Neurology Pt 2 Epilepsy Flashcards
Seizure vs. Epilepsy
- Seizure =
- Epilepsy =
- Decision to treat is multi-factorial
- Cause of seizure, risk of recurrence, patient, toxicities
- Transient alteration of brain dysfunction resulting from abnormal discharge of cerebral neurons
- Chronic disease state characterized by periodic and unpredictable occurrences of seizures
Resting Membrane Potential (RMP)
- ____ of neuron during ___-excited state (-70mV)
- Overall net charge _____ the neuron is ____ (relative to the outside)
- Membrane is selective of the ions that can enter/exit (via ion ____)
- At rest, ______ easily crosses
- ____:____ pump transports __ Na+ __ for every __ K+ __ the cell
- State, non-excited
- inside, negative
- channels
- K+
- Sodium (Na+): Potassium (K+), 3 NA+ out, 2 K+ in
Action Potential
- stimulus increases voltage in the cell*
- Threshold level is reached -> action potential is activated*
- 2 channels open both Na and Ca rush in (which are both CATIONS) = makes inside more positive*
- Action potential peaks -> Na channesl start to close, K+ channels start to open*
- Hyperpolarization = relaxation phase (this is normal, this is how our neurons communicate)*
Pathophysiology
How do Antiepileptic Drugs Work?
- Three primary mechanisms
1. _____ excessive action potentials - Target voltage -activated ___ channels
- Target voltage - activated ___ channels
- _____ GABA - mediated synaptic inhibiton
* Target pre-post ______ GABA activity - ______ Glutamate mediated excitatory responses
* Antagonize ____ or ____ receptors
- Inhibit
- Na+
- Ca2+
- Enhance
* synaptic - Attenuate (decrease)
* AMPA, NMDA
* In epilepsy there’s excessive action potentials - so we treat by blocking those Na+ and Ca+ channels*
* Since GABA is inhibitory and seizures are pretty excitatory = we want more gaba*
* Glutamate is excitatory so we want inhibiit Glutamate*
Classification of Seizures
Where, Awareness, Features?
- Focal Onset
- Generalized Onset
Treatment will depend on:
- Focal Onset (Aware/Impaired Awareness)
- Motor or Non-Motor
- Focal to bilateral Tonic Clonic
- Generalized Onset (Impaired Awareness)
- Motor
- Tonic Clonic Other motor
-
Non-Motor
- Absence
type
- How many parts of the brain affected? (focal is one part, general is all)*
- Generalized = you lose consciousness (more severe) - Not many treatments for NON-MOTOR ABSENCE (pts are unaware that it occurs and you don’t see tonic clonic)*
- Many drugs are broad and treat focal and general but depends*
Na+ Channel Blockers
(4)
Phenytoin (Dilantin)
Carbamazepine (Tegretol)
Zonisamide (Zonegran)
Lamotrigine (Banzel)
Phenytoin (Dilantin)
Indications
Focalized and Generalized (motor)
No activity against absence seizures
Phenytoin (Dilantin)
Routes
- Available in __ and ___
- IV formulated with _____ _____ causes _____ (loading doses)
- Max infusion rate: ___-___ mg/min
- Lower rate decreases risk for _____
- PO, IV
- propylene glycol, hypotension
- 25-50 mg/min
- hypotension
- Hypotension classicly seen during loading dose therefore there is a max loding dose*
- Story: ICU pt admitted dt hypotension from phenytoin IV infusion*
- Especially in elderly more like 15-25 mg/min loading dose over 2 hours*
Phenytoin Pharmacokinetics
- Half Life ~ ______
- Highly ____ bound (~90%)
- Metabolized by the ____
- Dose dependent (Michaelis Mentin also known as _______ kinetics)
- Enzyme system becomes ______
- Small increase in dose may result in:
- Dose dependent (Michaelis Mentin also known as _______ kinetics)
- 24 hrs
- Protein
- Liver
- nonlinear
- saturated
- large increase in drug exposure
- nonlinear
- Takes about 5 days to achieve steady state bc Equilibrium takes 5 half lives*
- You have a pt that got phenytoin day before and is still having seizures (this makes sense)*
- Bounded = NON ACTIVE*
- If pt has low protein = more unbound drug = more AE*
- If you give 2 protein bound drugs, you can displace one another = more AE*
Phenytoin (Dilantin)
- Does it require serum concentrations?
