Epilepsy is among the most commonneurological disorders, affecting approximately50 million people worldwide. Partial onset seizureare the most common type of seizures in adults.SEIZURE: is a paroxysmal event due toabnormal, excessive, hyper synchronousdischarges from an aggregate of central nervoussystem, neurons.EPILEPSY: describes a condition in which a personhas recurrent seizures due to chronic underlyingprocess.
are those in which the seizure activity isrestricted to discrete areas of the cerebral cortex. SIMPLE PARTIAL SEIZURES: Clinical manifestation + consciousness is fullypreserved during seizures COMPLEX PARTIAL SEIZURES focal seizure activity + impairment ofconciousness PARTIAL SEIZURES WITH SECONDARYGENERALIZATION seizures that begin as partial seizures and thenspread diffusely throughout the cortex
Pharmacological therapy is initial option forthe treatment of patients with newlydiagnosed epilepsy. Focused area is to reduce seizure frequencywith seizure freedom is ultimate goal. without side effects. Monotherapy is preferable.
Epilepsy a serious and potentially lifethreatening condition In spite of many approved pharmacologicalagents, many patients are not adequatelytreated with currently available option. Nearly a third patients with epilepsy haveeither intractable or uncontrolled seizures orhave significant adverse side effectssecondary to medication.
Monotherapy is preferable to limit drug druginteractions and side effects… but Epilepsy patient need more than one AED toachieve therapeutics success. In spite of that adequate seizure control isnot achieved. So the new drug should have minimal druginteractions and minimal side effect
Synonyms:Retigabine-(INN- international nonproprietary name)Ezogabine- (USAN- U.S. adopted name)
Recently approved as an adjunctive treatmentfor partial onset seizure for patients byFDAin June 2011EMEAin March 2011
Opening of neuronal voltage-gated potassiumchannels, which enhances inhibitory M-typepotassium current. The principal mechanism by which membranerepolarisation occurs after an action potential isan outward potassium current, termed the M-current . Selectively enhance M-currents through KCNQ2/3and KCNQ3/5 No effect on KCNQ1- present in cardiac cellsKCNQ4-present in auditory system
Does not directly open the potassium channelAct as prop or doorstopBinding into hydrophobic pocket within ‘’gate’’ region ofKv7.2 and 3 channlesWihich is the site for molecular ‘’hinge’’Once lodges within this pocketIt bends the hinge slightly openDecreasing the angle through which the gate must swingto full open.
Linear pharmacokinetic profile with dosageup to 1200mg/day Rapidly absorbed after oral administration Bioavailibility of oral EZG is about 60% Protien binding is approximately 80% Volume of distribution at steady state isabout 2-3 L/kg
Metabolized by:N-acetylation to the mono-acetylated metabolite,glucuronidation to form N-glucronide structure Metabolites have minimal pharmacological activity Majority of drug and metabolites excreted throughkidney. Small amount excreted through feces. Plasma half life is 8 hrs for drug and metabolites.
Low potential for drug interaction No potential to inhibit major cytochromeP450 isoenzyme. It is neither substrate nor inhibitor of P-glycoprotein transporter.
No clinically significant effects of thefollowing AEDs on Ezogabinepharmacokinetics: Carbamazepine Levetiracetam Oxcarbazepine Phenobarbitol Phenytoin Topiramate Valproate
However lamotrigine increase 15% concentration ofezogabin Ezogabine plasma levels may be reduced byconcomitant administration of phenytoin orcarbamazepine. N-acetyl metabolite of ezogabine may inhibit renalclearance of digoxin
Indicated for adjunctive treatment for Partial onset seizures With or without generalization For patients 18 years of age and older.
Patients can be considered drug resistantwhen Failed to have seizure control with 2 or moreAEDs Used appropriately Tolerated by the patient.
The initial dosage should be 100 mg 3 timesdaily (300 mg per day) for 1 week. Titrate to maintenance dosage by increasingthe dosage at weekly intervals by no morethan 150 mg per day. Optimize effective dosage between 200 mg 3times daily (600 mg per day) to 400 mg 3times daily (1,200 mg per day).
When discontinuing EZOGABINE, reduce thedosage gradually over a period of at least 3weeks. Dosing adjustments are required for geriatricpatients and patients with moderate to severerenal or hepatic impairment.
Urinary retention Urinary hesitancy This is because of Inhibition of bladder contractility secondaryto ezogabine’s effect on KCNQ channels indetrusor muscle of the bladder.
urologic symptoms should be carefullymonitored. Closer monitoring is recommended for, benign prostatic hyperplasia [BPH] cognitively impaired patients anticholinergics
Monitor for dizziness and somnolence QT prolongation: QT interval should bemonitored in patients taking concomitantmedications known to increase the QTinterval or with certain heart conditions. when EZOGABINE is discontinued, it shouldbe withdrawn gradually when possible tominimize the potential of increased seizurefrequency
STUDY 205:Amulticenter, randomized, double-blind, placebo-controlled trial was performedof retigabine for partial-onset seizures. CONCLUSION: Adjunctive therapy withretigabine is well tolerated and reduces thefrequency of partial-onset seizures in a dose-dependent manner.
Study 301: multicenter, randomized, double-blind, parallel-group trial of ezogabine(retigabine) in partial epilepsy. CONCLUSION: EZG(RTG) is effective as add-on therapy for reducing seizure frequency inpatients with drug-resistant partial-onsetseizures.
STUDY 302: This was amulticenter, randomized, double-blind, placebo-controlled trial in adults with≥4 partial-onset seizures per monthreceiving 1 to 3 antiepileptic drugs. CONCLUSIONS: In this dose-ranging, placebo-controlled trial, adjunctiveEZG (RTG) was effective and generally welltolerated in adults with refractory partial-onset seizures
first antiepileptic drug with a very specificeffect on central nervous system potassiumchannels. Having minimal drug interactions Mostly renal excretion few safety concerns most side effects are those typically seenwith antiepileptic agents.
There are no adequate and well-controlledstudies in pregnant women.
French J, Abou-Khalil B, Leroy R, Yacubian E, ShinP, et al. Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) inpartial epilepsy. Neurology. 2011 May3;76(18):1555-63. Brodie M, Lerche H, Gil-Nagel A, Elger C, HallS, et al. Efficacy and safety of adjunctiveezogabine (retigabine) in refractory partialepilepsy. 2010 Nov.Neurology. 16:75:1817-24. Wikipedia and various internet sites Steve chung, kirsten M Kelly, Courtney Schussee;Neurology research international journal, 20 june2011.