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Pharmacology of Seizure Disorders Cheat Sheet by

Pharmacology of Seizure Disorders

Seizure vs. Epilepsy

Seizure: high electrical discharge from an area of the CNS (foci), they are one and done, and there is usually a reason such as: vascular, infection, trauma, autoim­mune, metabolic disorders, neoplasm, or idiopa­thic.
Epilepsy: two or more seizures that do not resolve (they may become chronic) there is no VITAMIN reason.

Types of Epileptic Seizures

Focal/­Partial Seizures
Simple
 
Complex
Genera­lized Seizures
Genera­lized tonic-­clonic: grand mal seizure, LOC, convul­sions, muscle rigidity
Absence
usually in children, brief loss of consci­ous­ness, blanks out, stares off into space.
Myoclonic
sporadic (isola­ted), jerking movements
Clonic
Repeti­tive, jerking movements
Tonic
Muscle stiffness, rigidity
Atonic
drop seizures, loss of muscle tone

Epileptic "­Spa­sms­"

Benign Rolando
Twitching, numbness, or tingling or one side of tongue­/face
West Syndrome
Infantile wiggles
 
"­Jac­kKn­ife­" seizures (legs fly up)
 
Leads to autism or intell­ectual disabi­lities later in life.
Lennox­-Ga­staut Syndrome
Multiple seizures every day (18-20)
 
Cannabis may eliminate these seizures.

Carbam­azepine (Teg­ret­ol) (Carba­trol, Equetro)

Class:
Na+ Channel blocker
MOA:
Blocks Na+ channel blocker, a tricyclic compound (similar structure to TCA, no high affinity for MAO)
Indica­tions:
Genera­lized or focal seizures *one of the most widely used, mostly for focal seizure. 1st line treatment for trigeminal neuralgia.
Formul­ations:
Carbatrol and Equetro (ER capsule), tablet, Tegretol (suspe­nsion), chewable tablet, XR tablet
 
Not a controlled substance
Side Effects:
N/V, dizziness, blurry vision, diplopia, sedation at high doses, benign leukop­enia.
Serious ADRs:
Hypona­tremia, Bone marrow suppre­ssion, SJS/TEN, osteom­alacia, hepato­tox­icity (very rare). Rash and hypona­tremia are most common reasons for discon­tin­uation. May worsen myoclonic seizures.
Drug Intera­tions:
Potent CYP inducer
 
Induces CYP3A4, 2C9, 2C19, PgP (will decrease levels of drugs metabo­lized by these)
 
Substrate of CYP3A4, 2C8, PgP
 
VPA and Lamotr­igine can increases carbam­azepine levels
 
Do not use with hormonal contra­ception (decreases efficacy of BC)
Consid­era­tions:
requires lab monito­ring, can induce its own metabolism so levels may decrease over time. Not a sedative so a good choice if that is a concern.

Oxcarb­azepine

Class:
Na+ channel blocker
MOA:
Na+ channel blocker, less potent than carbam­aze­pine. Pro-drug for S+lica­rba­zepine
Indica­tions:
adjunct therapy for partial seizures
Formul­ations:
tablet, oral suspen­sion, ER tablet (Oxtellar XR)
 
Not a controlled substance
Side Effects:
may have less than carbam­azepine but similar, higher risk of hypona­tremia
Consid­era­tions:
Less drug intera­ctions than carbam­aze­pine, check Na+ levels
 
weak CYP3A4 inducer, does not auto-i­nduce metabolism like carbam­azepine

Phenytoin (Dil­ant­in)

Class:
Na+ Channel blocker
MOA:
Na+ Channel blocker (works similarly to Carbam­aze­pine) oldest non-se­dating epileptic drug
Indica­tions:
focal (partial) onset seizure, genera­lized onset seizure (NOT first line), Status Epilep­ticus
Formul­ations:
capsule, injection, oral suspen­sion, chewable tablet
 
Not a controlled substance
Side Effects:
Hirsutism, sedation, gingival hyperp­lasia (enlarged gums),
 
TOXIC EFFECTS: nystagmus, diplopia, ataxia
Serious ADRs:
SJS/TEN (espec­ially asian), osteom­alacia, peripheral neurop­athy, tissue necrosis when IV, arrhyt­hmias
Consid­era­tions:
may worsen other seizure types (absence, juvenile myoclonic, Dravet's syndrome)
 
When switching formul­ations keep in mind different dosage forms contain different amounts of PHT (ex. caps and injection are 92% and susp. and chewable tablets are 100%)
Drug Intera­ctions:
Extens­ively bound to albumin, free PTH is what is active. Drug or conditions that alter albumin will affect PHT levels. Many drugs compete with bound PHT and may cause displa­cement and lead to toxicity. Patients with liver disease, hypoal­bum­inemia, or renal failure can lead to abnormally high levels of PHT (toxic levels)
 
Metabo­lized by CYP2C19 and 2C9, induces 3A4, 2C9, 2C19, and 1A2.
 
