1. PHCL-3720 Pharmacology II  Dr. William Messer  Department of Pharmacology  The University of Toledo  March 25, 2002

2. Anticonvulsants Lamotrigine (Lamictal ® ).  Decreases Na + channel activity.  Prolongs Na + channel inactivation.  Inhibits N- and P-type Ca 2+ channel.

3. Anticonvulsants Tiagabine (Gabatril ® ).  Inhibits neuronal and glial uptake of GABA.  Potentiates GABA activity. Topiramate (Topamax ® ).  Blocks voltage-sensitive Na + channels.  Augments GABA activity.  Inhibits NMDA-glutamate receptors.

4. Phenobarbital disposition Absorption.  ~ 90 %. Distribution.  Protein binding ~50 %.  V 1 l/kg.  Rapid CNS distribution.

5. Phenobarbital disposition Elimination.  65 % hepatic oxidation, 35 % excreted in urine.  Half-life 24-140 hrs. in adults, 40-70 in children. Therapeutic range.  15-40 mg/L.

6. Primidone disposition Absorption.  ~ 90 %. Distribution.  Protein binding ~ 20 %. Elimination.  Hepatic oxidation to phenobarbital.  Ring opening to phenethylmalonamide.  Half-life ~ 30 hrs. Therapeutic range.  5-15 mg/L.

7. Carbamazepine disposition Absorption.  ~ 75 %. Distribution.  Protein binding ~ 75 %. Elimination.  Hepatic oxidation 74 %; excretion in feces 25 %, urine < 1 %.  Half-life 30-60 hr. initially, 12-15 hrs. after autoinduction. Therapeutic range.  5-10 mg/L.

8. Ethosuximide disposition Absorption.  ~100 %. Distribution.  No plasma binding.  V ~ 0.65 – 0.7 l/kg. Elimination.  Hepatic oxidation 80 %.  Half-life 60 hrs. in adults, 30 in children. Therapeutic range.  40-100 mg/L.

9. Clonazepam disposition Absorption.  100 %. Distribution.  Protein binding 82 %.  V ~2-6 l/kg. Elimination.  Extensive hepatic metabolism.  Half-life 20-95 hrs. Therapeutic range.  0.02-0.07 mg/L.

10. Valproic acid disposition Absorption.  90-95 %. Distribution.  Protein binding 80-95 %.  V ~0.1-0.5 l/kg. Elimination.  Hepatic metabolism; oxidation, glucuronidation.  Half-life 8-20 hrs. Therapeutic range.  50-100 mg/L.

11. Phenytoin disposition Absorption.  98 %. Distribution.  Protein binding 90 %.  V ~0.6-0.8 l/kg. Elimination.  Hepatic metabolism; oxidation, glucuronidation.  Unusual kinetics. Therapeutic range.  10-20 mg/L.

12. Felbamate disposition Absorption.  90 %. Distribution.  Protein binding 90 %.  V ~0.6-0.8 l/kg. Elimination.  60 % excreted unchanged; 40 % metabolized.  Half-life 24 hrs., decreases with co- administration of other anticonvulsants.

13. Gabapentin disposition Absorption.  24-60 %. Distribution.  Protein binding low.  V ~ 0.8 l/kg. Elimination.  Not metabolized.  100 % excreted intact in urine.  Half-life ~ 6 hrs. Therapeutic level.  ~2 mg/L.

14. Lamotrigine disposition Absorption.  100 %. Elimination.  Glucuronidation (70 %).  Induces own metabolism.  Half-life 24-30 hrs.  Accelerated by phenobarbital, carbamazepine.

15. Topiramate disposition Absorption.  Rapid. Elimination.  Largely (70 %) excreted in urine.  Half-life 21 hrs.

16. Tiagabine disposition Absorption.  90 - 95 %. Distribution.  Binding to plasma proteins 95 %. Elimination.  Metabolized by CYP3A4.  Glucuronidation.  Half-life 8 hrs. with monotherapy; 4- 7 hrs. with other antiepileptic drugs; even lower in children.

17. Adverse effects Barbiturates.  Sedation, ataxia.  Allergic reactions.

18. Adverse effects Phenytoin.  Allergic reactions.  Symptoms (pruritis, fever, rash) appear within a few weeks.  Hepatotoxicity.  Reactive epoxide intermediate in patients deficient in epoxide hydrolase.  Dose-related toxicities.  Nystagmus, blurred vision; ataxia; dysarthria; confusion.

19. Adverse effects Phenytoin (continued).  Chronic toxicities.  Gingival hyperplasia.  Hirsutism.  Folate deficiency.  Hypocacemia and osteomalacia.  Fetal anomalies.

20. Adverse effects Carbamazepine.  Neurological.  Disequilibrium, drowsiness, headache, confusion, blurred vision.  Hematological.  Transient leukopenia (decrease in white cell count).  Metabolic.  Hyponatremia (low blood Na + ).  Osteomalacia (bone softening).

21. Adverse effects Benzodiazepines.  Sedation.  Ataxia.

22. Adverse effects Valproic acid.  Low sedation or ataxia.  Nausea, GI irritation.  Pancreatitis.  Acute hepatic necrosis.  Occurs after 1-6 months of treatment.  Oxidation of valproic acid to alkene intermediate.  Allopecia.  Hair thinning in children.  Blood clotting impaired.  Avoid in patients with bleeding disorders.

23. Adverse effects Succinimides.  Transient leukopenia.  Occasional pancytopenia (decrease in blood cellular elements).  GI distress.  Sedation, dizziness, anxiety, inability to concentrate, headache.  Allergic reactions.  Urticaria (localized swelling of skin).

24. Adverse effects Felbamate.  Aplastic anemia.  Liver failure.  Insomnia, headache, somnolence, fatigue.  Dyspepsia, vomiting, nausea, anorexia.  Recommended as second line therapy only by FDA.

25. Adverse effects Lamotrigine.  Rash.  May be life threatening.  Not recommended for children.  Binding in melanin rich tissues (e.g., eye), visual disturbances.  Neurological effects.  Dizziness, drowsiness, confusion, depression, emotional lability, tremor.

26. Adverse effects Gabapentin.  Fatigue.  Weight gain (average 16 lbs.).  Drowsiness, tremor, nervousness, irritability.  Dyspepsia, constipation.

27. Adverse effects Topiramate.  Neurological.  Dizziness, drowsiness, ataxia, nystagmus, parasthesias.  GI.  Dyspepsia, constipation, nausea, vomiting, abdominal pain.  Miscellaneous.  Nephrolithiasis (2-4x higher risk).  Patients with kidney stone history should increase fluid intake.

28. Adverse effects Tiagabine.  Neurological (high incidence).  Dizziness, light-headedness, drowsiness, tremor, anxiety, impaired cognition, ataxia.  GI.  Abdominal pain, nausea, vomiting,.  Cutaneous.  Serious rash (Steven’s Johnson).  Teratogenic in animals.  Avoid use during pregnancy.

29. End of presentation Next topic – Uses of anticonvulsant drugs. Copyright 2002, The University of Toledo