Disclosures. Mechanism of Action Importance. Advances in Epilepsy Management: Does Mechanism-of- Action Matter?

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1 Advances in Epilepsy Management: Does Mechanism-of- Action Matter? Barry E. Gidal, PharmD University of Wisconsin-Madison School of Pharmacy & Dept. of Neurology Disclosures Speaking honoraria: UCB, Eisai, Sunovion Consultant: UCB, Eisai, Sunovion, Upsher-Smith, Acorda, Epilepsy Consortium Mechanism of Action Importance Understanding mechanisms of seizure generation leads to development of AEDs Understanding AED MOA leads to better understanding of mechanisms of seizure generation MOA understanding may help in appropriate AED selection MOA considered in combination therapy Adverse effects of AEDs may be dependent on MOA

2 Mechanism(s) of Action Epilepsy = Inherited or acquired malfunction of neuronal channels or neurotransmitter systems Imbalance between excitatory and inhibitory processes Current AEDs work by modulating: Sodium channels Calcium channels Potassium channels GABA Receptors Glutamate Receptors Carbonic Anhydrase Each AED has a very distinct MOA Rogawski M, Cavasos J. Mechanisms of Action of Antiepileptic Drugs. In : Treatment of Epilepsy. Principles and Practice. Wyllie eds. 6 th. Ed AED Mechanisms of Action Inhibitory Synapse Excitatory Synapse GABA Glutamate GABA B SV2A CI - K + mglur VGPC Intracellular signaling pathways regulating excitability in the postsynaptic neuron =voltage-gated sodium channel; SV2A=synaptic vesicle protein; =voltage-gated calcium channel; VGPC=voltagegated potassium channel; AMPA=α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA=N-methyl-D-aspartate receptor; mglur=metabotropic glutamate receptor. Adapted from Johannessen Landmark C, et al. Drugs. 2008;68: Löscher W, Schmidt D. (2012) Nat. Rev. Neurol. doi: /nrneurol

3 Physiology of Voltage-Gated Sodium Channels Classical AEDs Carbamazepine, phenytoin, lamotrgine Repolarization Resting membrane potential Resting state Inactivated statefast (within ms) Depolarization Inactivated stateslow (within sec and beyond) Local anesthetics lidocaine Open state Regulation of sodium channel long-term availability Lacosamide Beyreuther BK, et al. CNS Drug Rev. 2007;13: Sodium Channel Subtypes Alpha subunit gene Channel Notes SCN1A Na v 1.1 SCN2A Na v 1.2 SCN3A Na v 1.3 Major channel in inhibitory neurons Major channel in excitatory neurons Mostly in immature brain In axon initial segment Mostly in immature brain SCN8A Na v 1.6 Major channel in excitatory neurons Prevalent during maturation Löscher W, Schmidt D. (2012) Nat. Rev. Neurol. doi: /nrneurol

4 Voltage-Gated Calcium Channels Contribute to excitability of neurons Closely involved in burst firing Control neurotransmitter release at pre synaptic nerve terminal Calcium Channel Subtypes Category Highvoltageactivated Low Channel Type N P/Q R L Notes Involved pre-synaptic neurotransmitter release Involved pre-synaptic neurotransmitter release Involved pre-synaptic neurotransmitter release Involved with processing synaptic inputs at somatodendritic level Open in response to modest depolarizations Affect intrinsic oscillatory Calcium Channel Morphology Single alpha-subunit Pore-forming region Ion sensor 7 known subtypes Beta-subunit Modulate function Gamma-subunit Modulate function Alpha 2 -delta subunit Modulate function On presynaptic membrane /941

