“SCREENING OF ANTIEPILEPTICS”               Kishan Singh               M.pharm.(pharmacology)               GLAIPR        ...
Definitions:-   It is a Chronic medical condition characterized by    two or more unprovoked seizures.   It is not a dis...
 Seizure:   The clinical manifestations (signs and symptoms) of    excessive and hyper synchronous, usually             ...
Seizures A seizure is a transient alteration of behavior due  to abnormal synchronous electrical activity in the  brain ...
2.Releasing    chemicals     called      neurotransmitters  (gamma aminobutyric acid).  The change in salt concentration c...
Types of seizure                             s(focal)                 Primary                                  6
Treatment: Up to 80% of parts can expect partial or complete  control of seizures with appropriate treatment.  Antiepile...
TREATMENT OF SEIZURESSeizure disorder              DrugsTonic-clonic(Grand mal)       Carbamazepine orDrug of Choice      ...
Treatment cont,dAbsence ( petit mal)   Valproate orDrug of choice         EthosuximideAlternatives:          Clonazepam   ...
Mechanism of Action    Reducing electrical excitability of cell     membranes, possibly through inhibition of sodium     ...
Mechanism of Action A few drugs appear to act by a third mechanism,  namely inhibition of T-type calcium channels. Newer...
SCREENING METHODS  IN VITRO METHOD  IN VIVO METHOD                     12
IN VITRO METHODS1.   Hippocampal slices2. Electrical recording from isolated brain cells                                  ...
IN VIVO METHODS1.   ELECTRICALLY INDUCED SEIZURE2. CHEMICALLY INDUCED CONVULSION3. SEIZURES INDUCED BY FOCAL LESIONS4. OTH...
HIPPOCAMPAL SLICES   Procedure and Evaluation:-   Choose Rodent                decapitated & hippocampus is dissected     ...
ADVANTAGES mechanical stable Useful model for studying the neurophysiologic mechanisms of convulsant and antiepileptic d...
ELECTRICAL RECORDING FROMISOLATED BRAIN CELLS Procedure :-                             Put in bath               Patch pi...
Evaluation Effect of drug on capacitative component of current Ic    is seen   Ic = Cdv/dt   Where C = specific membran...
IN VIVO METHODElectrically induced seizuresThese are three types1. Threshold model2. Maximal electroshock seizures (MES)te...
Threshold modelProcedure and evaluation:-Male mice of 18-30g              Corneal or ear electrode arein group of 8-10 are...
Maximal electroshock seizure (MES)TEST                                 Electrical                                         ...
EvaluationSuppression of tonic hind limb extension istaken as measure of efficacy in this test andanticonvulsant potency i...
KINDLED RAT SEIZURE MODEL(epilepsy induces epilepsy)PROCEDURE:-   Female sprague-            Electrode is implanted  Dawel...
 Class - 1 Immobility , eye closure Class- 2 Facial clonus and head nodding Class- 3 Facial clonus and head nodding & f...
Evaluation :-Four different measure of drug efficacy are measured for kindling:- Seizure latency Seizure severity Seizu...
Chemical induced convulsions1. Chemoconvulsionsants inducing generalized seizures after   systemic administration :-    e....
METHODS OF CHEMICALLY INDUCED CONVULSIONS:-• Pentylentetrazol(PTZ) test:-Procedure:-8-10 mice are taken and 1% solution of...
SEIZURES INDUCED BY FOCAL LSIONS CORTICALLY IMPLANTED MODEL ALUMINIUM HYDROXIDE GEL MODEL                               ...
GENETIC ANIMAL MODELS OF EPILEPSY Photosensitive baboons Seizure-prone mice strains Mongolian gerbils Miscellaneous ge...
CONCLUSIONCharacteristics for ideal model:- Development of spontaneously occurring seizure Type of seizure similar to th...
