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.
Top Related