Anticonvulsant Drugs - Bettinger

What are Seizures?

Behavioral consequence of a transient episode of abnormal electrical activity in the brain.

• Disordered synchronous and rhythmic firing of neurons. Primarily arise from cerebral cortex.

What is Epilepsy?

Repeated, unpredictable seizures

• many causes, most unknown

What Are the 2 main Seizure types + the kinds of those?

1. Focal

   1. Focal aware (consciousness preserved)

   2. Focal with Impaired Awareness (consciousness altered)

   3. Focal to Bilateral Tonic-Clonic

2. Generalized

   1. Absence

   2. Myoclonic

   3. Tonic-Clonic

What does it mean to have a “FOCAL” seizure?

they begin FOCALLY in a cortical site

What does it mean to have a FOCAL with impaired awareness seizure?

Impaired consciousness lasting 30sec to 2 min often associated with purposeless movements

• most originate in temporal lobe

• can be difficult to control

What is a General Seizure and what does it compose of?

Loss of consciousness —→ involves both hemispheres

• abrupt onset with staring and cessation of activities

• Typically 30 sec or less

What is a General ABSENCE Seizure and what does it compose of?

• Loss of consciousness

• Petit mal seizures

• BRIEF (less than 30 sec)

• Bilaterally synchronous 3 second spike and wave in EEG pattern

What is a General MYOCLONIC Seizure and what does it compose of?

• Brief

• 1 second shock-like contraction of muscles

• May be generalized or restricted to one extremity

What is a General TONIC-CLONIC Seizure and what does it compose of?

• Loss of consciousness

• Grand mal seizure

  • sustained contraction of muscles (tonic) throughout body followed by periods of thryhmic limb movement (clonic)

  • 1-2 minutes

What is status epilepticus

• An emergency situation —→ Hypoxia can result in morbidity

• Seizure that lasts more than 5 minutes OR multiple prolonged seizures without full recovery between episodes

• Has both convulsive and non-convulsive type seizures

• Treatments include:

  • Diazepam

  • Lorazepam

Treatment Points for treating Seizures

• Only treat symptoms

• NO PPX, NO CURE

• MOA —→ All prevent excessive discharge of affected neurons, OR prevent spread of excessive activity of normal neurons

• ASM’s control seizures in 60-80%

Epilepsy Mechanisms seen by EEG

1. Enhanced excitatory activity

   1. IONIC: Na+, Ca2+

   2. NT: glutamate

2. Reduced Inhibitory Activity

   1. IONIC: Cl-, K+

   2. NT: GABA

ASM’s treat seizures generally by ______

stabilizing neuronal activity by regulating the balance between excitation and inhibition

The four main MOAs of anti seizure medications

1. Modulation of cation channels (N+, K+, Ca2+)

2. Enhance GABA transmission (inhibitory)

   1. Actiate GABAa, decrease GABA metabolism, inhibit GABA reuptake

3. Modulate synaptic transmission

   1. Act on SV2A, act on Ca2+ channels

4. Decrease Glutamate transmission (excitatory)

   1. Decreased AMPA currents

What is the MOA of Antiseizure meds blocking Na+ channels, and what are the drugs in this class? (Class #1)

• These drugs promote the inactive state of the Na+ channel

  • Phenytoin

  • Carbamazepine

  • Oxcarbazepine

  • Lacosamide

  • Lamotrigine (maybe)

Points about Phenytoin

• Widely used to treat partial AND tonic-clonic seizures

• Effective for ALL seizure types EXCEPT ABSENCE

• Side effects:

  • N/V, rashes, darkening of skin, abnormal hair growth, constipation

  • Alters metabolism of drugs (Warfarin, induces CYP, oral contraceptives, teratogenic)

Points about Carbamazepine

• Related to TCAs

• WIDELY used to treat partial AND tonic clinic seizures

• Effective for all types EXCEPT ABSENCE

• Also used treat BIPOLAR DISORDER

• SE’s

  • dry mouth, potentially fatal skin reactions

Points about Oxcarbazepine

• Used to treat partial seizures

• SE’s

  • Dizziness, fatigue, nausea, tremor, ataxia

Points about Lacosamide

• Used to treat partial and clonic-tonic seizures

• SE’s

  • Dizziness, fatigue, nausea, tremor, heart rhythm changes

Points about Lamotrigine

• UNCERTAIN but probable blockade of Na+ channels

• Used to treat partial seizures effective against more types than phenytoin

• May also target the AMPA

• SE’s

  • potentially fatal skin reactions, HA, insomnia, acne (women)

What is the MOA of Antiseizure meds enhancing GABA transmission (activate GABA, decrease GABA metabolism, inhibit GABA reuptake), and what are the drugs in this class? (Class #2)

1. GABA receptors allow CL- ions into neurons —→ Cause increase in negative charge inside cell —→ HYPERPOLARIZATION —→ Inhibits neuron activity

2. THESE DRUGS potentiate GABA receptors

   1. Barbiturates

      1. Phenobarbital

   2. BZDs

      1. Clonazepam

      2. Midazolam

   3. VPA

   4. Vigabatrin

   5. Tiagabine

   6. Stripentol

Points about Phenobarbital

• Enhances length of opening of GABA receptors (more Cl- in)