Thank youThank you for your attention                               31
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Kishan singh

  1. 1. “SCREENING OF ANTIEPILEPTICS” Kishan Singh M.pharm.(pharmacology) GLAIPR 1
  2. 2. Definitions:- It is a Chronic medical condition characterized by two or more unprovoked seizures. It is not a disease, it is a syndrome What is the difference between seizure & epilepsy ? 2
  3. 3.  Seizure:  The clinical manifestations (signs and symptoms) of excessive and hyper synchronous, usually self limited, activity of neurons in the cerebral cortex. Epilepsy:  Epilepsy is a broad term for a variety of brain disorders characterized by seizures, or convulsions. Epilepsy can result from a direct injury to the brain at birth or from a metabolic disturbance in the brain at any time later in life. 3
  4. 4. Seizures A seizure is a transient alteration of behavior due to abnormal synchronous electrical activity in the brain A seizure can be defined as abnormal, uncontrolled electrical activity in brain cells. Nerve cells transmit signals from the brain in two ways by 1. altering the concentrations of salts (sodium, potassium calcium,) within the cell 4
  5. 5. 2.Releasing chemicals called neurotransmitters (gamma aminobutyric acid). The change in salt concentration conducts the impulse from 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. 6. Types of seizure s(focal) Primary 6
  7. 7. Treatment: Up to 80% of parts can expect partial or complete control of seizures with appropriate treatment. Antiepileptic drugs suppress but do not cure seizures Antiepileptic are indicated when there is two or more seizures occurred in short interval An initial therapeutic aim is to use only one drug monotherapy) 7
  8. 8. TREATMENT OF SEIZURESSeizure disorder DrugsTonic-clonic(Grand mal) Carbamazepine orDrug of Choice Valproate or Phenytoin or Phenobarbital or TopiramteAlternatives: Lamotrigine (as adjunct or alone) Gabapentin (as adjunct)Partial (simple or complex) Carbamazepine or LamotrigineDrug of choice orTopiramte or Phenytoin or ValproateAlternatives: Phenobarbital Gabapentin (as adjunct ) Zonisamide
  9. 9. Treatment cont,dAbsence ( petit mal) Valproate orDrug of choice EthosuximideAlternatives: Clonazepam LamotrigineMyoclonic, Atonic ValproateDrug of choiceAlternatives: ClonazepamFebrile Seizures Diazepam, rectal Diazepam ,i.v Valproate
  10. 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. 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 acid receptors are effective in animal models, but not yet developed for clinical use. 11
  12. 12. SCREENING METHODS  IN VITRO METHOD  IN VIVO METHOD 12
  13. 13. IN VITRO METHODS1. Hippocampal slices2. Electrical recording from isolated brain cells 13
  14. 14. IN VIVO METHODS1. ELECTRICALLY INDUCED SEIZURE2. CHEMICALLY INDUCED CONVULSION3. SEIZURES INDUCED BY FOCAL LESIONS4. OTHERS 14
  15. 15. HIPPOCAMPAL SLICES Procedure and Evaluation:- Choose Rodent decapitated & hippocampus is dissected 0.5mm Preincubate for 2 hr thickness slices Slices are at 28c warm saline are 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. 16. ADVANTAGES mechanical stable Useful model for studying the neurophysiologic mechanisms of convulsant and antiepileptic drugs For screening of antiepileptic drugs 16
  17. 17. ELECTRICAL RECORDING FROMISOLATED BRAIN CELLS Procedure :- Put in bath Patch pipettesTaken isolated neuron are filled with containing salts at 7.3 pH same solution recording of capacitative currents Drug are added is done ,at room temp.(21-24c) in bath solution 17
  18. 18. Evaluation Effect of drug on capacitative component of current Ic is seen Ic = Cdv/dt Where C = specific membrane capacitance dv/dt rate of change of membrane potential Using this technique find out the sensitivity of calcium and potassium channels to neurotransmitters 18
  19. 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. 20. Threshold modelProcedure and evaluation:-Male mice of 18-30g Corneal or ear electrode arein group of 8-10 are used to provide constant taken current at frequency of 50- 60/sec for 0.2 sec Threshold is Elevation of determined as a voltage threshold by test drug inducing hind limb is taken as measure of extension in 50% mice efficacyAdvantage: This test determine the ability of drug to alter the seizure threshold for tonic limb extension 20
  21. 21. Maximal electroshock seizure (MES)TEST Electrical Electrode are moistened with stimulation is saline solution before applied by corneal application or ear electrode current Stimulation for Measures 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 rat 21
  22. 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 extension 22
  23. 23. KINDLED RAT SEIZURE MODEL(epilepsy induces epilepsy)PROCEDURE:- Female sprague- Electrode is implanted Dawely rats of 270- in right amygdala for 400g are taken electrical stimulation Daily electrical stimulus of 400 – 500 µ A are applied During the daily electrically in following 5 stages ….. stimulation of amygdala, seizures develop which ,as classified by Racine 23
  24. 24.  Class - 1 Immobility , eye closure Class- 2 Facial clonus and head nodding Class- 3 Facial clonus and head nodding & fore limb clonus Class- 4 Rearing, often accompanied by bilateral fore limb clonus Class-5 Rearing with loss of balance and falling accompanied and generalized clonic 24
  25. 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 as against the fully kindled state can be measured 25
  26. 26. Chemical induced convulsions1. Chemoconvulsionsants inducing generalized seizures after systemic administration :- e.g.pentylenetetrazol, picrotoxin, isonizid,pencillin, strychine,p ilocarpine,NMDA,DDT,methioninen ,sulfoxime bicculine2. Chemoconvulsant inducing focal seizure after central administration :- e.g.pencillin.,quinolinic acid, ptz 26
  27. 27. METHODS OF CHEMICALLY INDUCED CONVULSIONS:-• Pentylentetrazol(PTZ) test:-Procedure:-8-10 mice are taken and 1% solution of PTZ are administered i.v. infusion Seizure are developed in following manner1. jerks(first twitch)2. Generalized clonic seizure with loss of lightening reflexes3. Maximal tonic clonic seizure 27
  28. 28. SEIZURES INDUCED BY FOCAL LSIONS CORTICALLY IMPLANTED MODEL ALUMINIUM HYDROXIDE GEL MODEL 28
  29. 29. GENETIC ANIMAL MODELS OF EPILEPSY Photosensitive baboons Seizure-prone mice strains Mongolian gerbils Miscellaneous genetically seizure-prone animals 29
  30. 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 criteria only genetic model come close to above criteria. 30
  31. 31. Thank youThank you for your attention 31
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