Saddam AnsariAchiever’s AcademyIntroduction and Drugsused to Treat Epilepsy
Epilepsy? Second most common neurologicaldisorder. Family of different recurrent seizuresdisorders that have in common t...
Types of EpilepsyPrimary or Idiopathic Epilepsy: No specific anatomic cause for the seizure Inherited abnormality Treat...
Continued…Secondary Epilepsy: Reversible disturbances such as tumors, headinjury , hypoglycemia , meningeal infection orw...
Classification of SeizuresPartial Seizure Simple partial Complex partial
Continued…Generalized Seizure Tonic-clonic (grand mal) Absence (petit mal) Myoclonic Febrile seizure Status epilepticus
Mechanism of action ofantiepileptic drugs Block the initiation of the electric dischargefrom the focal area Prevent the ...
Primary Antiepileptic Drugs Phenytoin Carbamazepine Oxcarbazepine Phenobarbital Primidone Valproic acid Ethosuximid...
Adjunct Drugs Felbamate Gabapentin Lamotrigine Levetiracetam Tiagabine Topiramate Zonisamide
Phenytoin Formerly called as diphenylhydantoin Effective in suppressing tonic-clonic andpartial seizures Choice for ini...
Continued…Mechanism of action: Blocks voltage – gated sodium channels Selectively binds to the channels ininactive state...
Continued…Actions: Reduces the propagation of abnormalimpulses in the brain Is not a generalized CNS depressantlike the ...
Continued…Therapeutic uses: Highly effective for all partial seizures ,tonic – clonic seizures and in the statusepileptic...
Continued…Absorption and fate: Oral absorption is slow but distribution israpid and brain concentration are high Chronic...
Continued…Absorption and fate: At low doses, half life is 24 hours Hydroxylation system becomessaturated as dose increas...
Continued…Adverse effects: Depression of CNS particularly incerebellum and vestibular system –nystagmus and ataxia GIT p...
Continued…Adverse effects: Megaloblastic anemia – B12 reactions Confusion, hallucination and drowsiness Inhibition of a...
Continued…Teratogenic effects: “Fetal Hydantoin Syndrome” includescleft lip, cleft palate and congenital heartdisease St...
Continued…Drug InteractionsDrugs that affect phenytoin metabolism:Chloramphenicol, dicumarol , cimetidine,sulfonamides and...
Continued…Drug InteractionsIncreased metabolism of other drugscaused by phenytoin:Induces the cytochrome P450 systemResult...
CarbamazepineActions: Reduces the propagation of abnormalimpulses in the brain by blocking sodiumchannels Inhibits the g...
Continued…Therapeutic uses: Highly effective for all partial seizures ,first choice drug Effective in tonic-clonic seizu...
Continued…Absorption and Fate: Absorbed slowly through oral administration Highly lipid solubility Half life – 5 to 7 d...
Continued…Adverse effects: Chronic administration can cause stupor,coma and respiratory depression along withdrowsiness, ...
Continued…Drug interaction:Hepatic metabolism of carbamazepine isinhibited byCimetidineDiltiazemErythromycinIsoniazid...
Oxcarbazepine 10-keto derivative of carbamazepine Reduces to 10-monohydroxy metaboliteand blocks sodium channels prevent...
PhenobarbitalActions: Limiting the spread of seizuredischarges in the brain and elevating theseizures threshold Exact me...
Continued…Therapeutic uses: 50% favorable response rate for simplepartial seizures Not very effective for complex partia...
Continued…Actions: Used to treat recurrent tonic-clonicseizures (if diazepam and phenytoin isnonresponsive) Mild sedativ...
Continued…Absorption and Fate: Well absorbed orally Freely penetrates the brain Approximately 75 % drug is inactivatedb...
Continued…Adverse effects: Sedation Ataxia Nystagmus Vertigo Acute psychotic reaction with chronicuse
Continued…Adverse effects: Nausea and vomiting with morbilliformrash Agitation and confusion at high doses Rebound seiz...
Primidone Related to phenobarbital Alternate choice in partial and tonic-clonic seizures Often used with carbamazepine ...
Valproic Acid Blocks sodium channel Enhancement of GABAergictransmission Broad-spectrum anticonvulsant Most effective ...
Continued… Its second choice of drug due itshepatotoxicity Reduces the incidence and severity oftonic-clonic seizures E...
Continued… 3% excreted unchanged Metabolized by CYP
Continued…Adverse effects Nausea and vomiting Sedation, ataxia and tremor arecommon Rare hepatic toxicity Rash and alo...
Ethosuximide Introduced in 1960 in the USA. Ethosuximide has very little activity againstmaximal electroshock Considera...
