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Anticonvulsants IBrian J. Piper, Ph.D., M.S.   piperbj@husson.edu                February 6, 2013
Objectives• At the end of this lecture, pharmacy students  should be able to:  – describe the overall neurochemistry of se...
Epidemiology of Epilepsy    •   200K new cases/year    •   Age: 20: 1%; 75: 3%    •   Minorities > Caucasians    •   Devel...
Seizure Classification  • Partial (focal): origin of seizure is localized         – simple partial: consciousness maintain...
Normal CNS Function
Hyperexcitability reflects bothincreased excitation and decreased            inhibition                        Inhibition ...
ComparisonGlutamate                      GABA• Ionotropic                   • Ionotropic   – NMDA                         ...
Overall Incidence of Convulsive Disorders: Increased     frequency at extremes of age (Rochester, MN 1935-84)             ...
*                                       *        *                                       *        *                       ...
GABA Biosynthesis & Breakdown              (so many drug targets)• GAD: glutamic acid decarboxylase  converts glutamate to...
GABAA & Adult Brain                                                 Vm : membrane potential                               ...
Mechanisms of Action: GABA-ergic AEDs
History of AEDs   •    1857: Sir Charles Locock reports on KBr for hysterical epilepsy   •    1912: Alfred Hauptmann’s sle...
Phenytoin (1938)    • History: less sedative than      phenobarbital    • MOA: decreased recovery of      voltage gated Na...
Phenytoin & Category D• ↓ growth                                                AED Syndrome?• Facial Abnormalities     – ...
Pentylenetetrazol (1938)    • MOA: GABA antagonist    EEG                          fMRI shows thalamus activation 4 s befo...
Valproate (1962) • History: Pierre Eymard is using pentylenetetrazol   to induce convulsions with valproate as   solvent/v...
Valproate: Category D     • 2% risk of spina bifida     • ↓ Cmax     • folic acid supplementationPerukka, E. (2002). CNS D...
Status Epilecticus (SE)    • continuous, unremitting seizure lasting > 5      min    • convulsive > non-convulsive    • mo...
Lorazepam (1977)• MOA: GABAA α1,2,3,5• Dose: 2 mg/ml per min x 2• Adverse Effects: heavy sedation, especially  with alcoho...
Summary                MOA                     Concernphenobarbital   GABAA                   sedation                Cl- ...
GABAA & Neonatal Brain                                                 Vm : membrane potential                            ...
Brodie, M. J. (2010). Seizure, 19, 650-665.
Summary• MES and PTZ have been used to identify many  AED.• Pharmacotherapy for epilepsy is complex and  polypharmacy is c...
Self-Test• Match the AED on the left  with the potential adverse  effect.  – valproic acid  – phenytoin  – phenobarbital
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Anticonvulsants Part I

This PPT is part of a lecture given to second year pharmacy students in a pharmacology & toxicology class.

