Antiepileptic Drugs and Epilepsy Overview

Objectives of Antiepileptic Drugs

• Classify major seizure types based on EEG or clinical signs.
• List drugs of choice for each seizure type.
• Describe the GABA hypothesis of epilepsy and the roles of glutamate and NMDA receptors.
• Describe status epilepticus and its treatment.
• List general mechanisms of antiepileptic drugs.
• For each antiepileptic chemical class, characterize: primary use, major toxicity, mechanism of action, time to onset, kinetics, and termination.
• Explain pharmacokinetic interactions caused by anticonvulsant combinations.
• Indicate goals of polypharmacy in epilepsy and precautions for dosage changes.
• Describe how a patient's clinical status affects drug and dose choice.
• Describe potential interactions between anticonvulsants, oral contraceptives, and the folic acid system.
• Describe potential effects of antiepileptics on a fetus.

Epilepsy Overview

• Epilepsy is a chronic convulsive disorder with various causes.
• It results in hypersynchronous discharges of CNS neurons.
• Epilepsy affects 1-2% of the world's population.
• Epilepsy occurs at any age and in any racial group.
• Symptoms depend on the brain region affected.
• Untreated epilepsy can lead to anoxic brain damage.

General Principles of Drug Therapy

• Drugs do not cure epilepsy.
• Drugs prevent futher attacks without impairing CNS function.
• Drug therapy is chronic.
• Choose proper drug.
• Accurately diagnose seizure type based on EEG and clinical signs.

Success Rate of Antiepileptic Therapy

• Absence seizure total suppression is at 50%, with significant improvement at 25%.
• Tonic-Clonic seizure total suppression is at 60%, with significant improvement at 20%.
• Complex Partial seizure total suppression is <30%, with significant improvment at <50%. Complex partial seizures are most difficult to control.

Pathophysiology

• Can be idiopathic or primary with genetic predisposition, e.g. generalized seizures
• Can be symptomatic or secondary, induced by trauma, neoplasm, infection, strokes, drug withdrawal, drug-induced occurrences etc.
• Characterized via behavioral & EEG patterns

Seizures

• Partial Seizures/Focal Seizures: ~60%
  • Simple Partial - (Jacksonian march)
  • Complex Partial - (Temporal lobe or Psychomotor)
  • Secondary Generalized Partial (Focal/Grand Mal)
• Generalized Seizures: ~40%
  • Absence (Petit mal) type
    • brief, abrupt loss of consciousness
    • with or without clonic motor activity
    • Generalized 3 per second spike EEG activity
  • Grand Mal (Tonic-clonic)
    • Tonic contraction
    • Clonic jerking
    • Prolonged Postictal depression of CNS activity
    • Loss of consciousness
    • Generalized high voltage EEG spikes
• Status Epilepticus
  • It is a leading cause of death in epileptics.
  • This is a continuous seizure activity without recovery of consciousness for > 30 minutes.
  • Generalized tonic-clonic type is life-threatening.
  • Can be produced by sudden withdrawal of CNS depressants or antiepileptic agents.
• Pathophysiology of Seizures
  • Involves GABA Hypothesis of Epilepsy which is excitation/inhibition balance
• Use-Dependent Block of Na+ Channels
  • Delays Recovery of Inactivated Na+ Channels, Preferentially binds to inactivated channels.
  • Use-dependent effect means Neurons need to be discharging. Preferential inhibition of abnormal discharges in seizure focus
  • Treat Partial & Generalized Tonic-Clonic Seizures
• Hydantoins: Phenytoin (Dilantin)

Hydantoins : Phenytoin (Dilantin)

• Prevents seizures without general CNS depression.
• Mechanism: use-dependent block of Na+ Channels, inhibiting repetitive action potentials.
• Slow and variable oral absorption, must use brand name.
• Has extensive first pass effect; 98% metabolized by liver.
• Exhibits Dose-Dependent 1st Order Kinetics, zero order elimination at high doses from saturation of metabolic enzymes.
• Must use Therapeutic Drug Monitoring.
• Slow/fast metabolizers cause patient variability in levels.

Phenytoin (Dilantin) Variant

• Fosphenytoin (Cerebyx): IV water-soluble prodrug for status epilepticus .
• Less cardiotoxic by lacking propylene glycol to dissolve phenytoin.

