Phenytoin is metabolized into reactive intermediates like arene oxide and catechol that can bind to proteins and trigger immune responses. These metabolites are deactivated by enzymes like epoxide hydrolase and glutathione transferase. Phenytoin strongly induces several CYP450 isozymes and drug metabolizing enzymes. Carbamazepine is metabolized by CYP3A4 into an epoxide metabolite suspected of causing idiosyncratic reactions. Gabapentin and pregabalin modulate calcium influx and stimulate GABA biosynthesis without being metabolized. Felbamate undergoes hydroxylation and hydrolysis to form a toxic metabolite, 2-phenylpropanal. Future anticonvulsants

1. ANTICONVULSANTS
By: Jhon Fred A. Ralisay

2. Hypersensitivity to Phenytoin
(Idiosyncratic Toxicity)
result of reactions of reactive intermediates (arene
oxide, catechol, or ο- quinone ) with hepatic enzymes
or other cellular proteins forming covalently bonded
haptens.
Haptens - are molecules that triggers immune response

3. Hypersensitivity to Phenytoin
(Idiosyncratic Toxicity)
Arene oxide
-mediates teratogenecity of phenytoin
-deactivated by either epoxide hydrolase to
dihydrodiol (major urinary metabolite) or by GSH and
glutathione transferase
Epoxide hydrolase
-use as biomarker for determination of risk fetal hydantoin
syndrome

4. Hypersensitivity to Phenytoin
(Idiosyncratic Toxicity)
Catechol
-acts with phenytoin producing phenytoin-
induced-toxicity
-reduced by normal amount of COMT in liver
making it easily oxidized into ο-quinone

5. Hypersensitivity to Phenytoin
(Idiosyncratic Toxicity)
Must remember:
Phenytoin is a potent enzyme inducer specifically
CYP450 isozymes CYP1A2, CYP2C9/19, CYP3A4 as well
as epoxide hydrolase and UDP-glucuronyl transferase.

6. PHENOBARBITAL AND
PRIMIDONE

7. PHENOBARBITAL AND PRIMIDONE
A. Phenobarbital
-only sedative-hypnotic
barbiturates that displays enough
anticonvulsant selectivity for use as
antiepileptic
-a minor metabolite of Primidone
by hepatic enyzme CYP2C9/19
-MOA:
=enhances GABAergic transmission

8. PHENOBARBITAL AND PRIMIDONE
B. Primidone (Mysoline)
-metabolized by CYP2C9/19
into phenobarbital and
phenylethylmalonamide
-anticonvulsant action is
due to its minor metabolite
which is phenobarbital

9. PHENOBARBITAL AND PRIMIDONE

10. CARBAMAZEPINE AND
OXCARBAZEPINE

11. CARBAMAZEPINE AND
OXCARBAZEPINE
A. Carbamazepine(Tegretol)
-5H dibenz[b,f]lazepine 5
carboxamide
-an iminostilbene derivative
of tricyclic antidepressants
-useful for generalized tonic-
clonic and partial seizures

12. CARBAMAZEPINE AND
OXCARBAZEPINE
-metabolized into stable metabolite; 10,11-CBZ epoxide
by CYP3A4
then further metabolized by epoxide hydrolase to inactive
form; 10,11-CBZ-diol which is excreted as glucuronides
-epoxide metabolite is suspected for idiosyncratic
reactions such as aplastic anaemia
MOA:
=Potentiates GABA receptor

13. CARBAMAZEPINE AND
OXCARBAZEPINE

14. CARBAMAZEPINE AND
OXCARBAZEPINE
B.
Oxcarbamazepine(Trileptal)
-has the same MOA to
carabamazepine
-not an enzyme inducer
-has much hepatic and
idiosyncratic side effects
than carabamazepine

