Anticonvulsants

General Mechanisms of Anticonvulsant Action

Introduction: Epilepsies are a group of disorders characterized by recurrent, paroxysmal discharges of neurons in the brain

Goal: to prevent discharge of neurons; to prevent spread of electrical activity from foci

Effectiveness: should be long-lasting; most anticonvulsants accumulate slowly to a steady state level

Strategy – three steps:

(1) Start with a standard drug; begin with low dose to minimize dose dependent side effects
(2) If seizures are not controlled, add 2^nd anticonvulsant of a different class

(3) If seizures are controlled with addition of 2^nd drug, try withdrawing the initial drug slowly

Mechanism of Drug Action Overview

(1) Modify activity of voltage gated ion channels

Na⁺ channel blockers: phenytoin, carbamazapine, lamotrigine, felbamate, topiramate, valproate
Ca⁺ channels blockers: ethosuximide, gabapentin

K⁺ channel agonist: No current drugs available

(2) Enhance effect of the inhibitory neurotransmitter g -aminobutyric acid (GABA):

GABA receptor agonists: barbiturates (phenobarbital and primidone), benzodiazepines (clonazepam and diazepam)
Inhibit GABA catabolism: valproate; triagabin (blocks reuptake), vigabatrin (blocks degradation)

(3) Inhibit effect of the excitatory neurotransmitter glutamate

Glutamate receptor antagonists: topiramate, felbamate

Inhibit glutamate release: lamotrigine

Drugs which Modify the Activity of Voltage Gated Channels

cells are maintained at a resting potential, intracellular environment is negative to the extracellular environment

action potential (AP) caused by influx of Na⁺ and Ca⁺⁺ through voltage dependent channels (depolarization) and then repolarization through; hyperpolarization by influx of K ⁺ through voltage dependent channels

Na⁺ Channel Blockers

Phenytoin: primary drug for treatment of epilepsies; blocks Na⁺ channels

Structure: member of hydantoin class

Pharmokinetics: weak acid; slow oral absorption; rapid distribution; 90% protein bound; T_1/2= 18-24 hrs.

Metabolism: hepatic, major metabolites are inactive, rate of metabolism may change with age, liver disease or with addition of other drugs

Elimination: at [ß ] 1^st order kinetics; at [Ý ] 0 order kinetics Þ with Ý drug levels the process of biotransformation is saturated and metabolism is slowed leading to a prolonged T_1/2

Toxicity: CNS depression, gum hyperplasia, hirsuitism; interaction with other drugs

Carbamazepine: primary drug for treatment of all types of epilepsy; blocks Na⁺channels

Structure: similar to tricyclic antidepressants

Pharmokinetics: slow oral absorption; rapidly distributed to all tissues; 75% protein bound; T_1/2= 8-15 hrs, T_1/2 ß if phenobarbital is given concurrently

Metabolism: metabolized to epoxide (active) and inactive metabolites

Toxicity: drowsiness, dizziness, GI distress

Valproate – newest anticonvulsant; also may enhance GABA action (inhibit GABA metabolism)

Structure: branched chain fatty acid

Pharmokinetics: complete oral absorption;90% protein bound; T_1/2= 8-10 hrs; Tmax = 1-4 hrs

Metabolism: hepatic and mitochondrial, some metabolites have anticonvulsant actions

Toxicity: hepatotoxic, GI intolerance, tremor,

Lanotrigine: blocks repetitive firing of cells, inhibits glutamate release and blocks Na⁺ channels

Structure: developed as folate antagonist

Pharmokinetics: almost completely absorbed (linear); T_1/2= 23-37 hrs; Tmax = 1.5-4 hrs, 56% protein bound

Metabolism: 43-87% recovered in urine as glucuronide metabolite

Toxicity: skin rashes

Ca⁺⁺ Channel Blockers:

Ethosuximide:

Pharmokinetics: complete, rapid oral absorption; T_1/2= 20 hrs; Tmax = 3 hrs; not significantly protein bound

Metabolism: largely hepatic

Toxicity: relatively nontoxic

Gabapentin: Theory: binds Ca⁺⁺ channels acts as a Ca⁺⁺ antagonist

Structure: structurally similar to GABA, but does not bind GABA receptors

Pharmokinetics: satisfactory rate of absorption, 0% protein bound; T_1/2= 5-7 hrs

Metabolism: No metabolites; 93% excreted unchanged in urine

Toxicity: low

Modulators of GABAergic Transmission

either act directly at GABA receptors (barbiturates and benzodiazepines) or indirectly by inhibiting GABA catabolism or Ý GABA concentration (valproate)

GABA: inhibitory amino acid neurotransmitter found throughout the brain, found in [Ý ] (m m/g of tissue)

formed from glutamic acid by glutamic acid decarboxylase; released in synaptic vesicles at receptor sites

binding of GABA to the GABA receptor causes Ý in membrane conductance to chloride ions

GABA receptor: composed of multiple subunits; three receptors are known GABAa, GABAb and GABAc (only GABAa binds currently used anticonvulsants)

Termination of GABA action: GABA and a ketoglutarate are converted to succinic semialdehyde and glutamate by GABA glutamic acid transaminase

Act Directly at GABA Receptor

Barbiturates

Phenobarbital: also interfere with sodium and potassium transport

Pharmokinetics: slow but complete orally; T_1/2= 96 hrs; Tmax = several hours; 40-60% plasma bound

Metabolism: microsomal enzymes; 25% excreted unchanged

Toxicity: sedation and ataxia, also hyperactivity

Primidone: structurally related to phenobarbital

Phamokinetics: complete oral absorption; T_1/2= 6-12 hrs; Tmax = 2-4 hrs; little protein bound

Metabolism: metabolized in liver to phenobarbital and phenylethmalonamide

Toxicity: sedation and ataxia

Benzodiazepines: Clonazepam and Diazepam

Pharmokinetics: long lasting

Metabolism: liver, no active metabolite

Clonazepam: tolerance develops and can not be used for long term

Other

Tiagabine: prevents reuptake of GABA

Pharmokinetics: rapid oral absorption; T_1/2= 5-8 hrs; highly protein bound

Metabolism: liver

Vigabatrin blocks degradation of GABA

Pharmokinetics: rapid oral absorption; T_1/2= 6-8 hrs; little protein bound

Metabolism: kidney

Modulators of Glutaminergic Transmission

Glutamate: main excitatory neurotransmitter in the CNS; found throughout the brain; action terminated by reuptake

Glutamate Receptor:

NMDA: ionotropic
Non NMDA: ionotropic; binds AMPA and kainate
G protein linked receptor: not used for treatment of epilepsy

Lamotrigine: inhibits GLUT release and blocks Na⁺ channels

Structure: developed as folate antagonist

Pharmokinetics: rapidly absorbed; T_1/2= 23-37 hrs; Tmax = 3 hrs, 56% protein bound

Metabolism: 43-87% recovered in urine as glucuronide metabolite

Toxicity: skin rashes

Felbamate: glutamate receptor antagonist; prevents NMDA-induced seizures possible through interaction with the strychnine-insensitive glycine recognition site on the NMDA receptor complex

Structure: a dicarbamate

Pharmokinetics: almost completely absorbed T_1/2= 20 hrs

Metabolism: metabolites inactive

Toxicity: liver toxicity; interaction with many other antiepileptic medications

Topiramate: multiple mechanism of action; Ý GABA, inhibits glutamate activity

Pharmokinetics: rapidly and completely absorbed; T_1/2= 20 hrs; Tmax = 0.8-4.3 hrs