- Target concentration taken when?
- Total concentration: __-__ mcg/mL
- Free concentration __-__ mcg/mL
- Concentration dependent _ _
- > ___mcg/mL =
- > ___ mcg/mL =
- > ___mcg/mL =
- YES
-
5 days after dosing
- 10-20 mcg/mL
- 1-2 mcg/mL
- SE
- >20 = nystagmus
- > 30 = ataxia, seizure
- > 40 = lethargy, coma
- Has a narrow therapeutic index*
- Waiting 5 days to see most accurate concentration*
- Nystagmus is very troubling to the pt*
Interpretation of Serum Phenytoin Concentrations
- Very important to remember that phenytoin is?
- Adjust _____ phenytoin level if:
- ____ ______ (<_._ mg/dL)
- Conditions that may predispose (4)
- ____ ______ (<_._ mg/dL)
- highly protein bound
-
total
-
Low albumin (<3.2mg/dL)
- Renal disease, malnutrition, cancer, liver failure
-
Low albumin (<3.2mg/dL)
- Dt hypoalbinumia = actually supratherapeutic of 30mcg/mL and needs dose reduction*
- DON”T NEED TO CALCULATE FOR EXAM- just recognize there are pts that are predisposed to low albumin that are on phenytoin, let me check the adjusted levels*
Phenytoin
Adverse Effects
Dependent on the route of administration, dosage, and duration of exposure
- Nystagmus/Diplopia/Ataxia -indication to check lvl (may be dosed too high)
- Phenytoin anticonvulsant hypersensitivity syndrome (AHS): rash, ^LFTs, fever
- Gingival hyperplasia ~20% of chronic use
- Hirsutism can be dose related (extra hair growth)
- Purple glove syndrome -extravasation of phenytoin
- Leukopenia, Thrombocytopenia, Anemia
- Cardiovascular: hypotension, bradycardia
- hypotension form IV bc of poly glycol (not from phenytoin)*
- If gotten extravasation cannot use phenytoin anymore*
- AE really for all Antiepileptic drugs = always look for these AE*
Phenytoin Drug Interactions
Metabolism (2)
Drug Interations (3)
- potent inducer, is a substrate
- Other highly protein bound drugs (valproic acid) (it gets displaced)
- Tube feedings
- Antacids (Ca2+, Al+3, Mg+2) sign reduction in bioavailability (absorption), so if on phenytoin space dosing by 2 hrs
- Displacement and reduction of total absorption is why we have to space them out from other protein bound drugs*
- Pt takes ensure, you didn’t know and concentrations are so high! You can ask, hey have you changed your diet instead of automatically decreasing dose*
Carbamazepine (Tegretol)
Indications
Focal and Generalized (Motor) Seizures
Carbamazepine (Tegretol)
Routes
PO only
Give with food to avoid GI upset
Carbamazepine Pharmacokinetics
- Highy ______ bound (~75%)
- Does it require serum concentration levels?
- Protein
- Yes (goal 6-10mcg/mL)
Carbamazepine Metabolism
(2)
-
Inducer*
- AUTOINDUCTION: Up regulates and induces its own metabolism
- Substrate*
Carbamazepine
AE
(some tolerance can develop)
- CNS: blurred vision, unsteadiness, HA, sedation
- Nausea/GI upset (take with food)
- Transient elevations in LFTs
- Transiet Leukopenia
- Hyponatremia (SIADH) - more common in elderly
- Boxed Warnings: dermatologic reactions, blood dyscrasias (AHS)
- Lots of AE -> so check BMP, CBCs*
- AHS!! - from HLA-B protein found on outer portion of our white cells - can cause T cell/autoimmune response = this allele is more commonly seen in pts of southeast asian decent - therefore this allele is v common*
- ABSOLUTELY MUST TEST FOR THIS ALLELE BEFORE STARTING DRUG*
Carbamazepine
Drug Interactions (2)
- Induces metabolism of many drugs: ex) ORAL CONTRACEPTIVES*
- High protein bound -> Displacement interactions
PO contraceptives failure and a lot of anticonvulsants are teratogenic so v dangerous to the baby - they have to get off PO contraceptives and change to something else/have backup
Poll
Which drug is most at risk for causing hypotension?
