NJN - Epilepsy

• The content discusses drugs for epilepsy, emphasizing their mechanisms, uses, and adverse effects.
• Epilepsy involves recurrent seizures due to high electrical discharge in the central nervous system.
• Seizures are single events, while epilepsy is a chronic condition with multiple, unresolved seizures.

Types of Seizures

• Focal: Originates in a specific brain area; can occur with or without loss of consciousness.
  • Symptoms vary based on the affected cortex area (motor, sensory, etc.).
• Generalized: Affects multiple areas of the cortex, usually with loss of consciousness.
  • Includes tonic-clonic (grand mal), tonic (increased muscle tone), clonic (jerking), atonic (loss of muscle tone), myoclonic (quick, jerky movements) and absence (petit mal) seizures.
• Epileptic Spasms: A category including:
  • Benign rolandic spasms.
  • West syndrome.
  • Lennox-Gastaut syndrome (severe, multiple daily seizures).

Cause of Seizures

• Different drugs target specific seizure types.
• An irritable brain area triggers abnormal electrical discharges.
• Use the mnemonic VITAMIN DE to remember potential seizure triggers:
  • Vascular etiologies (bleeds, stroke)
  • Infections (meningitis, encephalitis)
  • Trauma (head injury)
  • Autoimmune diseases (SLE), or paraneoplastic syndromes.
  • Metabolic imbalances (hyponatremia, glucose, thyroid, lipid disorders)
  • Idiopathic (unknown cause)
  • Neoplasia (tumors)
  • Drugs and toxins
  • Eclampsia (in pregnant patients)

Mechanism of Epilepsy

• Excessive glutamate activity and/or decreased GABA activity.
• Glutamate release:
  • Action potentials travel down an axon.
  • Voltage-gated sodium channels open and allow Na+ influx, causing depolarization.
  • Depolarization opens voltage-gated calcium channels, allowing Ca2+ influx.
• Calcium binds to proteins/vesicles, leading to fusion of vesicles with the cell membrane and glutamate release.
• Glutamate binds to receptors, opening channels for Na+ and Ca2+ influx, increasing action potential and seizures.
• GABA release:
  • Action potentials stimulate vesicles to fuse with the membrane and release GABA.
  • GABA binds to GABAa receptors, allowing chloride (Cl-) influx into the cell.
  • Chloride influx makes the cell negative, inhibiting action potentials and hyperpolarizing the cell.
• Dysfunction in GABA release or GABAa receptors can lead to decreased chloride influx, reduced inhibition of action potentials, and stimulation of seizures.
• GABA is recycled or metabolized after release.
• Increased GABA reuptake or breakdown reduces available GABA, decreasing inhibition and increasing seizures.

Mechanism of Action for Anti-Epileptic Drugs (AEDs)

• The goal is to decrease increased action potentials by managing glutamate and GABA activity.
• Block sodium influx with drugs like carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, lamotrigine, topiramate, valproate, and lacosamide to prevent depolarization.
• Block calcium influx with calcium channel blockers like ethosuximide.
• Block fusion of vesicles with the membrane using drugs like levetiracetam (SV2A receptor blocker).
• Block glutamate from binding to receptors using AMPA receptor blockers (felbamate) or NMDA receptor blockers (ketamine).
• Increase GABA activity.
  • Stimulate GABAa receptors by using GABAa receptor agonists like benzodiazepines (lorazepam, midazolam, diazepam, clobazam, clonazepam) and barbiturates (phenobarbital, pentobarbital).
  • Benzodiazepines increase the frequency of chloride channel openings.
  • Barbiturates increase the duration of chloride channel openings.
  • Propofol and topiramate also enhance GABAa receptor activity.
• Inhibit GABA reuptake using tiagabine, helpful for refractory focal seizures.
• Prevent GABA breakdown with vigabatrin and valproate, increasing GABA recycling and release.
  • Valproate, like topiramate, both decreases glutamate activity (sodium channel blocker) and increases GABA activity.

Treatment Approach to Epilepsy

• Treat the underlying cause first to potentially avoid needing AEDs.
• If AEDs are necessary, select one based on seizure type and minimal adverse effects.
• If seizures persist, add a second AED while titrating down the first.
• If issues continue, consider combo therapy or a third AED.
• If seizures remain uncontrolled, consider alternatives like a vagal nerve stimulator (VNS).

Specific Seizure Types and Treatments

• Focal Seizures:
  • Carbamazepine and oxcarbazepine are highly effective.
  • Other options: Levetiracetam, lamotrigine, phenytoin, fosphenytoin, valproate, topiramate.
  • Phenobarbital is best for neonates.
• Absence Seizures:
  • Ethosuximide is preferred, especially in children.
  • Alternatives: Valproate, lamotrigine.
• Myoclonic Seizures:
  • Valproate and levetiracetam are very effective.
  • Lamotrigine and benzodiazepines can also be used.
• Tonic-Clonic Seizures:
  • Valproate and levetiracetam are good options.
  • Can also use lamotrigine, topiramate, phenytoin, fosphenytoin, and phenobarbital (especially in neonates).
• Status Epilepticus:
  • Initiate treatment with benzodiazepines (lorazepam, diazepam, midazolam).
  • Add prophylactic drugs like fosphenytoin, valproate, levetiracetam, or lacosamide.
  • If seizures continue, use propofol or ketamine.
  • As a last resort, use barbiturates (phenobarbital or pentobarbital).
• Epileptic Spasms:
  • Lamotrigine

Specific Syndromes

• West Syndrome:
  • Vigabatrin

Lennox-Gastaut Syndrome

• Is often refractory to treatment, requiring multiple AEDs.
  • Options: valproate, topiramate, lamotrigine, cannabidiol.
  • Refractory cases may need felbamate or a VNS.

Adverse Effects of AEDs

• Cardiac and Respiratory Depression:
  • Benzodiazepines, barbiturates, propofol.
  • Phenytoin and fosphenytoin can cause CNS depression, leading to mild bradycardia, hypotension, and respiratory depression.
• Stevens-Johnson Syndrome:
  • Ethosuximide, carbamazepine, lamotrigine.
  • Some association with phenytoin and fosphenytoin.
• Hepatotoxicity:
  • Valproate, carbamazepine, felbamate.
  • Monitor liver function (LFTs, AST, ALT).
• Drug-Drug Interactions:
  • Cytochrome P450 inducers (decrease efficacy of other drugs): barbiturates, phenytoin, carbamazepine.
  • Cytochrome P450 inhibitors (increase efficacy of other drugs): valproate.
• Teratogenic Effects (Dangerous in Pregnancy):
  • Valproate: neural tube defects due to folate inhibition.
  • Phenytoin/Fosphenytoin: fetal hydantoin syndrome.
  • Carbamazepine: cleft lip and palate.

Additional Specific Adverse Effects

• Valproate: pancreatitis, thrombocytopenia.
• Carbamazepine: SIADH (hyponatremia).
• Phenytoin/Fosphenytoin: gingival hyperplasia.
• Vigabatrin: vision loss.
• Topiramate: metabolic acidosis, kidney stones, glaucoma (rare).