Neuropharmacology of Antiepileptic Drugs

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.  1857 - Bromides  1912 - Phenobarbital  1937 - Phenytoin  1954 - Primidone  1960 - Ethosuximide

5. History of Antiepileptic Drug Therapy in the U.S.  1974 - Carbamazepine  1975 - Clonazepam  1978 - Valproate  1993 - Felbamate, Gabapentin  1995 - Lamotrigine  1997 - Topiramate, Tiagabine  1999 - Levetiracetam  2000 - Oxcarbazepine, Zonisamide

6. Antiepileptic Drug TherapyStructures 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 TherapyStructures of Commonly Used AEDs

8. Antiepileptic Drug TherapyStructures of Commonly Used AEDs Levetiracetam Oxcarbazepine Zonisamide

9. Antiepileptic Drug TherapyStructures 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 InducersInhibitors 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 • UDP glucuronosyltransferase (UGT)  plasma concentrations of Lamotrigine, Lorazepam • CYP2C19  plasma concentrations of Phenytoin, Phenobarbital  Topiramate & Oxcarbazepine • CYP2C19  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 AED Serum Concentration (mg/l) Carbamazepine 4-12 Ethosuximide 40-100 Phenobarbital 10-40 Phenytoin 10-20 Valproic acid 50-100

36. Potential Target Range of AED Serum Concentrations AED Serum Concentration (mg/l) Gabapentin 6-21 Lamotrigine 5-18 Levetiracetam 10-40 Oxcarbazepine 12-24 (MHD) Pregabalin ?? Tiagabine ? Topiramate 4.0-25 Zonisamide 7-40

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 ResidentCase Studies American Epilepsy Society Medical Education Program

50. Pharmacology ResidentCase 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.