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Ezogabine,an update
 

Ezogabine,an update

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  • b. As an adjunctive therapy

Ezogabine,an update Ezogabine,an update Presentation Transcript

  • DR.JITENDRA AGRAWALFIRST YEAR RESIDENT
  • 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.
  •  1. Partial seizuresa. Simple partial seizures (with motor, sensory,autonomic, or psychic signs)b. Complex partial seizuresc. Partial seizures with secondarygeneralization
  • 2. Primarily generalized seizuresa. Absence (petit mal)b. Tonic-clonic (grand mal)c. Tonicd. Atonice. Myoclonic3. Unclassified seizuresa. Neonatal seizuresb. Infantile spasms
  •  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.
  •  First-Linea. Carbamazepineb. Phenytoinc. Lamotrigined. Oxcarbazepinee. Valproic acid Alternativesa. Levetiracetamb. Topiramatec. Tiagabined. Zonisamidee. Gabapentinf. Phenobarbitalg. Primidoneh. Felbamate
  •  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.
  •  May increase the QTc interval.
  •  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.
  • Most frequent Somnolence Dizziness Confusion Asthenialess frequent Speech disorder Vertigo Tremor Amnesia
  •  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.
  •  Harrision’s principles of internalmedicine, 17th edition Ezogabine: A New Angle On PotassiumGates.Epilepsy Currents, Vol. 11, No. 3(May/June) 2011 pp. 75–78© AmericanEpilepsy Society. Porter RJ, Partiot A, Sachdeo R, NohriaV, Alves WM. Randomized, multicenter, dose-ranging trail of retigabine for partial-onsetseizures. Neurology. 2007;68:1197-204.
  •  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.