Anti-eplleptic therapy

Carbamazepine

Clinical utility:

• Monotherapy and adjunctive therapy in tonic-clonic and focal seizures Mechanism of action:

• Enhances inactivation of voltage-gated sodium channels Therapeutic drug monitoring:

• Steady-state concentration = 4-12 mcg/mL

Significant interactions:

• Auto-inducer of CYP 3A4

• Inducer of CYP 1A2, 2B6, 2C9, 2C19 Adverse drug effects:

• Dermatologic – HLA-B*1502

• Blood dyscrasias

• Hyponatremia – SIADH

• Osteoporosis

Clonazepam

Clinical utility:

• Monotherapy or adjunctive therapy for myoclonic, akinetic, and absence seizures

Mechanism of action:

• Competitively binds the GABA-A receptor and potentiates the effects of GABA via modulation of chloride efflux

Therapeutic drug monitoring:

• Not routinely completed

Significant interactions and adverse drug effects:

• Black Box Warning of respiratory depression when combined with opioids

Clinical pearls:

• Physiologic dependence and withdrawal are common upon abrupt discontinuation of maintenance therapy

• Significant CNS depressive effects

• May cause hallucinations, worsen ICU delirium, and increase aggression in patients

Ethosuximide

Clinical utility:

• Monotherapy or adjunctive therapy for absence seizures

• Drug of choice for absence seizures

Mechanism of action:

• Inhibition of T-type calcium channels

Therapeutic drug monitoring:

• 40-100 mcg/mL

Significant interactions and adverse drug effects:

• Valproic acid may increase or decrease levels

• Likely to affect levels of phenytoin, carbamazepine, phenobarbital, and phenytoin

Clinical pearls:

• Worsens tonic-clonic seizures

• Most reported adverse effect is hiccups

Phenobarbital

Clinical utility:

• Generalized and focal seizures Mechanism of action:

• Binds GABA-A receptor and potentiates GABA via modulation of chloride efflux

Therapeutic drug monitoring: 10-40 mcg/mL

Significant interactions and adverse drug effects:

• Interactions with most other anti-epileptic drugs

• Hydantoin structure = SJS/TEN Clinical pearls:

• Not FDA approved for any indication

• Used off-label for alcohol withdrawal

Primidone

Prodrug of phenobarbital:

• Converted to active intermediary metabolite phenylethylmalo-n-amide

Not commonly utilized for seizure disorders:

• Primarily used in the management of essential tremor

Phenytoin

Clinical utility:

• Focal seizures, tonic-clonic seizures

• Seizure prophylaxis post-operatively and in traumatic brain injury

Mechanism of action:

• Enhances inactivation of voltage-gated ion channels

Therapeutic drug monitoring:

• 10-20 mcg/mL (total)

• 1-2 mcg/mL (free)

Significant interactions and adverse drug effects:

• Hydantoin structure – SJS/TEN

Major drug-drug interactions with CYP3A4 (warfarin)

Phlebitis and Purple Glove Syndrome (IV)

Clinical pearls:

• • Pediatric patients typically tolerate fosphenytoin better

• • Extravasation risk is significant – counteract with hyaluronic acid

Fosphenytoin

Clinical utility:

• Focal seizures, tonic-clonic seizures

• Seizure prophylaxis post-operatively and in traumatic brain injury

Mechanism of action:

• Enhances inactivation of voltage-gated ion channels

• Phosphorylated pro-drug of phenytoin, activated by serum esterases

Therapeutic drug monitoring: • Monitor phenytoin levels

Significant interactions:

• Same as phenyotin

Clinical pearls:

• Rate of infusion is three times faster than phenytoin

• Phenytoin = 50 mg/min

• Fosphenytoin = 150 mg/min

• Potentially nullified by time-to-activation

• Less incidence of phlebitis

VPA and Derivatives

Clinical utility:

• Focal seizures, general seizure disorders

• Most utilized drug for absence seizures in patients >10

Mechanism of action:

• Hypothesized to mediate GABA transmission

• Exact mechanism unknown

Therapeutic drug monitoring: • 50-100 mcg/mL

Significant interactions and adverse drug effects:

• Black Box Warning for hepatoxicity

• Hyperammonemia

• Associated with nail bed abnormalities, hirsutism, alopecia

Clinical pearls:

• Contraindicated in urea cycle disorders

• Pregnancy Category D

Used off-label for migraines, mood/behavioral augmentation

Levocarnitine

Naturally-occurring amino acid

• Synthesized endogenously via combination of lysine and methionine

• Occurs in the liver and kidneys

Important in metabolism of foreign materials (pharmaceuticals) Found in large quantities in:

• Liver

• Kidneys

• CNS

Initial loading dose

• 100 mg/kg IV x1 dose (maximum of 6000 mg)

• Administered as 2-3 minute push or 10-15 minute infusion

Maintenance dose

• 50 mg/kg IV q6-8h (maximum of 3000 mg)

• Continued until decreases in ammonia level present and clinical improvement noted

• Generally ≤ 72 hours

• Administered as 2-3 minute push or 10-15 minute infusion

Felbamate

Clinical utility:

