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 AnticonvulsantsAction on Ion

ChannelsEnhance GABA

Transmission

Inhibit EAA

TransmissionNa+:

Phenytoin, Carbamazepine, Lamotrigine

Topiramate

Valproic acid

Ca++:

Ethosuximide

Valproic acid

Benzodiazepines

(diazepam, clonazepam) Barbiturates (phenobarbital)

Valproic acid

Gabapentin

Vigabatrin

Topiramate

Felbamate

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

Phenytoin

Phenobarbital Carbamazepine

Ethosuximide Trimethadione

Valproic Acid

R1

R2

R3

X

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.

Dose (mg/day)

Pla

sma

Con

cen

trat

ion

(m

g/L

)Relationship between Phenytoin Daily Dose and

Plasma Concentration In 5 Patients

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.

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

– Osteomalacia– Hirsutism– Hyperglycemia

Phenytoin – Toxicity

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.

Phenytoin – Toxicity and Adverse Events

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 ChannelsEthosuximide

• 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.

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.

Enhancers of GABA Transmission

GABA-A ReceptorBinding Sites

Cl-

• 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.

Enhancers of GABA Transmission

VigabatrinGABA

Tiagabine Gabapentin

TGB

VGBBZD

TPM

VGB

GBP

GABA-T

GABA-T

Modulators of GABA Transmission

TGB

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.