chapter 14

1. Dy, Claire Anne R.
Chapter 14
Anticonvulsants

2. Phenobarbital
Primidone (Mysoline)

3. Phenobarbital and Primidone
(Mysoline)
 Primidone is metabolized by CPY2C9/19 to
phenobarbital and phenylethylmalonamide
(PEMA)

4. Phenobarbital and Primidone
(Mysoline)
 The pharmacological action of primidone is
mainly a result of the minor metabolite,
phenobarbital.
 Primidone is much less potent/toxic than
phenobarbital because most of the drug is
rapidly degraded to the less potent metabolite,
PEMA

5. Carbamazepine (Tegretol)
Oxcarbazepine (Trileptal)

6. Carbamazepine (Tegretol)
 CBZ, 5H dibenz[b,f]lazepine 5 carboxamide is an
iminostilbene derivative of tricyclic depressants
 useful in generalized tonic-clonic and partial
seizures
 The major metabolite pathway of CBZ is the
formation of a stable metabolite, 10,11-CBZ
expoide by cytochrome P450 isozyme CYP3A4
 This reactive metabolite is further deacvtivated by
the action of epoxide hydrolase to give inactive
inactive 10,11-CBZ-diol that is excreted as the
corresponding glucuronide

7. Oxcarbazepine (Trileptal)
 similar mechanism of action to CBZ except for its
metabolic inactivation pathway
 Not a liver enzyme inducer
 With the presence of a carbonyl function at the C-
10 carbon, OXC is reduced to the corresponding
CBZ-10-ol by the action of alcohol
dehydrogenase that is excreted as its O-
glucuronide or can be further oxidized to the
10,11-CBZ-diol as an inactive metabolite
 Have much fewer hepatic and idiosyncratic side
effects associated with CBZ

8. Carbamazepine (Tegretol)
Oxcarbazepine (Trileptal)

9. Oxcarbazepine (Trileptal)
 OXC is a weak inducer of CYP3A4 and UDP-
glucuroyl transferase and also inhibits CYP2C19
 Drug-drug interactions with medications
metabolized by these enzymes are to be
expected

10. Gabapentin (Neurontin)
Pregabalin (Lyrica)

11. Gabapentin (Neurontin)
Pregabalin (Lyrica)
 Are broad spectrum anticonvulsants with multiple
mechanism of action
 They compete for the biosynthesis of L-glutamic
acid because of their structural similarity to L-
leucine

12. Gabapentin (Neurontin)
Pregabalin (Lyrica)
 Have very little liability for causing metabolic
based drug-drug interactions because they are
not metabolized in humans
 95% of drug is excreted unchanged through the
kidney
 Gabapentin exhibits 65% bioavailability in low
doses
 Pregabalin exhibits 98% bioavailability

13. Felbamate (Felbatol)
Flurofelbamate
 Broad spectrum of action
 A carbamate ester of 2-phenyl-1, 3-propanediol
 Stable to esterases
 Provides good oral bioavailability
 Associated with severe side effects such as
aplastic anemia, idiosyncratic reactions and
hepatic failures

14. Felbamate (Felbatol)
Flurofelbamate

15. Novel Broad-Spectrum
Anticonvulsants

16. Lamotrigine (Lamictal)

17. Lamotrigine (Lamictal)
 Effective against refractory partial seizures
 MOA – blockade of sodium channels that is both
voltage and use dependent
 metabolized by glucuronidation
 Major inactive urinary metabolites isolated are 2-
N-glucuronide (76%) and 5-N-glucuronide (10%)
 Coadministration with valproate increases the
incidence of its idiosyncratic reactions

18. Topiramate (Topamax)

19. Topiramate (Topamax)
 derivative of naturally occurring sugar D-fructose
 a sulphamate substituted monosaccharide
 exhibits broad and potent antiepileptic drug
actions at glutamate and GABA receptors

20. Topiramate (Topamax)
similar structure to D-glucose
oral bioavailability of 85% and 95%
only 20% is eliminated by CYP2C19 and the
remaining drug is excreted unchanged

21. Zonisamide (Zonegran,
Excegran)
 A sulfonamide type anticonvulsant
 Recently approved for adjunctive therapy in the
treatment of partial seizures
 Primarily metabolized by reductive ring cleavage
of the 1,2-benzisoxazole ring to 2-sulfamoyl-
acteyl-phenol

22. Levetiracetam (Keppra)

23. Levetiracetam (Keppra)
 Analog of the nootropic agent, piracetam
 does not have affinity to AMPA receptor thereby
has no nootropic activity for treatment of
Alzheimer’s disease
 have no affinity to GABA receptors, BZD
receptors, various excitatory amino acid related
receptors, or the voltage-gated ion channels

24. Anticonvulsants
acts on a Selective Molecular Target

25. Anticonvulsants
acts on a Selective Molecular Target
 Tiagabine
 Ethosuximide
 Methsuximide
 Vigabatrin
 Benzodiazepines

26. Tiagabine (Gabitril)
 Blocks GABA reuptake as a major mode of its
anticonvulsant activity
 Used against partial seizures
 Nipecotic acis is a potent inhibitor of GABA
reuptake into synaptosomal membranes,
neurons, and glial cells
 90% is metabolized by CYP3A4 isozymes
 Primary site of metabolic attack is the oxidation of
the thiophen rings leading to 5-oxo-tiagabine

27. Tiagabine (Gabitril)

28. Ethosuximide (Zarontin)
Methsuximide (Celontin)

29. Ethosuximide (Zarontin)
Methsuximide (Celontin)
 Ethosuximide is needed for treating patients with
absence seizures
 Works by blocking the low threshold T-type
calcium channels, thereby reducing the
hyperexcitability of thalamic neurons that is
specifically associated with absence seizure

30. Vigabatrin (Sabril)

31. Vigabatrin (Sabril)
 A 4-vinyl analog of GABA
 Produces pharmacological action by irreversibly
blocking GABA catabolism catalyzed by GABA-T
 Treatment of partial seizures

32. Benzodiazepines
Clonazepam (Klonopin)
Diazepam (Valium, Diastat)

33. Clonazepam (Klonopin)

34. Clonazepam (Klonopin)
 Useful in absence seizures and in myoclonic
seizures
 Tolerance often developed quickly
 metabolized by hydroxylation at C-3 position
followed by glucuronidation and nitro group
reduction and acetylation

35. Diazepam (Valium, Diastat)

36. Diazepam (Valium, Diastat)
 Valium is given orally
 Diastat is given rectally
 As an adjunctive treatment of generalized tonic-
clonic status epilepticus or with refractory
epilepsy in combination with other AEDs