Inman Anti-Seizure Phrmacology

Inhibitory

GABA

GABA-A is a Cl channel
-Activation inhibits the action potential

BZDs: Clobazam, Clonazepam, Diazepam, Lorazepam
-Reserved for emergency due to tolerance
-MOA: Positive allosteric modulators of GABA-A, increase freq of GABA-Activated Cl channel opening

Lorazepam/diazepam 1st line for status epileptics (IV)
-Abrupt DC of clobazam may cause withdrawal symptoms (convulsions, psychosis, hallucinations, anxiety, tremor)

Phenobarbital/Primadone (also Na blocker)

Pheno:
-has the least sedative effect in its class
-long half-life (5 days), induces CYP/UGT
-v strong sedation, cog impairment, behavioral changes
-hepatotoxicity, SJS, toxic epidermal necrolysis, risk of dependence

Tiagabine:
-95% protein bound
-inc incidence of seizures and status epileptics

Vigabatrin:
-1st line for infantile spasm, adj for partial seizures
-may aggravate seizures + psychiatric effects in pts. w/ depression, psychosis
-progressively reduces visual field in high % of pts, hepatotoxicity

Stiripentol: only used as adj for driver syndrome w/ clobazam

Glycine

Excitatory

Glutamic acid

Activation leads to:
-inc influx of Ca/Na
-member depolarization
-encourages generation of action potential

Drug: Perampanel - Glutamate/AMPA receptor antagonist
-90% protein bound, many DDI
-Partial + generalized seizures

Aspartic acid

Ion Channels

-Absence seizure has high levels of T-type Ca channel

Drugs: Valproic acid and ethosuximide are T-channel blockers, they reduce excitation

Ethox:
-effective against absence (only use)
GI disturbances

-Iminostilbenes (zepines)

Carba: slow/erratic oral absorption
-autoinducer (aka it induces its own metabolism = lower blood conc. at higher doses)
-Asplastic anemia, leukopenia, hepatic toxicity, teratogenicity, hyponatremia

Oxca/Eslic: good/complete oral absorption
-hyponatremia
-less potent inducer of liver enzymes/no autoinduction

MOA: Slow recovery of voltage-gated Na Channels in neurons

Lacosamide:
-1st line partial seizures
-Class V controlled

Lamotrigine:
-1st/2nd line for most seizures, broad spectrum
-metabolism inhibited by UGT (DDI valproate)
-Stevens-Johnson syndrome/rash

Phenytoin/Fosphenytoin:
-narrow therapeutic window
-Gingival hyperplasia
-skin thickening; hirsutism; acne

Rufinamide:
-When all else fails, use this
May increase convulsion in some pts.

Zonisamide:
-works on both Na/T-type Ca channels
-Kidney stones, weight loss, oligohidrosis

Other drugs:
Primadone (not much to say)

Ezogabine:
-adj + alt for partial seizure
Unique MOA: Neuronal KCNQ/Kv7 K channel opener

ADE: QT prolongation, blue skin discoloration, retina pigment changes

Drugs: Gaba/pregaba

Pregabalin 3-10x more potent
-does NOT mimic GABA effects
-not metabolized, not bound to protein, no DDI, well tolerated
-weight gain

Divalproex/Valproic Acid/Sodium Valproate

Broad-spectrum, multiple potential MOA
-highly bound to plasma protein
-inhibits CYP2C9, UGT (DDI w/ pheny, pheno, lamotrigine, lorazepine)
-weight gain, teratogenicity, liver toxicity (Rare/fatal)

Felbamate

Broad spectrum, multiple MOA
-inhibits CYP2C19, CYP3A4
-aplastic anemia (black box), hepatic failure
-reserved for extreme refractory epilepsies (esp lennox-gastaut syndrome)

Topiramate

Broad spec, approved for migraine, multiple MOA
-inhibits CYP2C9
-kidney stones, weight loss
-cleft palate in newborns

Levetriacetam/Briva

-Reduce NT release
-well absorbed, not metabolized, few DDI

Fenfluramine

-Stimulation of 5-HT to increase GABA activity

Cannabidiol

Well tolerated, AEs are diarrhea, and sleepiness
-seizures asso. w/ lennox-gastaut or dravet

All iminostilbenes:
-Carbamazepine
-Ocarba
-Escli

Carbamazepine
Phenobarbital
Vigabatrin
Valproic Acid/Valproate, Divalproex
Felbamate

Lamotrigine
Phenobarbital

Loss:
Zonisamide
Topiramate

Gain:
Valproic acid, sodium valproate, divalproex
Gabapentin/Pregabalin

Carbamazepine
Valproic Acid/Valproate/Divalproex

Carbamazepine
Felbamate

Zonisamide
Topiramate