1. Neuropharmacology of Antiepileptic Drugs
American Epilepsy Society

2. Definitions
 Seizure: the clinical manifestation of an abnormal synchronization and excessive excitation of a population of cortical neurons
 Epilepsy: a tendency toward recurrent seizures unprovoked by acute systemic or neurologic insults

3. Antiepileptic Drug
 A drug which decreases the frequency and/or severity of seizures in people with epilepsy
 Treats the symptom of seizures, not the underlying epileptic condition
 Goal—maximize quality of life by minimizing seizures and adverse drug effects

4. History of Antiepileptic Drug Therapy in the U.S.
 Bromides
 Phenobarbital
 Phenytoin
 Primidone
 Ethosuximide

5. History of Antiepileptic Drug Therapy in the U.S.
 Carbamazepine
 Clonazepam
 Valproate
 Felbamate, Gabapentin
 Lamotrigine
 Topiramate, Tiagabine
 Levetiracetam
 Oxcarbazepine, Zonisamide

6. Antiepileptic Drug Therapy Structures of Commonly Used AEDs
Chemical formulas of commonly used old and new antiepileptic drugs
Adapted from Rogawski and Porter, 1993, and Engel, 1989

7. Antiepileptic Drug Therapy Structures of Commonly Used AEDs

8. Antiepileptic Drug Therapy Structures of Commonly Used AEDs
Levetiracetam
Oxcarbazepine
Zonisamide

9. Antiepileptic Drug Therapy Structures of Commonly Used AEDs
Pregabalin

10. Cellular Mechanisms of Seizure Generation
 Excitation (too much)
Ionic-inward Na+, Ca++ currents
Neurotransmitter: glutamate, aspartate
 Inhibition (too little)
Ionic-inward CI-, outward K+ currents
Neurotransmitter: GABA

11. AEDs: Molecular and Cellular Mechanisms
 Phenytoin, Carbamazepine
Block voltage-dependent sodium channels at high firing frequencies
 Barbiturates
Prolong GABA-mediated chloride channel openings
Some blockade of voltage-dependent sodium channels
 Benzodiazepines
Increase frequency of GABA-mediated chloride channel openings

12. AEDs: Molecular and Cellular Mechanisms
 Felbamate
May block voltage-dependent sodium channels at high firing frequencies
May modulate NMDA receptor via strychnine-insensitive glycine receptor
 Gabapentin
Increases neuronal GABA concentration
Enhances GABA mediated inhibition
 Lamotrigine
Blocks voltage-dependent sodium channels at high firing frequencies
May interfere with pathologic glutamate release

13. AEDs: Molecular and Cellular Mechanisms
 Ethosuximide
Blocks low threshold, “transient” (T-type) calcium channels in thalamic neurons
 Valproate
May enhance GABA transmission in specific circuits
Blocks voltage-dependent sodium channels
 Vigabatrin
Irreversibly inhibits GABA-transaminase

14. AEDs: Molecular and Cellular Mechanisms
 Topiramate
Blocks voltage-dependent sodium channels at high firing frequencies
Increases frequency at which GABA opens Cl- channels (different site than benzodiazepines)
Antagonizes glutamate action at AMPA/kainate receptor subtype
Inhibition of carbonic anydrase
 Tiagabine
Interferes with GABA re-uptake

15. AEDs: Molecular and Cellular Mechanisms
 Levetiracetam
Binding of reversible saturable specific binding site
Reduces high-voltsge- activated Ca2+ currents
Reverses inhibition of GABA and glycine gated currents induced by negative allosteric modulators
 Oxcarbazepine
Blocks voltage-dependent sodium channels at high firing frequencies
Exerts effect on K+ channels
 Zonisamide
Blocks voltage-dependent sodium channels and T-type calcium channels

16. AEDs: Molecular and Cellular Mechanisms
Pregabalin
Increases neuronal GABA
Increase in glutamic acid decarboxylase
Decrease in neuronal calcium currents by binding of alpha 2 delta subunit of the voltage gated calcium channel

17. The GABA System The GABA system and its associated chloride channel
From Engel, 1989

18. Pharmacokinetic Principles
 Absorption: entry of drug into the blood
Essentially complete for all AEDs (except gabapentin)
Timing varies widely by drug, formulation, patient characteristics
Generally slowed by food in stomach (CBZ may be exception)
Usually takes several hours (importance for interpreting blood levels)

19. The Cytochrome P-450 Enzyme System
Inducers Inhibitors
phenobarbital erythromycin
primidone nifedipine/verapamil
phenytoin trimethoprim/sulfa
carbamazepine propoxyphene
tobacco/cigarettes cimetidine
valproate

