1. SCREENING OF ANTIEPILEPTICS Kishan Singh M.pharm.(pharmacology) GLAIPR1

2. Definitions:- It is a Chronic medical condition characterized bytwo or more unprovoked seizures. It is not a disease, it is a syndrome What is the difference between seizure & epilepsy ?2 3. Seizure: The clinical manifestations (signs and symptoms) ofexcessive and hyper synchronous, usually selflimited, activity of neurons in the cerebral cortex. Epilepsy: Epilepsy is a broad term for a variety of brain disorderscharacterized by seizures, or convulsions. Epilepsy canresult from a direct injury to the brain at birth or from ametabolic disturbance in the brain at any time later in life.3 4. Seizures A seizure is a transient alteration of behavior dueto abnormal synchronous electrical activity in thebrain A seizure can be defined as abnormal, uncontrolled electricalactivity in brain cells. Nerve cells transmit signals from thebrain in two ways by 1. altering the concentrations of salts (sodium, potassiumcalcium,) within the cell 4 5. 2.Releasingchemicals calledneurotransmitters(gamma aminobutyric acid).The change in salt concentration conducts the impulsefrom one end of the nerve cell to the other.EpilepsyEpilepsy is a chronic neurological conditioncharacterized by recurrent seizures that are causedby abnormal cerebral nerve cell activity.5 6. Types of seizure s(focal) Primary6 7. Treatment: Up to 80% of parts can expect partial or completecontrol of seizures with appropriate treatment.Antiepileptic drugs suppress but do not cureseizures Antiepileptic are indicated when there is two ormore seizures occurred in short interval An initial therapeutic aim is to use only one drugmonotherapy) 7 8. TREATMENT OF SEIZURESSeizure disorderDrugsTonic-clonic(Grand mal) Carbamazepine orDrug of ChoiceValproate orPhenytoin orPhenobarbital orTopiramteAlternatives: Lamotrigine (as adjunct or alone)Gabapentin (as adjunct)Partial (simple or complex)Carbamazepine or LamotrigineDrug of choiceorTopiramte or Phenytoin orValproateAlternatives:Phenobarbital Gabapentin (as adjunct ) Zonisamide 9. Treatment cont,dAbsence ( petit mal) Valproate orDrug of choice EthosuximideAlternatives:Clonazepam LamotrigineMyoclonic, AtonicValproateDrug of choiceAlternatives:ClonazepamFebrile Seizures Diazepam, rectal Diazepam ,i.v Valproate 10. Mechanism of Action Reducing electrical excitability of cell membranes, possibly through inhibition of sodium channel. Enhancing GABA-mediated synaptic inhibition. This may be achieved by an enhanced pre- or post- synaptic action of GABA, by inhibiting GABA-transaminase, or by drugs with direct GABA-agonist properties. 10 11. Mechanism of Action A few drugs appear to act by a third mechanism,namely inhibition of T-type calcium channels. Newer drugs act by other mechanism, yet to be elucidated. Drugs that block excitatory amino acidreceptors are effective in animal models, butnot yet developed for clinical use.11 12. SCREENING METHODS IN VITRO METHOD IN VIVO METHOD 12 13. IN VITRO METHODS1. Hippocampal slices2. Electrical recording from isolated brain cells13 14. IN VIVO METHODS1. ELECTRICALLY INDUCED SEIZURE2. CHEMICALLY INDUCED CONVULSION3. SEIZURES INDUCED BY FOCAL LESIONS4. OTHERS 14 15. HIPPOCAMPAL SLICES Procedure and Evaluation:- Choose Rodentdecapitated & hippocampus is dissected 0.5mm Preincubate for 2 hrthickness slices Slices are at 28c warm salineare made transferred in with 95%O2 &5% Perspex chamber CO2Intracellular recording frompyramidal neuron in the slice Drug are added in Record the shockare done by passing saline medium induce neuronsmicropipettes under firingmicroscope 15 16. ADVANTAGES mechanical stable Useful model for studying the neurophysiologic mechanisms of convulsant and antiepileptic drugs For screening of antiepileptic drugs16 17. ELECTRICAL RECORDING FROMISOLATED BRAIN CELLS Procedure :- Put in bath Patch pipettesTaken isolated neuronare filled with containing salts at 7.3 pH same solutionrecording of capacitative currentsDrug are added is done ,at room temp.