Antiepileptic drugs


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Antiepileptic drugs

  1. 1. AntiepilepticAntiepileptic DrugsDrugs
  2. 2. SEIZURESSEIZURES  Transient disturbance of cerebralTransient disturbance of cerebral functionfunction  Abnormal paroxysmal neuronalAbnormal paroxysmal neuronal dischargedischarge  It can beIt can be a. acutea. acute b. chronicb. chronic
  3. 3. EPILEPSYEPILEPSY  Collective name for group of CNSCollective name for group of CNS disordersdisorders  With repeated occurrence of sudden andWith repeated occurrence of sudden and transitory seizurestransitory seizures  It can beIt can be a. primary or idiopathica. primary or idiopathic b. secondary or symptomaticb. secondary or symptomatic
  4. 4. Nature of epilepsyNature of epilepsy  Epilepsy affects about 0.5% of theEpilepsy affects about 0.5% of the population.population.  Seizure and convulsionsSeizure and convulsions  Caused by an asynchronous high-Caused by an asynchronous high- frequency discharge of a group offrequency discharge of a group of neuronsneurons  Partial seizures affect localized brainPartial seizures affect localized brain regionsregions  Generalised seizures affect the wholeGeneralised seizures affect the whole brain.brain.
  5. 5. Nature of epilepsyNature of epilepsy  Two common forms of epilepsy are the tonic-Two common forms of epilepsy are the tonic- clonic fit (grand mal) and the absence seizureclonic fit (grand mal) and the absence seizure (petit mal).(petit mal).  Animal modelsAnimal models  It may be associatedIt may be associated  with enhanced excitatory amino acid transmissionwith enhanced excitatory amino acid transmission  impaired inhibitory transmissionimpaired inhibitory transmission  abnormal electrical properties of the affected cells.abnormal electrical properties of the affected cells.  glutamate content in areas surrounding an epilepticglutamate content in areas surrounding an epileptic focus may be increasedfocus may be increased
  6. 6. CLASSIFFICATION OFCLASSIFFICATION OF SEIZURESSEIZURES  Partial SeizurePartial Seizure  Focal area in the brain is involvedFocal area in the brain is involved  Types:Types: a. Simple partiala. Simple partial  No impairment of consciousnessNo impairment of consciousness  motor or sensory symptomsmotor or sensory symptoms  b. complexb. complex  with impairment of consciousnesswith impairment of consciousness  with automatismswith automatisms
  7. 7.  GeneralizedGeneralized  Entire brain is involvedEntire brain is involved  Tonic-clonic/ Grand malTonic-clonic/ Grand mal  Tonic phase- loss of consciousness, rigidityTonic phase- loss of consciousness, rigidity  Clonic phase- jerking movements of entireClonic phase- jerking movements of entire bodybody  Absence/ Petit malAbsence/ Petit mal  In childrenIn children  brief loss of consciousness (10s) blank stare,brief loss of consciousness (10s) blank stare, blinking, facial twitchingblinking, facial twitching  MyoclonicMyoclonic  brief jerksbrief jerks
  8. 8. MOA OF DRUGSMOA OF DRUGS 1.1. Reduced the spread of excitation fromReduced the spread of excitation from seizure foci to normal neuronsseizure foci to normal neurons 2.2. Enhancement of GABA mediated inhibitoryEnhancement of GABA mediated inhibitory transmissiontransmission 3.3. Prevent or reduced excessive discharge ofPrevent or reduced excessive discharge of altered neurons of seizure focialtered neurons of seizure foci 4.4. Diminution of glutaminergic excitatoryDiminution of glutaminergic excitatory transmissiontransmission 5.5. Modification of ionic conductanceModification of ionic conductance
  9. 9. Where Does DiffusionWhere Does Diffusion Take the Ion?Take the Ion? Exterior Interior K+ 5 mM K+ 5 mM Cl- Low Cl- Low Cl- High Cl- High K+ 150 mM K+ 150 mM Na+ 15 mM Na+ 15 mM Na+ 150 mM Na+ 150 mM O U T O U T I N I N I N I N
  10. 10. Action PotentialAction Potential ComponentsComponents MembranePotential(mV) -50 -70 0 +30 Time (msec) Threshold Potential Threshold Potential Resting Membrane Potential Resting Membrane Potential Na+ equilibriumNa+ equilibrium Action Potential Action Potential Depolarization!Depolarization! HyperpolarizedHyperpolarized
  11. 11. MembraneMembrane PermeabilityPermeability MembranePotential(mV) -50 -70 0 +30 Time (msec) Threshold Potential Threshold Potential Resting Membrane Potential Resting Membrane Potential Na+ Influx K+Efflux
  12. 12. MembranePotential(mV) -50 -70 0 +30 Time (msec) Threshold Potential Threshold Potential Resting Membrane Potential Resting Membrane Potential Na+ Influx K+Efflux It gets hyperpolarized! It gets hyperpolarized! What Happens to the Membrane If Cl- Rushes Into the Cell During Repolarization?
