Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... ·...
Transcript of Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... ·...
Basic and Clinical Pharmacology of Newer Anti-Seizure Drugs
SATURDAY, OCTOBER 14th
BREAKOUT SESSION 2-AHarbourfront Ballroom 1
Löscher et al, Nat Rev Drug Discov 2014
Brivaracetam (Brivlera)Stiripentol (Diacomit)
NEWER ASDsSince 1993
Basic and Clinical Pharmacology ofNewer Anti-Seizure Drugs
• Mechanistic Overview of Anti-Seizure Drugs• Dr. Tara Klassen, University of British Columbia
• Pharmacokinetic Profiles of Newer Anti-Seizure Drugs
• Dr. Jong M. Rho, University of Calgary
• Clinical Efficacy of Newer Anti-Seizure Drugs• Dr. Jorge Burneo, Western University
• Adverse Effect Profiles of Newer Anti-Seizure Drugs• Dr. Lionel Carmant, Université de Montréal
Jong M. Rho, MD
Mechanistic Overview ofAnti-Seizure Drugs
40th Annual Meeting of the Canadian League Against EpilepsyVancouver, British Columbia
October 14, 2017
Disclosures Research Grants
– Canadian Institutes of Health Research (CIHR)– Alberta Children’s Hospital Research Institute (ACHRI),
University of Calgary; Alberta Children’s Hospital Foundation– Brain Canada Platform Support Grant
Scientific Advisory Boards– Citizens United for Research in Epilepsy (Chicago, IL)– The Charlie Foundation (Santa Monica, CA)– Matthew’s Friends Foundation (Surrey, United Kingdom)
Consultant Activity– Danone Nutricia– Accera, Inc.– Xenon Pharma– Ajinomoto USA
Newer Anti-Seizure Drugs
•Rufinamide
•Lacosamide
•Stiripentol
•Perampanel
•Eslicarbazepine
•Brivaracetam
The ParoxysmalDepolarization Shift(PDS)
Classification of ASD Mechanisms
K+ K+
HCN channel
NMDA receptorAMPA/kainate receptor
Na+(Ca )2+Na ,
+ K+
Ca2+, Na+
OUTSIDE
INSIDE
Postsynapticmembrane
Propagated actionpotential
Glutamate
Voltage-dependent sodium channel
Na+
Depolarization
Multiple sub-types voltage-dependent calcium channels
Ca2+Vesicular release
SV2A synapticvesicle protein
Felbamate
LamotrigineGabapentin
Topiramate
LamotrigineFelbamate
TopiramateOxcarbazepineLevetiracetam
GabapentinPregabalin
PhenytoinCarbamazepineOxcarbazepineValproic acidLamotrigineFelbamateTopiramateZonisamideRufinamideLacosamide
a
Levetiracetam
Central Excitatory Synapse
Central Inhibitory Synapse
GABA transporter
Glutamate
GAD
GABA
GABA-T
semi-aldehyde
GABA
Glial Cell
GABA transporter
GABA-TGABASuccinic
semi-aldehyde Succinic
OUTSIDE
INSIDE
Postsynapticmembrane
Cl–
GABA ReceptorsA
Tiagabine
Vigabatrin
FelbamateTopiramate
Benzodiazepines
Barbiturates
Voltage-Gated Sodium Channels
Eslicarbazepine
Rufinamide
An Overview of Sodium Channel Modulation
Open Channel Block Fast InactivationEnhancement of Slow Inactivation
DrugsLocal anesthetic drugs (eg, lidocaine)
Classical AEDs (eg, DPH, CBZ, LTG)
Lacosamide
Functional implication
Blocks action potential propagation (ie, neuronal activity)
Responsible for use dependence
Governs availability of Na+ channels
Consequence of overdose
Paralysis, death Neuronal slowing Exaggerated CNS effects
Time course ImmediatelyDelay by milliseconds
Delay by secondsto minutes
Molecular mechanism
Open channel (pore) block“Hinged-lid” mechanism
Conformation change of channel pore
Beyreuther BK, et al. CNS Drug Rev. 2007;13:21-42. Cummins TR, et al. Expert Rev Neurotherapeutics. 2007;7:1597-1612. Errington AC, et al. Mol Pharmacol. 2008;73:157-169.
Glutamate Receptors
CentralExcitatory
Synapse
Ionotropic Glutamate Receptor Blockers
Perampanel
Pre-synaptic NeurotransmitterRelease
Synaptic Vesicle Proteins
Singh & Brashier, Muller J Med Sci Res 2014
LevetiracetamBrivaracetam
Metabolism at theNeurovascular Unit
Stiripentol
• STP reduces synaptosomal GABA uptake (IC50 5x10-5
M)
• STP slightly increases (+22%) brain concentrations of GABA after “in vivo” administration (300 mg/kg i.p.)
• STP is a positive allosteric modulator of GABAA
receptors (those containing 3 subunits)
Science 2015
Noebels, Nat Neurosci 2015
Single and Multigenic Biological Complexityin Epileptic Brain
Summary
• Newer ASDs possess novel mechanisms of action (albeit with some variations on a theme)
• Yet, whether these mechanisms can afford greater clinical efficacy has yet to be demonstrated
• Stiripentol represents an ASD that has a paradigm-altering action (i.e., influencing metabolism at the synapse)
• Epilepsy is inherently a biological system that has many levels of complexity
• Thus, single/narrow mechanistic approaches are less likely to render complete control in all patients