NEURO 09: Anti-Seizure Medication Pharmacology

Understanding Seizures and How ASDs Work

Seizures happen because there is too much excitatory activity (neurons firing uncontrollably) or not enough inhibitory control in the brain.

• Excitatory neurotransmitter = Glutamate (increases neuron firing 🚀)

• Inhibitory neurotransmitter = GABA (decreases neuron firing 🛑)

So, the goal of ASDs is to reduce excessive excitation or enhance inhibition to stop seizures.

Main Pharmacological Targets of ASDs

Think of the brain like a balance between an exciting party (glutamate) and a chill meditation session (GABA). ASDs act at 4 main targets:

1. Excitatory Pathway (↓ Excitation = Fewer Seizures)

👉 Presynaptic Neuron (before the signal is sent)

• Voltage-gated sodium (Na+) channels 🔥

  • Control the firing of action potentials (the “on” switch for neurons).

  • Blocking Na+ channels slows down rapid neuron firing.

• Voltage-gated calcium (Ca2+) channels ⚡

  • Control the release of neurotransmitters.

  • Blocking Ca2+ channels = Less glutamate release (less excitement).

• Glutamate vesicle release 🎈

  • ASDs can reduce how much glutamate is released into the synapse.

👉 Postsynaptic Neuron (after the signal is sent)

• AMPA receptors & NMDA receptors 🧠

  • These are glutamate receptors (like "docking stations" for glutamate).

  • Blocking these receptors prevents neurons from getting overexcited.

• T-type calcium channels

  • Found in thalamic neurons (important for absence seizures).

  • Blocking these stops rhythmic, uncontrolled firing.

2. Inhibitory Pathway (↑ Inhibition = Fewer Seizures)

👉 Presynaptic Neuron (where GABA is released)

• GABA reuptake (GAT-1 transporters) 🏗

  • Normally, GABA gets taken back up into the presynaptic neuron.

  • Blocking GAT-1 = More GABA stays in the synapse (more inhibition).

• GABA breakdown (GABA-T enzyme) 🏭

  • GABA is broken down by GABA-T.

  • Blocking this enzyme = More GABA available = More inhibition.

👉 Postsynaptic Neuron (where GABA acts)

• GABA-A chloride (Cl⁻) channels 💨

  • When GABA binds to these, chloride ions (Cl⁻) enter the neuron, making it harder to fire.

  • ASDs can enhance GABA-A receptor activity to boost inhibition.

Mechanism of Action of Antiseizure Drugs (ASDs)

Now that we know the targets, let’s go into how the drugs work!

1. Sodium Channel Blockers (Na+ channel blockers) 🔥

📌 How they work: These drugs slow down rapid neuron firing by blocking voltage-gated Na+ channels.

🔹 Fast inactivation blockers (bind to the inactivated state)

• Drugs: Phenytoin, Valproic Acid, Lamotrigine, Carbamazepine, Oxcarbazepine, Eslicarbazepine, Topiramate, Zonisamide, Rufinamide, Cenobamate

• What they do: Prevent channels from reopening too quickly = Less repetitive firing

🔹 Slow inactivation blockers (help keep channels inactive longer)

• Drug: Lacosamide

• What it does: Enhances slow inactivation so that overactive neurons don’t recover as quickly = Less seizure activity

🔴 Side effects (general for Na+ blockers):

• CNS: Dizziness, ataxia (loss of balance), sedation

• GI: Nausea, vomiting

• Serious: Rash (especially with Lamotrigine and Carbamazepine – risk of Stevens-Johnson Syndrome!)

2. Calcium Channel Blockers (Ca2+ channel blockers) ⚡

📌 How they work: Reduce calcium entry, which decreases glutamate release = Less excitation

• Drugs: Valproic Acid, Ethosuximide (T-type Ca2+ blocker, used for absence seizures)

• Side effects: GI upset, dizziness, sedation

3. Glutamate Receptor Blockers (AMPA/NMDA blockers) 🎯

📌 How they work: Block AMPA/NMDA receptors to prevent neurons from getting overexcited.

