Introduce the classification of Antiepileptic drug (AED)(generation, mechanism, spectrum) and focus on the mechanism of different AED.

1. Antiepileptic Drug Overview
Part 1. Classification, Mechanism and Introduction
2020 June
By Yung-Tsai Chu

2. References
• 台灣癲癇醫學會(2019)。癲癇診療指引。台北市：台灣癲癇醫學會
• Abou-Khalil BW. Update on Antiepileptic Drugs 2019. Continuum (Minneap
Minn). 2019;25(2):508-536.
• Gavvala JR, Schuele SU. New-Onset Seizure in Adults and Adolescents: A
Review. JAMA. 2016;316(24):2657-2668.
• Rogawski MA, Loscher W, Rho JM. Mechanisms of Action of Antiseizure
Drugs and the Ketogenic Diet. Cold Spring Harb Perspect Med. 2016;6(5).
• Schmidt D, Schachter SC. Drug treatment of epilepsy in adults. BMJ.
2014;348:g254.
• Stafstrom CE. The pathophysiology of epileptic seizures: a primer for
pediatricians. Pediatr Rev. 1998;19(10):342-351.

3. Classification
• Generation
• Old: more experience and solid efficacy, lower cost
• New: less drug-drug interaction or side effect
• Mechanism/Spectrum
• Voltage gated ion channel: Na, Ca, etc.
• Neurotransmitter: GABA, Glutamate(AMPA, NMDA receptor)
• Other: carbonic anhydrase inhibitor, SV2A inhibitor
• Indication
• Types of seizure
• Monotherapy or adjunctive therapy

4. Classification, Mechanism and
Introduction

5. Old generation
• Low cost, proven efficacy, more side effect or require more
monitoring
• BZD: Clonazepam, Clobazam
• Barbiturate: phenobarbital
• Phenytoin
• Carbamazepine – Focal seizure
• Valproate – Effective in generalized epilepsy and absence seizures

6. Mechanism/Spectrum
• Broad spectrum: no clear definition or standard
• Effective in both generalized and focal-onset seizures
• Valproate
• Levetiracetam
• Topiramate
• Zonisamide
• Lamotrigine
• Perampanel
Gavvala JR, Schuele SU. New-Onset Seizure in Adults and Adolescents: A Review. JAMA. 2016;316(24):2657-2668.

7. Action Potential
Na K
P/Q
Ca
NMDA
T
Ca
AMPA
GABA
SV2A
Glutamate
Synapse
Inhibitory
Excitatory
Excitatory
Excitatory
Vesicle release
Rogawski MA, Loscher W, Rho JM. Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet. Cold Spring Harb Perspect Med. 2016;6(5).

8. Action Potential
Na K
T
Ca
Synapse
Excitatory
Rogawski MA, Loscher W, Rho JM. Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet. Cold Spring Harb Perspect Med. 2016;6(5).

9. Action Potential
Na K
T
Ca
Synapse
Excitatory
Rogawski MA, Loscher W, Rho JM. Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet. Cold Spring Harb Perspect Med. 2016;6(5).
Phenytoin
Carbamazepine, Oxcarbazepine
Lamotrigine
Lacosamide
Zonisamide
Topiramate
Ethosuximide
Valproate
Lamotrigine
Zonisamide

10. Action Potential
Na K
P/Q
Ca
SV2A
Synapse
Vesicle release
Rogawski MA, Loscher W, Rho JM. Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet. Cold Spring Harb Perspect Med. 2016;6(5).

11. Action Potential
Na K
P/Q
Ca
SV2A
Synapse
Vesicle release
Rogawski MA, Loscher W, Rho JM. Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet. Cold Spring Harb Perspect Med. 2016;6(5).
Levetiracetam
Brivaracetam
Gabapentin
Pregabalin

12. Action Potential
Na K
P/Q
Ca
NMDA
AMPASV2A
Glutamate
Synapse
Excitatory
Excitatory
Vesicle release
Rogawski MA, Loscher W, Rho JM. Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet. Cold Spring Harb Perspect Med. 2016;6(5).