  13. 13. MembranePotential(mV) -50 -70 0 +30 Time (msec) It decreases! It decreases! What Happens to the Frequency of Action Potentials If the Membrane Gets Hyperpolarized?
  14. 14. Clinical Correlation  Remember that it is the rate of action potentialRemember that it is the rate of action potential propagation that determines neurologic function.propagation that determines neurologic function.  Determined by frequency of action potentials.Determined by frequency of action potentials. What is a seizure?What is a seizure? What would be the effect on the membrane of ⇑ Cl- influx during a seizure? What would be the effect on the membrane of ⇑ Cl- influx during a seizure? Hyperpolarization & … ⇓ seizure activity!
  15. 15. Gamma Amino ButyricGamma Amino Butyric Acid ReceptorsAcid Receptors GABA Receptor GABA Receptor Exterior Interior Cl -Cl - Hyperpolarized!Hyperpolarized!
  16. 16. GABA+Bz ComplexGABA+Bz Complex Bz Receptor Bz Receptor GABA Receptor GABA Receptor Exterior Interior Cl -Cl - Profoundly Hyperpolarized! Profoundly Hyperpolarized!
  17. 17. Anti-SeizureAnti-Seizure MedicationsMedications BenzodiazepinesBenzodiazepines  diazepam (Valium®)diazepam (Valium®)  lorazepam (Ativanlorazepam (Ativan®® )) BarbituratesBarbiturates  phenobarbitalphenobarbital (Luminal(Luminal®® )) Ion Channel InhibitorsIon Channel Inhibitors  carbamazepinecarbamazepine (Tegretol(Tegretol®® ))  phenytoin (Dilantin®)phenytoin (Dilantin®) Misc. AgentsMisc. Agents  valproic acidvalproic acid (Depakote®)(Depakote®)
  18. 18.  MOAs:MOAs:  1. Sodium channel blockers1. Sodium channel blockers  - Phenytoin, carbamazepine, valproic acid- Phenytoin, carbamazepine, valproic acid  2.Calcium channel blockers2.Calcium channel blockers  EthosuximideEthosuximide  3. GABA-mediated3. GABA-mediated  Benzodiazepines, phenobarbital, gabapentin,Benzodiazepines, phenobarbital, gabapentin, tiagabinetiagabine
  19. 19.  IndicationsIndications  1. GTC and partial seizures1. GTC and partial seizures  - valproic acid, carbamazepine, phenytoin- valproic acid, carbamazepine, phenytoin  2. Absence2. Absence  - ethosuximide, valproic acid- ethosuximide, valproic acid  3. Myoclonic3. Myoclonic  - clonazepam, valproic acid- clonazepam, valproic acid  4. Status epilepticus4. Status epilepticus  - diazepam, lorazepam, phenytoin- diazepam, lorazepam, phenytoin  5. Febrile seizures-5. Febrile seizures- phenobarbitalphenobarbital
  20. 20. Adverse effectsAdverse effects  TeratogenicTeratogenic  valproic acid- neural tube defectsvalproic acid- neural tube defects  Phenytoin- craniofacial abnormalities, spinaPhenytoin- craniofacial abnormalities, spina bifidabifida  Phenytoin- fetal hydantoin syndromePhenytoin- fetal hydantoin syndrome  CNS, respiratory depressionCNS, respiratory depression
  21. 21. Adverse effectsAdverse effects  PhenytoinPhenytoin  Nystagmus, diplopia, ataxia, gingivalNystagmus, diplopia, ataxia, gingival hyperplasia, hirsutism, anemia,facialhyperplasia, hirsutism, anemia,facial coarseningcoarsening  CarbamazepineCarbamazepine  Diplopia, ataxia, blood dyscrasiaDiplopia, ataxia, blood dyscrasia  Valproic acidValproic acid  GI distress, hepatotoxicityGI distress, hepatotoxicity
