1. Saddam AnsariAchievers AcademyIntroduction and Drugsused to Treat Epilepsy

2. Epilepsy? Second most common neurologicaldisorder. Family of different recurrent seizuresdisorders that have in common thesudden, excessive and synchronousdischarge of cerebral neurons. Abnormal movements or perceptionsthat are of short duration but tend to 3. Types of EpilepsyPrimary or Idiopathic Epilepsy: No specific anatomic cause for the seizure Inherited abnormality Treated often for lifetime with antiepilepticdrugs 4. ContinuedSecondary Epilepsy: Reversible disturbances such as tumors, headinjury , hypoglycemia , meningeal infection orwithdrawal Antiepileptic are given until primary cause iscorrected Seizures secondary to stroke or trauma maycause irreversible CNS damage. 5. Classification of SeizuresPartial Seizure Simple partial Complex partial 6. ContinuedGeneralized Seizure Tonic-clonic (grand mal) Absence (petit mal) Myoclonic Febrile seizure Status epilepticus 7. Mechanism of action ofantiepileptic drugs Block the initiation of the electric dischargefrom the focal area Prevent the spread of the abnormal electricaldischarge to adjacent brain areas Blockade of voltage gated channels Enhancement of GABAergic impulses Interference with glutamate transmission 8. Primary Antiepileptic Drugs Phenytoin Carbamazepine Oxcarbazepine Phenobarbital Primidone Valproic acid Ethosuximide Benzodiazepines 9. Adjunct Drugs Felbamate Gabapentin Lamotrigine Levetiracetam Tiagabine Topiramate Zonisamide 10. Phenytoin Formerly called as diphenylhydantoin Effective in suppressing tonic-clonic andpartial seizures Choice for initial therapy , particularly inadults 11. ContinuedMechanism of action: Blocks voltage gated sodium channels Selectively binds to the channels ininactive state and recovery rate slowsdown At higher concentration block voltagedependent calcium channels andinterfere with the release ofmonoaminergic neurotransmitters 12. ContinuedActions: Reduces the propagation of abnormalimpulses in the brain Is not a generalized CNS depressantlike the barbiturates But produces some degree ofdrowsiness and lethargy withoutprogression to hypnosis 13. ContinuedTherapeutic uses: Highly effective for all partial seizures ,tonic clonic seizures and in the statusepilepticus caused by recurrent tonic-clonic seizures Not effective in absence seizures , mayworsen if treated with this drug 14. ContinuedAbsorption and fate: Oral absorption is slow but distribution israpid and brain concentration are high Chronic administration of phenytoin isalways oral Largely bound to plasma albumin Metabolized by hepatic cytochrome P450system to an inactive metabolite 15. ContinuedAbsorption and fate: At low doses, half life is 24 hours Hydroxylation system becomessaturated as dose increases Increase in plasma concentration resultsin drug induced toxicity In status epilepticus IV in form offosphenytoin 16. ContinuedAdverse effects: Depression of CNS particularly incerebellum and vestibular system nystagmus and ataxia GIT problems nausea and vomiting Gingival hyperplasia particularly inchildren Coarsening of facial features occurs inchildren 17. ContinuedAdverse effects: Megaloblastic anemia B12 reactions Confusion, hallucination and drowsiness Inhibition of antidiuretic hormone Insulin secretion Should not be stopped abruptly 18. ContinuedTeratogenic effects: Fetal Hydantoin Syndrome includescleft lip, cleft palate and congenital heartdisease Stunted growth Mental deficiency Congenital birth defects in untreatedmothers Drugs are given at the lowest possibledose in pregnant women 19. ContinuedDrug InteractionsDrugs that affect phenytoin metabolism:Chloramphenicol, dicumarol , cimetidine,sulfonamides and isoniazidMicrosomal metabolism is inhibited by thesedrugs in the liverPhenytoin metabolism is enhanced bycarbamzepine 20. ContinuedDrug InteractionsIncreased metabolism of other drugscaused by phenytoin:Induces the cytochrome P450 systemResults in increased metabolism of otherantiepileptics, anticoagulants, oralcontraceptives, quinidine, doxycycline,cyclosporine, mexiletine, methadone, andlevodopa. 