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Anticonvulsants Part I

  1. 1. Anticonvulsants IBrian J. Piper, Ph.D., M.S. piperbj@husson.edu February 6, 2013
  2. 2. Objectives• At the end of this lecture, pharmacy students should be able to: – describe the overall neurochemistry of seizures (AED targets). – list the procedures to induce seizures. – contrast by PD and AE the different 1st generation AED.
  3. 3. Epidemiology of Epilepsy • 200K new cases/year • Age: 20: 1%; 75: 3% • Minorities > Caucasians • Developing (2) : Developed (1) Condition % mental retardation 26 stroke 22 Cerebral palsy 13 Alzheimer’s Disease 10Ngugi et al. (2011). Neurology, 77, 1005-1012http://www.epilepsyfoundation.org/aboutepilepsy/whatisepilepsy/statistics.cfm
  4. 4. Seizure Classification • Partial (focal): origin of seizure is localized – simple partial: consciousness maintained – complex partial: consciousness lost • Generalized: origin of seizure is distributed – tonic-clonic (grand malg): • tonic: continuous muscle contraction • clonic: rapid contraction & relaxation – absence (petit malp): brief loss of consciousnessg(0:40 to 1:20) Skip Ad: http://www.youtube.com/watch?v=MRZY2a2jnuwp(0:35 to 1:10) Skip Ad: http://www.youtube.com/watch?v=DruJDZVO7Ko
  5. 5. Normal CNS Function
  6. 6. Hyperexcitability reflects bothincreased excitation and decreased inhibition Inhibition Excitation GABA glutamate aspartate
  7. 7. ComparisonGlutamate GABA• Ionotropic • Ionotropic – NMDA – GABAA – AMPA – kainate • Metabotropic• Metabotropic – GABAB – mGluR1 – mGluR2 – mGluR3 – mGluR4 GABA – mGluR5 – mGluR6 – mGluR7 – mGluR8 AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
  8. 8. Overall Incidence of Convulsive Disorders: Increased frequency at extremes of age (Rochester, MN 1935-84) 300 Incidence Per 100,000 Patient Years 250 Alcohol Other provoked Epilepsy 200 Single 150 Total 100 50 0 0 20 40 60 80 100 AgeHauser, W. A. et al. (1995). Epilepsia, 34(3), 453-458.
  9. 9. * * * * * * -> ->White (2005). American Epilepsy Proceedings.
  10. 10. GABA Biosynthesis & Breakdown (so many drug targets)• GAD: glutamic acid decarboxylase converts glutamate to GABA• VGAT: vesicular GABA transporter• GAT-1, GAT-2: membrane GABA transporter found on neurons & astrocytes• GAT-3: membrane GABA transporter found on astrocytes• GABA-T: GABA Aminotransferase, begins conversion of GABA to succinic semialdehyde (SSA)Meyer & Quezner (2008). Psychopharmacology, Chapter 7.
  11. 11. GABAA & Adult Brain Vm : membrane potential cotransporter: transports ions against concentration gradient GABA Neuron <- Cl- poolWhite, H. S. & Rho, J. M. (2010). Mechanisms of AED, p. 67.
  12. 12. Mechanisms of Action: GABA-ergic AEDs
  13. 13. History of AEDs • 1857: Sir Charles Locock reports on KBr for hysterical epilepsy • 1912: Alfred Hauptmann’s sleep problems lead to phenobarbital • 1938: Maximal electroshock seizure (epilepsy?) model used to identify phenytoin 1) Apply electrode to cornea 2) Apply current 3) Rate tonic-clonic behavior 4) Repeat 1-3 with drugBrodie, M. J. (2010). Seizure, 19, 650-665; Castel-Branco et al. (2009). Meth Find Clin Exp Pharma, 31(2), 101-106.
  14. 14. Phenytoin (1938) • History: less sedative than phenobarbital • MOA: decreased recovery of voltage gated Na+ channels from inactivation • PK: 3A4 inducer • Adverse Events: lethargy (transient), gingival hyperplasiaGoodwin & Gillman (2011). p. 588.Sharma & Dasroy (2000). NEJM, 342, 325.
  15. 15. Phenytoin & Category D• ↓ growth AED Syndrome?• Facial Abnormalities – nasal hypoplasia – maxilla hypoplasia – flat philtrum• ↓ IQ (variable)• ↓ K+Howe et al. (1995). American Journal of Medical Genetics, 58, 238-248.
  16. 16. Pentylenetetrazol (1938) • MOA: GABA antagonist EEG fMRI shows thalamus activation 4 s before PTZ seizure.Brevard et al. (2006). Epilepsia, 47(4), 745-754.
  17. 17. Valproate (1962) • History: Pierre Eymard is using pentylenetetrazol to induce convulsions with valproate as solvent/vehicle. • Uses: different seizure types • MOA: ?, ↑GABA, ↓ aspartateStahl (2008).Essential Psychopharm, p. 678.
  18. 18. Valproate: Category D • 2% risk of spina bifida • ↓ Cmax • folic acid supplementationPerukka, E. (2002). CNS Drugs, 16(10), 695-714.
  19. 19. Status Epilecticus (SE) • continuous, unremitting seizure lasting > 5 min • convulsive > non-convulsive • mortality = 20% • medical emergencyTrinka et al. (2012). Epilepsia, 53(4), 127-138.
  20. 20. Lorazepam (1977)• MOA: GABAA α1,2,3,5• Dose: 2 mg/ml per min x 2• Adverse Effects: heavy sedation, especially with alcohol• t1/2 : 12 hours
  21. 21. Summary MOA Concernphenobarbital GABAA sedation Cl- channel durationphenytoin voltage gated Category D Na+ channelslorazepam GABAA α1,2,3,5 addiction (Schedule IV) Cl- channel frequencyvalproate ↑ GABA (?) Category D
  22. 22. GABAA & Neonatal Brain Vm : membrane potential cotransporter: transports ions against concentration gradient GABA Neuron <- Cl- poolWhite, H. S. & Rho, J. M. (2010). Mechanisms of AED, p. 67.
  23. 23. Brodie, M. J. (2010). Seizure, 19, 650-665.
  24. 24. Summary• MES and PTZ have been used to identify many AED.• Pharmacotherapy for epilepsy is complex and polypharmacy is common.
  25. 25. Self-Test• Match the AED on the left with the potential adverse effect. – valproic acid – phenytoin – phenobarbital

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