20. The Cytochrome P-450 Enzyme System
 Substrates (metabolism enhanced by inducers):
steroid hormones
theophylline
tricyclic antidepressants
vitamins
warfarin
(many more)

21. The Cytochrome P-450 Isozyme System
 The enzymes most involved with drug metabolism
 Nomenclature based upon homology of amino acid sequences
 Enzymes have broad substrate specificity, and individual drugs may be substrates for several enzymes
 The principle enzymes involved with AED metabolism include CYP2C9, CYP2C19, CYP3A4

22. Drug Metabolizing Enzymes: UDP- Glucuronyltransferase (UGT)
 Important pathway for drug metabolism/inactivation
 Currently less well described than CYP
 Several isozymes that are involved in AED metabolism include: UGT1A9 (VPA), UGT2B7 (VPA, lorazepam), UGT1A4 (LTG)

23. Drug Metabolizing Isozymes and AEDs
AEDs that do not appear to be either inducers or inhibitors of the CYP
system include: gabapentin, lamotrigine, tiagabine, levetiracetam,
zonisamide.

24. Enzyme Inducers/Inhibitors: General Considerations
 Inducers: Increase clearance and decrease steady-state concentrations of other substrates
 Inhibitors: Decrease clearance and increase steady-state concentrations of other substrates

25. Pharmacokinetic Principles
 Elimination: removal of active drug from the blood by metabolism and excretion
Metabolism/biotransformation — generally hepatic; usually rate-limiting step
Excretion — mostly renal
Active and inactive metabolites
Changes in metabolism over time (auto-induction with carbamazepine) or with polytherapy (enzyme induction or inhibition)
Differences in metabolism by age, systemic disease

26. AED Inducers: General Considerations
 Results from synthesis of new enzyme
 Tends to be slower in onset/offset than inhibition interactions
 Broad Spectrum Inducers:
Carbamazepine
Phenytoin
Phenobarbital/primidone
 Selective CYP3A Inducers:
Felbamate, Topiramate, Oxcarbazepine

27. Inhibition  Competition at specific hepatic enzyme site
 Onset typically rapid and concentration (inhibitor) dependent
 Possible to predict potential interactions by knowledge of specific hepatic enzymes and major pathways of AED metabolism

28. AED Inhibitors  Valproate  Topiramate & Oxcarbazepine  Felbamate
UDP glucuronosyltransferase (UGT)
 plasma concentrations of Lamotrigine, Lorazepam
CYP2C19
 plasma concentrations of Phenytoin, Phenobarbital
 Topiramate & Oxcarbazepine
 plasma concentrations of Phenytoin
 Felbamate
CYP2C19  plasma concentrations of Phenytoin, Phenobarbital

29. Hepatic Drug Metabolizing Enzymes and Specific AED Interactions
 Phenytoin CYP2C9 CYP2C19
Inhibitors: valproate, ticlopidine, fluoxetine, topiramate, fluconazole
 Carbamazepine CYP3A4 CYP2C8 CYP1A2
Inhibitors: ketoconazole, fluconazole, erythromycin, diltiazem
 Lamotrigine UGT 1A4
Inhibitor: valproate

30. Isozyme Specific Drug Interactions

31. Therapeutic Index  T.I. = ED 5O% /TD 50%
 “Therapeutic range” of AED serum concentrations
Limited data
Broad generalization
Individual differences

32. Steady State and Half Life
From Engel, 1989

33. AED Serum Concentrations
 In general, AED serum concentrations can be used as a guide for evaluating the efficacy of medication therapy for epilepsy.
 Serum concentrations are useful when optimizing AED therapy, assessing compliance, or teasing out drug-drug interactions.
 They should be used to monitor pharmacodynamic and pharmacokinetic interactions.

34. AED Serum Concentrations
 Serum concentrations are also useful when documenting positive or negative outcomes associated with AED therapy.
 Most often individual patients define their own “ therapeutic range” for AEDs.
 For the new AEDs there is no clearly defined “therapeutic range”.