• Drugs: Topiramate (blocks AMPA), Felbamate (blocks NMDA)

• Side effects: Cognitive issues (memory, attention problems), weight loss (Topiramate)

4. GABA Enhancers (Boost inhibition) 🛑

📌 How they work: Increase GABA levels or GABA receptor activity to calm down neurons.

🔹 Increase GABA levels

• Block GABA breakdown (GABA-T enzyme) → Valproic Acid

• Block GABA reuptake (GAT-1 transporter) → Tiagabine

🔹 Enhance GABA receptor activity

• Directly activate GABA-A receptors → Benzodiazepines (Diazepam, Lorazepam)

• Side effects: Sedation, dependence (benzos), liver toxicity (Valproic Acid)

Specific Drug Summaries & Important Side Effects

Phenytoin (Na+ blocker)

• Metabolism: Saturable, 90% protein-bound

• Side effects:

  • CNS: Ataxia, nystagmus, slurred speech

  • Oral: Gingival hyperplasia

  • Other: Hirsutism (hair growth), acne

Valproic Acid (Multiple MOAs)

• Blocks Na+ channels, blocks Ca2+ channels, increases GABA

• Side effects:

  • CNS: Tremor, sedation

  • GI: Nausea, vomiting

  • Liver: Hyperammonemia, hepatotoxicity

  • Other: Weight gain, alopecia, teratogenicity (avoid in pregnancy!)

Lamotrigine (Na+ blocker)

• Metabolism: Hepatic, interacts with Valproic Acid

• Side effects:

  • Rash (SJS/TENS) → VERY high risk if titrated too fast or combined with Valproic Acid!

  • Heme: Pancytopenia, neutropenia

Carbamazepine (Na+ blocker)

• Metabolism: Autoinduction (induces its own metabolism over time)

• Side effects:

  • CNS: Dizziness, sedation

  • Heme: Leukopenia, thrombocytopenia

  • Rash: Risk increased with HLA-B*1502 allele (common in Asian populations)

Topiramate (Na+ & AMPA blocker, GABA enhancer)

• Side effects:

  • Cognitive dysfunction ("Dopiramate") → Memory, language problems

  • Metabolic: Weight loss, metabolic acidosis, kidney stones

Excitatory Pathway: Voltage-Gated Calcium Channels

How Voltage-Gated Calcium Channels Work

• Calcium (Ca²⁺) channels in neurons initiate synaptic transmission, meaning they help neurons communicate.

• These channels open in response to electrical signals, allowing calcium ions to enter the neuron.

• The influx of Ca²⁺ triggers the release of neurotransmitters (like glutamate) into the synapse.

• There are 10 different types of voltage-gated calcium channels, classified by the types of current they conduct.

Types of Calcium Channels in Neurons

1. Low Voltage-Activated (LVA) T-type calcium channels

   • Found in thalamic neurons and are important in absence seizures.

   • Blockers:

     • Ethosuximide

     • Zonisamide

     • Valproic acid

2. High Voltage-Activated (HVA) calcium channels

   • Found in presynaptic neurons and regulate neurotransmitter release.

   • Blockers:

     • Gabapentin

     • Pregabalin

     • These two drugs work by binding the α2δ1 subunit of the channel, reducing calcium influx and dampening excessive neurotransmitter release.

Drugs That Block Calcium Channels

1. T-Type Calcium Channel Blockers

• Ethosuximide

  • Used for: Generalized absence seizures (first-line treatment).

  • Mechanism: Blocks T-type calcium channels in the thalamus, preventing excessive neuronal firing.

  • Side effects: Mostly gastrointestinal (GI) issues:

    • Nausea

    • Vomiting

    • Cramps

    • Diarrhea

    • Dyspepsia (indigestion)

    • Anorexia (loss of appetite)

• Valproic Acid

  • Has multiple mechanisms (also blocks Na⁺ channels and increases GABA).

