Anti-epileptic Drugs

Classification of Seizures
Partial: simple or complex
Generalized: absence, tonic, clonic, tonic-clonic,
myoclonic, febrile

Animal Models of Seizures

Chemical-induced: pentylenetetrazole, kainic acid,

Maximal electrochock
Kindling

Pathophysiology of Seizures
The Interictal Spike (paroxysmal
depolarization shift)
Increased excitability
Membrane depolarization, potassium buildup
Increased excitatory (EAA, glutamate) input
Decreased inhibitory (GABA) input

Evidence for the

Pathophysiology of Seizures
Increased EAA
Increased Excitatory
Amino Acid Transmission
Increased sensitivity to
EAA
Progressive increase in
glutamate release during
kindling
Increased glutamate and
aspartate at start of seizure
Upregulation of NMDA
receptors in kindled rats

Decreased GABA
Decreased binding of
GABA and
benzodiazepines
Decreased Cl- currents in
response to GABA
Decreased glutamate
decarboxylase activity
(synthesizes GABA)
Interfere with GABA
causes seizures

Strategies in Treatment
Stabilize membrane and prevent
depolarization by action on ion
channels
Increase GABAergic transmission
Decrease EAA transmission

Classification of Anticonvulsants
Action on Ion
Channels

Enhance GABA
Transmission

Na+:
Phenytoin,
Carbamazepine,
Lamotrigine
Topiramate
Valproic acid
Ca++:
Ethosuximide
Valproic acid

Benzodiazepines
(diazepam, clonazepam)
Barbiturates
(phenobarbital)
Valproic acid
Gabapentin
Vigabatrin
Topiramate
Felbamate

Na+:
For general tonic-clonic
and partial seizures
Ca++:
For Absence seizures

Most effective in
myoclonic but also in
tonic-clonic and partial
Clonazepam: for Absence

Inhibit EAA
Transmission
Felbamate
Topiramate

Classification of Anticonvulsants
Newer

Classical

Phenytoin
Phenobarbital
Primidone
Carbamazepine
Ethosuximide
Valproic Acid
Trimethadione

Lamotrigine
Felbamate
Topiramate
Gabapentin
Tiagabine
Vigabatrin
Oxycarbazepine
Levetiracetam
Fosphenytoin
Others

R1
R2

R3

Phenytoin

Ethosuximide

Trimethadione

Phenobarbital

Carbamazepine

Valproic Acid

Phenytoin or Diphenylhydantoin

Limited water solubility not given i.m.

Slow, incomplete and variable absorption.
Extensive binding to plasma protein.
Metabolized by hepatic ER by hydroxylation.
Chance for drug interactions.
Therapeutic plasma concentration: 10-20 g/ml
Shift from first to zero order elimination within
therapeutic concentration range.

Plasma Concentration (mg/L)

Relationship between Phenytoin Daily Dose and

Plasma Concentration In 5 Patients

Dose (mg/day)

Phenytoin Toxicity and

Adverse Events
Acute Toxicity
High i.v. rate: cardiac arrhythmias
hypotension; CNS depression.
Acute oral overdose: cerebellar and
vestibular symptoms and signs:
nystagmus, ataxia, diplopia vertigo.

Phenytoin Toxicity

Chronic Toxicity
Dose related vestibular/cerebellar effects
Behavioral changes
Gingival Hyperplasia
GI Disturbances
Sexual-Endocrine Effects:
Osteomalacia
Hirsutism
Hyperglycemia

Phenytoin Toxicity and

Adverse Events

Chronic Toxicity
Folate Deficiency - megaloblastic anemia
Hypoprothrombinemia and hemorrhage in newborns
Hypersenstivity Reactions could be severe. SLE, fatal
hepatic necrosis, Stevens-Johnson syndrome.
Pseudolymphoma syndrome
Teratogenic
Drug Interactions: decrease (cimetidine, isoniazid) or
increase (phenobarbital, other AEDs) rate of
metabolism; competition for protein binding sites.