5 Calcium Channel Blocking AEDs AED Ethosuximide, zonisamide, valproate Lamotrigine Target Receptor T-type N- and P/Q-type Levetiracetam Phenobarbital, topiramate, felbamate Gabapentin, pregabalin Partial blockade N-type HVA, exact type unknown Bind to alpha2-delta subunit Potassium Channel Morphology More than 40 types of alpha-subunits Responsible for repolarization of cell membrane Regulate input and output balance Four alpha-subunits arranged around a potassium pore All alpha-subunits from same family 12 sub-families, K v 1 to K v 12 large.jpg AED Mechanisms of Action Inhibitory Synapse Excitatory Synapse GABA Glutamate GABA B SV2A CI - K + mglur VGPC Intracellular signaling pathways regulating excitability in the postsynaptic neuron =voltage-gated sodium channel; SV2A=synaptic vesicle protein; =voltage-gated calcium channel; VGPC=voltagegated potassium channel; AMPA=α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA=N-methyl-D-aspartate receptor; mglur=metabotropic glutamate receptor. Adapted from Johannessen Landmark C, et al. Drugs. 2008;68:

6 Inhibitory Neurotransmission GABA predominant inhibitory neurotransmitter Synthesized by enzyme glutamic acid decarboxylase Acts on GABA A and GABA B receptors GABA removed from synaptic cleft by transporter protein family GAT-1, GAT-2, GAT-3, BGT-1 GABA recycled to readily releasable pool or inactivated by GABA-transaminase Rogawski M, Cavasos J. Mechanisms of Action of Antiepileptic Drugs. In : Treatment of Epilepsy. Principles and Practice. Wyllie eds. 6 th. Ed GABA A Receptor Agonist AEDs AED Subunits Notes Barbiturates Benzodiazepi ne (except clobazam) Clobazam Felbamate, topiramate At least 1 alpha At least 1 beta 2 alpha (1,2 or 3) 2 beta 1 gamma 2 alpha (1,5) 2 beta 1 gamma Unknown Increase duration of channel opening Direct activation of GABA A receptor in absence of GABA Increase frequency of channel opening Delta subunit containing receptors insensitive to benzodiazepines Similar effects as other benzodiazepines Less tolerance, sedation GABA Turnover AEDs AED Notes Vigabatrin Irreversible inhibitor of GABAtransaminase Tiagabine Blocks GABA transport out of synaptic cleft Selective for GAT-1 GAT-1 more prevalent in hippocampus and neocortex Valproate, gabapentin, topiramate Influence GABA turnover, exact mechanism unknown gy/gaba_transporter_biology/ Rogawski M, Cavasos J. Mechanisms of Action of Antiepileptic Drugs. In : Treatment of Epilepsy. Principles and Practice. Wyllie eds. 6 th. Ed

7 Glutamate Receptors and Their Role in the CNS 1-3 Glutamate is the principal excitatory neurotransmitter in the CNS Ionotropic glutamate receptors AMPA, NMDA, and kainate Mediate the rapid actions at the glutamate excitatory synapse Normally they are in the closed state. However, binding of glutamate causes the receptors to gate to the open state AMPA and NMDA receptors have distinct roles AMPA and NMDA are main types that mediate fast glutamatergic neurotransmission, with AMPA mediating normal synaptic transmission 3 NMDA receptors are relatively stable at synapses, versus AMPA receptors, which dynamically move into and out of the postsynaptic membrane 3 Post-synaptic Neuron Excitatory Pre-Synaptic Terminal K + NMDA Recepto r, Propagated Action Potential Depolarizatio n Vesicular Release Glutamat e K + AMPA Receptor, Voltage-dependent sodium channel Outside Kainate Receptor Inside CNS=central nervous system. 1. Rogawski MA. Epilepsy Curr. 2011;11: Rho JM, Sankar R. Epilepsia. 1999;40: Rogawski MA. Acta Neurol Scand. 2013;127(Suppl 197): AMPA Receptor Structure AMPA receptors 1 : Transduce the glutamate signal into a depolarization of the postsynaptic neuron (EPSP) 1,2 Mediate the bulk of fast excitatory neurotransmission in the brain Are critical to the generation of seizure activity in seizure foci and also to the spread of seizures within the brain Are primary contributors to the depolarization phase of the paroxysmal depolarization shift (PDS), which reflects interictal activity 1,2 1. Rogawski MA. Epilepsy Curr. 2011;11: Westbrook GL. Seizures and epilepsy. In: Kandel ER et al, eds. Principles of Neural Science. 5th ed. New York, NY: McGraw-Hill; AMPA Receptors Are Obligatory to Seizure-Like Discharges Guinea pig hippocampal slices in presence of 50 µm picrotoxin generate electrographic seizurelike discharges Bath application of NMDA receptor block (200 µm APV) eliminates late bursting but does not affect triggering of the initial epileptiform discharge AMPA receptor block (20 µm CNQX) eliminates the seizure-like discharge AMPA and NMDA receptors generate the depolarization underlying seizure-like discharges NMDA receptors contribute, but pharmacologically removing NMDA receptors does not eliminate seizure-like discharges AMPA receptors are obligatory to seizure-like discharges Rogawski MA. Acta Neurol Scand. 2013;127(Suppl 197):

