《临床药物治疗学 Clinical Pharmacotherapeutics》阅读资料：Latest Developments in Neuroscience Drug Therapy（melody）

Eab 00 Latest Developments in Neuroscience Drug Therapy o000oc0= Melody ryan, PharmD, MPH Associate professor Departments of Pharmacy Practice Science and neurology KENTUCKY College of Pharmacy

Latest Developments in Neuroscience Drug Therapy Melody Ryan, PharmD, MPH Associate Professor Departments of Pharmacy Practice & Science and Neurology

Objectives oS. Describe new medications and/or new oE: safety concerns for the following therapeutic areas Epilepsy o000oc0= Multiple sclerosis - Stroke Alzheimer's disease KENTUCKY College of Pharmacy

Objectives • Describe new medications and/or new safety concerns for the following therapeutic areas: – Epilepsy – Multiple sclerosis – Stroke – Alzheimer’s disease

Epilepsy · New medications 00 Lacosamide Ezogabine/retigabine Clobazam o000oc0= Perampanel Brivaracetam KENTUCKY College of Pharmacy

Epilepsy • New medications – Lacosamide – Ezogabine/retigabine – Clobazam – Perampanel – Brivaracetam

Lacosamide 8· Mechanism of action 00 Enhances slow sodium channel inactivation Binds to the collapsin-response mediator protein 2(CRMP-2) o000oc0= May help prevent rearrangement of neuronal connections May protect neurons from excitotoxicity and apoptosIs KENTUCKY College of Pharmacy

Lacosamide • Mechanism of action – Enhances slow sodium channel inactivation – Binds to the collapsin-response mediator protein 2 (CRMP-2) • May help prevent rearrangement of neuronal connections • May protect neurons from excitotoxicity and apoptosis

Eab Physiology of Voltage-Gated Sodium Channels Classical AEDs Repolarization 00 Inactivated state- fast Local anesthetics Eo (within msec) Resting Depolarization Open o000oc0= g state state Inactivated state- slow (within sec and beyond) ①○×① Regulation of sodium channel long-term availability o%Adapted from Beyreuther, et al msec=milliseconds: Nat=sodium: sec=seconds LACOSAMIDE KENTUCKY CNS Drug Rev 2007; 13(1): 21-42 College of Pharmacy

LACOSAMIDE Adapted from Beyreuther, et al. CNS Drug Rev 2007;13(1):21–42. msec=milliseconds; Na+=sodium; sec=seconds Regulation of sodium channel long-term availability Local anesthetics Classical AEDs Resting state Resting membrane potential Open state Depolarization (within sec and beyond) Inactivated state-slow Repolarization Physiology of Voltage-Gated Sodium Channels Inactivated state-fast (within msec)

Eab Lacosamide Pharmacokinetics 00 Low protein binding(<15%) Metabolized by CyP2C19 Half-life 13 hours o000oc0= Adverse effects Common -sedation dizziness, nausea, ataxia nystagmus Rare- PR interval prolongation Euphoria, especially at 800 mg dose KENTUCKY College of Pharmacy

Lacosamide • Pharmacokinetics – Low protein binding (<15%) – Metabolized by CYP2C19 – Half-life 13 hours • Adverse effects – Common – sedation, dizziness, nausea, ataxia, nystagmus – Rare – PR interval prolongation – Euphoria, especially at 800 mg dose

Eab EZogabine/Retigabine Opens voltage-gated potassium channels " Enhances the outgoing, M-type potassium current Repolarizes the membrane back towards resting o000oc0= potential and suppressing repetitive firing ax. May also augment GABA-mediated currents Indicated for adjunctive treatment of partial- onset seizures KENTUCKY College of Pharmacy

Ezogabine/Retigabine • Opens voltage-gated potassium channels • Enhances the outgoing, M-type potassium current – Repolarizes the membrane back towards resting potential and suppressing repetitive firing • May also augment GABA-mediated currents • Indicated for adjunctive treatment of partial￾onset seizures

Eab EZogabine/Retigabine Pharmacokinetics 00 Excreted renally Carbamazepine and phenytoin decrease ezogabine Adverse effects o000oc0= Somnolence. dizziness, tremor Confusion(9%), hallucinations(2%), psychosis(1%) Urinary retention 2% QT interval prolongation KENTUCKY College of Pharmacy

Ezogabine/Retigabine • Pharmacokinetics – Excreted renally – Carbamazepine and phenytoin decrease ezogabine • Adverse effects – Somnolence, dizziness, tremor – Confusion (9%), hallucinations (2%), psychosis (1%) – Urinary retention 2% – QT interval prolongation

EZogabine/Retigabine :· FDA warning4/26/13 o". Pigment changes in the retina Blue skin discoloration Lips, nail beds face legs, sclera, conjunctiva Average of 4 years of treatment Recommendation: baseline and periodic a. eye exams with visual acuity testing and a: dilated fundus photography KENTUCKY College of Pharmacy

Ezogabine/Retigabine • FDA warning 4/26/13 • Pigment changes in the retina • Blue skin discoloration – Lips, nail beds, face legs, sclera, conjunctiva – Average of 4 years of treatment • Recommendation: baseline and periodic eye exams with visual acuity testing and dilated fundus photography

Eab Ezogabine/ retigabine 00 Discoloration AE-Lips o000oc0= KENTUCKY College of Pharmacy

Ezogabine/Retigabine