DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

models—together with careful attention to clinically
relevant concentrations of the drugs—led to clarification
of their mechanisms. Although it is difficult to
prove unequivocally that a given drug effect observed in
vitro is both necessary and sufficient to inhibit a seizure
in an animal or humans in vivo, there is an excellent
likelihood that the putative mechanisms identified do
in fact underlie the clinically relevant anti-seizure
effects. Table 21–2 summarizes putative mechanisms
of action of anti-seizure drugs.
Electrophysiological analyses of individual neurons
during a partial seizure demonstrate that the neurons
undergo depolarization and fire action potentials at
high frequencies (Figure 21–1). This pattern of neuronal
firing is characteristic of a seizure and is uncommon
during physiological neuronal activity. Thus, selective
inhibition of this pattern of firing would be expected to
reduce seizures with minimal unwanted effects.
Carbamazepine, lamotrigine, phenytoin, and valproic
acid inhibit high-frequency firing at concentrations
Table 21–2
Proposed Mechanisms of Action of Anti-Seizure Drugs
MOLECULAR TARGET AND ACTIVITY DRUG CONSEQUENCES OF ACTION
Na + channel modulators that:
enhance fast inactivation PHT, CBZ, LTG, • block action potential propagation
FBM, OxCBZ, • stabilize neuronal membranes
TPM, VPA
• b neurotransmitter release, focal firing, and seizure spread
enhance slow inactivation LCM • a spike frequency adaptation
• b AP bursts, focal firing, and seizure spread
• stabilize neuronal membrane
Ca 2+ channel blockers ESM, VPA, LTG • b neurotransmitter release (N- & P-types)
• b slow-depolarization (T-type) and spike-wave discharges
α2δ ligands GBP, PGB • modulate neurotransmitter release
GABA A
receptor allosteric BZDs, PB, FBM, • a membrane hyperpolarization and seizure threshold
modulators TPM, CBZ, OxCBZ • b focal firing
BZDs—attenuate spike-wave discharges
PB, CBZ, OxCBZ—aggravate spike-wave discharges
GABA uptake inhibitors/ TGB, VGB • a extrasynaptic GABA levels and membrane
GABA-transaminase inhibitors
hyperpolarization
• b focal firing
• aggravate spike-wave discharges
NMDA receptor antagonists FBM • b slow excitatory neurotransmission
• b excitatory amino acid neurotoxicity
• delay epileptogenesis
AMPA/kainate receptor PB, TPM • b fast excitatory neurotransmission and focal firing
antagonists
Enhancers of HCN channel LTG • buffers large hyperpolarizing and depolarizing inputs
activity
• suppresses action potential initiation by dendritic inputs
SV2A protein ligand LEV • unknown; may decrease transmitter release
Inhibitors of brain carbonic ACZ, TPM, ZNS • a HCN-mediated currents
anhydrase
• b NMDA-mediated currents
• a GABA-mediated inhibition
ACZ, acetazolamide; BZDs, benzodiazepines; CBZ, carbamazepine; FBM, felbamate; GBP, gabapentin; LEV, levetiracetam; LCM, lacosamide;
LTG, Lamotrigine; OxCBZ, oxcarbazepine; PB, phenobarbital; PGB, pregagalin; PHT, phenytoin; TGB, tiagabine; TPM, topiramate; VGB, vigabatrin;
VPA, valproic acid; ZNA, zonisamide. Modified with permission from Leppik IE, Kelly KM, deToledo-Morrell L et al. Basic research in
epilepsy and aging. Epilepsy Res, 2006, 68 (Suppl 1): 21. Copyright© Elsevier.