca²⁺ blockade; carbonic anhydrase activity
Perampanel
Main indications
Focal seizures and generalized tonic-clonic seizures
Mechanism
Non-competitive AMPA receptor antagonist
Cenobamate
Main indications
Focal-onset seizures in adults
Mechanism
Na⁺ channel modulation plus positive allosteric GABA-A effects
Clobazam
Main indications
Lennox–Gastaut; adjunctive/rescue strategies
Mechanism
1,5-benzodiazepine; GABA-A potentiation
Clonazepam
Main indications
Myoclonic and selected generalized seizures
Mechanism
Benzodiazepine; GABA-A potentiation
Diazepam
Main indications
Acute seizure rescue/status epilepticus
Mechanism
Benzodiazepine; GABA-A potentiation
Lorazepam
Main indications
Convulsive status epilepticus
Mechanism
Benzodiazepine; GABA-A potentiation
Midazolam
Main indications
Acute seizures/status via buccal, intranasal, IM or IV routes depending protocol
Mechanism
Benzodiazepine; GABA-A potentiation
Gabapentin
Main indications
Adjunctive focal seizures; neuropathic pain
Mechanism
α2δ subunit modulation of voltage-gated Ca²⁺ channels
Pregabalin
Main indications
Adjunctive focal seizures; neuropathic pain/anxiety indications vary
Mechanism
α2δ subunit modulation of voltage-gated Ca²⁺ channels
Rufinamide
Main indications
Lennox–Gastaut syndrome
Mechanism
Prolongs inactive state of Na⁺ channels
Vigabatrin
Main indications
Infantile spasms; selected refractory focal epilepsy
Mechanism
Irreversible GABA-transaminase inhibition
Tiagabine
Main indications
Adjunctive focal seizures
Mechanism
GAT-1 GABA reuptake inhibition
Felbamate
Main indications
Refractory epilepsy, especially Lennox–Gastaut
Mechanism
NMDA antagonism plus GABAergic effects
Stiripentol
Main indications
Dravet syndrome, usually with clobazam/valproate
Mechanism
Enhances GABAergic transmission and inhibits CYP enzymes
Cannabidiol
Main indications
Dravet, Lennox–Gastaut and selected syndromes depending jurisdiction
Mechanism
Multiple mechanisms including modulation of neuronal signalling
Fenfluramine
Main indications
Dravet syndrome and selected developmental epileptic encephalopathies depending jurisdiction
Mechanism
Serotonergic and sigma-1 receptor effects
View the complete drug reference table
| Drug | Main mechanism | Approximate half-life | Important adverse effects | Main indications | Typical place in therapy |
|---|---|---|---|---|---|
| Phenytoin | Fast voltage-gated Na⁺ channel inactivation | ~22 h; nonlinear kinetics | Ataxia, diplopia, gingival hyperplasia, rash, osteopenia; many interactions | Focal seizures; established convulsive status epilepticus follow-on therapy | Older effective focal agent; usually not preferred for routine long-term initiation when better-tolerated options are suitable. |
| Phenobarbital | GABA-A potentiation | ~53–118 h | Sedation, cognitive impairment, mood effects, dependence, enzyme induction | Focal/generalized seizures; neonatal seizures; selected status settings | Highly effective but burdened by sedation, cognition and interactions; remains important in selected and resource-limited settings. |
| Primidone | Converted partly to phenobarbital; GABAergic effects | ~10–15 h (parent) | Sedation, dizziness, ataxia | Focal seizures; essential tremor | Older option, now rarely a preferred epilepsy medicine because of tolerability and interaction burden. |
| Carbamazepine | Use-dependent Na⁺ channel blockade | ~12–17 h after autoinduction | Diplopia, dizziness, hyponatraemia, leukopenia, rash; enzyme induction | Focal epilepsy; trigeminal neuralgia | Strong focal-seizure efficacy; avoid in several generalized epilepsies because it can worsen absence/myoclonic seizures. |
| Oxcarbazepine | Na⁺ channel blockade via active monohydroxy metabolite | Active metabolite ~9 h | Hyponatraemia, dizziness, diplopia | Focal epilepsy | Useful focal option with fewer enzyme interactions than carbamazepine, but hyponatraemia can be limiting. |
| Eslicarbazepine acetate | Slow/inactivated-state Na⁺ channel modulation | ~20–24 h | Hyponatraemia, dizziness, diplopia | Focal epilepsy | Once-daily focal option; consider renal function and sodium. |