  • Used for absence, generalized, and focal seizures.

• Zonisamide

  • Works similarly to ethosuximide and valproic acid.

  • Used as an adjunct therapy for focal seizures.

2. Calcium Channel α2δ1 Subunit Blockers

• Gabapentin & Pregabalin

  • Mechanism: Bind to the α2δ1 subunit of high-voltage Ca²⁺ channels, reducing calcium entry and decreasing neurotransmitter release (glutamate).

  • Used for:

    • Adjunct therapy for focal seizures

    • Neuropathic pain (off-label)

  • Side effects:

    • CNS: Sedation, dizziness

    • Psychiatric: Emotional lability, agitation

Excitatory Pathway: Glutamate Release

How Glutamate is Released

• Glutamate is an excitatory neurotransmitter.

• It is stored in synaptic vesicles and released when calcium channels open.

• The SV2A protein is found on these vesicles and regulates glutamate release.

Drugs That Block Glutamate Release

• Levetiracetam & Brivaracetam

  • Mechanism: Bind to the SV2A protein on synaptic vesicles, blocking glutamate release.

  • Result: Less excitatory neurotransmission, preventing excessive firing.

  • Levetiracetam Pharmacokinetics:

    • 100% oral bioavailability

    • Metabolized by hydrolysis (not CYP enzymes)

    • Eliminated by kidneys (dose adjustments in renal impairment)

    • T½ = 6-8 hours (short half-life)

  • Side effects:

    • CNS: Dizziness, sedation, ataxia

    • Psychiatric: Behavioral changes (aggression, agitation, anxiety, depression, paranoia, hallucinations, suicidal ideation)

Excitatory Pathway: Postsynaptic Glutamate Receptors

• Once glutamate is released, it binds to postsynaptic glutamate receptors to trigger an action potential in the next neuron.

• Two major glutamate receptor types:

  1. AMPA receptors: Allow Na⁺ entry.

  2. NMDA receptors: Allow Ca²⁺ entry.

• Blocking these receptors reduces excitatory signaling.

Drugs That Block Postsynaptic Glutamate Receptors

1. AMPA Receptor Blockers

• Perampanel

  • Mechanism: Binds AMPA receptors, preventing glutamate from activating them.

  • Result: Less Na⁺ entry → Less excitatory firing.

  • Pharmacokinetics:

    • 100% oral bioavailability

    • Metabolized by CYP3A4/5 (drug interactions likely)

    • T½ = 105 hours (long half-life, dosed once daily)

  • Side effects:

    • CNS: Dizziness, sedation, ataxia

    • Psychiatric: Severe aggression, irritability, homicidal ideation (most often in first 6 weeks).

• Topiramate (also blocks Na⁺ channels and enhances GABA activity).

2. NMDA Receptor Blockers

• Felbamate (Only available through the Special Access Program in Canada)

  • Mechanism: Blocks NMDA receptors, preventing Ca²⁺ influx and excessive excitatory transmission.

  • Used for: Severe epilepsy (Lennox-Gastaut Syndrome, refractory epilepsy)

  • Not widely available due to serious side effects.

Key Takeaways

1. Calcium Channels:

   • T-type (LVA) → Absence seizures → Blocked by ethosuximide, zonisamide, valproic acid.

   • HVA (presynaptic, α2δ1 subunit) → Glutamate release → Blocked by gabapentin & pregabalin.

2. Glutamate Release:

   • SV2A protein regulates glutamate vesicles → Blocked by levetiracetam & brivaracetam.

3. Postsynaptic Glutamate Receptors:

   • AMPA (Na⁺) → Blocked by perampanel.

   • NMDA (Ca²⁺) → Blocked by felbamate.

1. Enhancing GABA-A Receptor Activity (Chloride Channel Activation)

GABA-A receptors are ligand-gated chloride (Cl⁻) channels.

• When GABA binds, it opens the Cl⁻ channel, hyperpolarizing the neuron (making it harder to fire an action potential).

