Epilepsy (green slides) (copy)

What are the four mechanisms of antiepileptic drugs?

• Inhibit voltage-activated Na+ channels

  • stunts AP — stops or slows the action potential = less brain excitability = fewer seizures.

  • most common

• Inhibit voltage-activated Ca2+ channels

  • stunts AP — stops or slows the action potential = less brain excitability = fewer seizures.

• Enhance GABA-mediated synaptic inhibitor which target pre- and post-synaptic GABA activity

  • GABA is inhibitory

• Attenuate glutamate-mediated excitatory responses which antagonize AMPA or NMDA receptors

What are the of Na+ channel blockers

• Phenytoin

• Carbamazepine

• Oxcarbazepine

• Zonisamide

• Lamotrigine

• Lacosamide

What is Phenytoin (Dilantin)?

A Na+ channel blocker used for focal and generalized seizures

What forms is Phenytoin (Dilantin) given in?

• Available in oral and IV

• IV form can cause HYPOTENSION because PROPYLENE GLYCOL

What is the max infusion rate for Phenytoin (Dilantin)?

• 25-50 mg/min

• to decrease rate of hypotension, infuse over 1-2 hours

  • Even lower for older patients above 65 years of age

• oral has no risk for HTN

What is the Phenytoin (Dilantin) pharmacokinetics?

• Half-life ~24 hours

  • takes 4-5 days to reach steady state

• It is highly protein bound (to albumin)

• It is metabolized by the liver meaning that it is dose-dependent

  • Michaelis Mentin kinetics = non-linear kinetics → small increase in dose may result in large increase in drug exposure (1+1 does not = 2)

What is protein binding?

• If bound, then drug is in INACTIVE FORM

• Needs to be unbound to reach the brain in order to have therapeutic effect

• Therefore if you give two drugs that are both HIGHLY protein bound, then they will compete for binding sites therefore leaving more of each drug unbound

• As a result this increases risk for TOXICITY

What may happen if a pt who has low albumin levels is taking phenytoin?

highly protein bound drug SO low albumin = less drug bound → more drug is active → pt needs a lower dose!

What pt populations are we concerned with in regard to phenytoin concentration?

Low albumin pts - cancer, liver failure, renal disease, malnutrition

What is the monitoring needed for Phenytoin (Dilantin)?

• Requires monitoring of serum concentrations

• Measure concentrations 5 days after starting medication or any dose change

Target concentration after 5 days of dosing for Phenytoin?

• Total: 10-20 mcg/mL

• Free: 1-2 mcg/mL

  • do not need to adjust for albumin levels if lab tests for this

• These are therapeutic levels

What does free Phenytoin concentration mean?

Amount of drug unbound

What does total Phenytoin concentration mean?

Includes bound and unbound

*phenytoin has 90% bound

When should TOTAL phenytoin level be adjusted?

• Low albumin (< 3.2 mg/dL)

• If total concentration lab result is LOW, must account for that information

• The level that we are getting back is likely underrepresented in individuals with renal disease, malnutrition, cancer, liver failure because these individuals naturally have low albumin

What are the adverse effects of Phenytoin?

• Adverse effects dependent on the route of administration, dosage and duration of exposure

• Nystagmus/diplopia/ataxia which is an indication to check level (may be too high)

• Anticonvulsant hypersensitivity syndrome (AHS): rash, increased LFTs, and fever

  • If this happens patient can NEVER take again

• Gingival hyperplasia

• Hirsutism

• Purple glove syndrome = extravasation of phenytoin

• Bone marrow suppression = leukopenia, thrombocytopenia, anemia

• Cardiovascular hypotension, bradycardia which is seen with IV formulation

What are Phenytoin drug interactions?

• potent INDUCER of CYP 3A4

• There are displacement interactions with other highly protein bound drugs

  • e.g. valproic acid

  • Whichever is displaced is now unbound and now active and you will see more effects of that drug

• Tube feedings and antacids of heavy cations (Ca2+, Al3+, Mg2+) cause a significant reduction in bioavailability (absorption)

  • You should space dosing by 2 hours to avoid chelatation (binding) of the drug

  • also concern with pts who take protein shakes at home

What is carbamazepine (Tegretol)?

It is a Na+ channel blocker

What forms is Carbamazepine available in?

Oral formulation only

What are the pharmacokinetics of Carbamazepine (Tegretol)?

• Highly protein bound

• Requires monitoring of serum concentrations

  • goal 6-10 mcg/mL **

• Substrate AND inducer of CYP 3A4 and others

  • auto inducer: upregulates CYP enzymes and induces its own metabolism within 6 weeks and possibly cause breakthrough seizures

What is the goal serum concentration for Carbamazepine (Tegretol)?

