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Antiepileptics I & Ii


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Antiepileptics I & Ii

  2. 2. Definition <ul><li>The epilepsies are a group of disorders characterized by chronic recurrent paroxysmal changes in neurologic function caused by abnormalities in the electrical activity of the brain </li></ul>
  3. 3. SELECTED EPILEPSY TERMS Epilepsy: A clinical paroxysmal disorder of recurring seizures Seizure: A transient dysfunction of brain due to an abnormal firing of cerebral neurons, which may or may not have a clinical manifestation.
  4. 4. Myoclonus: A single abrupt shock like extensor movement of a limb. myoclonic seizures. Petit Mal : Used to describe absence seizures as well as atypical absence. Tonic : Sustained contraction of one or more muscle groups, independent of position (i.e. can be flexed, extended, or opisthotonic). Aura: A generic term for a warning. A colloquial term for simple partial seizure. Convulsion: Tonic , clonic or tonic-clonic seizure
  5. 5. <ul><li>Status </li></ul><ul><li>A pathological state different from a single seizure by the Epilepticus (a bsence or reduction of inhibitory processes to terminate the seizure). </li></ul><ul><li>Applies to any seizure type. The length of time required to differentiate seizure from status is both empirical and practical. </li></ul><ul><li>Convulsive, myoclonic status: 10-30 minutes. </li></ul>
  6. 6. Differential diagnosis of seizures <ul><li>Syncope </li></ul><ul><li>Drop attacks </li></ul><ul><li>Narcolepsy-Cataplexy </li></ul><ul><li>Pseudoseizures </li></ul><ul><li>Panic attacks </li></ul><ul><li>Hypoglycemia </li></ul><ul><li>Migraine </li></ul>
  7. 7. Epidemiology <ul><li>Incidence: </li></ul><ul><li>Developed countries: 40-70 per one lakh </li></ul><ul><li>Developing countries: 100-190 per one lakh </li></ul><ul><li>Prevalence: </li></ul><ul><li>Developed countries: 4-10 per 10,000 </li></ul><ul><li>Developing countries: 57 per 10,000 </li></ul><ul><li>Partial seizures with or without generalization is most common </li></ul>
  8. 8. <ul><ul><li>Bimodal age distribution : </li></ul></ul><ul><ul><li>< 1 and > 60. Less sharp in developing countries </li></ul></ul><ul><ul><li>Common causes : Perinatal disorders associated with cerebral palsy & mental retardation, Head trauma, CNS infections, Stroke, Brain tumors, Alcohol and other drugs </li></ul></ul><ul><li>Men affected 1-2.4 times: compared to women </li></ul>
  9. 9. Revised ILAE (International League Against Epilepsy) Seizure Classification I. PARTIAL (FOCAL, LOCAL) SEIZURES A. Simple partial seizures B. Complex partial seizure C. Partial seizures evolving to generalized tonic-clonic convulsions (GTC)
  10. 10. II. GENERALIZED SEIZURES A. 1. Absence seizures 2. Atypical absence B. Myoclonic seizures, Myoclonic jerks (simple or multiple) C. Clonic seizures D. Tonic seizures E. Tonic-clonic seizures F. Atonic seizures (astatic)
  11. 11. III. UNCLASSIFIED EPILEPTIC SEIZURES Includes all seizures that cannot be classified because of inadequate or incomplete data and some that defy classification in hitherto described categories. This includes some neonatal seizures, e.g., rhythmic eye movements, chewing, and swimming movements .
