chapter 14 anticonvulsants
TRANSCRIPT
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Dy, Claire Anne R.
Chapter 14
Anticonvulsants
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Phenobarbital
Primidone (Mysoline)
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Phenobarbital and Primidone
(Mysoline)
Primidone is metabolized by CPY2C9/19 to
phenobarbital and phenylethylmalonamide
(PEMA)
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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
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Carbamazepine (Tegretol)
Oxcarbazepine (Trileptal)
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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
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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
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Carbamazepine (Tegretol)
Oxcarbazepine (Trileptal)
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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
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Gabapentin (Neurontin)
Pregabalin (Lyrica)
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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
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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
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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
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Felbamate (Felbatol)
Flurofelbamate
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Novel Broad-Spectrum
Anticonvulsants
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Lamotrigine (Lamictal)
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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
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Topiramate (Topamax)
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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
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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
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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
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Levetiracetam (Keppra)
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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
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Anticonvulsants
acts on a Selective Molecular Target
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Anticonvulsants
acts on a Selective Molecular Target
Tiagabine
Ethosuximide
Methsuximide
Vigabatrin
Benzodiazepines
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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
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Tiagabine (Gabitril)
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Ethosuximide (Zarontin)
Methsuximide (Celontin)
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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
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Vigabatrin (Sabril)
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Vigabatrin (Sabril)
A 4-vinyl analog of GABA
Produces pharmacological action by irreversibly
blocking GABA catabolism catalyzed by GABA-T
Treatment of partial seizures
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Benzodiazepines
Clonazepam (Klonopin)
Diazepam (Valium, Diastat)
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Clonazepam (Klonopin)
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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
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Diazepam (Valium, Diastat)
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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