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

Enhance GABA Transmission

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

Inhibit EAA Transmission

Felbamate Topiramate

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

Classification of Anticonvulsants
Classical
Phenytoin Phenobarbital Primidone Carbamazepine Ethosuximide Valproic Acid Trimethadione

Newer
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.

Relationship between Phenytoin Daily Dose and Plasma Concentration In 5 Patients

Plasma Concentration (mg/L)

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

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.