chapter 14 phchem

1. Dy, Claire Anne R.
BSP-3B
Chapter14: ANTICONVULSANTS
Phenobarbital and Primidone (Mysoline)
 Primidone ismetabolizedbyCPY2C9/19to phenobarbital and phenylethylmalonamide (PEMA)
 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)
 CBZ, 5H dibenz[b,f]lazepine 5carboxamide isaniminostilbenederivative of tricyclicdepressants
 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
 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) and Pregabalin (Lyrica)
 Are broad spectrum anticonvulsants with multiple mechanism of action
 Theycompete forthe biosynthesis of L-glutamic acid because of their structural similarity to L-
leucine
 Have verylittle liabilityforcausingmetabolicbaseddrug-druginteractionsbecause 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) and Flurofelbamate
 Broad spectrum of action
 A carbamate ester of 2-phenyl-1, 3-propanediol
 Stable to esterases
 Provides good oral bioavailability
 Associatedwithsevere sideeffectssuch as aplastic anemia, idiosyncratic reactions and hepatic
failures

2. Novel Broad-Spectrum Anticonvulsants
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)
 derivative of naturally occurring sugar D-fructose
 a sulphamate substituted monosaccharide
 exhibits broad and potent antiepileptic drug actions at glutamate and GABA receptors
 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
 Primarilymetabolized by reductive ring cleavage of the 1,2-benzisoxazole ring to 2-sulfamoyl-
acteyl-phenol
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
Tiagabine (Gabitril)
 BlocksGABA reuptake asa majormode of itsanticonvulsantactivity
 Usedagainstpartial seizures
 Nipecoticacisisa potentinhibitorof GABA reuptake intosynaptosomal membranes,neurons,
and glial cells
 90% ismetabolizedby CYP3A4 isozymes
 Primarysite of metabolicattackisthe oxidationof the thiophenringsleadingto5-oxo-tiagabine
Ethosuximide (Zarontin) and Methsuximide (Celontin)
 Ethosuximide isneededfortreatingpatientswithabsence seizures
 Works byblockingthe lowthresholdT-type calciumchannels,therebyreducingthe
hyperexcitabilityof thalamicneuronsthatisspecificallyassociatedwithabsenceseizure
Vigabatrin (Sabril)
 A 4-vinyl analogof GABA
 Producespharmacological actionbyirreversiblyblockingGABA catabolismcatalyzedbyGABA-T
 Treatmentof partial seizures

3. Clonazepam(Klonopin)
 Useful inabsence seizuresandinmyoclonicseizures
 Tolerance oftendevelopedquickly
 metabolizedbyhydroxylationatC-3 positionfollowedbyglucuronidationandnitrogroup
reductionandacetylation
Diazepam (Valium,Diastat)
 Valiumisgivenorally
 Diastatis givenrectally
 As an adjunctive treatmentof generalizedtonic-clonicstatusepilepticusorwithrefractory
epilepsyincombinationwithotherAEDs