Anti epileptic drugs

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Anti epileptic drugs

  1. 1. Anti-epileptic Drugs <ul><li>Classification of Seizures </li></ul><ul><ul><li>Partial: simple or complex </li></ul></ul><ul><ul><li>Generalized: absence, tonic, clonic, tonic-clonic, myoclonic, febrile </li></ul></ul><ul><li>Animal Models of Seizures </li></ul><ul><ul><li>C hemical-induced: pentylenetetrazole, kainic acid, </li></ul></ul><ul><ul><li>Maximal electrochock </li></ul></ul><ul><ul><li>Kindling </li></ul></ul>
  2. 2. Pathophysiology of Seizures <ul><li>The Interictal Spike (paroxysmal depolarization shift) </li></ul><ul><li>Increased excitability </li></ul><ul><ul><li>Membrane depolarization, potassium buildup </li></ul></ul><ul><ul><li>Increased excitatory (EAA, glutamate) input </li></ul></ul><ul><ul><li>Decreased inhibitory (GABA) input </li></ul></ul>
  3. 4. Evidence for the Pathophysiology of Seizures <ul><li>Increased EAA </li></ul><ul><li>Increased Excitatory Amino Acid Transmission </li></ul><ul><li>Increased sensitivity to EAA </li></ul><ul><li>Progressive increase in glutamate release during kindling </li></ul><ul><li>Increased glutamate and aspartate at start of seizure </li></ul><ul><li>Upregulation of NMDA receptors in kindled rats </li></ul><ul><li>Decreased GABA </li></ul><ul><li>Decreased binding of GABA and benzodiazepines </li></ul><ul><li>Decreased Cl - currents in response to GABA </li></ul><ul><li>Decreased glutamate decarboxylase activity (synthesizes GABA) </li></ul><ul><li>Interfere with GABA causes seizures </li></ul>
  4. 6. Strategies in Treatment <ul><li>Stabilize membrane and prevent depolarization by action on ion channels </li></ul><ul><li>Increase GABAergic transmission </li></ul><ul><li>Decrease EAA transmission </li></ul>
  5. 7. Classification of Anticonvulsants Felbamate Topiramate Benzodiazepines (diazepam, clonazepam) Barbiturates (phenobarbital) Valproic acid Gabapentin Vigabatrin Topiramate Felbamate Na + : Phenytoin, Carbamazepine, Lamotrigine Topiramate Valproic acid Ca ++ : Ethosuximide Valproic acid Most effective in myoclonic but also in tonic-clonic and partial Clonazepam: for Absence Na + : For general tonic-clonic and partial seizures Ca ++ : For Absence seizures Inhibit EAA Transmission Enhance GABA Transmission Action on Ion Channels
  6. 8. Classification of Anticonvulsants <ul><li>Classical </li></ul><ul><li>Phenytoin </li></ul><ul><li>Phenobarbital </li></ul><ul><li>Primidone </li></ul><ul><li>Carbamazepine </li></ul><ul><li>Ethosuximide </li></ul><ul><li>Valproic Acid </li></ul><ul><li>Trimethadione </li></ul><ul><li>Newer </li></ul><ul><li>Lamotrigine </li></ul><ul><li>Felbamate </li></ul><ul><li>Topiramate </li></ul><ul><li>Gabapentin </li></ul><ul><li>Tiagabine </li></ul><ul><li>Vigabatrin </li></ul><ul><li>Oxycarbazepine </li></ul><ul><li>Levetiracetam </li></ul><ul><li>Fosphenytoin </li></ul><ul><li>Others </li></ul>
  7. 9. Phenytoin Phenobarbital Carbamazepine Ethosuximide Trimethadione Valproic Acid R 1 R 2 R 3 X
  8. 10. Phenytoin or Diphenylhydantoin <ul><li>Limited water solubility – not given i.m. </li></ul><ul><li>Slow, incomplete and variable absorption. </li></ul><ul><li>Extensive binding to plasma protein. </li></ul><ul><li>Metabolized by hepatic ER by hydroxylation. Chance for drug interactions. </li></ul><ul><li>Therapeutic plasma concentration: 10-20 µg/ml </li></ul><ul><li>Shift from first to zero order elimination within therapeutic concentration range. </li></ul>
  9. 12. Dose (mg/day) Plasma Concentration (mg/L) Relationship between Phenytoin Daily Dose and Plasma Concentration In 5 Patients
  10. 13. Phenytoin – Toxicity and Adverse Events <ul><li>Acute Toxicity </li></ul><ul><li>High i.v. rate: cardiac arrhythmias ± hypotension; CNS depression. </li></ul><ul><li>Acute oral overdose: cerebellar and vestibular symptoms and signs: </li></ul><ul><li>nystagmus, ataxia, diplopia vertigo. </li></ul>
  11. 14. <ul><li>Chronic Toxicity </li></ul><ul><li>Dose related vestibular/cerebellar effects </li></ul><ul><li>Behavioral changes </li></ul><ul><li>Gingival Hyperplasia </li></ul><ul><li>GI Disturbances </li></ul><ul><li>Sexual-Endocrine Effects: </li></ul><ul><ul><li>Osteomalacia </li></ul></ul><ul><ul><li>Hirsutism </li></ul></ul><ul><ul><li>Hyperglycemia </li></ul></ul>Phenytoin – Toxicity
  12. 17. <ul><li>Chronic Toxicity </li></ul><ul><li>Folate Deficiency - megaloblastic anemia </li></ul><ul><li>Hypoprothrombinemia and hemorrhage in newborns </li></ul><ul><li>Hypersenstivity Reactions – could be severe. SLE, fatal hepatic necrosis, Stevens-Johnson syndrome. </li></ul><ul><li>Pseudolymphoma syndrome </li></ul><ul><li>Teratogenic </li></ul><ul><li>Drug Interactions: decrease (cimetidine, isoniazid) or increase (phenobarbital, other AED’s) rate of metabolism; competition for protein binding sites. </li></ul>Phenytoin – Toxicity and Adverse Events
