Neurology Pt 2 Epilepsy Flashcards

(70 cards)

1
Q

Seizure vs. Epilepsy

  • Seizure =
  • Epilepsy =
  • Decision to treat is multi-factorial
    • Cause of seizure, risk of recurrence, patient, toxicities
A
  • Transient alteration of brain dysfunction resulting from abnormal discharge of cerebral neurons
  • Chronic disease state characterized by periodic and unpredictable occurrences of seizures
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2
Q

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
A
  • State, non-excited
  • inside, negative
  • channels
  • K+
  • Sodium (Na+): Potassium (K+), 3 NA+ out, 2 K+ in
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3
Q

Action Potential

A
  • 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)*
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4
Q

Pathophysiology

A
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5
Q

How do Antiepileptic Drugs Work?

  • Three primary mechanisms
    1. _____ excessive action potentials
  • Target voltage -activated ___ channels
  • Target voltage - activated ___ channels

  1. _____ GABA - mediated synaptic inhibiton
    * Target pre-post ______ GABA activity
  2. ______ Glutamate mediated excitatory responses
    * Antagonize ____ or ____ receptors
A
  1. Inhibit
  • Na+
  • Ca2+
  1. Enhance
    * synaptic
  2. 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*
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6
Q

Classification of Seizures

Where, Awareness, Features?

  1. Focal Onset
  2. Generalized Onset

Treatment will depend on:

A
  1. Focal Onset (Aware/Impaired Awareness)
  • Motor or Non-Motor
  • Focal to bilateral Tonic Clonic
  1. 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*
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7
Q

Na+ Channel Blockers

(4)

A

Phenytoin (Dilantin)

Carbamazepine (Tegretol)

Zonisamide (Zonegran)

Lamotrigine (Banzel)

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8
Q

Phenytoin (Dilantin)

Indications

A

Focalized and Generalized (motor)

No activity against absence seizures

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9
Q

Phenytoin (Dilantin)

Routes

  • Available in __ and ___
    • IV formulated with _____ _____ causes _____ (loading doses)
  • Max infusion rate: ___-___ mg/min
    • Lower rate decreases risk for _____
A
  • 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*
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10
Q

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:
A
  • 24 hrs
  • Protein
  • Liver
    • nonlinear
      • saturated
      • large increase in drug exposure
  • 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*
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11
Q

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 =
A
  • 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*
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12
Q

Interpretation of Serum Phenytoin Concentrations

  • Very important to remember that phenytoin is?
  • Adjust _____ phenytoin level if:
    • ____ ______ (<_._ mg/dL)
      • Conditions that may predispose (4)
A
  • highly protein bound
  • total
    • Low albumin (<3.2mg/dL)
      • Renal disease, malnutrition, cancer, liver failure
  • 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*
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13
Q

Phenytoin

Adverse Effects

A

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*
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14
Q

Phenytoin Drug Interactions

Metabolism (2)

Drug Interations (3)

A
  • 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*
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15
Q

Carbamazepine (Tegretol)

Indications

A

Focal and Generalized (Motor) Seizures

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16
Q

Carbamazepine (Tegretol)

Routes

A

PO only

Give with food to avoid GI upset

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17
Q

Carbamazepine Pharmacokinetics

  • Highy ______ bound (~75%)
  • Does it require serum concentration levels?
A
  • Protein
  • Yes (goal 6-10mcg/mL)
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18
Q

Carbamazepine Metabolism

(2)

A
  • Inducer*
    • ​AUTOINDUCTION: Up regulates and induces its own metabolism
  • Substrate*
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19
Q

Carbamazepine

AE

A

(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*
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20
Q

Carbamazepine

Drug Interactions (2)

A
  • 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

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21
Q

Poll

Which drug is most at risk for causing hypotension?