Adverse Effects of Phenytoin

• Acute: Ataxia & Diplopia are common, Nystagmus, Drowsiness, ataxia, dysarthria, irritability at high doses.
• Chronic: Peripheral neuropathy.
• Affects gingival hyperplasia (50%), hirsutism, coarsening facial features, folate metabolism (DNA synthesis) causing megaloblastic anemia.
• Interferes with Vitamin D metabolism, causes osteomalacia, rash, and exfoliative dermatitis.

Teratogenicity of Antiepileptics

• Increased incidence of birth defects is common.
• Phenytoin may cause Fetal Hydantoin Syndrome, ~10%: craniofacial defects, spina bifida.
• Other things that may cause this include Phenobarbital, Carbamazepine, Trimethadione, and Valproic acid resulting in 1-2% spina bifida.
• Uncontrolled seizure is also damaging to fetus.
• Lowest effective dose, one medication is recommended.
• Supplementary vitamin K & folic acid is required for newborns & pregnant women.
• Phenytoin increases vitamin K metabolism.

Drug Interactions

• P450 enzymes Inhibitors: Chloramphenicol, dicumarol, disulfiram, isoniazid, sulfonamides, cimetidine.
• Decrease metabolism of phenytoin, increasing the plasma level.
• P450 Inducers: carbamazepine, alcohol, phenobarbital.
• Increase metabolism of phenytoin, decreasing the plasma level
• Phenytoin induces P450 enzymes
  • Decrease Effectiveness of oral contraceptives, anticoagulants, antiretrovirals, and some other antiepileptics by increasing their metabolism.

Phenytoin Uses

• Effective for all types of seizures except absence.
• Used for tonic-clonic seizures in adults & children older than 5, but effects on appearance limit use in children.
• Class 1B antiarrhythmic

Carbamazepine (Tegretol)

• Works through Use-dependent block of Na+ channels
• Has slow and often erratic oral absorption
• Metabolized by liver via enzyme induction
• Causes Significant Autoinduction that requires many dosage adjustments early in therapy.

Carbamazepine Adverse Effects

• Overall incidence of adverse effects is low.
• Diplopia & Ataxia are most common dose-related effects.
• Other dose related effects include drowsiness, dizziness, nystagmus, nausea, vomiting, visual hallucinations.
• Can cause Rashes, including Stevens-Johnson syndrome, Hyponatremia, and Blood dyscrasias
  • Agranulocytosis is a possible adverse affect.
  • aplastic anemia is rare.
• Hepatotoxicity, Potentially teratogenic.

Carbamazepine Drug Interactions

• Metabolism may be increased by phenytoin & phenobarbital.
• May increase metabolism of phenytoin, primidone, clonazepam, valproic acid & itself.

Carbamazepine Therapeutic Indications

• Treats Generalized tonic-clonic and partial seizures.
• Can treat Trigeminal & glossopharyngeal neuralgia and Antimania.
• Note: Phenytoin & carbamazepine may worsen Absence seizures!!!!!

Oxcarbazepine (Trileptal); Eslicarbazepine Stedesa

• These are Prodrugs that are structurally related to carbamazepine
• Same mechanism and clinical uses of carbamazepine
• Fewer side effects
  • Hyponatremia in 2.5%
  • Treats partial seizures

Lamotrigine (Lamictal)

• Causes Use-dependent Block of Na+ channels.
• Apparent use-dependent block of presynaptic Ca2+ channels reduces glutamate release during repetitive firing or during ischemia
• Metabolized by glucuronidation & renally excreted.
• Has No P450 enzyme induction!

Lamotrigine Adverse Effects and Uses

• Rash is common cause for discontinuance.
  • Also dizziness, headache, diplopia, nausea, somnolence, ataxia, tremor, menstrual abnormalities
• Severe, potentially life-threatening rash is Steven-Johnson syndrome.
  • Affects 1-2% of pediatric patients and 1 in 1000 adults
• Can cause Exacerbation of myoclonic seizures in adults
• Does not affect the plasma concentrations of enzyme-inducing antiepileptics.
• Enzyme-inducing antiepileptics increase clearance of Lamotrigine.
• Valproic acid reduces clearance of Lamotrigine.
• It is an adjunct or monotherapy for partial and generalized tonic-clonic seizures
• Treats Absence and myoclonic seizures in children
• Treats Seizure control in the Lennox-Gastaut syndrome and Bipolar disorder

Topiramate (Topamax)

• Mechanism: Use-dependent block of Na+ channels, increases GABA activity differently than benzodiazepines & barbiturates, inhibits AMPA subtype of glutamate receptors.
• Adverse Effects are Sedation, mental dulling, kidney stones, weight loss, reduced sweating, metabolic acidosis, psychosis
• Drug Interactions include no enzyme induction. -Phenytoin & carbamazepine decrease plasma concentrations of topiramate, valproic acid reduces plasma concentration of topiramate