6-10 mcg/mL

Should Carbamazepine (Tegretol) be given with food?

YES to avoid GI upset

What are the adverse effects of Carbamazepine (Tegretol)?

• Some tolerance can develop

• CNS: blurred vision, unsteadiness, drowsiness

• Nausea/GI upset (take with food)

• Transient elevations in LFTs

• Hyponatremia (SIADH) - more common in elderly

• dermatologic reactions, blood dyscrasias, anticonvulsant hypersensitivity syndrome/AHS

What is the boxed warning for Carbamazepine?

BOXED WARNINGS: dermatologic reactions, blood dyscrasias, anticonvulsant hypersensitivity syndrome/AHS

What are the drug interactions of Carbamazepine (Tegretol)?

• Induces metabolism of many drugs (CYP 3A4)

• Displacement interactions when given with other highly protein bound drugs

• autoinducer → potential breakthrough seizures

What allele should you test for when prescribing Carbamazepine (Tegretol)?

• HLAB1502 - Increases your risk of anticonvulsant hypersensitivity syndrome (AHS)

• Often seen in patients with south East Asian decent so must screen these pts

What is anticonvulsant hypersensitivity syndrome (AHS)?

• Rare, life-threatening immunologic adverse drug reaction

• Associated with several anticonvulsants

• Symptoms include fever, malaise, rash/skin eruption, systemic organ involvement

• Can result in Steven Johnson Syndrome

• Treatment involves supportive care, corticosteroids, and removal of offending agent

Zonisamide (Zonegran)

Na+ channel blocker

What forms is Zonisamide (Zonegran) available in?

Oral formulation only

What is the pharmacokinetics of Zonisamide (Zonegran)?

• It is a substrate of CYP 3A4

• It is primarily excreted by kidneys and therefore requires closer monitoring for ADEs in patients with renal impairment

What are the adverse effects with Zonisamide (Zonegran)?

• Drowsiness, ataxia, anorexia, agitation

• Less common/rare: renal stones, suicidal ideation

What is the contraindication for Zonisamide (Zonegran)?

SULFA allergy → skin rxn

What is Lamotrigine (Lamictal)?

Na+ channel blocker

What forms is Lamotrigine (Lamictal) available in?

Oral formulation only

What are the adverse effects of Lamotrigine (Lamictal)

• Dizziness, blurred vision, headaches

• Cardiac: exhibits class 1B antiarrhythmic properties in vitro therefore — avoid in patients with a history of heart failure, ischemia, ventricular arrhythmias, cardiac conduction disorders

• boxed warning: AHS skin rxn

What is the boxed warning for Lamotrigine (Lamictal)?

BOXED WARNING: skin reactions (AHS) and should be discontinue at first sign

What are the drug interactions of lamotrigine (Lamictal)?

• oral contraceptives

  • patient could have reduced concentrations of both = less effective meds

• Fosphenytoin/phenytoin

  • can induce lamotrigine metabolism → decreased levels of lamotrigine

• Valproate

  • can inhibit metabolism of lamotrigine — need to lower dose of lamotrigine

What is Lacosamide (Vimpat)

• Na+ channel blocker

• great drug to use after pt is stabilized

What forms is Lacosamide (Vimpat) available in?

Oral and IV formulations

What are pharmacokinetics of Lacosamide (Vimpat)?

• Excellent bioavailability, minimal protein binding

• There is no significant drug interactions

• It is safer and no therapeutic monitoring required

Which Na+ channel blocker drug is a controlled-substance (schedule V)

Lacosamide (Vimpat)

What are the adverse effects of lacosamide (Vimpat)?

• Diplopia

• vertigo

• headache

• dizziness

• somnolence

What are the Ca2+ channel blockers?

Ethosuximide (Zarontin)

What is the MOA of Ethosuximide (Zarontin)?

To reduces Ca2+ influx by blocking calcium channels

What forms is Ethosuximide (Zarontin) avialable in?

Oral formulation

What is the pharmacokinetics of Ethosuximide (Zarontin)?

• Metabolized by the liver

• Requires serum concentration monitoring = 40-100 mcg/mL

What is the goal serum concentration for Ethosuximide (Zarontin)?

40-100 mcg/mL

What are the adverse effects of Ethosuximide (Zarontin)?

• GI related adverse events: nausea, vomiting, cramps, wt loss

  • divide dose to reduce risk

• CNS: suicidal ideation, psychosis, mania, sleep terrors, aggressiveness

• Blood dycrasias

• Skin reactions

What are the drugs that affect GABA?

• Phenobarbital

• Valproate

What is the MOA of Phenobarbital (Luminal)

Inhances post-synaptic GABA receptor (increase duration of Cl- influx and prolongs hyperpolarization) = resulting in an inhibitory response

What is pharmacokinetics of Phenobarbital (Luminal)?