  22. 22. Gingival hyperplasiaGingival hyperplasia
  23. 23. PharmacokineticsPharmacokinetics  Drug metabolism inducersDrug metabolism inducers  Phenytoin, carbamazepinePhenytoin, carbamazepine  Drug metabolism inhibitorsDrug metabolism inhibitors  Valproic acidValproic acid
  24. 24. CLASSIFICATION OFCLASSIFICATION OF ANTICONVULSANTSANTICONVULSANTS  BARBITURATESBARBITURATES PhenobarbitalPhenobarbital MephobarbitalMephobarbital MetharbitalMetharbital PrimidonePrimidone
  25. 25. BARBITURATESBARBITURATES  Hypnotic –sedativeHypnotic –sedative  AnesthesiaAnesthesia  Tolerance and addictionTolerance and addiction  anticonvulsantanticonvulsant
  26. 26. MOAMOA SPECIFICSPECIFIC - enhances GABA receptor mediated- enhances GABA receptor mediated current by opening chloride channelscurrent by opening chloride channels - blocks excitatory responses induced by- blocks excitatory responses induced by glutamateglutamate - high concentration blocks Na and Ca- high concentration blocks Na and Ca conductancesconductances
  27. 27. TOXICITYTOXICITY  Morbilliform rashMorbilliform rash  HypoprothrombinemiaHypoprothrombinemia  Megaloblastic anemiaMegaloblastic anemia  OsteomalaciaOsteomalacia
  28. 28. HYDANTOINSHYDANTOINS  AnticonvulsantAnticonvulsant  Anti-arrhythmicAnti-arrhythmic
  29. 29. MOAMOA  Prolongs inactivated state of NaProlongs inactivated state of Na channelchannel  Alters K and Ca conductanceAlters K and Ca conductance TOXICITYTOXICITY gingival hyperplasiagingival hyperplasia megaloblastic anemiamegaloblastic anemia
  30. 30. HYDANTOINSHYDANTOINS  PhenytoinPhenytoin  MephenytoinMephenytoin  ethotoinethotoin
  31. 31. BENZODIAZEPINESBENZODIAZEPINES  AntianxietyAntianxiety  Sedative-hypnoticSedative-hypnotic  Muscle relaxantMuscle relaxant  PreanestheticPreanesthetic  AnticonvulsantAnticonvulsant
  32. 32. CARBAMAZEPINECARBAMAZEPINE  Decrease spread of seizureDecrease spread of seizure activity from an active focusactivity from an active focus  Blocks Na channelsBlocks Na channels
  33. 33. Anti-Epileptic DrugsAnti-Epileptic Drugs  Carbamazepine:Carbamazepine:  derivative of tricyclic antidepressantsderivative of tricyclic antidepressants  Partial and tonic clonic 1Partial and tonic clonic 1stst lineline  similar profile of that of phenytoin, but with fewersimilar profile of that of phenytoin, but with fewer unwanted effectsunwanted effects  effective in most forms of epilepsy (except absenceeffective in most forms of epilepsy (except absence seizures); particularly effective in psychomotorseizures); particularly effective in psychomotor epilepsy; also useful in trigenimal neuralgiaepilepsy; also useful in trigenimal neuralgia  strong enzyme-inducing agent; therefore, manystrong enzyme-inducing agent; therefore, many drug interactionsdrug interactions  low incidence of unwanted effects; principallylow incidence of unwanted effects; principally sedation, ataxia, mental disturbances, watersedation, ataxia, mental disturbances, water retention.retention.
