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Advanced Pharmacology > Neurology Pt 2 Epilepsy > Flashcards

Neurology Pt 2 Epilepsy Flashcards

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
Q

Zonisamide (Zonegran)

Indications

A

Focal, Generalized (motor), and unknown seizures

Again doesn’t cover NON MOTOR GENERALIZED (ABSENCE)

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26
Q

Zonisamide

Routes

A

PO Only

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27
Q

Zonisamide Pharmacokinetics

  • Inhibitor, Inducer, Substrate?
  • Excretion
    • Titrate dose _____, monitor closer for ___ in pts with ____ impairment
A
  • Substrate
  • Primarily by the Kidneys
    • slower, ADE, renal

Renal *** increases risk for AE

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28
Q

Zonisamide

AE

A
  • 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*
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29
Q

Zonisamide

Contraindications

A

Sulfa Allergy (skin reaction)

VVV important, Can’t use this drug!

30
Q

Lamotrigine (Lamictal)

Indications

A

Focal, Generalized (motor), and unknown seizures

31
Q

Lamotrigine

Routes

A

PO only

32
Q

Lamotrigine

AE

A
  • 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
Q

Lamotrigine

Drug Interactions (3)

A
  • 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
Q

Drug interactions are common with antieplipetic drugs due to which pharmacokinetic (PK) characteristic?

  • Bioavailability
  • Low protein binding
  • CYP induction
  • All of the above
A

CYP Induction

35
Q

Ca2+ Channel Blockers

Agents

A

Ethosuximide (Zarontin)

36
Q

Ethosuximide (Zarontin)

Indications

A

*******ABSENT SEIZURES*******

First one that treats Absent seizures!

37
Q

Ethosuximide

MOA

A

Reduces Ca2+ influx by inhibiting channels

38
Q

Ethosuximide

Routes

A

PO only

39
Q

Ethosuximide Pharmacokinetics

Metabolism

Does it need serum concentration monitoring?

A

Metabolized by the Liver

Yes (goal 40-100mcg/mL)

40
Q

Ethosuximide

AE

A
  • 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
Q

GABA Agonists

Agents

A

Phenobarbital (Luminal)

Valproic Acid (Depakote)

42
Q

Phenobarbital (Luminal)

Indications

A

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
Q

Phenobarbital

MOA

A

Enhances post-synaptic GABA-A receptor

(increases duration of Cl- influx and prolongs hyperpolarization) = inhibitory response

44
Q

Phenobarbital

Routes

A

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
Q

Phenobarbital Pharmacokinetics

Inhibitor, Inducer, Substrate?

Serum concentration levels required?

A

strong INDUCER

YES (goal 10-40ug/mL)

46
Q

Phenobarbital

AE

A
  • 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
Q

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
A

Sodium Channel Blocker

(Carbamazepine = autoinducer)

48
Q

Valproate (Depakote)

Indications

A

Focal, Generalized motor, and ABSENCE* (Generalized non motor)

FIRST LINE FOR GENERALIZED seizures based on years of study and efficacy INCLUDING ABSENCE*

49
Q

Valproate (Depakote)

MOA

A

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
Q

Valproate

Routes

A

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)
51
Q

Valproate Pharmacokinetics

Inhibitor, Inducer, Substrate, Protein bound?

Needs serum concentrations?

A
  • Inhibitor
  • Highly Protein bound
  • YES (target 50-140mcg/ml)
52
Q

Valproate

AE

A
  • 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*
53
Q

Valproate

Drug Interactions

A
  • 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
Q

Glutamate Antagonists

Agents

A

Topiramate (Topamax)

Levetiracetam (Keppra)

  • Remember Glutamate is our primary excitatory we want to block*
  • INHIBITS NMDA RECEPTORS*
55
Q

Topiramate (Topamax)

Indications

Extra Indications

A

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
Q

Topiramate

MOA

A
  • AMPA glutamate receptor antagonist
    • Also inhibits Na+ channels
    • Prolongs K+ efflux (hyperpolarization)
    • Enhances GABA
57
Q

Topiramate Pharmacokinetics

Inhibitor, Inducor, Substrate, Protein binding?

Metabolism

Excretion

A

Inducer and Inhibitor of diff enzymes

Low protein binding

Primarily excreted unchanged in urine - decrease dose for renal impairment

58
Q

Topiramate

AE

A

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
Q

Levetiracetam (Keppra)

Indications

A

Focal and Generalized (motor)

60
Q

Levetiracetam (Keppra)

MOA

A

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

61
Q

Levetiracetam (Keppra)

Routes

A

PO or IV

62
Q

Levetiracetam (Keppra) Pharmacokinetics

Inhibitor, Inducer, Substrate, Protein binding?

Serum concentration monitoring?

A
  • 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*
63
Q

Levetiracetam (Keppra)

AE

A
  • 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
Q

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
A

Carbamazepine: HLA B 1502 allele

65
Q

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 _______
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
Q

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:
A
  • emergency
    • 5
    • 5
  • imbalance
  • Benzodiazepines
67
Q

Benzodiazepines

  • MOA: Enhances activity of _____ (enhances rate of __-channel opening)
  • Hospital recommendations (IV or IM)
    • Lorazepam (Ativan):
    • Diazepam (Valium):
    • Midazolam (Versed):
  • AE (3)
  • Subsequently:
A
  • 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
Q

What meds treat focal, generalized motor, generalized non motor

A
69
Q

Which drugs are CYP Substrates, Inducers, Inhibitors

Chart 1

A
70
Q

Is the drug a CYP Substrate, CYP Inducer, or CYP Inducer

Chart 2

A

Advanced Pharmacology (14 decks)

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