  13. 18. Fosphenytoin <ul><li>A Prodrug. Given i.v. or i.m. and rapidly converted to phenytoin in the body. </li></ul><ul><li>Avoids local complications associated with phenytoin: vein irritation, tissue damage, pain and burning at site, muscle necrosis with i.m. injection, need for large fluid volumes. </li></ul><ul><li>Otherwise similar toxicities to phenytoin. </li></ul>
  14. 19. Other Na Channel Blockers <ul><li>Carbamazepine: may have adrenergic mechanism as well. Serious hematological toxicity: aplastic anemia. Antidiuretic effect (anti ADH). </li></ul><ul><li>Also for trigeminal neuralgia </li></ul><ul><li>Lamotrigine: possible other mechanisms. Effective in Absence seizures and has antidepressant effects in bipolar depression. No chronic associated effects. </li></ul>
  15. 20. Inhibitors of Calcium Channels Ethosuximide <ul><li>Drug of choice for Absence. Blocks Ca ++ currents (T-currents) in the thalamus. </li></ul><ul><li>Not effective in other seizure types </li></ul><ul><li>GI complaints most common </li></ul><ul><li>CNS effects: drowsiness lethargy). </li></ul><ul><li>Has dopamine antagonist activity (? In seizure control) but causes Parkinsonian like symptoms. </li></ul><ul><li>Potentially fatal bone marrow toxicity and skin reactions (both rare) </li></ul>
  16. 21. Enhancers of GABA Transmission <ul><li>Phenobarbital </li></ul><ul><li>The only barbiturate with selective anticonvulsant effect. </li></ul><ul><li>Bind at allosteric site on GABA receptor and ↑ duration of opening of Cl channel. </li></ul><ul><li>↓ Ca-dependent release of neurotransmitters at high doses. </li></ul><ul><li>Inducer of microsomal enzymes – drug interactions. </li></ul><ul><li>Toxic effects: sedation (early; tolerance develops); nystagmus & ataxia at higher dose; osteomalacia, folate deficiency and vit. K deficiency. </li></ul><ul><li>In children: paradoxical irritability, hyperactivity and behavioral changes. </li></ul><ul><li>Deoxybarbiturates: primidone: active but also converted to phenobarbital. Some serious additional ADR’s: leukopenia, SLE-like. </li></ul>
  17. 22. <ul><li>Benzodiazepines </li></ul><ul><li>Sedative - hypnotic- anxiolytic drugs. </li></ul><ul><li>Bind to another site on GABA receptor. Other mechanisms may contribute. ↑ frequency of opening of Cl channel. </li></ul><ul><li>Clonazepam and clorazepate for long term treatment of some epilepsies. </li></ul><ul><li>Diazepam and lorazepam: for control of status epilepticus. Disadvantage: short acting. </li></ul><ul><li>Toxicities: chronic: lethargy drowsiness. </li></ul><ul><li>in status epilepticus: iv administration: respiratory and cardiovascular depression. Phenytoin and PB also used. </li></ul>Enhancers of GABA Transmission
  18. 23. GABA-A Receptor Binding Sites Cl -
  19. 24. <ul><li>Gabapentin: Developed as GABA analogue. Mechanism: Increases release of GABA by unknown mechanism. </li></ul><ul><li>Vigabatrin: Irreversible inhibitor of GABA transaminase. Potential to cause psychiatric disorders (depression and psychosis). </li></ul><ul><li>Tiagabine: decreases GABA uptake by neuronal and extraneuronal tissues. </li></ul>Enhancers of GABA Transmission
  20. 25. Vigabatrin GABA Tiagabine Gabapentin
  21. 26. TGB VGB BZD TPM VGB GBP GABA-T GABA-T Modulators of GABA Transmission TGB
  22. 27. Valproic Acid <ul><li>Effective in multiple seizure types. </li></ul><ul><li>Blocks Na and Ca channels. Inhibits GABA transaminase. Increases GABA synthesis. </li></ul><ul><li>Toxicity: most serious: fulminant hepatitis. More common if antiepileptic polytherapy in children < 2 years old. (?) Toxic metabolites involved. </li></ul><ul><li>Drug interactions: inhibits phenobarbital and phenytoin metabolism. </li></ul>
  23. 28. Other Drugs <ul><li>Topiramate; multiple mechanisms of action (Na channel, GABA enhancement like BZD, antagonist at AMPA subtype of glutamate receptors (not NMDA). </li></ul><ul><li>Felbamate: multiple mechanisms: Na channel block; modulates glutamate transmission interacts with glycine site. Serious hematological and hepatic toxicities. </li></ul>
  24. 30. Treatment of Epilepsy <ul><li>Start with a single agent. Raise to maximum tolerated dose before shifting to another. </li></ul><ul><li>If therapy fails may use combination of drugs. </li></ul><ul><li>Frequent physician visits early on and therapeutic drug monitoring. </li></ul><ul><li>Importance of compliance. </li></ul><ul><li>Aim and duration of therapy. </li></ul>

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