  12. 13. Antiepileptic drug (AED) <ul><li>A drug which decreases the frequency and /or severity of seizures in people with epilepsy. </li></ul><ul><li>Treats the symptom of seizures, not the underlying epileptic condition. </li></ul><ul><li>Improves quality of life by minimizing seizures. </li></ul>
  13. 14. CLASSIFICATION OF ANTIEPILEPTICS: <ul><li>B arbiturates: Phenobarbitone </li></ul><ul><li>D eoxybarbiturate: Primidone </li></ul><ul><li>H ydantoin: Phenytoin </li></ul><ul><li>I munostilbene: Carbamazepine </li></ul><ul><li>S uccinimide: Ethosuximide </li></ul><ul><li>A liphatic carboxylic acid: Valproate </li></ul><ul><li>B enzodiazepine: Clonazepam, Diazepam </li></ul><ul><li>C yclic GABA- analogue: Gabapentin </li></ul><ul><li>P henyltriazine: Lamotrigine </li></ul><ul><li>N ewer drugs: Vigabatrin, Topiramate, Tiagabine, Levetiracetam </li></ul>i i e i a
  15. 16. History of Antiepileptic Drug Therapy <ul><li>1857 - Bromides </li></ul><ul><li>1912 - Phenobarbitone </li></ul><ul><li>1937 - Phenytoin </li></ul><ul><li>1944 - Trimethadione </li></ul><ul><li>1954 - Primidone </li></ul><ul><li>1960 - Ethosuximide </li></ul>
  16. 17. History of AED therapy <ul><li>1974 – Carbamazepine, Oxcarbazepine </li></ul><ul><li>1975 - Clonazepam </li></ul><ul><li>1978 - Valproate </li></ul><ul><li>1993 - Felbamate, Gabapentin </li></ul><ul><li>1995 – Lamotrigine, Levetiracetam </li></ul><ul><li>1997 - Topiramate, Tiagabine </li></ul>
  17. 18. Principles of AED Selection <ul><li>Correct diagnosis of the type of epilepsy influences treatment, prognosis and genetic counseling. </li></ul><ul><li>One best drug to fit the fit, fit the patient; Sequential monotherapy </li></ul><ul><li>Use the least expensive AED (all things being equal, like efficacy). </li></ul><ul><li>Prefer AEDs which can be taken od over bid / tid. </li></ul><ul><li>AEDs almost never need qid dosing </li></ul>
  18. 19. <ul><li>Newer is not better, and almost certainly more expensive </li></ul><ul><li>Start with one AED and push the dose to clinical toxicity or seizure control. </li></ul><ul><li>Withdraw AEDs that are not effective. </li></ul><ul><li>Never have a patient on more than three (3) AEDs. </li></ul>Principles of AED Selection…cont.
  19. 20. Principles of AED Selection…cont. <ul><li>Don't use combination medications (e.g., phenytoin with phenobarbital). </li></ul><ul><li>No proof that multiple AEDs are synergistic in the treatment of epilepsy. </li></ul><ul><li>Polypharmacy is expensive, increases side effects and increases the complexity of adjusting AEDs in the refractory patient. </li></ul>
  20. 21. Therapeutic Drug Monitoring Use AED levels to assess: i. Poor clinical control (compliance, metabolism) ii. Dose-related side effect iii. Drug or disease interaction iv. &quot;Routine&quot; levels on controlled, nontoxic patients are not indicated.
  21. 22. Applied Pharmacokinetics of Antiepileptic Drugs (AEDs)
  22. 23. Absorption <ul><li>Aqueous solubility - Poor aqueous solubility </li></ul><ul><li>Impairs absorption from GIT – carbamazepine </li></ul><ul><li>Erratic absorption from parenteral (SC, IM) sites - phenytoin </li></ul><ul><li>Poor oral bioavailability – phenytoin </li></ul><ul><li>Slows time to attain peak plasma levels – carbamazepine </li></ul><ul><li>May cause physical drug interactions during IV infusions </li></ul>
  23. 24. Absorption <ul><li>Lipid solubility – Good lipid solubility </li></ul><ul><li>Enhances absorption across membranes </li></ul><ul><li>Quicker absorption </li></ul><ul><li>Crosses BBB easily – reaches good levels in CSF </li></ul><ul><li>Excreted in breast milk, can cross placenta </li></ul>
  24. 25. Mechanism of action of Antiepileptic Drugs
  25. 26. Cellular Mechanisms of Seizure Generation <ul><li>Excitation (too much) </li></ul><ul><li>• Ionic-inward Na + ,Ca ++ currents </li></ul><ul><li>• Neurotransmitter: glutamate, </li></ul><ul><li> aspartate </li></ul><ul><li>Inhibition (too little) </li></ul><ul><li>• Ionic-inward Cl; outward K + currents </li></ul><ul><li>• Neurotransmitter: GABA </li></ul>Inhibition Stimulation
  26. 27. AEDs: Molecular and Cellular Mechanisms <ul><ul><li>Phenytoin, Carbamazepine </li></ul></ul><ul><li>• Block voltage-dependent sodium </li></ul><ul><li>channels at high firing frequencies </li></ul>
  27. 28. Open Na + Na + Na + Inactivation gate Activation gate Carbamazepine Phenytoin Felbamate Lamotrigine Inactivated channel Blocked channel firing at high frequencies Barbiturates Topiramate Na + Na+ Na+ Na+