• Drugs that enhance GABA-A activity increase Cl⁻ influx, making neurons less excitable.

Barbiturates vs. Benzodiazepines

These drug classes both enhance GABA-A, but they work differently:

Barbiturates: Phenobarbital & Primidone

• Phenobarbital:

  • Long half-life (79 hours, range 53-118 hours)

  • Metabolism: CYP2C9 (major), CYP2C19 & CYP2E1 (minor)

  • CYP inducer → increases metabolism of other drugs (drug interactions!)

  • Side effects:

    • CNS: Dizziness, sedation, ataxia, cognitive dysfunction

    • Respiratory: Respiratory depression (esp. IV)

    • Cardiovascular: Hypotension, bradycardia

    • Immunologic: Risk of severe skin reactions (SJS, TEN, DRESS) in patients with HLA-B13:01, HLA-B*1502

• Primidone: A prodrug that is metabolized into phenobarbital.

Benzodiazepines: Clobazam, Lorazepam, Diazepam, Midazolam

• Clobazam:

  • Used for: Adjunct treatment of epilepsy

  • Metabolism: CYP3A4 (major), CYP2C19, CYP2B6 (minor)

  • Half-life: 36-42 hours

  • Side effects:

    • CNS: Dizziness, sedation, confusion

• Lorazepam, Diazepam, Midazolam: Used for status epilepticus (rapid IV effect).

2. Preventing GABA Reuptake & Metabolism

Once GABA is released, it is cleared from the synapse by:

1. Reuptake via GAT-1 transporter (removes GABA from synapse).

2. Metabolism via GABA-T (GABA-transaminase) (breaks GABA down).

Drugs can increase GABA availability by blocking these processes.

Drugs That Block GABA Reuptake & Breakdown

• Tiagabine

  • Mechanism: Blocks GAT-1 → More GABA stays in synapse → Enhanced inhibition.

  • Used for: Adjunct therapy for focal seizures.

• Vigabatrin

  • Mechanism: Irreversibly inhibits GABA-T → Prevents GABA breakdown → More GABA available.

  • Major risk: Permanent vision loss (retinopathy) → Regular vision monitoring needed.

• Valproic Acid

  • Dual mechanism: Blocks GABA-T + inhibits Na⁺ & T-type Ca²⁺ channels.

  • Used for: Generalized & focal seizures, absence seizures, bipolar disorder, migraine prophylaxis.

• Zonisamide

  • Also inhibits Na⁺ & T-type Ca²⁺ channels (multi-action).

Key Takeaways

1. GABA-A Chloride Channel Activation:

   • Barbiturates (Phenobarbital, Primidone) → Increase duration of Cl⁻ channel opening.

   • Benzodiazepines (Clobazam, Lorazepam, Diazepam, Midazolam) → Increase frequency of Cl⁻ channel opening.

2. GABA Reuptake & Breakdown Inhibition:

   • Tiagabine → Blocks GABA reuptake (GAT-1).

   • Vigabatrin → Blocks GABA breakdown (GABA-T).

   • Valproic Acid & Zonisamide → Both inhibit GABA metabolism & reuptake

SUMMARY!!

Voltage-Gated Calcium Channel Blockers

T-type Calcium Channel Blockers (Used for absence seizures)

• Ethosuximide

  • Indication: Generalized absence seizures

  • Side Effects: GI (nausea, vomiting, cramps, diarrhea, dyspepsia, anorexia)

• Valproic Acid (also affects GABA metabolism)

  • Indications: Absence seizures, generalized seizures, focal seizures, bipolar disorder, migraine prophylaxis

  • Side Effects: GI distress, hepatotoxicity, pancreatitis, weight gain, teratogenicity

• Zonisamide (also downregulates GAT-1 expression for GABA recycling)

  • Indications: Focal and generalized seizures

  • Side Effects: CNS effects (sedation, dizziness), weight loss, kidney stones, metabolic acidosis

High-Voltage Activated (HVA) Calcium Channel Blockers (affects glutamate release)