IV Phenytoin
Anticonvulsant Hypersensitivity Syndrome (AHS)
- =
- Occurs in one case per every 1000-10,000 exposures
- Mortality has been reported up to 40%
- Associated with several _________
- Phenytoin, Carbamazepine, Lamotrigine, others
- Variable onset: __-__ wks after exposure
- ____-reactivity between agents can occur
- Rare, Life-threatening immunologic adverse drug reaction
- Anticonvulsants
- 2-12 weeks so can occur like 3 months after start! RARE, HIGH MORTALITY
- Cross
AHS
- Pathophys largely _____
- Thought to involve __-cell activation (from metabolites)
- Deficiency or abnormality in epoxide hydroxylase enzyme
- _____ predisposition with certain ___ subtypes
- Tx: _____ care, cortico_____, and ____ of agent
- unknown
- T
- Ethnic, HLA
- supportive, steroids, removal
AHS: Triad of Symptoms
(3)
- Fever, malaise
- Rash/skin eruption
- can range from mild exanthematous eruption to steven johnsons, present in 90% of pts
- Systemic organ involvement
- hepatitis, nephritis, cervical lymphadenopathy, eosinophilia, blood dyscrasias
Zonisamide (Zonegran)
Indications
Focal, Generalized (motor), and unknown seizures
Again doesn’t cover NON MOTOR GENERALIZED (ABSENCE)
Zonisamide
Routes
PO Only
Zonisamide Pharmacokinetics
- Inhibitor, Inducer, Substrate?
- Excretion
- Titrate dose _____, monitor closer for ___ in pts with ____ impairment
- Substrate
- Primarily by the Kidneys
- slower, ADE, renal
Renal *** increases risk for AE
Zonisamide
AE
- Significant adverse effects
- Somnolence, ataxia, anorexia, nervousness, fatigue
- Renal stones (rare)
- Suicidal ideations (rare)
- Metabolic acidosis (rare-renal dx, severe diarrhea)
- Monitor bicarbonate levels before and periodic after start
- They’ll feel a lot more tired/fatigued*
- Renal stones, SI*, metabolic acidosis - so V important to start low*
Zonisamide
Contraindications
Sulfa Allergy (skin reaction)
VVV important, Can’t use this drug!
Lamotrigine (Lamictal)
Indications
Focal, Generalized (motor), and unknown seizures
Lamotrigine
Routes
PO only
Lamotrigine
AE
- Diziness, blurred vision, headaches
- Boxed Warning: Skin reactions - AHS - discontinue at first sign
VV Important to slowly titrate! Must ask do you have any RASH ANYWERE?!
Lamotrigine
Drug Interactions (3)
- Oral contraceptives (both lamotrigine and oral contraceptives can have reduced concentrations)
- Fosphenytoin/Phenytoin can induce lamotrigine metabolism (decrease levels)
- Valproate can inhibit metabolism of lamotrigine - must lower dose of lamotrigine if adding valproate
When you have a pt on Lamotrigine and PO contraceptive- they can reduce each other - have very thorough converstaion about using backup concentration
Drug interactions are common with antieplipetic drugs due to which pharmacokinetic (PK) characteristic?
- Bioavailability
- Low protein binding
- CYP induction
- All of the above
CYP Induction
Ca2+ Channel Blockers
Agents
Ethosuximide (Zarontin)
Ethosuximide (Zarontin)
Indications
*******ABSENT SEIZURES*******
First one that treats Absent seizures!
Ethosuximide
MOA
Reduces Ca2+ influx by inhibiting channels
Ethosuximide
Routes
PO only
Ethosuximide Pharmacokinetics
Metabolism
Does it need serum concentration monitoring?