• It is a STRONG INDUCER of CYP 3A4

• Requires serum monitoring with a goal of 10-40 ug/mL

• It is reserved for refractory cases

What are the adverse effects of Phenobarbital (Luminal)?

• Hypotension

  • IV - due to addition of propylene glycol

  • never push!! Always infuse

• CNS: somnolence, irritability, nightmares, hallucinations, agitation, altered loc, abuse

• Toxicity: respiratory depression

True/false: Phenobarbital can be given IV push

False

Rationale: The propylene glycol can cause hypotension so must be given slowly through infusion to avoid BP crash

What is the MOA of Valproate (Depakote)?

• Stimulates glutamic acid decarboxylase (enzyme that converts glutamate to GABA) and inhibits GABA degradation = increases GABA

• Blocks Na+ channels

• Blocks Ca2+ channels

What form is Valproate (Depakote)?

Many different oral formulations that are not interchangeable

What is pharmacokinetics of Valproate (Depakote)?

• Highly protein bound

• Inhibitor of CYP2C9, 3A4 (many drug interactions)

  • increases concentration of substrate

• Serum concentration monitoring (Goal 50 - 140 mcg/ml)

What is the serum concentration goal of Valproate (Depakote)?

50 - 140 mcg/ml

What is the boxed warning for Valproate (Depakote)?

BOXED WARNINGS: pancreatitis (rare), hepatotoxicity, teratogenicity (neural tube defects)

What are the adverse effects of Valproate (Depakote)?

• Transient GI symptoms (anorexia, nausea, vomiting)

• Alopecia

• CNS: headache, dizziness, somnolence, sedation, tremor

• Weight gain (chronic use)

• Thrombocytopenia

• Elevated hepatic transaminases

• BOXED WARNINGS: pancreatitis (rare), hepatotoxicity, teratogenicity (neural tube defects)

What are the drug interactions of Valproate (Depakote)?

• Displacement reactions with other highly protein binding drugs

  • e.g. phenytoin

• CYP-mediated

  • inhibits metabolism of phenytoin, phenobarbital, carbamazepine

• Increases lamotrigine levels (serious skin rxn)

• do not use in pregnant pts

How should you titrate Valproate (Depakote)?

SLOWLY

What are the drugs that affect glutamate?

• Gabapentin (Neurontin)

• Perampanel (Fycompa)

• Levetiracetam (Keppra)

What is the MOA of Perampanel (Fycompa)?

Glutamate receptor antagonist

What are pharmacokinetics of Peramanel (Fycompa)?

• Highly protein bound

• Substrate of CYP 3A4

• Use not recommended with CrCl < 30 mL/min

• Class III medication

What form is Perampanel (Fycompa) available in?

Available in oral formulation only

What are the adverse effects of Perampanel (Fycompa)?

• Weight gain, nausea, dizziness, headache

• hx of psych disorders WILL NOT be the drug of choice bc of boxed warnings

What is the black boxed warning for Perampanel (Fycompa)?

BOXED WARNING: serious psychiatric and behavioral disorder (aggression, anger, hostility, irritability)

What is the MOA of Levetiracetam (Keppra)

Binds to a synaptic vesicle protein (SV2A) - responsible for reducing presynaptic glutamate release

What is pharmacokinetics of Levetiracetam (Keppra)?

• Low protein binding and low drug interactions

• Some advocate for therapeutic drug monitoring although it is not routine, but helps to check for compliance if there are breakthrough seizures

What form is Levetiracetam (Keppra) available in?

Available in oral and IV

What are the adverse effects of Levetiracetam (Keppra)?

• Overall it is well-tolerated

• Somnolence, fatigue, coordination difficulties, bad dreams, hallucinations

What are some adverse effects of anti epileptic drugs in pregnancy?

• Patients who are pregnant and are diagnosed with epilepsy are at a 2-fold greater risk of delivering a baby with major congenital malformations and cognitive impairment such as heart defects, cleft palate, neural tube defects

• There is no completely safe AED

• Drug interactions may reduce efficacy of oral contraceptives via induction of the oral contraceptive metabolism including up to 4 weeks after stopping AED

• CYP inducers also induce vitamin K metabolism which can lead to coagulopathy/ICH in baby so it is best to supplement during the last gestational month

• Refer pregnant patient to specialist

Which antieplieptic drugs should be avoided during pregnancy?

AVOID use of phenytoin, carbamazepine, valproate, phenobarbital, topiramate, others

Which antiepileptic drugs have lower complications in pregnancy?

Levetiracetam (Keppra) and lamotrigine appear to have lower rate of complications in pregnancy compared to others