• Gabapentin / Pregabalin (binds to alpha-2-delta-1 subunit of calcium channels)

  • Indications: Adjunct for focal seizures, neuropathic pain

  • Side Effects: CNS depression (sedation, dizziness), psychiatric (emotional lability, agitation)

SV2A Inhibitors (Glutamate Release Blockade)

• Levetiracetam / Brivaracetam

  • MOA: Binds SV2A protein on glutamate vesicle → prevents glutamate release

  • Indications: Broad-spectrum seizure treatment

  • Formulations: IV, Oral (100% bioavailability)

  • Metabolism: Hepatic (non-CYP), renal clearance (adjust for renal impairment)

  • Side Effects: CNS (dizziness, sedation, ataxia), psychiatric (agitation, aggression, anxiety, paranoia, suicidal ideation, hallucinations)

Post-Synaptic Glutamate Receptor Blockers

AMPA Receptor Blockers

• Perampanel

  • MOA: Blocks AMPA receptor → decreases Na+ influx → prevents excitatory signal propagation

  • Formulation: Oral (100% bioavailability)

  • Metabolism: Hepatic (CYP3A4/5 major, CYP1A2 & CYP2B6 minor)

  • T½: 105 hours

  • Side Effects: CNS (dizziness, sedation, ataxia), psychiatric (aggression, irritability, homicidal ideation - especially in first 6 weeks)

• Topiramate (also affects GABA receptors)

  • Indications: Focal & generalized seizures, migraine prophylaxis

  • Side Effects: Weight loss, kidney stones, cognitive dysfunction ("dopamax" effect)

NMDA Receptor Blockers

• Felbamate (only available via Special Access Program in Canada)

  • MOA: Blocks NMDA receptors → decreases Ca²⁺ influx → prevents excitatory signal propagation

  • Indications: Refractory seizures

  • Side Effects: Aplastic anemia, hepatotoxicity

GABAergic Drugs (Inhibitory Pathway Enhancers)

GABA-A Receptor Agonists (Increases Cl⁻ influx → neuronal inhibition)

• Phenobarbital / Primidone (Barbiturates)

  • MOA: Binds barbiturate site on GABA-A receptor → increases duration of Cl⁻ channel opening

  • Metabolism: Hepatic (CYP2C9 major, CYP2C19 & CYP2E1 minor) Induces CYP2C/3A

  • T½: 79 hours (range: 53-118 hours)

  • Side Effects: CNS (dizziness, sedation, ataxia, cognitive impairment), respiratory depression, cardiovascular (hypotension, bradycardia), rash (SJS/TEN) - risk with HLA-B13:01, HLA-B*1502

• Clobazam / Lorazepam / Diazepam / Midazolam (Benzodiazepines)

  • MOA: Binds benzodiazepine site on GABA-A receptor → increases frequency of Cl⁻ channel opening

  • Clobazam Pharmacokinetics:

    • Absorption: 100%

    • Metabolism: Hepatic (CYP3A4 major, CYP2C19 & CYP2B6 minor)

    • T½: 36-42 hours

    • Onset of max effect: 5-9 days

  • Side Effects: CNS (dizziness, sedation, confusion)

GABA Reuptake & Metabolism Inhibitors

• Tiagabine (GABA reuptake inhibitor)

  • MOA: Blocks GAT-1 (GABA-transporter 1 protein) → prevents GABA reuptake

• Vigabatrin (GABA metabolism inhibitor)

  • MOA: Blocks GABA-T (GABA-transaminase) → prevents GABA breakdown

  • Side Effects: Permanent vision loss (requires regular vision monitoring)

• Valproic Acid (also affects T-type Ca²⁺ channels)

  • MOA: Blocks GABA-T → prevents GABA breakdown

  • Indications: Absence, generalized, focal seizures, bipolar disorder, migraine prophylaxis

  • Side Effects: GI distress, hepatotoxicity, pancreatitis, weight gain, teratogenicity

Summary Table: Drug Classes & Targets