Topiramate Uses

• Useful as an Adjunct for Partial and Generalized tonic-clonic Seizures, Lennox-Gastaut syndrome; may be effective in infantile spasms, even absence seizures, and treatment of migraine headaches

Zonisamide (Zonegran)

• Newer oral sulfonamide anticonvulsant.
• Has several mechanisms of action
  • Use-dependent block of Na+ channels
  • Blocks T-type Ca2+ channels and inhibits glutamate release
• Adverse reactions Include drowsiness, cognitive impairment, skin rashes, kidney stones: oligohidrosis
• Effective in a broad range of seizures, including absence seizures.
• Approved for adjunctive treatment of partial seizures patients >16 years
• Contraindicated in patients with allergy to sulfonamides

Lacosamide (Vimpat)

• Amino acid-related compound
• Enhances slow inactivation of voltage-gated Na+ channels
• Adverse effects are Dizziness, headache, nausea, diplopia, and suicidal thoughts
• Has No active metabolites, minimal protein binding, no affects on P450 enzymes, and negligible drug interactions
• Adjunctive therapy of partial seizures in patients >17 years old, and adjunctive therapy for primary generalized tonic-clonic seizures in patients ≥ 4 years

Rufinamide (Banzel)

• Prolongs the inactive state of the Na+ channel
• Can cause Somnolence, vomiting, pyrexia, and diarrhea
• Adjunct for seizures associated with the Lennox-Gastaut syndrome in patients > 4 years old

Drugs for Partial & Generalized Tonic-Clonic Seizures: Increase GABA

• This can be donw with barbiturates(Phenobarbital, Primidone), benzodiazepines(Diazepam, Clonazepam), gabapentin, tiagabine, or vigabatrin

Barbiturates: Phenobarbital & Primidone

• Primidone is metabolized to phenobarbital & PEMA which has antiepileptic effects
• Allosterically prolongs of GABAA channel openings
• Higher doses direct stimulation of GABAA receptor
• Reduces glutamate-mediated excitation
• Metabolized by liver, causes cytochrome P450 enzyme induction

Barbiturates Drug Interactions

• Interacts with phenytoin with variable results.
  • It can compete for microsomal enzymes, induce enzyme for metabolism, or displacement from plasma protein binding.
• Phenytoin increases conversion of Primidone to phenobarbital.
• Can alter plasma level of anticoagulants and have additive effects with other CNS depressants
• Requires Therapeutic Drug Monitoring

Barbiturates Adverse Effects and Treats

• These drugs cause Sedation, nystagmus, ataxia.
• Cause Tolerance & dependence and Sudden withdrawal after chronic use may precipitate status epilepticus.
• Alternative drug for Generalized Tonic-clonic, psychomotor, and partial seizures

Benzodiazepines

• Common medications incluse Diazepam, Lorazepam, Clonazepam, and Clobazam.
• These facilitate GABAA-mediated inhibition resulting in sedation as an adverse effect
• Tolerance and dependence develops and Abrupt withdrawal may lead to status epilepticus .
• Diazepam or lorazepam are drugs of choice for status epilepticus, Clonazepam treats absence & myoclonic seizures in children, and Therapeutic Drug Monitoring is used.
• Potentiates CNS depressant effects of antipsychotics, tricyclic antidepressants, sedative-hypnotics and alcohol.

Gabapentin and Pregabalin

• GABA Analogs that increase GABA levels, perhaps by increasing GABA release.
• Blocks α2δ subunit of voltage-gated N-type Ca2+ channels to decrease presynaptic Ca2+ entry to decrease the synaptic release of glutamate
• Renally excreted unchanged and does not induce hepatic enzymes or alters plasma levels of other antiepileptics.
• Side Effects include Sedation, Ataxia, nystagmus, & tremor, and weight gain.
• Useful with aggressive behavior, mood lability, hyperactivity.
• They are also an adjunct for Partial & Generalized tonic-clonic seizures, painful diabetic neuropathy, and Postherpetic neuralgia

Tiagabine (Gabitril)

• GABA uptake inhibitor.
• Blocks GAT-1 to increase GABA levels in forebrain and hippocampus, resulting in prolonged inhibitory action of synaptically released GABA
• Causes Dizziness, tremor, and depression.
• Does NOT inhibit or induce hepatic enzymes or alter plasma levels of other antiepileptics, but is an adjunct treatment for partial seizures in patients 12 years or older