• Used to treat complex and simple and tonic-clonic seizures

• Major SE is sedation, but tolerance develops to sedation w/o tolerance to anticonvulsants effects —→ Produces physical dependence

Points about clonazepam / Midazolam

• enhances frequency of opening of GABA receptors

• used to treat absence and myoclonic seizures

• major SE is sedation

• Midazolam is rapid onset —→ only in emergencies for STATUS EPILEPTICUS

Points about Valproic Acid

• Inhibits GABA-T

• Enhances opening of GABA receptor cl- channels

• Promotes inactive state of Na+ channels

• AND acts on T-type Ca2+ channels

• Used to treat Partial, tonic-clonic, absence, and myoclonic seizures

• SE’s

  • hepatic toxicity (inhibits CYp2C9), fatal pancreatitis (children), teratogenic: neural tube defects

Points about Vigabatrin

• Binds to and inactivates GABA-T which is the enzyme responsible for metabolizing and eliminating GABA

• Results in increased GABA in brain

• IRREVERSIBLE inhibition

• SE’s

  • Permanent vision damage in 30-60% of people (kills ganglion cells)

Points about Tiagabine

• Binds to GABA recognition sites on the GAT-1 GABA reuptake transporter —→ Prevents reuptake of released GABA, results in increases in GABA

• Treats FOCAL seizures

• SE’s

  • Confusion, sedation, slurring of speech, paresthesias

Points about Stiripentol

• Treatment of DRAVET syndrome (combo treatment)

• Enhances frequency of opening of GABAa receptors, especially a3-containing receptors (in immature brain)

• Inhibits GAT

• Inhibits GABA-T

• INhibits p450 enzymes to increase other ASM concentrations (clobazam)

What is the MOA of Antiseizure meds that modulate synaptic transmission (act on SV2A, act on Ca2+ channels, with a2delta subunit), and what are the drugs in this class? (Class #3)

• Limit voltage-regulated Ca2+ channel activity

• Probably acting on SV2A in synapses

• ABSENCE seizures have reciprocal firing in thalamus and Cortex

• Thalamic neurons have large T voltage regulated Ca2+ current

• If you can limit the Ca2+ function, you can limit ABSENCE seizures

• Drugs:

  • Ethosuximide

  • Zonisamide

  • Levetiracetam

Points about Ethosuximide

• MOA not completely elucidated

• Suggested that it BLOCKS T-Currents

• Physically blocks the channels (the hypothesis)

Points about Zonisamide

• It reduces T-Currents (inhibits T-type Ca2+channels)

• Also blocks Na+ currents (stabilizes the inactive state)

Points about Levetiracetam

• MOA not completely known

• Eliminates burst firing without affecting normal neuronal excitability —→ may prevent propagation of seizure firing

• Has been shown to bind to SV2A protein in synaptic vesicles, and the kinetics suggest that this binding is involved in the anti-seizure activity of the drug

ASM’s with relatively UNKNOWN MOA

• Pregabalin / Gabapentin

• Topiramate / Felbamate

• Cannabidiol

• Fenfluramine

Points about Gabapentin / Pregabalin

Gabapentin

• appears to increase GABA levels, bind to a2delta subunit of voltage Ca2+channels —→ regulates channel # and activity

Pregabalin

• MOA unclear, but DOES bind to a2delta subunit of voltage Ca2+ channel

Neither of these drugs subject to metabolism (primarily renal excretion, and does NOT induce hepatic enzymes)

Points about Topiramate

Four POSSIBLE MOA’s:

1. Blocks voltage-dependent Na+ channels

2. Enhances GABA signaling at some subtypes of GABAa receptor

3. Antagonizes the kainite/AMPA glutamate receptor

4. Inhibits carbonic anhydrase enzyme

Points about Felbamate

• MOA unclear

• Blocks glycine binding site of NMDA

• SE’s

  • VERY SERIOUS

  • Hepatotoxic

  • aplastic anemia

  • Used for refractory seizure control

Points about CBD

• blocks activation of GPR55

  • acts in both excitatory and inhibitory synapses

• Effective in SEVERAL pediatric epilepsies

• Under consideration as an adjunct therapy with traditional AEDs

Fenfluramine

• Potentiates 5-HT receptors

• Sigma-1 receptor

• Used in Dravet and Lennox-Gastaut syndromes

Major Side effects of ASM’s

Most Drugs induce hepatic cytochrome P450 enzymes

• Drugs that INDUCE liver enzymes

  • COPPVL

    • Carbamazepine, Oxcarbazepine, Phenobarbital, Phenytoin, Vigabatrin, Lamotrigine

• Drugs that are accelerated metabolism

  • ETTVZ

    • Ethosuximide, Tiagabine, Topiramate, Valproate, Zonisamide

Can decrease effectiveness of some lipid soluble drugs

• Oral contraceptives, anticoagulants, immunosuppressants

OTHER major side effects of ASMs

GI reactions

• Anorexia, nausea

  • Minimized when taken with food

Additive CNS depression

• some ASM produce sedation that is additive with other CNS depressants

Teratogenic effects

• Many traditional ASM generate a greater risk (~2x) of congenital malformations of a variety of types.