| Lamotrigine | Na⁺ channel blockade; reduced glutamate release | ~25–33 h; longer with valproate | Rash/SJS risk, dizziness, diplopia, insomnia; levels fall in pregnancy | Focal and generalized epilepsies | Versatile, generally cognitively well tolerated. Slow titration is essential; can occasionally worsen myoclonus. |
| Lacosamide | Enhances slow Na⁺ channel inactivation | ~13 h | Dizziness, diplopia, ataxia, PR prolongation | Focal seizures; add-on in generalized tonic-clonic in some jurisdictions | Useful focal option with few interactions; review conduction disease and interacting cardiac medicines. |
| Valproate / sodium valproate | Multimodal: ↑GABA, Na⁺ and T-type Ca²⁺ effects | ~9–16 h | Weight gain, tremor, thrombocytopenia, hepatic/pancreatic toxicity; major reproductive risks | Broad-spectrum, especially generalized/myoclonic epilepsies | Often highly effective for generalized epilepsies but reproductive risks can dominate choice. Requires explicit pregnancy/family-planning counselling and current regulatory guidance. |
| Ethosuximide | T-type Ca²⁺ channel blockade | ~40–60 h | GI upset, fatigue, headache, rare blood dyscrasias | Typical absence seizures | A focused first-line option when absence seizures occur without other seizure types. |
| Levetiracetam | SV2A synaptic vesicle binding | ~6–8 h | Irritability, aggression/mood change, somnolence, dizziness | Focal and generalized epilepsies, including myoclonic seizures | Important broad-use medicine with few interactions and rapid titration. Behavioural vulnerability and reflex default prescribing deserve deliberate consideration. |
| Brivaracetam | High-affinity SV2A binding | ~9 h | Somnolence, dizziness, irritability | Focal seizures; broader use varies by jurisdiction | Useful SV2A alternative; do not generally combine with levetiracetam because they share the same target. |
| Topiramate | Na⁺ block, AMPA antagonism, GABA effects, carbonic anhydrase inhibition | ~21 h | Cognitive slowing, word-finding difficulty, weight loss, paraesthesia, nephrolithiasis, metabolic acidosis | Focal/generalized seizures; Lennox–Gastaut; migraine prevention | Broad-spectrum but cognitive and metabolic adverse effects often determine suitability; reproductive safety requires attention. |
| Zonisamide | Na⁺ and T-type Ca²⁺ blockade; carbonic anhydrase activity | ~46–63 h | Weight loss, cognitive effects, kidney stones, metabolic acidosis, rash | Focal seizures; broader-spectrum use | Convenient long half-life; consider renal stones, weight and sulfonamide-related concerns. |
| Perampanel | Non-competitive AMPA receptor antagonist | ~105 h | Dizziness, gait disturbance, irritability/aggression | Focal seizures and generalized tonic-clonic seizures | Once-daily broad adjunctive option; behavioural adverse effects and long half-life need anticipation. |
| Cenobamate | Na⁺ channel modulation plus positive allosteric GABA-A effects | ~50–60 h | Somnolence, dizziness, drug interactions; DRESS risk with rapid titration; QT shortening | Focal-onset seizures in adults | Highly effective newer focal option for selected adults, usually after prior treatment failure; requires slow titration and interaction review. |
| Clobazam | 1,5-benzodiazepine; GABA-A potentiation | ~36–42 h; active metabolite longer | Sedation, tolerance, dependence, drooling | Lennox–Gastaut; adjunctive/rescue strategies | Useful adjunct where intermittent or syndrome-specific benzodiazepine therapy is appropriate; plan for tolerance/dependence. |
| Clonazepam | Benzodiazepine; GABA-A potentiation | ~30–40 h | Sedation, tolerance, dependence | Myoclonic and selected generalized seizures | Can be effective for myoclonus but long-term use is limited by sedation and tolerance. |
| Diazepam | Benzodiazepine; GABA-A potentiation | ~20–50 h | Sedation, respiratory depression | Acute seizure rescue/status epilepticus | Emergency/rescue medicine rather than routine maintenance therapy. |