21. CarbamazepineActions: Reduces the propagation of abnormalimpulses in the brain by blocking sodiumchannels Inhibits the generation of repetitiveaction potentials in the epileptic focusand preventing their spread 22. ContinuedTherapeutic uses: Highly effective for all partial seizures ,first choice drug Effective in tonic-clonic seizures Used in treatment of trigeminal neuralgia Used in manic-depressive patients toameliorate the symptoms 23. ContinuedAbsorption and Fate: Absorbed slowly through oral administration Highly lipid solubility Half life 5 to 7 days Half life decreases with chronic administration Induces cytochrome P450 system,cytochrome P450 isozyme, CYP3A4 24. ContinuedAdverse effects: Chronic administration can cause stupor,coma and respiratory depression along withdrowsiness, vertigo, ataxia, blurred vision andrash. GIT nausea and vomiting Liver toxicity Blood dyscrasias ( 10,11- epoxide metaboliteof drug) Leukopenia and aplastic anemia Hyponatremia in elderly people 25. ContinuedDrug interaction:Hepatic metabolism of carbamazepine isinhibited byCimetidineDiltiazemErythromycinIsoniazidPropoxypheneToxic symptoms may arise if dose is notadjusted 26. Oxcarbazepine 10-keto derivative of carbamazepine Reduces to 10-monohydroxy metaboliteand blocks sodium channels preventingthe spread of the abnormal discharge Anticonvulsant spectrum and toxicitiesare similar to that of carbamazepine Less potent inducer of drug-metabolizing enzyme Reduced effectiveness of oralcontraceptives 27. PhenobarbitalActions: Limiting the spread of seizuredischarges in the brain and elevating theseizures threshold Exact mechanism is unknown Believed that potentiation of GABAneurons 28. ContinuedTherapeutic uses: 50% favorable response rate for simplepartial seizures Not very effective for complex partialseizures First choice of drug for recurrentseizures in children including febrileseizure ,diazepam is also effective 29. ContinuedActions: Used to treat recurrent tonic-clonicseizures (if diazepam and phenytoin isnonresponsive) Mild sedative to relieve anxiety , nervoustension, insomnia but benzodiazepinesare superior 30. ContinuedAbsorption and Fate: Well absorbed orally Freely penetrates the brain Approximately 75 % drug is inactivatedby the hepatic microsomal system Remaining drug is excreted unchangedby the kidney Potent inducer of cytochrome P450system 31. ContinuedAdverse effects: Sedation Ataxia Nystagmus Vertigo Acute psychotic reaction with chronicuse 32. ContinuedAdverse effects: Nausea and vomiting with morbilliformrash Agitation and confusion at high doses Rebound seizures can occur ondiscontinuance of phenobarbital 33. Primidone Related to phenobarbital Alternate choice in partial and tonic-clonic seizures Often used with carbamazepine andphenytoin Ineffective in absence seizures Well absorbed orally but poor proteinbinding Adverse effects is same asphenobarbital 34. Valproic Acid Blocks sodium channel Enhancement of GABAergictransmission Broad-spectrum anticonvulsant Most effective in myoclonic seizures 35. Continued Its second choice of drug due itshepatotoxicity Reduces the incidence and severity oftonic-clonic seizures Effective orally and rapidly absorbed About 90% bound to plasma proteins 36. Continued 3% excreted unchanged Metabolized by CYP 37. ContinuedAdverse effects Nausea and vomiting Sedation, ataxia and tremor arecommon Rare hepatic toxicity Rash and alopecia Thrombocytopenia Inhibits the metabolism of otherantiepileptic drugs 38. Ethosuximide Introduced in 1960 in the USA. Ethosuximide has very little activity againstmaximal electroshock Considerable efficacy againstpentylenetetrazol seizures; it was introducedas a "pure petit mal" drug. 39. ContinuedMechanism of Action Ethosuximide has an important effect on Ca2+currents, reducing the low-threshold (T-type)current. This effect is seen at therapeutically relevantconcentrations in thalamic neurons. The T-type calcium currents are thought toprovide a pacemaker current in thalamic neuronsresponsible for absence seizures. (INHIBITION ofthalamic neurons) 40. ContinuedTherapeutic uses: Particularly effective against absence seizures Very narrow spectrum of clinical activity Documentation of its effectiveness in humanabsence seizures was achieved with long-termelectroencephalographic recording techniques 41. ContinuedPharmacokinetics Absorption is complete following administration ofthe oral dosage forms. Peak levels are observed 37 hours after oraladministration Ethosuximide is not protein-bound. Ethosuximide is completely metabolized,principally by hydroxylation, to inactivemetabolites. 42. Continued The drug has a very low total body clearance(0.25 L/kg/d) This corresponds to a half-life of approximately40 hours, although values from 18 to 72 hourshave been reported. 43. ContinuedTherapeutic Levels & Dosage Therapeutic levels of 60100 mcg/mL can beachieved in adults with dosages of 7501500mg/d Although lower or higher dosages and bloodlevels (up to 125 mcg/mL) may be necessary andtolerated in some patients. 44. ContinuedDrug Interactions Administration of ethosuximide with valproic acidresults in a decrease in ethosuximide clearanceand higher steady-state concentrations. No other important drug interactions have beenreported for the succinimides. 