Potent CYP inducer
 
Substrate and inducer of PgP and interacts with most oral contra­cep­tives (decreases efficacy)
Lab monitoring
Free phenytoin levels should be checked in patients with hypoal­bum­inemia and renal failure. If you can't check free, check total and use given equations to adjust.
Therap­eutic Levels
Total 10-20 mg/L
 
Free 1-2.5 mg/L
 
Toxic >30 mg/L
 
Lethal level >100 mg/L
 
Draw levels within 2-3 days of starting therapy and then get second level within 5-8 days of therapy initiation and with subsequent dose adjest­ments
 
In stable patients, can draw levels at 3-12 month intervals
 
Phenytoin kinetic are non liner -> a small dose increase may cause a BIG increase in plasma concen­tration

Fosphe­nytoin (Cerebyx)

Class:
Na+ Channel blocker
Indica­tion:
Same as phenytoin, preferred over phenytoin for parenteral admini­str­ation if needed.
 
Still prefer Benzos in SE because of delayed effects
Formul­ations:
injection
 
not a controlled substance
Side Effects:
same as phenytoin
Drug Intera­ctions:
same as phenytoin
Special Notes:
a prodrug of phenytoin (each mL= 50mg of phenytoin equiva­lents)

Take Home Points

Skin rashes­/hy­per­sen­sit­ivities (SJS, TEN, rash)- highest risk with: lamotr­igine, phenytoin, carbam­aze­pine, phenob­arbital
DO NOT USE VPA in women of childb­earing age, especially if they are not on effective birth control
Phenytoin levels needs to be checked.
Safer pregnancy option: lamotr­igine, leveti­racetam (Use as monoth­erapy when at all possible. Pregnancy can lower drug levels so dose adjust­ments may be required)
Most of the medica­tions decrease effect­iveness of hormonal contra­cep­tives.
Therapy is seizure and patient specific.
If a patient doesn't respond to monoth­erapy, those meds with similar MOAs will likely not be effective so choose another med as adjunct.
Some medica­tions are chosen due to comorb­idi­ties.
VPA is mood disorder or migraine.
Pregabalin in neurop­athic pain

Epileptic Spasms

Benign Rolando
Lamotr­igine
West Syndrome
Vigabatrin
Lennox­-Ga­staut Syndrome
Valproate
 
Topiramate
 
Lamotr­igine
 
Cannab­idiol
 
If really refractory Felbamate

Adverse Reactions

SJS
Ethosu­ximide
 
Carbam­azepine
 
Lamotr­igine
Cardio­/Re­spi­ratory Depression
Benzos
 
Barbit­urates
 
Propofol
Hepato­tox­icity
Valproate
 
Carbam­azepine
 
Felbamate
 
Barbit­urates
 

Pathop­hys­iology of Seizure

Overactive glutamate in the brain (over excita­tion) that continues to cause Na+ and Ca2+ influx leading to continuous action potentials and stimul­ation.
To improve that we want to increase actions of GABA which is inhibi­tory, and decreases the effects of Glutamate.
We can work on the voltage gated channels, directly on GABA, etc.. to decrease seizure activity.
Seizures can be provoked or unprov­oked. Provoked could be due to electr­olyte distur­bances, infection, TBI, inflam­mation, fever, toxici­ties, etc. Unprovoked could be epilepsy (genetic or chronic pathologic process)

Three Major Seizure Patterns

Focal
One area of the cortex, isolated to motor of sensory.
 