35. Potential Target Range of AED Serum Concentrations
(mg/l)
Carbamazepine
Ethosuximide
Phenobarbital
Phenytoin
Valproic acid

36. Potential Target Range of AED Serum Concentrations
(mg/l)
Gabapentin
Lamotrigine
Levetiracetam
Oxcarbazepine (MHD)
Pregabalin ??
Tiagabine ?
Topiramate
Zonisamide

37. AEDs and Drug Interactions
 Although many AEDs can cause pharmacokinetic interactions, several agents appear to be less problematic.
 AEDs that do not appear to be either inducers or inhibitors of the CYP system include:
Gabapentin
Lamotrigine
Pregabalin
Tiagabine
Levetiracetam
Zonisamide

38. Pharmacodynamic Interactions
 Wanted and unwanted effects on target organ
Efficacy — seizure control
Toxicity — adverse effects (dizziness, ataxia, nausea, etc.)

39. Pharmacokinetic Interactions: Possible Clinical Scenarios
Be aware that drug interactions may
occur when:
 Addition of a new medication when inducer/inhibitor is present
 Addition of inducer/inhibitor to existing medication regimen
 Removal of an inducer/inhibitor from chronic medication regimen

40. Pharmacokinetic Factors in the Elderly
 Absorption — little change
 Distribution
decrease in lean body mass important for highly lipid-soluble drugs
fall in albumin leading to higher free fraction
 Metabolism — decreased hepatic enzyme content and blood flow
 Excretion — decreased renal clearance

41. Pharmacokinetic Factors in Pediatrics
 Neonate—often lower per kg doses
Low protein binding
Low metabolic rate
 Children—higher, more frequent doses
Faster metabolism

42. Pharmacokinetics in Pregnancy
 Increased volume of distribution
 Lower serum albumin
 Faster metabolism
 Higher dose, but probably less than predicted by total level (measure free level)
 Consider more frequent dosing

43. Adverse Effects  Acute dose-related—reversible  Idiosyncratic—
uncommon rare
potentially serious or life threatening
 Chronic—reversibility and seriousness vary

44. Acute, Dose-Related Adverse Effects of AEDs
 Neurologic/Psychiatric – most common
Sedation, fatigue
Unsteadiness, uncoordination, dizziness
Tremor
Paresthesia
Diplopia, blurred vision
Mental/motor slowing or impairment
Mood or behavioral changes
Changes in libido or sexual function

45. Acute, Dose-Related Adverse Effects of AEDs (cont.)
 Gastrointestinal (nausea, heartburn)
 Mild to moderate laboratory changes
Hyponatremia (may be asymptomatic)
Increases in ALT or AST
Leukopenia
Thrombocytopenia
 Weight gain/appetite changes

46. Idiosyncratic Adverse Effects of AEDs
 Rash, Exfoliation
 Signs of potential Stevens-Johnson syndrome
Hepatic Damage
Early symptoms: abdominal pain, vomiting, jaundice
Laboratory monitoring probably not helpful in early detection
Patient education
Fever and mucus membrane involvement

47. Idiosyncratic Adverse Effects of AEDs
 Hematologic Damage (marrow aplasia, agranulocytosis)
Early symptoms: abnormal bleeding, acute onset of fever, symptoms of anemia
Laboratory monitoring probably not helpful in early detection
Patient education

48. Long-Term Adverse Effects of AEDs
 Neurologic:
Neuropathy
Cerebellar syndrome
 Endocrine/Metabolic Effects
Vitamin D – Osteomalacia, osteoporosis
Folate – Anemia, teratogenesis
Altered connective tissue metabolism or growth
 Facial coarsening
 Hirsutism
 Gingival hyperplasia

49. Pharmacology Resident Case Studies
American Epilepsy Society
Medical Education Program

50. Pharmacology Resident Case Studies
 Tommy is a 4 year old child with a history of intractable seizures and developmental delay since birth.
 He has been tried on several anticonvulsant regimens (i.e., carbamazepine, valproic acid, ethosuximide, phenytoin, and phenobarbital) without significant benefit.

51. Case #1 – Pediatric Con’t
 Tommy’s seizures are characterized as tonic seizures and atypical absence seizures and has been diagnosed with a type of childhood epilepsy known as Lennox-Gastaut Syndrome.

52. Case #1 – Pediatric Con’t
Briefly describe what characteristics are associated with Lennox-Gastaut Syndrome.
What anticonvulsants are currently FDA approved for Lennox-Gastaut Syndrome?

53. Case #1 – Pediatric Con’t
3. Tommy is currently being treated with ethosuximide 250 mg BID and valproic acid 250 mg BID. The neurologist wants to add another anticonvulsant onto Tommy’s current regimen and asks you for your recommendations. (Hint: Evaluate current anticonvulsants based on positive clinical benefit in combination therapy and adverse effect profile.)

54. Case #1 – Pediatric Con’t
4. Based on your recommendations above, what patient education points would you want to emphasize?