psych/neuro - Anticonvulsants

how can you measure seizure activity

EEG

what are the 3 key features of seizure classification?

1) where the seizure starts (onset)

2) pt level of awareness during a seizure

3) other symptoms during a seizure

why is understanding seizure onset important?

onset affects choice of seizure medication later on

what are the 2 categories of seizures?

(1) Focal (3-types)

(2) Generalized onset (2 major types)

what are the main types of focal seizures?

(1) focal aware

(2) focal impaired awareness

(3) focal to bilateral tonic-clonic convulsions (AKA grand mal = GTC)

what are the main types of generalized onset seizures?

(1) generalized onset w/ motor seizures (impaired awareness)

⚫️ generalized onset tonic-clinic "grand mal", "GTC"

(2) generalized onset w/ non-motor seizures (impaired awareness

⚫️ Childhood Absence Epilepsy (CAE)

____ of common epilepsies are drug-resistant

30-40%

what is the goal of therapy for ADEs

complete cessation of symptoms

what are subjective symptoms of epilepsy

seizures per pt and eyewitness report:

(1) motor

(2) non-motor

what are the motor symptoms of epilepsy

(1) stiffening (tonic)

(2) jerking (clonic)

(3) automatisms (lip-smacking, chewing, blocking)

what are non-motor symptoms of epilepsy

(1) sensory (visual, auditory, gustatory, olfactory)

(2) autonomic (increased HR, feeling in pit of stomach, nausea/vomiting)

(3) cognitive (sense of deja-vu)

what is focal onset w/o impaired awareness

starts with motor or non-symptoms + CAN remember events

what is focal onset w/ impaired awareness

starts with any motor or non-motor sx + CANNOT remember events (often progresses to "staring episodes" 1-2 minutes long)

what is focal-to-bilateral convulsions

(1) total loss of consciousness

(2) "flopping to ground"

(3) whole-body tonic-clonic convulsions, with tongue biting and urinary incontinence

what is generalized onset motor sxs

tonic-clonic

what is generalized onset non-motor sxs

short staring spellings 3-5 seconds long -> absence seizures are typical of childhood absence epilepsy (CAE)

what are objective clinical evaluation for epilepsy

(1) EEGs - gold standard for epilepsy diagnosis

(2) MRIs

what percent of the time will EEGs catch epilepsy

50%

does a single normal EEG rule epilepsy

no; need to repeat test 3x to be sure

what does a brain MRI show

abnormal brain damage (from stroke, traumatic brain injury)

does a normal MRI rule out epilepsy

no

epilepsy is a _______ diagnosis

clinical; not diagnosed by any single test

a diagnosis of epilepsy can be made if:

1) at least 2 unprovoked seizures occurring greater than 24 hours apart

2) 1 unprovoked seizure + 1 other finding

⚫️ (i.e. 1 seizure + abnormal EEG or MRI)

what are dose-related ASM side effects

(1) neurotoxic = sedation

(2) cognitive impairment

what is idiosyncratic ASM side effect

not dose related, can be severe

(1) rash progressing to SJS or TEN

(2) aplastic anemia (abnormal blood cells OR hepatotoxicity

what are long term ASM side effects

(1) gingival hyperplasia

(2) osteoporosis

what is the difference in efficacy of the >25 ASMs?

SIMILAR efficacy

what differs between ASMs

side effects, PK, DDIs

what are the steps when starting therapy for epilepsy

1) start with monotherapy first, check for side effects and efficacy

2) then try monotherapy with 2nd agent, check for side effects and efficacy

3) then try dual and combination therapies, check for side effects and efficacy

what are the first gen ASMs

(1) Carbamazepine

(2) Clonazepam

(3) Ethosuximide

(4) Phenytoin

(5) Phenobarbital

(6) Primidone

(7) Valproic Acid (Depakene)

-"C2E3PvalprOic"

Carbamazepine

(0) Indication + Generation

(1) Efficacy

(2) Comorbid conditions

(3) Side Effects

(4) DDI

(5) Therapeutic Range

Carbamazepine

(0) Indication: epilepsy - 1st gen ASM

(1) Efficacy: narrow: may exacerbate generalized sz d/o including CAE

(2) Comorbid conditions:

⚫️mood stabilizer (bipolar d/o)

⚫️trigeminal neuralgia

(3) Side Effects

⚫️ hepatotoxicity, hyponatremia

⚫️ idiosyncratic rash in Asians (risk of SJS/TEN) gene testing required

(4) DDI: INDUCER

⚫️ auto-induction (induces its OWN metabolism)

(5) Therapeutic Range: TMD required (narrow TR)

Ethosuximide

(0) Indication + Generation

(1) Efficacy

(2) Therapeutic Range

(3) Side effects

Ethosuximide

(0) Indication: epilepsy - 1st gen ASM

(1) Efficacy: gold standard for Childhood Absence Epilepsy (CAE)

(2) Therapeutic Range: TDM required (narrow)

(3) Side effects:

⚫️ hepatotoxicity

⚫️ rash

what is hyponatremia?

low Na+ levels in blood

what are the main AEDs associated with hyponatremia?