Metabolized by the Liver
Yes (goal 40-100mcg/mL)
Ethosuximide
AE
- Nausea and vomiting (divide dose), anorexia, weight loss, abdominal cramps
- Psychosis, mania, sleep terrors, aggressiveness
- CNS depression
- Parkinsonian movements (dose related)
- Blood dyscrasias (rare)
SEVERE N/V -> split dose bc noncompliance = breakthrough seizures
GABA Agonists
Agents
Phenobarbital (Luminal)
Valproic Acid (Depakote)
Phenobarbital (Luminal)
Indications
Focal, Generalized (motor), Status epilepticus
Reserved for refractory cases (better meds available)
Not a commonly used drug/for pts who don’t respond to new drugs- but the thing is its a very dangerous drug - so if you do see it know what you should be avoiding
Phenobarbital
MOA
Enhances post-synaptic GABA-A receptor
(increases duration of Cl- influx and prolongs hyperpolarization) = inhibitory response
Phenobarbital
Routes
PO and IV
Controlled medication - IV
IV formulations can NEVER BE PUSHED!** - ALWAYS QUESTION IV PUSH - can be given as drip but not IVP also dt propylene glycol*
Phenobarbital Pharmacokinetics
Inhibitor, Inducer, Substrate?
Serum concentration levels required?
strong INDUCER
YES (goal 10-40ug/mL)
Phenobarbital
AE
-
Hypotension/Respiratory Depression (IV)
- dt propylene glycol if infused too rapidly…which other drug can cause this?
- Sedation (may develop tolerance)
- Nystagmus and ataxia (toxicity)
- Irritability
- Confusion (more so in elderly)
I am an antiepileptic drug used to treat focal and generalized seizures. I have a boxed warning for causing serious dermatologic reactions and can induce my own metabolism during the first 6 weeks of treatment. What is my mechanism of action?
- Sodium Channel blocker
- Glutamate antagonist
- GABA agonist
- Calcium Channel Blocker
Sodium Channel Blocker
(Carbamazepine = autoinducer)
Valproate (Depakote)
Indications
Focal, Generalized motor, and ABSENCE* (Generalized non motor)
FIRST LINE FOR GENERALIZED seizures based on years of study and efficacy INCLUDING ABSENCE*
Valproate (Depakote)
MOA
Multiple MOA
- Stimulates glutamic acid decarboxylase (enzyme that converts glutamate to GABA) and inhibits GABA degradation
- Na+ channels, Ca2+ channels
Really the full gamet! Valproate inhibits
Valproate
Routes
Many different formulations (not interchangeable)
- We want to keep pts on their original formulation as much as possible - ex) pt was like I can ONLY take the blue and white pill (specific brand)*
- Mindfully convert - is not necessariyl 1:1 conversion*
- V diverse formulations (*DR/ER/DR tablets, capsule, Sodium Valproate IV form, Valproic acid oral solution)
Valproate Pharmacokinetics
Inhibitor, Inducer, Substrate, Protein bound?
Needs serum concentrations?
- Inhibitor
- Highly Protein bound
- YES (target 50-140mcg/ml)
Valproate
AE
- Boxed warnings: pancreatitis (rare), hepatotoxicity, teratogenicity (neural tube defects)
- Transient GI symptoms (anorexia, N/V) ~16%
- Alopecia
- CNS: HA, dizziness, somnolence, sedation, tremor
- Weight gain (chronic use)
- Thrombocytopenia (less common)
- Elevated hepatic transaminases (asymptomatic)
- Even though is recommended 1st line still a slew of AE*
- 1/5 will experience GI effects, Monitor LFT’s bc transaminitis*
Valproate
Drug Interactions
- Displacement reactions (e.g phenytoin)
- CYP-mediated (inhibits metabolism of phenytoin, phenobarbital, carbamazepine)
- Increases lamotrigine levels (serious skin reactions)
- slowly titrate doses
- remember its inhibitory /increases lamotrigine*
Glutamate Antagonists
Agents
Topiramate (Topamax)
Levetiracetam (Keppra)
- Remember Glutamate is our primary excitatory we want to block*
- INHIBITS NMDA RECEPTORS*
Topiramate (Topamax)
Indications
Extra Indications
Focal seizures (including LGS), Generalized motor, and Absence Generalized non-motor
Migraines, Weight loss
Fallen a bit out of favor but commonly prescribed for off label indications (migraines, weight loss)
Topiramate
MOA
- AMPA glutamate receptor antagonist
- Also inhibits Na+ channels
- Prolongs K+ efflux (hyperpolarization)
- Enhances GABA
Topiramate Pharmacokinetics
Inhibitor, Inducor, Substrate, Protein binding?