Continued…Mechanism of Action Ethosuximide has an important effect on Ca2+currents, reducing the low-threshold (T-type)cu...
Continued…Therapeutic uses: Particularly effective against absence seizures Very narrow spectrum of clinical activity D...
Continued…Pharmacokinetics Absorption is complete following administration ofthe oral dosage forms. Peak levels are obse...
Continued… The drug has a very low total body clearance(0.25 L/kg/d) This corresponds to a half-life of approximately40 ...
Continued…Therapeutic Levels & Dosage Therapeutic levels of 60–100 mcg/mL can beachieved in adults with dosages of 750–15...
Continued…Drug Interactions Administration of ethosuximide with valproic acidresults in a decrease in ethosuximide cleara...
Continued…Adverse effects and Toxicity Gastric distress, including pain, nausea, andvomiting. When an adverse effect occ...
Continued…Phensuximide & Methsuximide Phensuximide and Methsuximide arePhenylsuccinimides that were developed andmarketed...
continued… Unlike Ethosuximide, these two compoundshave some activity against maximalelectroshock seizures Methsuximide ...
Benzodiazepines Diazepam Potentiates GABAA responses Well absorbed orally , rectal administrationgives peak concentratio...
Continued… Clonazepam Action : As for diazepam >80% bioavailability extensively metabolizedbut no active metabolites , t...
Felbamate Blocking voltage-dependent sodium channels Competing with the glycine-coagonist bindingsite on the N-methyl-D-...
Continued… Potentiating the action of GABA. It is aninhibitor of drugs metabolized by CYP2C19and â-oxidation, and induces...
Gabapentin Decreases excitatory transmission by actingon Voltage-Gated Ca2+ channelspresynaptically Bioavailability 50%,...
Continued… t1/2 6–8 h Generalized tonic-clonic seizures, partialseizures, Adverse effects: Somnolence, dizziness,ataxia
Lamotrigine Prolongs inactivation of VG-Na+ channels Acts presynaptically on VG-Ca2+ channels Decreases glutamate relea...
Continued… Metabolized primarily to the N-2 glucuronidethrough the UGT pathway t1/2 25–35 h Generalized tonic-clonic se...
Levetiracetam Action on synaptic protein SV2A Well absorbed orally Not bound to plasma proteins , t1/2 6–11 h Generali...
Tiagabine Blocks GABA reuptake in forebrain byselective blockade of GAT-1 Well absorbed highly bound to plasmaproteins ...
Topiramate Broad spectrum antiseizure activity. Blocks voltage-dependent sodium channels Increase the frequency of chlo...
Continued… It is a carbonic anhydrase inhibitor and mayact at glutamate (NMDA) sites Effective and approved for use in p...
Continued… It inhibits CYP2C19 and is induced byphenytoin and carbamazepine Lamotrigine is reported to cause an increase...
Continued… Adverse effects include somnolence, weight loss,and paresthesias Renal stones are reported to occur at a high...
Zonisamide sulfonamide derivative that has a broad spectrumof action. The compound has multiple effects onneuronal system...
Continued… Approved for use in patients with partialepilepsy It is metabolized by the CYP3A4 isozyme andmay, to a lesser...
Introduction and drugs used to treat epilepsy
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Introduction to Epilepsy and its type and Drugs used in management of Epilepsy.