Fosphenytoin
A Prodrug. Given i.v. or i.m. and rapidly
converted to phenytoin in the body.
Avoids local complications associated with
phenytoin: vein irritation, tissue damage,
pain and burning at site, muscle necrosis
with i.m. injection, need for large fluid
volumes.
Otherwise similar toxicities to phenytoin.

Other Na Channel Blockers

Carbamazepine: may have adrenergic mechanism
as well. Serious hematological toxicity: aplastic
anemia. Antidiuretic effect (anti ADH).
Also for trigeminal neuralgia
Lamotrigine: possible other mechanisms.
Effective in Absence seizures and has
antidepressant effects in bipolar depression. No
chronic associated effects.

Inhibitors of Calcium Channels

Ethosuximide
Drug of choice for Absence. Blocks Ca++ currents
(T-currents) in the thalamus.
Not effective in other seizure types
GI complaints most common
CNS effects: drowsiness lethargy).
Has dopamine antagonist activity (? In seizure
control) but causes Parkinsonian like symptoms.
Potentially fatal bone marrow toxicity and skin
reactions (both rare)

Enhancers of GABA Transmission

Phenobarbital
The only barbiturate with selective anticonvulsant effect.
Bind at allosteric site on GABA receptor and duration of
opening of Cl channel.
Ca-dependent release of neurotransmitters at high doses.
Inducer of microsomal enzymes drug interactions.
Toxic effects: sedation (early; tolerance develops);
nystagmus & ataxia at higher dose; osteomalacia, folate
deficiency and vit. K deficiency.
In children: paradoxical irritability, hyperactivity and
behavioral changes.
Deoxybarbiturates: primidone: active but also converted to
phenobarbital. Some serious additional ADRs: leukopenia, SLElike.

Enhancers of GABA Transmission

Benzodiazepines
Sedative - hypnotic- anxiolytic drugs.
Bind to another site on GABA receptor. Other mechanisms
may contribute. frequency of opening of Cl channel.
Clonazepam and clorazepate for long term treatment of
some epilepsies.
Diazepam and lorazepam: for control of status epilepticus.
Disadvantage: short acting.
Toxicities: chronic: lethargy drowsiness.
in status epilepticus: iv administration: respiratory and
cardiovascular depression. Phenytoin and PB also used.

GABA-A Receptor
Binding Sites

Cl-

Enhancers of GABA Transmission

Gabapentin: Developed as GABA analogue.
Mechanism: Increases release of GABA by
unknown mechanism.
Vigabatrin: Irreversible inhibitor of GABA
transaminase. Potential to cause psychiatric
disorders (depression and psychosis).
Tiagabine: decreases GABA uptake by
neuronal and extraneuronal tissues.

GABA

Tiagabine

Vigabatrin

Gabapentin

Modulators of GABA Transmission

GBP
TPM

GABA-T

VGB

BZD

TGB
GABA-T

VGB

Valproic Acid
Effective in multiple seizure types.
Blocks Na and Ca channels. Inhibits GABA
transaminase. Increases GABA synthesis.
Toxicity: most serious: fulminant hepatitis. More
common if antiepileptic polytherapy in children <
2 years old. (?) Toxic metabolites involved.
Drug interactions: inhibits phenobarbital and
phenytoin metabolism.

Other Drugs
Topiramate; multiple mechanisms of action (Na
channel, GABA enhancement like BZD,
antagonist at AMPA subtype of glutamate
receptors (not NMDA).
Felbamate: multiple mechanisms: Na channel
block; modulates glutamate transmission interacts
with glycine site. Serious hematological and
hepatic toxicities.

Treatment of Epilepsy
Start with a single agent. Raise to maximum
tolerated dose before shifting to another.
If therapy fails may use combination of
drugs.
Frequent physician visits early on and
therapeutic drug monitoring.
Importance of compliance.
Aim and duration of therapy.