13. Action Potential
Na K
P/Q
Ca
NMDA
AMPASV2A
Synapse
Excitatory
Excitatory
Vesicle release
Rogawski MA, Loscher W, Rho JM. Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet. Cold Spring Harb Perspect Med. 2016;6(5).
Perampanel
Topiramate
Felbamate
(Ketamine)
Glutamate
Valproate
Phenobarbital

14. Action Potential
Na K
P/Q
Ca
NMDA
AMPASV2A
Glutamate
Synapse
Vesicle release
T
Ca
GABA Inhibitory
Excitatory
Rogawski MA, Loscher W, Rho JM. Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet. Cold Spring Harb Perspect Med. 2016;6(5).

15. Action Potential
Na K
P/Q
Ca
NMDA
AMPASV2A
Glutamate
Synapse
Vesicle release
T
Ca
GABA Inhibitory
Excitatory
Rogawski MA, Loscher W, Rho JM. Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet. Cold Spring Harb Perspect Med. 2016;6(5).
BZD
Barbiturate

16. Action Potential
Na K
P/Q
Ca
NMDA
T
Ca
AMPA
GABA
SV2A
Glutamate
Synapse
Inhibitory
Excitatory
Excitatory
Excitatory
Vesicle release
Rogawski MA, Loscher W, Rho JM. Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet. Cold Spring Harb Perspect Med. 2016;6(5).

17. Therapeutic Targets of AED
• Ion channel:
• Na, Action potential
• Ca, T-type: Membrane potential, P/Q type: neurotransmitter release
• K channel: potential target but few therapeutic options for now
• Neurotransmitter:
• GABA: inhibitory
• Glutamate(on AMPA and NMDA receptor): excitatory
• Overall neurotransmitter release(SV2A, P/Q type Ca channel)
• Alter neuronal excitability and electrical discharges
• Traditional thinking: decrease excitability, increase inhibition
• Could not full explain the seizure mechanism and the effect of AED and other Tx
Rogawski MA, Loscher W, Rho JM. Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet. Cold Spring Harb Perspect Med. 2016;6(5).

18. Sodium channel blocker
• Phenytoin(PHT)
• prolong its fast inactivated state, thus reducing high-frequency firing as might
occur during a seizure
• Carbamazepine(CBZ), Oxcarbazepine(OXC)
• Lamotrigine(LTG)
• Lacosamide(LCM) enhance slow inactivation state
• Other
• Zonisamide(ZNS)
• Topiramate(TPM)

19. Sodium channel blocker
• Effective for focal-onset seizure
• Could worsen absence or myoclonic seizures
• Common side effects: Dizziness, ataxia, diplopia, nystagmus
• Risk of skin rash(related to aromatic chemical structure), SJS
• CV risk: AV block(LCM) and arrhythmia(PHT)

20. Calcium channel blocker
• Not directly participate in action potential but are related to membrane
potential
• T-type Ca channel: Ethosuximide for absence Seizures
• Not available in Taiwan
• Valproate
• Lamotrigine
• Zonisamide
• α2δ subunit of P/Q-type Ca channel(pre-synaptic terminal, related to
excitatory neurotransmitter release)
• Gabapentin
• Pregabalin
• Adjunctive use only

21. GABA transmission
• Via GABA-A receptor
• BZD: Clonazepam, Clobazam(no clinical hepatotoxicity)
• Barbiturate: phenobarbital(with other pathway such as glutamate)
• Sedation
• Cardio-respiratory depression
• Tolerance, withdrawal and addiction
• Adjunctive use only
• GABA metabolism: Vigabatrin, Tiagabine
• Valproate
• Topiramate
• Gabapentin?