A

IV Phenytoin

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22
Q

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
A
  • Rare, Life-threatening immunologic adverse drug reaction
  • Anticonvulsants
  • 2-12 weeks so can occur like 3 months after start! RARE, HIGH MORTALITY
  • Cross
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23
Q

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
A
  • unknown
    • T
    • Ethnic, HLA
  • supportive, steroids, removal
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24
Q

AHS: Triad of Symptoms

(3)

A
  • 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
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25
**Zonisamide (Zonegran)** ## Footnote Indications
Focal, Generalized (motor), and unknown seizures *Again doesn't cover NON MOTOR GENERALIZED (ABSENCE)*
26
**Zonisamide** ## Footnote Routes
PO Only
27
**Zonisamide Pharmacokinetics** ## Footnote * 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*
28
**Zonisamide** ## Footnote 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*
29
**Zonisamide** ## Footnote Contraindications
Sulfa Allergy (skin reaction) *VVV important, Can't use this drug!*
30
**Lamotrigine (Lamictal)** Indications
Focal, Generalized (motor), and unknown seizures
31
**Lamotrigine** ## Footnote Routes
PO only
32
**Lamotrigine** ## Footnote 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?!*
33
**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*
34
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
35
**Ca2+ Channel Blockers** ## Footnote Agents
**Ethosuximide (Zarontin)**
36
**Ethosuximide (Zarontin)** ## Footnote Indications
**\*\*\*\*\*\*\*ABSENT SEIZURES\*\*\*\*\*\*\*** *First one that treats Absent seizures!*
37
**Ethosuximide** MOA
Reduces Ca2+ influx by inhibiting channels
38
**Ethosuximide** Routes
PO only
39
**Ethosuximide Pharmacokinetics** ## Footnote Metabolism Does it need serum concentration monitoring?
Metabolized by the Liver Yes (goal 40-100mcg/mL)
40
**Ethosuximide** ## Footnote 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*
41
**GABA Agonists** ## Footnote Agents
**Phenobarbital (Luminal)** **Valproic Acid (Depakote)**
42
**Phenobarbital (Luminal)** ## Footnote 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*
43
**Phenobarbital** ## Footnote MOA
Enhances post-synaptic GABA-A receptor (increases duration of Cl- influx and prolongs hyperpolarization) = inhibitory response
44
**Phenobarbital** ## Footnote 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\**
45
**Phenobarbital Pharmacokinetics** ## Footnote Inhibitor, Inducer, Substrate? Serum concentration levels required?
strong **INDUCER** **YES** (goal 10-40ug/mL)
46
**Phenobarbital** ## Footnote 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)
47
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)
48
**Valproate (Depakote)** ## Footnote Indications
Focal, Generalized motor, and ABSENCE\* (Generalized non motor) *FIRST LINE FOR GENERALIZED seizures based on years of study and efficacy INCLUDING ABSENCE\**
49
**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*
50
**Valproate** ## Footnote Routes
Many different formulations (**not interchangeable)** ## Footnote * 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)
51
**Valproate Pharmacokinetics** ## Footnote Inhibitor, Inducer, Substrate, Protein bound? Needs serum concentrations?
* **Inhibitor** * Highly **Protein** bound * YES (target 50-140mcg/ml)
52
**Valproate** ## Footnote 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) ## Footnote * Even though is recommended 1st line still a slew of AE* * 1/5 will experience GI effects, Monitor LFT's bc transaminitis*
53
**Valproate** ## Footnote 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*
54
Glutamate Antagonists ## Footnote Agents
**Topiramate (Topamax)** **Levetiracetam (Keppra)** * Remember Glutamate is our primary excitatory we want to block* * INHIBITS NMDA RECEPTORS*
55
**Topiramate (Topamax)** ## Footnote 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)*
56
**Topiramate** ## Footnote MOA
* AMPA glutamate receptor antagonist * Also inhibits Na+ channels * Prolongs K+ efflux (hyperpolarization) * Enhances GABA
57
**Topiramate Pharmacokinetics** ## Footnote 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
58
**Topiramate** ## Footnote 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_
59
**Levetiracetam (Keppra)** ## Footnote Indications
Focal and Generalized (motor)
60
**Levetiracetam (Keppra)** ## Footnote MOA
Binds to a synaptic vesicle protein (SV2A) - responsible for reducing presynaptic glutamate release
61
**Levetiracetam (Keppra)** Routes
PO or IV
62
**Levetiracetam (Keppra) Pharmacokinetics** ## Footnote 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 ## Footnote * 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*
63
**Levetiracetam (Keppra)** ## Footnote 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*
64
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
65
**Pregnancy** ## Footnote * 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*
66
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**
67
**Benzodiazepines** ## Footnote * 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)
68
What meds treat focal, generalized motor, generalized non motor
69
Which drugs are CYP Substrates, Inducers, Inhibitors Chart 1
70
Is the drug a CYP Substrate, CYP Inducer, or CYP Inducer Chart 2