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Introduction and drugs used to treat epilepsy

  1. 1. Saddam AnsariAchiever’s AcademyIntroduction and Drugsused to Treat Epilepsy
  2. 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. 3. Types of EpilepsyPrimary or Idiopathic Epilepsy: No specific anatomic cause for the seizure Inherited abnormality Treated often for lifetime with antiepilepticdrugs
  4. 4. Continued…Secondary 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. 5. Classification of SeizuresPartial Seizure Simple partial Complex partial
  6. 6. Continued…Generalized Seizure Tonic-clonic (grand mal) Absence (petit mal) Myoclonic Febrile seizure Status epilepticus
  7. 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. 8. Primary Antiepileptic Drugs Phenytoin Carbamazepine Oxcarbazepine Phenobarbital Primidone Valproic acid Ethosuximide Benzodiazepines
  9. 9. Adjunct Drugs Felbamate Gabapentin Lamotrigine Levetiracetam Tiagabine Topiramate Zonisamide
  10. 10. Phenytoin Formerly called as diphenylhydantoin Effective in suppressing tonic-clonic andpartial seizures Choice for initial therapy , particularly inadults
  11. 11. Continued…Mechanism 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. 12. Continued…Actions: 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. 13. Continued…Therapeutic 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. 14. Continued…Absorption 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. 15. Continued…Absorption 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. 16. Continued…Adverse 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. 17. Continued…Adverse effects: Megaloblastic anemia – B12 reactions Confusion, hallucination and drowsiness Inhibition of antidiuretic hormone Insulin secretion Should not be stopped abruptly
  18. 18. Continued…Teratogenic 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. 19. Continued…Drug InteractionsDrugs that affect phenytoin metabolism:Chloramphenicol, dicumarol , cimetidine,sulfonamides and isoniazidMicrosomal metabolism is inhibited by thesedrugs in the liverPhenytoin metabolism is enhanced bycarbamzepine
  20. 20. Continued…Drug 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. 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. 22. Continued…Therapeutic 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. 23. Continued…Absorption 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. 24. Continued…Adverse 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. 25. Continued…Drug interaction:Hepatic metabolism of carbamazepine isinhibited byCimetidineDiltiazemErythromycinIsoniazidPropoxypheneToxic symptoms may arise if dose is notadjusted
  26. 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. 27. PhenobarbitalActions: Limiting the spread of seizuredischarges in the brain and elevating theseizures threshold Exact mechanism is unknown Believed that potentiation of GABAneurons
  28. 28. Continued…Therapeutic 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. 29. Continued…Actions: Used to treat recurrent tonic-clonicseizures (if diazepam and phenytoin isnonresponsive) Mild sedative to relieve anxiety , nervoustension, insomnia but benzodiazepinesare superior
  30. 30. Continued…Absorption 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. 31. Continued…Adverse effects: Sedation Ataxia Nystagmus Vertigo Acute psychotic reaction with chronicuse
  32. 32. Continued…Adverse effects: Nausea and vomiting with morbilliformrash Agitation and confusion at high doses Rebound seizures can occur ondiscontinuance of phenobarbital
  33. 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. 34. Valproic Acid Blocks sodium channel Enhancement of GABAergictransmission Broad-spectrum anticonvulsant Most effective in myoclonic seizures
  35. 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. 36. Continued… 3% excreted unchanged Metabolized by CYP
  37. 37. Continued…Adverse effects Nausea and vomiting Sedation, ataxia and tremor arecommon Rare hepatic toxicity Rash and alopecia Thrombocytopenia Inhibits the metabolism of otherantiepileptic drugs
  38. 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. 39. Continued…Mechanism 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. 40. Continued…Therapeutic 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. 41. Continued…Pharmacokinetics Absorption is complete following administration ofthe oral dosage forms. Peak levels are observed 3–7 hours after oraladministration Ethosuximide is not protein-bound. Ethosuximide is completely metabolized,principally by hydroxylation, to inactivemetabolites.
  42. 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. 43. Continued…Therapeutic Levels & Dosage Therapeutic levels of 60–100 mcg/mL can beachieved in adults with dosages of 750–1500mg/d Although lower or higher dosages and bloodlevels (up to 125 mcg/mL) may be necessary andtolerated in some patients.
  44. 44. Continued…Drug 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. 45. Continued…Adverse 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. 46. Continued…Phensuximide & 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. 47. continued… Unlike Ethosuximide, these two compoundshave some activity against maximalelectroshock seizures Methsuximide has been used for partialseizures by some investigators
  48. 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. 49. Continued… Clonazepam Action : As for diazepam >80% bioavailability extensively metabolizedbut no active metabolites , t1/2 20–50 h Therapeutic uses: Absence seizures,myoclonic seizures, infantile spasms Toxicity: Similar to diazepam
  50. 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. 51. Continued… Potentiating the action of GABA. It is aninhibitor of drugs metabolized by CYP2C19and â-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. 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. 53. Continued… t1/2 6–8 h Generalized tonic-clonic seizures, partialseizures, Adverse effects: Somnolence, dizziness,ataxia
  54. 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. 55. Continued… Metabolized primarily to the N-2 glucuronidethrough the UGT pathway t1/2 25–35 h Generalized tonic-clonic seizures, generalizedseizures, partial seizures, generalized seizures,absence seizures Adverse effects: Dizziness, headache, diplopia,rash Interactions: Valproate, carbamazepine,oxcarbazepine
  56. 56. Levetiracetam Action on synaptic protein SV2A Well absorbed orally Not bound to plasma proteins , t1/2 6–11 h Generalized tonic-clonic seizures, partialseizures, generalized seizures Adverse effects: Nervousness, dizziness,depression, seizures Interactions: Phenobarbital, phenytoin,carbamazepine, primidone
  57. 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 4–8 h Partial seizures Adverse effects: Nervousness, dizziness,depression, seizures
  58. 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. 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. 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. 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. 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. 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 50–70 h In addition to typical CNS adverse effects, itmay cause kidney stones Oligohidrosis has been reported

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