With or without loss of consci­ousness
Genera­lized
starts in a foci and spreads over the entire cortex.
Epileptic "­Spa­ms"
Benign Rolando (around the central sulcus)
 
West Syndrome
 
Lennox­-Ga­staut's Syndrome

Overview of How These Drugs Work

Ultimate goal is to inhibit the local generation of seizure discharges to reduce the ability of neurons to fire at high rate and reduced neuronal synchr­oni­zation.
Modulate Na+, Ca2+, or K+ channels
Enhance fast acting GABA-m­ediated synaptic inhibition (we want to increase overall inhibi­tion, increase GABA)
Modifi­cation of synaptic release processes (sv2A, alpha2­del­ta-1)
Dimini­shing effects of fast glutamate mediated excitation (decreases excitatory effects, decreased Glutamate)

Lamotr­igine

MOA:
Na+ Channel blocker
Indica­tions:
adjunct for Lennox­-Ga­staut syndrome, adjunct for genera­lized tonic-­clonic, mono or adjunct for focal seizures.
Formul­ations:
tablet, chewable tablet, titration kits as well
 
not a controlled substance
Side Effects:
sometimes insomnia instead of sedation, dyspepsia, peripheral edema, HA, dizziness, rash
Serious ADRs:
Fatal Rash (SJS) worsened if combined with VPA use
Drug Intera­ctions:
VPA greatly increases levels of drug, increased SJS risk. OCPs or other estrogen containing medica­tions reduce lamotr­igine levels and may increase seizure occurr­ence.
Special Notes:
normally well tolerated and widely used, safer in pregnancy than others due to lower fetal risk. Rash (as a hypers­ens­iti­vity) can be reduced by a slow titration of the dose (children at higher risk)

Valproic Acid (Dep­ake­ne)

MOA:
exact mechanism unknown, has broad spectrum efficacy (multiple seizure types)
Indica­tions:
genera­lized tonic-­clonic, focal (may not be as effective as carbam­aze­pin­e/p­hen­ytoin) absence, myoclonic (juvenile myoclo­nic), atonic­/ak­inetic (Lenno­x-G­astaut)
Formul­ations:
capsule, DR sprinkle, oral solution, IV, DR tablet, ER tablet
 
Not a controlled drug
Side effects:
N/V. GI pain and heartburn (Dival­proex has lowest GI risk), weight gain, tremor (dose related) OP
Drug Intera­ctions:
a CYP inhibitor of metabolism (will increase levels of phenobar and ethosu­ximide) displaces phenytoin from albumin so increasing free phenytoin levels (toxic­ity). Increases levels of lamotr­igine by inhibiting it's clearance.
Warnings:
Do not use in women of childb­earing age, VPA induced hepatic failure (children <2 at most risk) The worst teratogen.
 
Highly protein bound like phenytoin
 
Initial dosing of 15 mg/kg recomm­ended with slow titration up to a therap­eutic dose.
 
Therap­eutic levels are usually anywhere from 50-100 mcg/mL

VPA

Ethosu­ximide

MOA:
CCB, inhibits low voltage activated T type Ca2+ channels
Indica­tion:
absence seizure (first line agent)
 
Long half life, taken once daily qhs
Formul­ations:
capsule, oral solution
 
not a controlled substance
Side effects:
N/V, HA, anorexia, lethargy, sedation, unstea­diness, urticaria, pruritus, hiccups
Serious ADRs:
Neutro­penia, SLE (Systemic Lupus Erythe­mat­osus), SJS, suicidal ideation
Drug intera­ctions:
Substrate for CYP3A4, can reduce VPA levels (reason unknown), very few other drug intera­ctions.

Barbit­urates (Pheno­bar­bital and Primidone)

MOA:
GABA receptor agonist, opens Cl- channels, can block AMPA receptors as well. Long half life, preferably taken once daily qhs. Primidone is metabo­lized to phenob­arbital and acts more on Na+ channels than phenob­arb­ital.
Indica­tions:
genera­lized tonic-­clonic (not first line), simple or complex with or without secondary genera­liz­ation (not first line), refractory status epilep­ticus
Formul­ations:
elixir, oral solution, injection, tablet
 
Schedule IV controlled substace
Side effects:
SEDATION, rashes, N/V, sedati­ve/­hyp­notic effects
Serious ADRs:
SJS/TEN, respir­atory depres­sion, narrow therap­eutic window, serum concen­tra­tions need to be 15-40 mcg/mL, drug accumu­lates in renal impairment
Drug Intera­ctions:
POTENT CYP INDUCER, also a substrate and inducer for PgP pump. Reduces efficacy or oral contra­cep­tives, including progestin only and etonog­estrel implant (Nexpl­anon)
Special Notes:
usually D/C due to ADRs so not a first line option, long term use leads to dependance with withdrawal leads to more seizures. May WORSEN infantile spasms and absence seizures.
 
It is the oldest anti-e­pil­eptic but no longer used.