15. CARBAMAZEPINE AND
OXCARBAZEPINE
-weak inducer of CYP3A4 and UDP-glucuronyl
transferase
-inhibits CYP2C19
-metabolized by alcohol dehydrogenase to CBZ-
ol as ο-glucuronide and further metabolized to
10,11-CBZ-diol

16. CARBAMAZEPINE AND
OXCARBAZEPINE

17. GABAPENTIN AND PREGABALIN

18. GABAPENTIN AND PREGABALIN
A. Gabapentin (Neurontin)
-(S)-3-isobutyl-GABA
-broad-spectrum
anticonvulsants
-similar structure to L-
Leucine

19. GABAPENTIN AND PREGABALIN

20. GABAPENTIN AND PREGABALIN
-MOA:
= modulation of calcium influx
= stimulation of GABA biosynthesis
= compete for biosynthesis of L-glutamic acid
-more than 95% is excreted unchanged in kidney
-has 60% bioavailability if given at low dose

21. GABAPENTIN AND PREGABALIN
B. Pregabalin (Lyrica)
-analogous in structure with
Gabapentin
-has similar structure with L-
Leucine
-has 98% bioavailability

22. GABAPENTIN AND PREGABALIN

23. FELBAMATE AND
FLUROFELBAMATE

24. FELBAMATE AND FLUROFELBAMATE
A. Felbamate (Felbatol)
-has broad spectrum action
-carbamate ester of 2-phenyl-1,
3-propanediol
-severe side effects such as
aplastic anaemia, idiosyncratic
reactions, and hepatic failures

25. FELBAMATE AND FLUROFELBAMATE
-metabolized by CYP450 mediated hydroxylations
with metabolites ρ-hydroxyfelbamate and 2-
hydroxyfelbamate
-also undergoes esterase-catalyzed hydrolysis
resulting into two minor metabolites 2-phenyl-1, 3-
propandiol monocarbamate and 3-carbamoyl-2-
phenylpropionic acid (CPPA)
-CPPA undergoes oxidative reduction resulting into
toxic reactive metabolite which is 2-phenylpropanal
(atropaldehyde)

26. FELBAMATE AND FLUROFELBAMATE
B. Fluorofelbamate
-a very potent anticonvulsant
-still under phase 2 clinical
trials
-a product of placement of
fluorine atom at the C-2
position of FBM

27. NOVEL BROAD-SPECTRUM
ANTCONVULSANTS

28. NOVEL BROAD-SPECTRUM
ANTCONVULSANTS
A. Lamotrigine (Lamictal)
-antiepileptic drugs of
phenyltriazine class
MOA:
= blockade of sodium
channels
= Inhibits the high-
threshold calcium channels

29. NOVEL BROAD-SPECTRUM
ANTCONVULSANTS
-effective for refractory partial seizures
-metabolized by glucuronidation
-metabolites are2-N-glucuronide (76%) and 5-N-
glucuronide (10%)
-co-administration with valproate may increase
idiosyncratic reaction

30. NOVEL BROAD-SPECTRUM
ANTCONVULSANTS
B. 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

31. NOVEL BROAD-SPECTRUM
ANTCONVULSANTS
-similar structure to D-glucose
-oral bioavailability of 85% and
95%
-only 20% is eliminated by
CYP2C19 and the remaining drug
is excreted unchanged

32. NOVEL BROAD-SPECTRUM
ANTCONVULSANTS
-MOA:
= inhibition glutamate release
Glutamate- an excitatory neurotransmitter
= antagonize glutamate kainic acid/AMPA (α-
amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)
receptors
= increase GABAergic transmission by binding on
the same sites of GABA receptors where
benzodiazepines and barbiturates bind

33. NOVEL BROAD-SPECTRUM
ANTCONVULSANTS
C. Zonisamide (Zonegram,
Excegram)
-sulfonamide type anticonvulsant
-use as adjunctive for partial
seizures in adults with epilepsy
-metabolized by reductive ring
cleavage from 1,2-benzisoxazole
ring to 2-sulfamoyl-acetyl-phenol