Metabolism
Excretion
Inducer and Inhibitor of diff enzymes
Low protein binding
Primarily excreted unchanged in urine - decrease dose for renal impairment
Topiramate
AE
Significant AE
- Somonolence, dizziness, difficulty with memory and concentration, aggressive behavior (if given alot uprent can present with irritability)
- Weight loss, oligohydrosis (decreased ability to sweat)
- Nephrolithiasis (counsel need for fluid intake)
- Metabolic acidosis (renal disease)
- Dose should be slowly titrated
Levetiracetam (Keppra)
Indications
Focal and Generalized (motor)
Levetiracetam (Keppra)
MOA
Binds to a synaptic vesicle protein (SV2A) - responsible for reducing presynaptic glutamate release
Levetiracetam (Keppra)
Routes
PO or IV
Levetiracetam (Keppra) Pharmacokinetics
Inhibitor, Inducer, Substrate, Protein binding?
Serum concentration monitoring?
- Low protein binding
- Some advocate for therapeutic drug monitoring
- Useful if patient is having seizure on medication-can help verify if pt is compliant with meds
- Only really monitor if pt has breakthrough seizures-since there not really any drug interactions*
- If pts serum concentration is zero they’re probably lying and not taking it*
Levetiracetam (Keppra)
AE
- Overall well tolerated
- Somonolence, fatigue, coordination difficulties, bad dreams, hallucinations
- “I get along with everybody, very well tolerated, I’m Keppra” - unlike other anticonvulsants very well tolerated however its not perfect*
- My friend had so many bad dreams*
Match the following epileptic drug with its respective relative or absolute contraindication.
- Zonisamide: HLA B 1502-Allele
- Phenytoin: Sulfonamide allergy
- Carbamazepine: HLA B 1502 allele
- Phenytoin: Hypotension
Carbamazepine: HLA B 1502 allele
Pregnancy
- Pregnant women with epilepsy are at 2 fold greater risk of having a baby with major congenital _______ and ______ impairment
- ____ defects, c____ palate, n_____ tube defects
- Are some antiepileptics safe?
- AVOID (5)
- Drug interactions may _____ efficacy of oral contraceptives via ____ of the oral contraceptive metabolism
- Including up to __ wks after stopping anti-epileptic
- CYP inducers also induce ________ metabolism which can lead to ______/_ _ _ in baby (best to ____ during ___ gestational month)
- ______ and _______ appear to have lower rate of complications in pregnancy compared to others
- Refer to a _______
- malformations, cognitive
- heart, cleft, neural
- No completely safe antiepileptic
- Phenytoin, carbamazepine, valproate, phenobarbital, topiramate
- reduce, induction
- 4
- Vitamin K, coagulopathy/ICH (supplement, last)
- Levetiracetam, Lamotrigine
- specialist
V V important- many drugs are teratogenic
Status Epilepticus
- Medical _______, defined by
- Continuous clinical and/or electrographic seizure activity for at least ___ minutes
- Recurrent seizure activity without recovery between seizures for at least __ minutes
- Convulsive and non-convulsive
- Results from an ________ of inhibitor and excitatory neurotransmitters
- Drug of choice:
- emergency
- 5
- 5
- imbalance
- Benzodiazepines
Benzodiazepines
- MOA: Enhances activity of _____ (enhances rate of __-channel opening)
- Hospital recommendations (IV or IM)
- Lorazepam (Ativan):
- Diazepam (Valium):
- Midazolam (Versed):
- AE (3)
- Subsequently:
- GABAa (Cl- channel opening)
- IV or IM
- IV
- IV, rectal
- IM (intranasal or buccal if IM not available)
- can also be given IV
- Depressed mental status, respiratory depression, hypotension
- load with chronic anticonvulsant (phenytoin, levetiracetam, others)
What meds treat focal, generalized motor, generalized non motor
Which drugs are CYP Substrates, Inducers, Inhibitors
Chart 1
Is the drug a CYP Substrate, CYP Inducer, or CYP Inducer
Chart 2
