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 Decreased GABA
• Increased Excitatory • Decreased binding of
Amino Acid Transmission GABA and
• Increased sensitivity to benzodiazepines
EAA • Decreased Cl- currents in
• Progressive increase in response to GABA
glutamate release during
kindling • Decreased glutamate
• Increased glutamate and
decarboxylase activity
aspartate at start of seizure (synthesizes GABA)
• Upregulation of NMDA • Interfere with GABA
receptors in kindled rats 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 Enhance GABA Inhibit EAA
Channels Transmission Transmission
Na+: Benzodiazepines Felbamate
Phenytoin, (diazepam, clonazepam) Topiramate
Carbamazepine, Barbiturates
Lamotrigine (phenobarbital)
Topiramate Valproic acid
Valproic acid Gabapentin
Ca++: Vigabatrin
Ethosuximide Topiramate
Valproic acid Felbamate
Na+: Most effective in
For general tonic-clonic myoclonic but also in
and partial seizures tonic-clonic and partial
Ca++: Clonazepam: for Absence
For Absence seizures
Classification of Anticonvulsants
Classical Newer
• • Lamotrigine
Phenytoin
• Felbamate
• Phenobarbital • Topiramate
• Primidone • Gabapentin
• Carbamazepine • Tiagabine
• Ethosuximide • Vigabatrin
• Oxycarbazepine
• Valproic Acid
• Levetiracetam
• Trimethadione • Fosphenytoin
• Others
R1
R2 X
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 µg/ml
• Shift from first to zero order elimination within
therapeutic concentration range.
Relationship between Phenytoin Daily Dose and
Plasma Concentration (mg/L) 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 AED’s) 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 ADR’s: leukopenia, SLE-
like.
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 Vigabatrin
Tiagabine 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.