45. ContinuedAdverse effects and Toxicity Gastric distress, including pain, nausea, andvomiting. When an adverse effect occur, temporary dosagereductions may allow adaptation. Other dose-related adverse effects are transientlethargy or fatigue and much less commonly,headache, dizziness, hiccup, and euphoria. Behavioral changes are usually in the direction ofimprovement. 46. ContinuedPhensuximide & Methsuximide Phensuximide and Methsuximide arePhenylsuccinimides that were developed andmarketed before Ethosuximide They are used primarily as anti-absence drugs Methsuximide is generally considered more toxic,and Phensuximide less effective, thanEthosuximide 47. continued Unlike Ethosuximide, these two compoundshave some activity against maximalelectroshock seizures Methsuximide has been used for partialseizures by some investigators 48. Benzodiazepines Diazepam Potentiates GABAA responses Well absorbed orally , rectal administrationgives peak concentration in ~1 h with 90%bioavailability IV for status epilepticus , highly protein-bound, extensively metabolized to several activemetabolites ,t1/2 ~2 d Status epilepticus, seizure clusters 49. Continued Clonazepam Action : As for diazepam >80% bioavailability extensively metabolizedbut no active metabolites , t1/2 2050 h Therapeutic uses: Absence seizures,myoclonic seizures, infantile spasms Toxicity: Similar to diazepam 50. Felbamate Blocking voltage-dependent sodium channels Competing with the glycine-coagonist bindingsite on the N-methyl-D-aspartate (NMDA)glutamate receptor Blocking calcium channels 51. Continued Potentiating the action of GABA. It is aninhibitor of drugs metabolized by CYP2C19and -oxidation, and induces drugsmetabolized by CYP3A4. It is reserved for use in refractory epilepsies(particularly Lennox-Gastaut syndrome)because of the risk of aplastic anemia (about1:4000) Hepatic failure. 52. Gabapentin Decreases excitatory transmission by actingon Voltage-Gated Ca2+ channelspresynaptically Bioavailability 50%, decreasing withincreasing doses not bound to plasma proteins Not metabolized , excreted through kidney 53. Continued t1/2 68 h Generalized tonic-clonic seizures, partialseizures, Adverse effects: Somnolence, dizziness,ataxia 54. Lamotrigine Prolongs inactivation of VG-Na+ channels Acts presynaptically on VG-Ca2+ channels Decreases glutamate release Well absorbed orally No significant protein binding 55. Continued Metabolized primarily to the N-2 glucuronidethrough the UGT pathway t1/2 2535 h Generalized tonic-clonic seizures, generalizedseizures, partial seizures, generalized seizures,absence seizures Adverse effects: Dizziness, headache, diplopia,rash Interactions: Valproate, carbamazepine,oxcarbazepine 56. Levetiracetam Action on synaptic protein SV2A Well absorbed orally Not bound to plasma proteins , t1/2 611 h Generalized tonic-clonic seizures, partialseizures, generalized seizures Adverse effects: Nervousness, dizziness,depression, seizures Interactions: Phenobarbital, phenytoin,carbamazepine, primidone 57. Tiagabine Blocks GABA reuptake in forebrain byselective blockade of GAT-1 Well absorbed highly bound to plasmaproteins Metabolism is mainly completed by theCYP3A family of enzymes t1/2 48 h Partial seizures Adverse effects: Nervousness, dizziness,depression, seizures 58. Topiramate Broad spectrum antiseizure activity. Blocks voltage-dependent sodium channels Increase the frequency of chloride channelopening by binding to the GABAA receptor High-voltage calcium currents (L type) arereduced 59. Continued It is a carbonic anhydrase inhibitor and mayact at glutamate (NMDA) sites Effective and approved for use in partial andprimary generalized epilepsy It is also approved for treatment of migraine Topiramate is eliminated renally t1/2 20 h 60. Continued It inhibits CYP2C19 and is induced byphenytoin and carbamazepine Lamotrigine is reported to cause an increasein topiramate concentration Coadministration of topiramate reducesethinyl estradiol 61. Continued Adverse effects include somnolence, weight loss,and paresthesias Renal stones are reported to occur at a higherincidence than in a non-treated population Glaucoma, oligohidrosis, and hyperthermia havealso been reported 62. Zonisamide sulfonamide derivative that has a broad spectrumof action. The compound has multiple effects onneuronal systems thought to be involved inseizure generation. These include blockade of both voltage-gatedsodium channels T-type calcium currents Its use should be monitored in patients withreported allergies. 63. Continued Approved for use in patients with partialepilepsy It is metabolized by the CYP3A4 isozyme andmay, to a lesser extent, be affected byCYP3A5 and CYP2C19 t1/2 5070 h In addition to typical CNS adverse effects, itmay cause kidney stones Oligohidrosis has been reported