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 Inhibit EAA Transmission 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
Felbamate Topiramate
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
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.
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 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, 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 â&#x20AC;˘ Topiramate; multiple mechanisms of action (Na channel, GABA enhancement like BZD, antagonist at AMPA subtype of glutamate receptors (not NMDA). â&#x20AC;˘ 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.