(1) Carbamazepine

(2) Oxcarbazepine

(3) Eslicarbazpine

-"COE"

If a pt already has hyponatremia, what do you want to avoid?

you want to avoid starting pts on "COE" as it will worsen the baseline hyponatremia

Phenytoin

(1) Indication + Class

(2) Efficacy

(3) Comorbid uses

(4) Side effects

(5) DDI

(6) Therapeutic Range

(7) PK

(8) Binding

Phenytoin

(1) Indication: epilepsy - 1st gen ASM

(2) Efficacy: narrow --- may exacerbate generalized seizures, including CAE

(3) Comorbid uses: N/A

(4) Side effects:

⚫️All Na+ channel inhibitors are "neurotoxic" - ataxia, sedation, decreased cognition

⚫️ Nystagmus common exam finding

⚫️ Long-term causes: gingival hyperplasia, osteoporosis

⚫️ idiosyncratic rash, hepatotoxicity

(5) DDI: INDUCER

(6) Therapeutic Range: TDM required (narrow)

(7) PK: Non-linear kinetics

(8) Binding: Lots of protein binding

Phenobarbital

(1) Indication + Class

(2) Efficacy

(3) Side Effects

(4) DDI

(5) Therapeutic Window

Phenobarbital

(1) Indication: epilepsy - 1st gen ASM

(2) Efficacy: exacerbate CAE

(3) Side Effects:

⚫️ rash

⚫️ hepatoxicity

(4) DDI: inducer

(5) Therapeutic Window: TDM required (narrow)

Primidone

(0) Class

(1) Indication

(2) Metabolic relationship

Primidone

(0) 1st gen ASM

(1) Indication: not really used in epilepsy = used in tremor

(2) Metabolic relationship: prodrug of phenobarbital

Valproic Acid (________)

(1) Indication + Class

(2) Additional Names

(3) Efficacy

(4) Cormorbid conditions

(5) Side effects

(6) DDI

(7) Therapeutic Range

Valproic Acid (Depakene)

(1) Indication: epilepsy - 1st gen ASM

(2) Additional names: divalproex (Depakote)

(3) Efficacy in different seizures:

⚫️Broad spectrum (good for both focal & generalized onset) (often used 2nd line in CAE)

(4) Comorbid conditions:

⚫️Bipolar d/o - mood stabilizer

⚫️Migraines - preventative treatment

(5) Side effects

⚫️ Hepatotoxicity

⚫️ Rash

⚫️ Teratogenic

⚫️ Weight gain

⚫️ Pancreatitis

(6) DDI: lots = "classic" inhibitor

(7) Therapeutic Range: TDM required (narrow)

what is the efficacy of carbamazepine

narrow

what might carbamazepeine exacerabate

generalized sz d/o including CAE

what comorbid conditions does carbamazepine treat

mood stabilizer (bipolar d/o), trigeminal neuralgia

what are the side effects for carbamazepine

hepatotoxicity, hyponatremia, idiosyncratic rash in Asians (risk of SJS/TEN) gene testing required

what are the DDIs for carbamazepine

INDUCER - auto induction

is TDM required for carbamazepine

yes

what is the efficacy for clonazepam

focal and generalized epilepsy

what comorbid conditions does clonazepam treat

sz d/o (clonazepam is a long-acting benzodiazepine)

t/f clonazepam may lead to drug abuse

true

what are the DDIs for clonazepam

none

what are the side effects for clonazepam

none

is TDM required for clonazepam

no

what is the efficacy for ethosuximide

gold standard for CAE

is TDM required in ethosuxide

no

what are the side effects for ethosuximide

hepatotoxicity and rash

what is hyponatremia

low Na+ levels

what AEDs may cause hypoatremia

carbamazepine, oxcarbazepine, eslicarbazepine

what is the efficacy for phenytoin

narrow

what might phenytoin exacerbate

generalized seizures including CAE

what are the comorbid uses for phenytoin

none

what are the side effects for phenytoin

all Na+ channels are neurotoxic - ataxia, sedation, decreased cognition, nystagmus, gingival hyperplasia, osteoporosis, idiosyncratic rash, hepatotoxicity

what are the DDIs for phenytoin

INDUCER

is TDM required for phenytoin

yes

what are the kinetics for phenytoin

non-linear

what does phenytoin bind a lot to

protein

does phenobarbital exacerbate CAE

yes

who uses phenobarbital a lot

kids

what are the side effects for phenobaribital

rash, hepatotoxicity, agression in kids

what are the DDIs for phenobarbital

INDUCER

is TDM required in phenobarbital

yes

what is primidone mainly used for

not used in epilepsy, used for essential tremor

what is primidone the prodrug of

phenobarbital

what is valproic acid also known as

divalproex and valproate sodium IV

what is the efficacy for valproic acid

broad spectrum (good for both focal and generalized onset)

valproic acid is often used _____ line for CAE

2nd line

what comorbid conditions does valproic acid also help

bipolar d/o, migraines

what are the side effects of valproic acid

hepatotoxicity, rash, teratogenic, weight gain, pancreatitis

what are the DDIs for valproic acid

lots = classic inhibitor

is TDM required for valproic acid

yes

what are the 2nd gen ASMs

(1) Felbamate

(2) Gabapentin

(3) Lamotrigine

(4) Levetiracetam

(5) Oxcabazepine

(6) Tiagabine

(7) Topiramate

(8) Zonisamide

-"ForGetLLOTTZ"