  28. 29. AEDs: Molecular and Cellular Mechanisms <ul><li>Barbiturates </li></ul><ul><li> • Prolong GABA-mediated chloride </li></ul><ul><li>channel openings </li></ul><ul><li> • Some blockade of voltage- </li></ul><ul><li>dependent sodium channels </li></ul><ul><li>Benzodiazepines </li></ul><ul><li> • Increase frequency of GABA-mediated chloride </li></ul><ul><li>channel openings </li></ul>
  29. 31. AEDs: Molecular and Cellular Mechanisms <ul><li>Valproate </li></ul><ul><li>May enhance GABA transmission in </li></ul><ul><li>specific circuits </li></ul><ul><li>Blocks voltage-dependent sodium channels </li></ul><ul><li>Blocks T-type calcium currents </li></ul><ul><li>Ethosuximide </li></ul><ul><li>• Blocks slow, threshold, “transient” </li></ul><ul><li>(T-type) calcium channels in </li></ul><ul><li>thalamic neurons </li></ul>
  30. 32. Ca ++ Ca ++ Voltage regulated Ca ++ current, low threshold “T” current in thalamus Involved in 3 per second spike and wave rhythm Ca ++ Ethosuximide Valproate Reduction in the flow of Ca ++ through T – type Ca ++ channels in thalamus Ca ++ Ethosuximide:
  31. 33. Newer AEDs: Molecular and cellular Mechanisms <ul><li>Vigabatrin </li></ul><ul><li> • Irreversibly inhibits GABA- transaminase </li></ul><ul><li>Tiagabine </li></ul><ul><li> • Interferes with GABA re-uptake </li></ul><ul><li>Felbamate </li></ul><ul><li> • May block voltage-dependent sodium channel at high </li></ul><ul><li>firing frequencies </li></ul><ul><li> • May modulate NMDA receptor via strychnine </li></ul><ul><li>insensitive glycine receptor </li></ul><ul><li>Lamotrigine </li></ul><ul><li> • Blocks voltage-dependent sodium channels at high </li></ul><ul><li>firing frequencies </li></ul><ul><li>• May interfere with pathologic glutamate release </li></ul>
  32. 34. Newer AEDs: Molecular and cellular Mechanisms <ul><li>Topiramate </li></ul><ul><ul><li>Blocks voltage-dependent sodium channels at high firing frequencies </li></ul></ul><ul><ul><li>Increases frequency at which GABA opens Cl - channels (different site from benzodiazepines) </li></ul></ul><ul><ul><li>Antagonizes glutamate actions at receptor subtype </li></ul></ul><ul><li>Gabapentin </li></ul><ul><li> • May modulate amino acid transport into brain </li></ul><ul><li> • May interfere with GABA re-uptake </li></ul>
  33. 36. GABA metabolites Succinic Semialdehyde Gabapentin GT: GABA transaminase SSD:Succinic semialdehyde dehydrogenase GT SSD Vigabatrin Valproate Benzodiazepines Barbiturates Cl - Gabapentin Tiagabine Topiramate
  34. 37. Status Epilepticus-Definition <ul><li>1. Major motor (convulsive) status </li></ul><ul><li>Three(3) seizures uninterrupted by consciousness or a single prolonged seizure greater than 1/2 hour. </li></ul><ul><li>2. Spike wave stupor (Absence or Petit mal status) and complex partial (psychomotor) status are prolonged alterations of consciousness verified by EEG as epileptic. </li></ul>
  35. 38. Status epilepticus <ul><li>It is a medical emergency – requires prompt and aggressive treatment </li></ul><ul><li>Therapy should be aimed at: </li></ul><ul><ul><li>Rapid termination of status epilepticus </li></ul></ul><ul><ul><li>Prevention of seizure recurrence </li></ul></ul><ul><ul><li>Treatment of underlying cause </li></ul></ul>
  36. 39. <ul><li>Immediate treatment </li></ul><ul><li>1. Secure IV line draw blood for analysis (including anticonvulsant levels). </li></ul><ul><li>2. Push 50 cc of 50% Dextrose i.v., </li></ul><ul><li>100mg thiamine i.v. </li></ul><ul><li>3. Monitor vital signs. </li></ul><ul><li>4. Examine patient. </li></ul><ul><li>5. Protect airway, tongue, head, never leave patient alone </li></ul><ul><li>6. Intubate all patients if first line drugs fail. </li></ul>
  37. 40. <ul><li>Non-specific </li></ul><ul><li>Correct electrolyte imbalance - acidosis lowers seizure threshold, treat with bicarbonate if pH<7.1 </li></ul><ul><li>Lower fever </li></ul><ul><li>Antibiotics/ LP if indicated </li></ul><ul><li>If neurologic exam dictates, treatment of underlying cause may proceed concurrently with drug therapy, e.g., neurosurgical decompression. </li></ul><ul><li>Hypotension – maintain BP </li></ul>Status Epilepticus - Definite Treatment
  38. 41. Status Epilepticus-Definitive Treatment <ul><li>Diazepam - 10mg IV push over 30-60 seconds repeat after 10-15mins upto 30mg (5mg/min) Repeat after 2-4hrs. 100mg/day </li></ul><ul><li>i.Good results, easy to administer. (fast acting, short lasting) </li></ul><ul><li>ii. If two doses fail to stop status, then further doses probably won't work either. </li></ul><ul><li>iii. Side effects -- hypotension, bradycardia, respiratory depression, cardiac arrest, depresses mental status. </li></ul>
  39. 42. OR Lorazepam - 4 mg IV push (2mg/min) may be repeated. i. Fast acting, medium lasting. ii. Respiratory depression only in the extubated patient.