Pregabalin (Lyr­ica)

MOA:
same as gabape­ntin, Ca2+ channel alpha2­delta subunit (even though structure is similar to GABA, doesn't bind to GABA receptors)
Indica­tions:
adjunct for focal onset (immediate release only) also more for neuropathy
Formul­ations:
capsule (IR only for seizure)
 
Schedule V Controlled Substance
Side Effects:
sedation, increased BP, dizziness, confusion, rash, nystagmus
Drug Intera­ctions:
none signif­icant
Special Notes:
additional indication for neuralgia and neurop­athic pain

Felbamate

MOA:
AMPA receptor antago­nist, although there is strong evidence that it can also block NMDA receptors. GABA potent­iation.
Indica­tions:
focal seizures, and Lennox­-Ga­staut syndrome (never first line)
Formul­ations:
tablet and suspension
 
Not a controlled substance
Side Effects:
N/V, HA, dizziness, hepato­tox­icity, anorexia
Serious ADRs:
Aplastic anemia (wipe out of bone marrow), Hepatic failure ONLY USE IF NO OTHER OPTION
Drug Intera­ctions:
Inhibits CYP2C19, reduces efficacy or oral contra­cep­tives
Special Notes:
REQUIRES INFORMED CONSENT COMPLETED AND SIGNED

Status Epilep­ticus

Definition
Occurrence of two or more convul­sions without recovery of consci­ousness between attacks.
 
A fixed and enduring epileptic condition (for 30 min or more)
Treatment
Initial treatment with IV Lorazepam (Benzo) 4mg or midazolam is usually helpful regardless of the type of status epilep­ticus.
 
Then if needed phenytoin, then carbam­aze­pine, and other drugs may also be needed to obtain and maintain control in complex partial status epilep­ticus.
 

Targets of Anti-S­eizure Meds

Targets of Anti-S­eizure Drugs

1
Na+ channels
2
Ca2+ channels (what allows the vesicles of glutamate to fuse with the membrane)
3
sv2A receptor on the glutamate filled vesicles.
4
AMPA or NMDA receptors
5
GABA-A receptor coupled with a Cl- channel
6
Targets the reuptake of GABA (inhibit the reuptake)
7
Targets GABA transa­minase that breaks down GABA (inhibit GABA breakdown)

Targets of Therapy

1- Na+ Channel Blockers
many drugs, pick and choose based on tolerance and contra­ind­ica­tions.
 
Carbam­azepine
 
Oxcarb­ama­zepine
 
Phenytoin
 
Fosphe­nytoin
 
Lomotr­igine
 
Topiramate
 
Valporate*
 
Lacosamide
2. Ca2+ Channel Blockers
Ethosu­ximide
 
Maybe gabape­ntin, but now used for anxiety and neurop­athy.
3. sv2A blockers
Leveti­racetam
4. AMPA/NMDA Receptor Blockers
Felbam­ate­-AMPA
 
Ketamine- NMDA
5. GABA-A Receptor Agonists
feel good drugs, puts you to sleep
 
Benzod­iaz­epines- lorazepam, midazolam, diazepam, clobazam (increase in the frequency of Cl- ion channel opening)
 
Barbit­urates- phenob­arb­ital, pentob­arbital (increase in the duration of Cl- channel opening)
 
Propofol
 
Topiramate (Dual action, also a Na+ channel blocker)
6. GABA reuptake inhibitors
Tiagabine (used in really refractory cases)
7. GABA Transa­minase Inhibitors
Valproate
 
Vigabatrin

Lacosamide

MOA:
Na+ Channel blocker
Indica­tions:
monoth­erapy or adjunct for focal (partial) seizure
Foruml­ations:
tablet, injection, oral solution
 
Controlled Schedule V drug
Side Effects:
dizziness, HA, N/V, diplopia, ataxia, blurry vision
Serious side effects:
slowed cardiac conduc­tion, monitor PR interval
Drug Intera­ctions:
substrate for CYP3A4, 2C9, 2C19, but intera­ctions are minimal (not an inducer or inhibitor)
Special Notes:
dose adjust for renal/­hepatic impair­ment, well tolerated

Topiramate

MOA:
broad spectrum, Na+ channels, GABA receptors, and AMPA glutamate receptors
Indica­tions:
Monoth­erapy or adjunct in focal onset or genera­lized tonic-­clonic, adjunct for Lennox­-Ga­staut
Formul­ations:
ER capsule, sprinkle capsule er and regular, tablet
 
