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
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.
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
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)