  34. 34. ETHOSUXIMIDEETHOSUXIMIDE  Blocks Ca channelsBlocks Ca channels  Inhibits Na and K atpaseInhibits Na and K atpase  Inhibits GABA aminotransferaseInhibits GABA aminotransferase
  35. 35. Anti-Epileptic DrugsAnti-Epileptic Drugs  Ethosuximide:Ethosuximide:  the main drug used to treat absencethe main drug used to treat absence seizures, may exacerbate other formsseizures, may exacerbate other forms  acts by blocking T-type calcium channelsacts by blocking T-type calcium channels  relatively few unwanted effects, mainlyrelatively few unwanted effects, mainly nausea and anorexia.nausea and anorexia.  Withdrawal is not a problemWithdrawal is not a problem
  36. 36. VALPROATESVALPROATES  Increase GABA mediatedIncrease GABA mediated transmissiontransmission  Blocks Na channels at lowBlocks Na channels at low concentrationconcentration  Blocks K channels at highBlocks K channels at high concentrationconcentration
  37. 37. Anti-Epileptic DrugsAnti-Epileptic Drugs  Valproate:Valproate:  chemically unrelated to other anti-epilepticchemically unrelated to other anti-epileptic drugsdrugs  Absence and tonic clonic 1Absence and tonic clonic 1stst line and partialline and partial 22ndnd lineline  mechanism of action not clear; weakmechanism of action not clear; weak inhibition of GABA transaminase; someinhibition of GABA transaminase; some effect on sodium channelseffect on sodium channels  related few unwanted effects: baldness,related few unwanted effects: baldness, teratogenicity, liver damage (rare, butteratogenicity, liver damage (rare, but serious).serious).
  38. 38. New Anti-Epileptic DrugsNew Anti-Epileptic Drugs  Topiramate:Topiramate:  complex actions, not fully understoodcomplex actions, not fully understood  Partial and tonic clonic 2Partial and tonic clonic 2ndnd lineline  similar to phenytoin with fewer side-effects andsimilar to phenytoin with fewer side-effects and simpler pharmacokineticssimpler pharmacokinetics  Risk of teratogenesisRisk of teratogenesis  Lamotrigine:Lamotrigine:  acts by inhibiting sodium channelsacts by inhibiting sodium channels  broad therapeutic profilebroad therapeutic profile  main side-effects are hypersensitivity reactionsmain side-effects are hypersensitivity reactions (especially skin rashes).(especially skin rashes).  Partial 2Partial 2ndnd lineline
  39. 39. New Anti-Epileptic drugsNew Anti-Epileptic drugs  Felbamate:Felbamate:  mechanisms of action unknownmechanisms of action unknown  Partial 3Partial 3rdrd lineline  use limited to intractable disease because of theuse limited to intractable disease because of the risk of severe hypersensitivity reactionsrisk of severe hypersensitivity reactions..  Gabapentin:Gabapentin:  mechanism of action not knownmechanism of action not known  Partial and tonic clonic 2Partial and tonic clonic 2ndnd lineline  saturable absorption; therefore, it is safe insaturable absorption; therefore, it is safe in overdoseoverdose  relatively free of side-effects.relatively free of side-effects.
  40. 40. Medications by SeizureMedications by Seizure TypeType (Generalized Seizures)(Generalized Seizures)  Absence (petit mal)Absence (petit mal)  brief period of unresponsiveness <30 sbrief period of unresponsiveness <30 s  11stst line ethosuximide, valproic acidline ethosuximide, valproic acid  22ndnd line lamotrigineline lamotrigine  Tonic-clonic (grand mal)Tonic-clonic (grand mal)  dramatic convulsions and loss ofdramatic convulsions and loss of consciousnessconsciousness  11stst line valproic acid,line valproic acid, carbamazepine,phenytoincarbamazepine,phenytoin  22ndnd line lamotrigine, phenobarbitalline lamotrigine, phenobarbital
  41. 41. Medications by SeizureMedications by Seizure TypeType (Partial Seizures)(Partial Seizures) Simple PartialSimple Partial  Sensory seizureSensory seizure  11stst line carbamazepine, phenytoinline carbamazepine, phenytoin  22ndnd line lamotrigine, gabapentin, valproic acidline lamotrigine, gabapentin, valproic acid  Complex PartialComplex Partial  Starts at simple partial and generalizesStarts at simple partial and generalizes  11stst line carbamazepine,phenytoinline carbamazepine,phenytoin  22ndnd line lamotrigine, gabapentinline lamotrigine, gabapentin  Unremitting seizureUnremitting seizure  respiratory compromiserespiratory compromise  11stst line lorazepam, diazepamline lorazepam, diazepam  22ndnd line phenytoinline phenytoin