34. NOVEL BROAD-SPECTRUM
ANTCONVULSANTS

35. NOVEL BROAD-SPECTRUM
ANTCONVULSANTS
D. Levetiracetam (Keppra)
-analog of 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

36. NOVEL BROAD-SPECTRUM
ANTCONVULSANTS

37. NOVEL BROAD-SPECTRUM
ANTCONVULSANTS
-MOA:
= modulate kainite/AMPA induced
excitatory synaptic currents
-antiepileptic action is mediated by parent drug
rather than its metabolite which is (S)-α-ethyl-2-
oxo-1-pyrrolidiniacetic acid via hydrolysis of
amide group

38. ANTICONVULSANTS ACTS ON A
SELECTIVE MOLECULAR TARGET

39. ANTICONVULSANTS ACTS ON A
SELECTIVE MOLECULAR TARGET
A. Tiagabine (Gabitril)
-an uptake inhibitor
-MOA:
= blocks GABA reuptake at
GABA transporter-1 increase
extracellular GABA concentration
in the hippocampus, striatum and
cortex
-use for partial seizures

40. ANTICONVULSANTS ACTS ON A
SELECTIVE MOLECULAR TARGET
-in his structure nipecotic acid a potent inhibitor of GABA
reuptake but fails to cross blood-brain barrier following
systemic administration because of its high degree of
ionization
-marketed as R( ̶ )-enantiomer a potent GAT-1 inhibitor
which is structurally related to nipecotic acid has the ability
to cross blood-brain barrier and metabolized by CYP3A4 to
5-oxo-tiagabine
-90% of tiagabine is metabolized by CYP3A4 which affects
the thiophen rings

41. ANTICONVULSANTS ACTS ON A
SELECTIVE MOLECULAR TARGET

42. ANTICONVULSANTS ACTS ON A
SELECTIVE MOLECULAR TARGET
B. Ethosuximide (Zarontin)
-prototypical
anticonvulsant for
patients with absence
seizures
-MOA:
= block threshold T-
type calcium channels

43. ANTICONVULSANTS ACTS ON A
SELECTIVE MOLECULAR TARGET
C.Methsuximide (Celontin)
-N-dealkylated active
metabolite of ethosuximide
-MOA:
= block threshold T-type
calcium channels

44. ANTICONVULSANTS ACTS ON A
SELECTIVE MOLECULAR TARGET
D. Vigabatrin (Sabril)
-a 4-vinyl analog of GABA
-MOA:
= irreversibly blocking
GABA catabolism catalysed by
GABA-T
-treatment for partial seizures

45. ANTICONVULSANTS ACTS ON A
SELECTIVE MOLECULAR TARGET
E. Benzodiazepines
Clonazepam (Klonopin)
-useful for absence seizures and myoclonic
seizures
-tolerance may develop quickly
-metabolized by hydroxylation at C-3 position
followed by glucuronidation and nitro group
reduction and acetylation
-MOA:
= enhances GABAergic transmission

46. ANTICONVULSANTS ACTS ON A
SELECTIVE MOLECULAR TARGET
E. Benzodiazepines
Diazepam (Valium and Diastat)
-Valium is orally and Diastat is rectally
-adjunctive treatment for generalized
tonic-clonic status epilepticus or
patients with refractory epilepsy
-MOA:
= enhances GABAergic
transmission

47. ANTICONVULSANTS ACTS ON A
SELECTIVE MOLECULAR TARGET

48. FUTURE DEVELOPMENT OF
ANTIEPILEPTIC DRUGS
-all AEDs worked only as prophylaxis against
symptoms of epilepsy
-future direction of developments of AEDs must
come from better understanding of epileptogenesis
especially the genetic mechanisms that underlie
disease progression or the development of
resistance after prolonged pharmacotherapy of
from an innovative design strategy that produce
new AEDs with unique mechanism