Emmitte Anti-Seizure Drugs

Barbiturates

MOA: Increase GABA activity

Drugs: Phenobarbital & Primidone

ADME:
~Inducers of CYP2C, CYP3A, UGT
~Pheno: low LogP -> SLOW onset -> LONG DOA
~Prim: Produces either pheno or PEMA (major metabolite, weaker anticonvulsant, more toxicity)

Hydantoins

Inactivation of Na+ channel

Drugs: Phenytoin & fosphenytoin

ADME:
~90% Protein bound
~Non-linear PK AKA metabolic route is saturable
~Induces CYP2C, CYP3A, & UGT
~High pH + cannot be diluted for infusion --> fosphenytoin prodrug for injection via IM/IV

Subtopic

succinamides

Blockade of T-type Ca2+ Channel

Drugs: ethosuximide

ADME:
~NOT an enzyme inducer
~CYP3A4 inducers decrease exposure bc it converts it to inactive

Drugs: Carbamazepine, oxcarbazepine & eslicarbazepine

Carba

SAR: most reactive site is C10-C11 double bond

ADME:
~toxic active metabolite
~reactive metabolite is electrophilic, reacts w thiols (GSH)
~Inducer of CYP2C, CYP3A, UGT, CYP1A2

Oxcarbazepine (2nd gen analog)

ADME:
~NO CYP3A4 metabolism
~No epoxide/reactive metabolites
~Licarbazepine is the active metabolite, >10 fold higher water solubility/plasma lvls

Eslicarbazepine (3rd gen analog)

ADME:
~Esli acetate = enantoipure prodrug converted to s-licarb
~Esli acetate = greater plasma exposure of active metabolite than oxcarb

Drugs: Gabapentin, pregabalin, gabapentin enacarbil, vigabatrin, tiagabine

Gabapentin

ADME:
~Main inhibitory transmitter, NO GABA agonist activity
~NOT metabolized/NO binding to plasma protein = renal elimination unchanged
~Transported via L-amino acid carrier protein via ACTIVE TRANSPORT

Pregabalin

ADME:
~NO GABA agonist activity
~Elimination/protein binding/active transport similar to Gabapentin
~3-10x more potent vs. gabapentin

Vigabatrin

ADME:
~IRREVERSIBLE (suicide) inhibitor of GABA-transaminase (enzyme that degrades GABA) --> increasing GABA in CNS

Tiagabine

ADME:
~Highly protein bound
~Oxidation by CYP3A4 --> CYP3A4 inducers reduce exposure
~Increased potency at GABA transporter

Drugs: Clobazam, clonazepam, clorazepate, diazepam, lorazepam

~Extent of protein binding correlates with lipid solubility
~Diaz reaches peak CNS conc. faster than Loraz but is more rapidly distributed to fat

Valproic Acid

ADME:
~Highly protein bound
~INHIBITOR of CYP2C9, UGT, epoxide hydrolase
~2-propyl-4-pentenoic acid is toxic metabolite

Felbamate

~34 cases of aplastic anemia (!3 ☠️) and 23 cases of hepatic failure (5 ☠️)
~Black box label warning

Lamotrigine

ADME:
~Blocks Na ion channels
~metabolized by N-glucuronidation + DDIs w/ drugs that induce or inhibit UGT

Topiramate

ADME:
~70-80% excreted unchanged renally, dose reduction req. for renal insufficiency
~Exhibits polypharmacology = broad spectrum anti-seizure activity

Levetriacetam, Brivaracetam

ADME:
~rapid + complete absorption
~min. protein binding, NOT metabolized by UGT/CYP450/epoxide hydrolase
~binds synaptic vesicle protein CV2A
~Brivaracetam introduced w/ increased affinity for SV2A + Na channel blocking

Zonisamide

ADME:
~Sulfonamide derivative
~CYP3A4 inducers (i.e. phony/carb) will alter PK -> reduce half-life + plasma conc.
~50% excreted as glucuronide conjugate SMAP, byproduct of CYP3A4 metabolism

Lacosamide

ADME:
~Synthetic derivative of D-serine
~converted via CYP2C19
~No effect on P450s/no DDI w/ other anti-seizure drugs

Rufinamide

ADME:
~major metabolite due to carboxylesterase-medziated hydrolysis
~low protein binding
~enzyme inducing anti-seizure drugs increases metabolism due to induction of carboxylesterases
~valproic acid increase conc. by 70%, DDI
~food increases oral absorption/solubility of drug

Ezogabine

ADME:
~acts on K channels
~metabolic pathway is N-glucuronidation by UGT (anti-seizure drugs that induce or inhibit UGT can alter metabolism)
~80% protein bound

Perampanel

ADME:
~highly protein bound
~metabolized by CYP3A

Cannabidiol

ADME:
~Cannabis sativa, no psychoactive THC
~CBD metabolized by CYP2C19, CYP3A4, UGT enzymes
~Inhibitor of CYP2C19

Stiripentol

ADME:
~Used in combo with clobazam in Dravet syndrome
~Increases GABA lvls in neuronal tissue
~Highly protein bound
~Inc. plasma conc. of clobazam via inhibition of CYP3A4 & CYP2C19

N-Glucuronidation

-Lamotrigine
-Ezogabine

Mnemonic: eating GLUCose every day makes you LAzy EAZILY. Understand Glucose To prevent this.
-GLUC = Glucuronidation
-LA = LAmotrigine
-EAZILY = EZogabine
-UGT = Understand Glucose To

Note:
Drugs that induce or inhibit UGT can alter the metabolism of both of them

-Perampanel

CBD: +CYP2C19, UGT

-Gabapentin
-Pregabalin
-Vigabatrin
-Levetiracetam

CYP2C9, CYP3A, UGT

-Phenytoin
-Phenobarbital
-Primidone

Carbamazepine: +CYP1A2

CYP2C9

Valproic acid: +UGT/epoxide hydrolase

CBD/Cannabidiol

Can decrease the exposure of:
-Ethosuximide
-Tiagabine

Reduce half-life and plasma conc. of:
-Zonisamide

Lamotrigine
Ezogabine

Increase metabolism of Rufinamide due to induction of carboxylates

Valproic acid increases rufinamide concentrations through unknown mechanisms