Felbamate

(0) Indication + Class

(1) Efficacy

(2) Side effects

(3) DDI

Felbamate

(0) Indication + Class: epilepy + 2nd gen ASM

(1) Efficacy: broad

(2) Side effects: powerful but limited by fatal side effects:

⚫️ aplastic anemia

⚫️ hepatotoxicity

(3) DDI: CYP3A4

Gabapentin

(0) Indication + Class

(1) Efficacy

(2) Side effects

(3) DDI

Gabapentin

(0) Indication + Class: most commonly use forneuropathic pain (not epilepsy) - 2nd gen ASM

(1) Efficacy: not great -- adjunct ony

(2) Side effects:

⚫️ sedation

⚫️ weight gain

⚫️ well-tolerated

(3) DDI: n/a bc renally cleared

Lamotrigine

(0) Indication + Class

(1) Efficacy

(2) Side effects

(3) DDI

(4) Comorbid contions

(5) Pregnancy

Lamotrigine

(0) Indication + Class: epilepsy - 2nd gen asm

(1) Efficacy: probably broad

(2) Side effects: rash SJS/TEN associated w/ fast titration

(3) DDI: valproate inhibits LTG metabolism

⚫️ CHZ, PHT, PHB induces LTG metabolism

(4) Comorbid contions: mood stabilizer (bipolar d/o); good for elderly b/c has least cognitive side effects

(5) Pregnancy: Follow levels in pregnancy

Levetiracetam

(0) Indication + Class

(1) Efficacy

(2) Side effects

(3) DDI

(4) Comorbid uses

Levetiracetam

(0) Indication + Class: epilepsy - 2nd gen asm

(1) Efficacy: most commonly used ASM

(2) Side effects: irritability

(3) DDI: n/a bc renally excreted

(4) Comorbid uses: n/a

Oxcarbazepine

(0) Indication + Class

(1) Efficacy

(2) Side effects

(3) DDI

(4) Comorbid uses

(5) Me too

Oxcarbazepine

(0) Indication + Class: epilepsy + 2nd gen ASM

(1) Efficacy: probably exacerbates primary generalized epilepsies

(2) Side effects: MORE hyponatremia than CBZ, less rash than CBZ

(3) DDI: less that carbamazepine

(4) Comorbid uses: can treat bipolar, neuropathic pain

(5) Me too: 2nd gen me too of CBZ

Topiramate

(0) Indication + Class

(1) Efficacy

(2) Side effects

(3) DDI

(4) Comorbid uses

(5) Additional Notes:

Topiramate

(0) Indication + Class: epilepsy - 2ng gen ASM

(1) Efficacy: probably broad (multiple MOA)

(2) Side effects: "DOPAMAX" - neurotoxic effects calls for slow titration

(3) DDI: high dose decreases oral contraceptives

(4) Comorbid uses: promotes weight loss, used in migraine prevention

(5) Additional Notes: carbonic anhydrase inhibitor -- small risk of kidney stones (keep well hydrated), acid/base distrubances

Zonisamide:

(0) Indication + Class

(1) Efficacy

(2) Side effects

(3) DDS

Zonisamide:

(0) Indication + Class: epilepsy - 2nd gen asm

(1) Efficacy: probably broad

(2) Side effects:

⚫️Na+ channel inbitor so > neurotoxic ADEs

⚫️Also carbonic anhydrase inhibitor ==> small risk of kidney stones (keep well hydrated)

(3) DDS: few/none

what is the efficacy for felbamate

broad

what are the side effects for felbamate

fatal side effects aplastic anemia and hepatotoxicity, not used a lot due to severe side effects

what are the DDIs for felbamate

CYP3A4

what is the efficacy of gabapentin

not great, adjunct only

what comorbid condition is gabapentin used for

neuropathic pain

what are the side effects for gabapentin

sedation, weight gain, well-tolerated

what are the DDIs for gabapentin

none b/c its renally cleared

what is the efficacy for lamotrigine

probably broad

what comorbid conditions does lamotrigine treat

bipolar d/o, good for elderly b/c has least cognitive side effects

what are the side effects for lamotrigine

rash (SJS/TEN)

when might a side effect for lamotrigine occur

fast titration

what are the DDIs for lamotrigine

valproate inhibits LTG metabolism, CBZ, PHT, PHB induces LTG metabolism

what should you do when pregnant people on lamotrigine

follow levels

what is SJS

life-threatening skin condition in which cell death causes the separation of inner and outer skin and mucous membrane