22. Glutamate-related pathway
• AMPA receptor
• Perampanel
• Topiramate
• NMDA receptor
• Felbamate(rarely used due to risk of liver failure)
• (Ketamine)
• Other AEDs may affect glutamate transmission
• Valproate
• Phenobarbital

23. Neurotransmitter Release
• SV2A(Synaptic vesicle glycoprotein 2A ) → inhibit excitatory
neurotransmitter release
• Levetiracetam(also Ca channel and GABA?)
• Brivaracetam
• α2δ subunit of P/Q-type Ca channel(pre-synaptic terminal, related to
excitatory neurotransmitter release)
• Gabapentin
• Pregabalin
• Adjunctive use for focal seizure only

24. Other Mechanism
• Carbonic anhydrase activity → metabolic acidosis, risk of renal stone
• Acetazolamide (for catamenial epilepsy)
• Topiramate(weak)
• Zonisamide(weak)

25. Action Potential
Na K
P/Q
Ca
NMDA
T
Ca
AMPA
GABA
SV2A
Glutamate
Synapse
Inhibitory
Excitatory
Excitatory
Excitatory
Vesicle release
Rogawski MA, Loscher W, Rho JM. Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet. Cold Spring Harb Perspect Med. 2016;6(5).

26. Consideration
• Types of seizure
• Some AED may exacerbate certain types of seizures, e.g. CBZ and PHT exacerbate
absence or myoclonic seizures
• Pharmacokinetic and dosing
• Metabolism, excretion, protein-binding
• Side effect profile
• Kidney, liver, CV, Skin side effect
• Teratogenicity (Extreme high risk: Valproate, Phenobarbital, low risk: Levetiracetam,
Oxacarbazepine, Lamotrigine)
• Weight, Osteoporosis
• Comorbidity
• Drug-drug interaction(both AED and non-AED)
• Other indication(migraine, mood stabilizer, neuropathic pain… etc.)

27. Types of Seizure(ILAE 2017)

28. Types of Seizure(ILAE 2017)
Onset: Focal, generalized, unknown1

29. Types of Seizure(ILAE 2017)
Onset: Focal, generalized, unknown1
2
• Focal: awareness? Motor/non-motor?
Secondary generalization? (Focal to Bilateral Tonic-Clonic)
• Generalized: Motor/non-motor?
• Motor- GTC(Generalized tonic-clonic seizures),
myoclonic(e.g. JME), etc.
• Non-motor
• Absence(Typical/Atypical) etc.
• Unknown-onset: broad spectrum first…

30. Summary of AED Mechanism
Mechanism
Seizure type
(Blue: broad spectrum)
Phenytoin Na(fast) Focal, GTC (may aggravate absence, myoclonic sx)
Carbamazepine Na(fast) Focal, GTC (may aggravate absence, myoclonic sx)
Oxcarbazepine Na(fast) Focal, GTC (may aggravate absence, myoclonic sx)
Lacosamide Na(slow) Focal
Lamotrigine Na(fast), Ca? Glutamate(pre) Focal, GTC, LGS, absence, myoclonic(somtimes aggravate)
Valproate Na, Ca(T), Glutamate(NMDA), GABA, etc. Focal, GTC, absence, myoclonic
Topiramate Na, CA inhibitor, Glutamate(AMPA) Focal, GTC, LGS
Zonisamide Na, Ca(T), CA inhibitor, Glutamate(pre) Focal, GTC
Levetiracetam SV2A, GABA? Ca? Focal, GTC, myoclonic, LGS
Ethosuximide T-type Ca absence
Perampanel AMPA receptor non-competitive antagonist Focal(mono), generalized(adjunctive)
Gabapentin α2δ P/Q-type Ca, GABA modulation Focal(adjunctive), (may aggravate absence, myoclonic sx)
Pregabalin α2δ P/Q-type Ca Focal(adjunctive), (may aggravate absence, myoclonic sx)
Phenobarbital GABA, Glutamate? Focal, GTC
Clobazam GABA(BZD) LGS(adjunctive)
Vigabatrin GABA (transaminase inhibitor) Focal, infantile spasm

31. Consideration to choose AED
• Type of seizure → Indication, risk of Seizure exacerbation
• Contraindication
• Renal/Liver/Heart conditions
• Drug-drug interaction, P450 enzyme inducer/inhibitor
• Side/Additional effect profile
• Scenario: pregnancy, post-stroke seizure, elderly, migraine,
neuropathic pain, mood disorder