Stiripentol (Diacomit)

• Enhances GABAergic transmission in the brain by way barbiturate-like prolonged opening of GABAA receptors, resulting in Increased GABA levels in the brain.
• Increases effect of other Antiepileptic drugs by slowing their inactivation by cytochrome P450
• It is a Potent inhibitor of CYP3A4, CYP1A2, and CYP2C19
• Adjunct for severe myoclonic epilepsy of infancy (SMEI, Dravet's syndrome) not adequately controlled with clobazam and is often used in combination to treat those syndromes in younger people

Drugs for Partial & Generalized Tonic-Clonic Seizures: Reduce Glutamate

• These are done with Levetiracetam or through postsynaptic Glutamate receptors with Felbamate or Perampanel

Levetiracetam (Keppra)

• Selectively binds to synaptic vesicle protein SV2A to presynaptically inhibit glutamate release
• Has a good oral bioavailability and minimal drug interactions
• Side effects are Somnolence, weakness, asthenia, ataxia, and dizziness with Less common mood and behavioral changes
• Treats Partial seizures in patients ≥ 4 years, Generalized tonic-clonic seizures in patients > 6 years, juvenile myoclonic seizures, myoclonic seizures in patients > 12 years, and status epilepticus

Felbamate

• A drug that causes Use-dependent block of NMDA receptors. It also Enhances GABAA responses causing headaches and fatigue with a risk of aplastic anemia and severe hepatitis
• Third-line drug for refractory cases of partial seizures and seizures that occur in Lennox-Gastaut syndrome.

Perampanel

• Allosteric AMPA receptor antagonist
• Is Orally active and extensively metabolized with many interactions with enzyme inducers
• Side effects are Dizziness, somnolence, and headache, weight gain, gait disturbances
• Some patients experienced life-threating behavioral adverse reactions including aggression, hostility, irritability, suicidal ideation
• Used as an Adjunct for partial seizures in patients 12 years or older

Generalized Absence Seizures

• Can be treated with Drugs that block T-type Ca2+ channels like Ethosuximide or Trimethadione and with Valproic acid
• Low-threshold T-type Ca2+ channels cause prolonged discharges in thalamic neurons
  • This is normally only seen in slow wave sleep.

Ethosuximide (Zarontin)

• A drug used for Absence seizures especially in children that blocks T-type Ca2+ channels
• Completely metabolized by liver can causes Therapeutic Drug Monitoring
• Generally safe & highly efficacious but can cause GI distress (nausea & vomiting), lethargy & fatigue, and headaches
• Valproic acid inhibits Ethosuximide metabolism.

Trimethadione (Tridione)

• A first-line effective option for Absence seizures
• Blocks T-type Ca2+ channels.
• Causes Sedation and photophobia and Dermatitis, blood disorders, hepatitis, as serious and sometimes fatal
• Its use in patients inadequately controlled by Ethosuximide is due to these adverse effects

Valproic Acid (Depakene)

• Treats Absence seizures especially in adults
• Also effective in in tonic-clonic, myoclonic, atonic generalized seizures, mixed absence and tonic-clonic epileptic seizures, spasms, neonatal or febrile seizures, tonic or atonic seizures in Lennox-Gastaut syndrome, and status epilepticus
• Can also treat Migraine prophylaxis and Bipolar disorder through depleting inositides
• It is causes ↑GABAergic inhibition by inhibiting GABA-T, blocking Na+ channels, decreasing aspartate levels, and inhibiting HDAC, resulting in a wide spectrum of action.
• Side effects are a low degree of toxicity with Gl distress and rare but idiosyncratic hepatotoxicity, requiring use of this drug with patients in mind
• Other adverse effects are hand tremors and weight gain
• This drug can also cause teratogenics, specifically spinal bifida

General Therapeutic Guidelines

• Start with a single drug and gradually adjust dosage.
• Employ Multiple drug therapy only if there are more than one seizure type or if a single drug fails to provide adequate control.
• When changing medication, decrease old drug as you increase the neew drug . compliance to prevent Status Epilepticus.
• Reduce and withdraw from dosage may occur in an extended seizure free period.

Monitor Serum Drug Levels!

• Often, therapeutic concentration is close to the toxic level, which requires frequent checks and adjustments.
• In particular, check drug levels with Change in dosage or regimen, inadequately controlled or recurrent seizures, signs of toxicity in multiple drug therapy, erratic absorption, drug interaction, and pregnancy.