Not a controlled drug
Side Effects:
dizziness, sedation, dose related impair­ment, suicidal thoughts, parest­hes­ia's, weight loss, speech diffic­ulties
Serious ADRs:
Kidney stones, metabolic acidosis, decreased sweati­ng/­hyp­ert­hermia, increased IOP, enceph­alo­pathy (when used with VPA)
Drug Intera­ctions:
inhibits CYP2C19, induces 3A4, substate of PgP, may increase lithium levels, CYP inducers will decrease topiramate levels, may decrease digoxin levels, may reduce efficacy of estrogen and progestin containing contra­cep­tives.
Special Notes:
Cognitive side effects are a big reason for discon­tin­uation

Leveti­racetam (Keppra)

MOA:
Broad spectrum, SVA2 binding on vesicle to decrease glutamate release
Indica­tions:
focal seizure, genera­lized: adjunct for juvenile myoclonic epilepsy, adjunct for primary tonic-­clonic
Formul­ations:
tablet, oral solution, IV, ER tablet, disint­egr­ating tablet
 
Not a controlled substance.
Side Effects:
HA, somnol­ence, N/V
Drug Intera­ctions:
not metabo­lized in the liver, so limited drug intera­ctions.
Special Notes:
favorable ADR profile, lack of drug intera­ctions almost complete oral absorption

Benzod­iaz­epines

MOA:
GABA receptor agonist clobazam is slightly different struct­urally from other benzos but acts similarly
Indica­tions:
adjunct genera­lized tonic-­clonic (cloba­zam), absence (clobazam, clonaz­epa­m-not first line), myoclonic (cloba­zam-not first line), Status Epilep­ticus (IV diazepam, midazolam, lorazepam) acute repeated or prolonged seizure in outpatient setting (diazepam rectal gel), atonic­/ak­inetic (clona­zepam), adjunct for simple or complex partial (clobazam, cloraz­epate) adjunct Lennox Gustaut (clobazam)
Formul­ations:
Clobazam (onfi tablet­/oral film "­Sym­paz­an"/­sus­pen­sion), Lorazepam ("at­iva­n" inject­ion), Clonazepam ("Kl­ono­pin­" tablet), Diazepam ("Di­ast­at" rectal gel/in­jec­tion), cloraz­epate ("Tr­anz­ene­" tablet), midazolam (injec­tio­n/nasal spray)
 
Schedule IV Controlled Substances
Side Effects:
Hypote­nsion and respir­atory arrest with IV use, sedation, slowed breathing.
Serious ADRs:
Clobazam can lead to SJS and TEN
Special Notes:
Clobazam, clonaz­epam, and cloraz­epate: check blood counts and LFTs period­ically
 
Among the most sedating of antiep­ile­ptics- CNS depres­sants
Drug Intera­ctions:
CYP2C19, CYP3A4

Gabapentin

MOA:
Ca2+ channels alpha2­delta subunit inhibition AP so explains analgesic, antico­nvu­lsant, and anxiolytic activity. (Even though struct­urally similar to GABA, doesn't bind to GABA receptors)
Indica­tions:
adjunct for focal (partial onset) seizure, more for neuropathy
Formul­ations:
capsule, solution, tablet (medic­ation cannot be crushed)
 
Controlled substance schedule V in Alabama (abuse potential)
Side Effects:
sedation, increased BP, dizziness, confusion, rash, nystagmus
Drug intera­ctions:
none signif­icant
Special Notes:
requires renal dose adjust­ments in impairment

Indica­tions

Focal Seizures
Carbam­azepine
 
Oxcarb­ama­zepine
 
Leveti­racetam
 
Lamotr­igine
 
Phenob­arbital (Neonates)
Genera­lized Absence Seizures
Ethosu­ximide (Prefe­rred)
 
Valproate 2nd
 
Lamotr­igine
Genera­lized Myoclonic Seizures
Valproate (BEST)
 
Leveti­rac­eta­m/L­amo­trigine
 
Benzos
Genera­lized Tonic-­Clonic Seizures
Valproate- very good
 
Leveti­racetam
 
Lamotr­igine
 
Topiramate
 
Phenyt­oin­/Fo­sph­enytoin
 
Phenob­arb­ital- neonates

Teratogens

Valpro­ate­-in­hibits folic acid- the most teratogen risk
Phenyt­oin­/Fo­sph­enytoin (Fetal hydantoin syndrome)
Carbam­azepine (Cleft palate, cleft lip)
 

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  • Published: 13th May, 2023

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