| Lorazepam | Benzodiazepine; GABA-A potentiation | ~12–15 h | Sedation, respiratory depression | Convulsive status epilepticus | Common first-line IV hospital treatment for status epilepticus. |
| Midazolam | Benzodiazepine; GABA-A potentiation | ~2–6 h | Sedation, respiratory depression | Acute seizures/status via buccal, intranasal, IM or IV routes depending protocol | Practical rescue medicine because non-IV routes are available; follow the individual's emergency plan. |
| Gabapentin | α2δ subunit modulation of voltage-gated Ca²⁺ channels | ~5–7 h | Somnolence, dizziness, oedema, weight gain | Adjunctive focal seizures; neuropathic pain | Usually more useful outside epilepsy than as a core antiseizure medicine; renal dosing required. |
| Pregabalin | α2δ subunit modulation of voltage-gated Ca²⁺ channels | ~6 h | Dizziness, somnolence, oedema, weight gain | Adjunctive focal seizures; neuropathic pain/anxiety indications vary | Generally not a preferred epilepsy drug when alternatives exist; renal dosing and misuse potential matter. |
| Rufinamide | Prolongs inactive state of Na⁺ channels | ~6–10 h | Dizziness, nausea, somnolence; QT shortening | Lennox–Gastaut syndrome | Syndrome-specific adjunct, particularly for drop attacks in Lennox–Gastaut. |
| Vigabatrin | Irreversible GABA-transaminase inhibition | ~5–8 h (effect lasts longer) | Permanent visual field loss risk, sedation, weight gain; MRI changes in infants | Infantile spasms; selected refractory focal epilepsy | Reserve/syndrome-specific therapy requiring visual-risk counselling and monitoring. |
| Tiagabine | GAT-1 GABA reuptake inhibition | ~7–9 h | Dizziness, confusion, tremor; can provoke seizures in people without epilepsy | Adjunctive focal seizures | Reserve adjunctive therapy, now infrequently used. |
| Felbamate | NMDA antagonism plus GABAergic effects | ~20 h | Aplastic anaemia and hepatic failure | Refractory epilepsy, especially Lennox–Gastaut | Reserve therapy only when potential benefit justifies rare but severe toxicity and monitoring burden. |
| Stiripentol | Enhances GABAergic transmission and inhibits CYP enzymes | ~13 h | Somnolence, appetite/weight loss, interactions | Dravet syndrome, usually with clobazam/valproate | Syndrome-specific therapy managed with attention to major pharmacokinetic interactions. |
| Cannabidiol | Multiple mechanisms including modulation of neuronal signalling | ~18–32 h | Diarrhoea, somnolence, appetite change, elevated transaminases; interactions | Dravet, Lennox–Gastaut and selected syndromes depending jurisdiction | Syndrome-specific adjunct; monitor liver function and interactions, especially with valproate/clobazam. |
| Fenfluramine | Serotonergic and sigma-1 receptor effects | ~20 h | Reduced appetite/weight; cardiac monitoring requirements | Dravet syndrome and selected developmental epileptic encephalopathies depending jurisdiction | Specialist syndrome-specific therapy with mandated cardiovascular surveillance. |
Special populations can reverse the ranking
Pregnancy potential, older age, renal or hepatic disease, mood disorder, cognitive vulnerability, obesity/low weight, nephrolithiasis, cardiac conduction disease, contraception and interacting medicines may be more important than a generic first-line list.
Pharmacokinetics matter
Half-life, renal clearance, enzyme induction/inhibition, nonlinear kinetics and active metabolites influence dosing, interactions, pregnancy management, therapeutic drug monitoring and how safely a medicine can be changed.
Source lineage: core comparative material adapted from Dr Balaji Kalband's ANZGMU 2026 presentation “Seizures: What do I do?” (final version 3), with updated terminology and a broader current medicine list. Clinical cross-checks: ILAE classification resources, NICE NG217 treatment guidance, Australian TGA safety communications and product information. Half-lives are approximate and can vary with age, organ function, interacting drugs, formulation and dose.