8 AMPA Receptor Morphology Consists of 4 homologous proteins, GluR1-4 GluR-2 subunit containing receptors have low permeability to calcium Responsible for generating EPSP Receptor phosphorylated by protein kinases Phosphorylated receptor further enhances ion flow, may lead to hyperactivity of glutaminergic system Advances in Understanding AMPA Receptor Structure Structure Begets Function Recent crystal structures have demonstrated intersubunit and interdomain receptor interactions, which are different between AMPA and The NMDA amino receptors terminal 1 domain and ligand binding domain are much more highly packed in NMDA receptors 1 Crystal structures widely reflect functional differences 1 AMPA receptor research supports central role in epilepsy including in vitro and animal studies demonstrating potential utility of AMPA receptors as a molecular target 2 1. Karakas E, Furukawa H, Science. 2014; 344: Rogawski MA. Acta Neurol Scand. 2013;127(Suppl 197): Glutamate Receptor Antagonist AEDs AED Notes Non-competitive AMPA receptor antagonist Binds to specific AMPA receptor site Perampanel Conformational change in receptor prevents glutamate action Reduces fast excitatory neurotransmission Blocks AMPA receptors at upper end Phenobarbital of therapeutic dose Felbamate Blocks NMDA receptors Topiramate Inhibits kainate receptors

9 AED Mechanisms of Action Inhibitory Synapse Excitatory Synapse GABA Glutamate GABA B SV2A CI - K + mglur VGPC Intracellular signaling pathways regulating excitability in the postsynaptic neuron =voltage-gated sodium channel; SV2A=synaptic vesicle protein; =voltage-gated calcium channel; VGPC=voltagegated potassium channel; AMPA=α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA=N-methyl-D-aspartate receptor; mglur=metabotropic glutamate receptor. Adapted from Johannessen Landmark C, et al. Drugs. 2008;68: Modulation of Synaptic Transmission Synaptic Vesicle Protein 2A SV2A membrane glycoprotein ubiquitous in synaptic vesicles Member of family of 3 related proteins; SV2A most common Precise physiological role of SV2A unclear Plays a role in vesicle dynamics; absence of SV2A results in reduction of available vesicles SV2A is binding site for levetiracetam & Breveracetam Differences in binding affinity

10 Rational Polypharmacy Patients not controlled on single AED need polypharmacy Rationale polypharmacy refers to combining AEDs with different MOA Little data to support such rational combinations Valproate and lamotrigine have supraadditive effect 1 Rationale polypharmacy may limit adverse effects Combining traditional sodium channel blocking drugs with lacosamide causes more adverse effects 2 1. Brodie MJ, Yeun AWC. Epilepsy Res, 1997;26:423-32; 2. Sake JK et al. CNS Drugs, 2010;24: Conclusions AEDs MOA involves reducing excitation or increasing inhibition Many drugs have several MOA Better understanding of epilepsy offers opportunity to target therapy What is rational polypharmacy?

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