Anticonvulsants

ANTICONVULSANTS

By: Jhon Fred A. Ralisay

Hypersensitivity to Phenytoin(Idiosyncratic Toxicity)

result of reactions of reactive intermediates (areneoxide, catechol, or ο- quinone ) with hepatic enzymes or other cellular proteins forming covalently bonded haptens.

Haptens - are molecules that triggers immune response

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

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

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.

PHENOBARBITAL AND PRIMIDONE

PHENOBARBITAL AND PRIMIDONE

A. Phenobarbital

-only sedative-hypnotic barbiturates that displays enough anticonvulsant selectivity for use as antiepileptic

-a minor metabolite of Primidoneby hepatic enyzme CYP2C9/19

-MOA:=enhances GABAergic transmission

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

PHENOBARBITAL AND PRIMIDONE

CARBAMAZEPINE AND OXCARBAZEPINE

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

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

CARBAMAZEPINE AND OXCARBAZEPINE

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

CARBAMAZEPINE AND OXCARBAZEPINE

-weak inducer of CYP3A4 and UDP-glucuronyltransferase

-inhibits CYP2C19

-metabolized by alcohol dehydrogenase to CBZ-ol as ο-glucuronide and further metabolized to 10,11-CBZ-diol

CARBAMAZEPINE AND OXCARBAZEPINE

GABAPENTIN AND PREGABALIN

GABAPENTIN AND PREGABALIN

A. Gabapentin (Neurontin)

-(S)-3-isobutyl-GABA

-broad-spectrum anticonvulsants

-similar structure to L-Leucine

GABAPENTIN AND PREGABALIN

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

GABAPENTIN AND PREGABALIN

B. Pregabalin (Lyrica)

-analogous in structure with Gabapentin

-has similar structure with L-Leucine

-has 98% bioavailability

GABAPENTIN AND PREGABALIN

FELBAMATE AND FLUROFELBAMATE

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

FELBAMATE AND FLUROFELBAMATE

-metabolized by CYP450 mediated hydroxylationswith 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)

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

NOVEL BROAD-SPECTRUM ANTCONVULSANTS

NOVEL BROAD-SPECTRUM ANTCONVULSANTS

A. Lamotrigine (Lamictal)

-antiepileptic drugs of phenyltriazine class

MOA:

= blockade of sodium channels

= Inhibits the high-threshold calcium channels

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

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

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

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

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

NOVEL BROAD-SPECTRUM ANTCONVULSANTS

NOVEL BROAD-SPECTRUM ANTCONVULSANTS

D. Levetiracetam (Keppra)

-analog of nootropic agent Piracetam

-does not have affinity to AMPA receptor thereby has no nootropicactivity 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

NOVEL BROAD-SPECTRUM ANTCONVULSANTS

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

ANTICONVULSANTS ACTS ON A SELECTIVE MOLECULAR TARGET

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

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

ANTICONVULSANTS ACTS ON A SELECTIVE MOLECULAR TARGET

ANTICONVULSANTS ACTS ON A SELECTIVE MOLECULAR TARGET

B. Ethosuximide (Zarontin)

-prototypical anticonvulsant for patients with absence seizures

-MOA:

= block threshold T-type calcium channels

ANTICONVULSANTS ACTS ON A SELECTIVE MOLECULAR TARGET

C.Methsuximide (Celontin)

-N-dealkylated active metabolite of ethosuximide

-MOA:

= block threshold T-type calcium channels

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

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

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

ANTICONVULSANTS ACTS ON A SELECTIVE MOLECULAR TARGET

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 epileptogenesisespecially 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