(21-24c) in bath solution 17 18. Evaluation Effect of drug on capacitative component of current Icis seen Ic = Cdv/dt Where C = specific membrane capacitance dv/dt rate of change of membrane potential Using this technique find out the sensitivity ofcalcium and potassium channels to neurotransmitters 18 19. IN VIVO METHODElectrically induced seizuresThese are three types1. Threshold model2. Maximal electroshock seizures (MES)test3 . Focal electrical stimulation such as kindling Corneal electroshock kindling Kindling by stimulation of the other brain areas Chemically induced kindling 19 20. Threshold modelProcedure and evaluation:-Male mice of 18-30gCorneal or ear electrode arein group of 8-10 areused to provide constant taken current at frequency of 50-60/sec for 0.2 secThreshold isElevation of determined as a voltagethreshold by test drug inducing hind limbis taken as measure of extension in 50% miceefficacyAdvantage: This test determine the ability of drug to alter the seizure threshold for tonic limb extension20 21. Maximal electroshock seizure (MES)TEST Electrical Electrode are moistened withstimulation is saline solution beforeapplied by cornealapplication or ear electrode current Stimulation forMeasures various phages: phage of mice 50mA&for rat 150mA tonic limb flexion for 1.5sec. followed and 250 voltage for mice & by tonic limb extension for 10 sec. 750 for rat21 22. EvaluationSuppression of tonic hind limb extension istaken as measure of efficacy in this test andanticonvulsant potency is determined bycalculation of ED5o for suppression of tonichind limb extension22 23. KINDLED RAT SEIZURE MODEL(epilepsy induces epilepsy)PROCEDURE:- Female sprague-Electrode is implantedDawely rats of 270-in right amygdala for400g are takenelectrical stimulation Daily electrical stimulus of 400 500 A are appliedDuring the daily electricallyin following 5 stages ..stimulation of amygdala, seizures develop which ,as classified byRacine 23 24. Class - 1 Immobility , eye closure Class- 2 Facial clonus and head nodding Class- 3 Facial clonus and head nodding & fore limbclonus Class- 4 Rearing, often accompanied by bilateral fore limbclonus Class-5 Rearing with loss of balance and fallingaccompanied and generalized clonic 24 25. Evaluation :-Four different measure of drug efficacy are measured for kindling:- Seizure latency Seizure severity Seizure duration After discharge durationMerits:-The efficacy of drug against the process of epileptogenesis as well asagainst the fully kindled state can be measured 25 26. Chemical induced convulsions1. Chemoconvulsionsants inducing generalized seizures after systemic administration :-e.g.pentylenetetrazol, picrotoxin, isonizid,pencillin, strychine,pilocarpine,NMDA,DDT,methioninen ,sulfoxime bicculine2. Chemoconvulsant inducing focal seizure after central administration :- e.g.pencillin.,quinolinic acid, ptz 26 27. METHODS OF CHEMICALLY INDUCED CONVULSIONS:- Pentylentetrazol(PTZ) test:-Procedure:-8-10 mice are taken and 1% solution of PTZ are administered i.v. infusionSeizure are developed in following manner1. jerks(first twitch)2. Generalized clonic seizure with loss of lightening reflexes3. Maximal tonic clonic seizure27 28. SEIZURES INDUCED BY FOCAL LSIONS CORTICALLY IMPLANTED MODEL ALUMINIUM HYDROXIDE GEL MODEL 28 29. GENETIC ANIMAL MODELS OF EPILEPSY Photosensitive baboons Seizure-prone mice strains Mongolian gerbils Miscellaneous genetically seizure-prone animals29 30. CONCLUSIONCharacteristics for ideal model:- Development of spontaneously occurring seizure Type of seizure similar to that seen in human epilepsy EEG correlates of epileptic like activity Age dependency in the onset of epilepsyAt present there is no models that satisfy all above criteriaonly genetic model come close to above criteria.30 31. Thank youThank you for your attention 31