• Focal onset seizures with or without tonic-clonic seizures

Mechanism of action:

• Antagonizes N-methyl-D-aspartic acid receptors as well as GABA-A receptors

Therapeutic drug monitoring: • 30-60 mcg/mL

Significant interactions and adverse drug effects:

• Black Box Warning for aplastic anemia and hepatoxicity

• Aplastic anemia risk = >100-fold increase from general population

Clinical pearls:

• Only indicated for super-refractory seizure

Gabapentin

Clinical utility:

• Adjunctive therapy in most seizure types, with the exception of absence seizures and tonic-clonic seizures Mechanism of action:

• Binds to alpha-2 subunit of calcium channel, with unknown effects on seizures

Therapeutic drug monitoring: • 2-20 mcg/mL

Clinical pearls:

• Rarely utilized in seizure disorders

• Commonly utilized in: • Neuropathic pain • Restless leg syndrome • Post-herpetic neuralgia • Alcohol withdrawal • Chronic refractory cough

Lamotrigine

Clinical utility:

• Adjunctive therapy for focal-onset seizures without tonic-clonic motion

Mechanism of action:

• Enhances fast inactivation of voltage-gated sodium channels

Therapeutic drug monitoring: • 4-20 mcg/mL

Significant interactions and adverse drug effects:

• Significant interaction with valproic acid: • Max dose of lamotrigine if on VPA: 500 mg

Clinical pearls:

• Utilized for bipolar disorder, headaches, and trigeminal neuralgia

Levetiracetam

Clinical utility:

• Workhorse of modern anti-epileptic agents

• Utilized in focal-onset, myoclonic, JME, tonic-clonic seizures

• Second or third line for absence seizure

Mechanism of action:

• Inhibits synaptic vesicle SV2A which prevents neurotransmitter release

Therapeutic drug monitoring: • 10-66 mcg/mL

• Not correlated with clinical efficacy or safety

• Not routinely measured other than to confirm adherence

Significant interactions and adverse drug effects:

• Minimal drug-drug interactions

• Negative behavior effects

Clinical pearls:

• 100% oral bioavailability

• Can be administered as an undiluted IV push

• Useful in status epilepticus

Oxcarbazepine

Clinical utility:

• Focal-onset seizures Mechanism of action:

• Enhances inactivation of voltage-gated sodium channels

Therapeutic drug monitoring: • Not routinely monitored

Significant interactions and adverse drug effects:

• Inhibitor of CYP 2C19 and inducer of CYP 3A4

• 3A4 less significant than carbamazepine

Clinical pearls:

• Structural analog of carbamazepine with fewer adverse effects

• Considered safer alternative with regard to dermatologic reactions

• Eslicarbazine (Aptiom) and oxcarbazepine are metabolized to same intermediary compound

Lacosamide

Clinical utility:

• Focal-onset seizures, generalized tonic-clonic, and status epilepticus

• Post-injury prophylaxis in neurologic injury/traumatic brain injury

Mechanism of action:

• Mediates voltage-gated ion channels

Therapeutic drug monitoring: • Not routinely monitored

Significant interactions and adverse drug effects:

• Substrate of CYP 3A4, 2C9, 2C19

• Requires dose adjustment in hepatic impairment

Clinical pearls:

• May be necessary to decrease doses of concomitant agents by up to 20%: • Carbamazepine • Phenytoin • Phenobarbital • Primidone

Perampanel

Clinical utility:

• Focal-onset seizures, tonic clonic seizures

• Commonly as adjunctive therapy

Mechanism of action:

• Non-competitive antagonist of glutamate receptors on post-synaptic neurons

Therapeutic drug monitoring: • Not routinely monitored

Significant interactions and adverse drug effects:

• Black Box Warning for significant psychiatric events, including suicidal and homicidal ideation

• Dose-dependent CYP enzymatic inducer Clinical pearls:

• Schedule III controlled substance

• Associated with weight gain

Clobazam

Clinical utility:

• Adjunctive therapy for non-absence seizure classifications

Mechanism of action:

• Binds GABA-A receptors and potentiates GABA via modulation of chloride conductance

Therapeutic drug monitoring: • 0.03 – 0.3 mcg/mL

Significant interactions and adverse drug effects:

• Black Box Warnings for: • Profound sedation and respiratory depression in combination with BZD’s and opioids • Abuse, misuse, and addiction • Physiologic dependence and withdrawal reactions • Inhibitor of CYP 2C9, inducer of CYP 3A4 Clinical pearls: • Schedule IV controlled substance • Moderate association with dermatologic reactions • Unique for benzodiazepines

Cannabidiol

Clinical utility:

• Primarily used in Dravet syndrome and Lennox-Gastaut Syndrome

• More commonly being prescribed for refractory status epilepticus, NORSE, and FIRES

Mechanism of action:

• Unknown – does not bind to CB1 or CB2 receptors Therapeutic drug monitoring:

• Not routinely monitored

Significant interactions and adverse drug effects:

• Increases lamotrigine levels

• Increases clobazam metabolite concentration by 300%

Clinical pearls: • Hepatotoxicity and respiratory failure are significant • May be associated with ICU delirium and poor sleep hygiene