Dy, Claire Anne R.

Chapter 14

Anticonvulsants

Phenobarbital

Primidone (Mysoline)

Phenobarbital and Primidone

(Mysoline)

Primidone is metabolized by CPY2C9/19 to

phenobarbital and phenylethylmalonamide

(PEMA)

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

Carbamazepine (Tegretol)

Oxcarbazepine (Trileptal)

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

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

Carbamazepine (Tegretol)

Oxcarbazepine (Trileptal)

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

Gabapentin (Neurontin)

Pregabalin (Lyrica)

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

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

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

Felbamate (Felbatol)

Flurofelbamate

Novel Broad-Spectrum

Anticonvulsants

Lamotrigine (Lamictal)

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

Topiramate (Topamax)

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

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

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

Levetiracetam (Keppra)

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

Anticonvulsants

acts on a Selective Molecular Target

Anticonvulsants

acts on a Selective Molecular Target

Tiagabine

Ethosuximide

Methsuximide

Vigabatrin

Benzodiazepines

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

Tiagabine (Gabitril)

Ethosuximide (Zarontin)

Methsuximide (Celontin)

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

Vigabatrin (Sabril)

Vigabatrin (Sabril)

A 4-vinyl analog of GABA

Produces pharmacological action by irreversibly

blocking GABA catabolism catalyzed by GABA-T

Treatment of partial seizures

Benzodiazepines

Clonazepam (Klonopin)

Diazepam (Valium, Diastat)

Clonazepam (Klonopin)

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

Diazepam (Valium, Diastat)

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