  40. 43. Status Epilepticus-Definite Treatment <ul><li>b. Phenytoin - 12-20mg/kg IV (slow IV push) (50mg/min) fast and long acting. </li></ul><ul><li>i. Presently used concomitantly with a benzodiazepine </li></ul><ul><li>ii. Its pH is 12, all i.v. fluids are pH 4-6. Do not add to dextrose drip as it precipitates. </li></ul><ul><li>iii. Monitor BP and ECG </li></ul>
  41. 44. <ul><li>IV Valproate - 25 mg/kg IV push, may repeat. </li></ul><ul><li>i. Generally not used because of lack of experience. Good results in both major motor and absence status. </li></ul><ul><li>ii. fast acting, long acting. </li></ul><ul><li>iii. Far less side effects than Diazepam and dilantin especially in unstable cardiac status, hypotension, hepatic failure etc. </li></ul>
  42. 45. Adverse effects of antiepileptics: <ul><li>Phenytoin: Gum hyperplasia,hirsutism, hypersensitivity, megaloblastic anemia, osteomalacia, hyperglycemia, fetal hydontoin syndrome, dose dependent vestibular & cerebellar toxicity & iv administration causes hypotension & arrhythmias </li></ul><ul><li>Carbamazepine: Dose dependent neurotoxicity, hypersensitivity, teratogenic. </li></ul><ul><li>Valproate: Well tolerated, however in children below 3 yrs cause fulminant hepatitis, pancreatitis in patients taking other hepatotoxic drugs & with liver disease. In pregnancy if given cause neural tube defects. </li></ul>
  43. 46. Drug interactions- points to consider <ul><li>Complex – refer to textbooks when possible </li></ul><ul><li>May enhance toxicity without a corresponding increase in antiepileptic effect. </li></ul><ul><li>Highly variable and unpredictable </li></ul>
  44. 47. Drug interactions- points to consider <ul><li>Usually caused by hepatic enzyme induction or hepatic enzyme inhibition </li></ul><ul><li>Interactions due to displacement from protein binding sites not significant. </li></ul><ul><li>TDM advisable with combination therapy </li></ul>
  45. 48. <ul><li>Carbamazepine often lowers plasma concentrations of: </li></ul><ul><li>Phenytoin (it may also raise phenytoin concentration) </li></ul><ul><li>Valproate </li></ul><ul><li>Phenobarbitone/primidone lowers plasma concentrations of: </li></ul><ul><li>Phenytoin (it may also raise phenytoin concentration) </li></ul><ul><li>Valproate </li></ul><ul><li>Carbamazepine </li></ul><ul><li>Clonazepam </li></ul><ul><li>Ethosuximide(sometimes) </li></ul><ul><li>Phenytoin often lowers plasma concentrations of: </li></ul><ul><li>valproate </li></ul><ul><li>carbamazepine </li></ul><ul><li>clonazepam </li></ul><ul><li>Ethosuximide and primidone (sometimes) </li></ul><ul><li>Often raises plasma concentrations of </li></ul><ul><li>Phenobarbitone </li></ul>
  46. 49. <ul><li>Valproate often lowers plasma concentrations of: </li></ul><ul><li>An active metabolite of Carbamazepine </li></ul><ul><li>Lamotrigine </li></ul><ul><li>phenobarbitone, primidone </li></ul><ul><li>Phenytoin (but may lower it too) </li></ul><ul><li>Sometimes raises plasma concentrations of </li></ul><ul><li>Ethosuximide </li></ul>
  47. 50. Thank you