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
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
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)*
4
Q
Pathophysiology
A
5
Q
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
A
- 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*
6
Q
Classification of Seizures
Where, Awareness, Features?
- Focal Onset
- Generalized Onset
Treatment will depend on:
A
- 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*
7
Q
Na+ Channel Blockers
(4)
A
Phenytoin (Dilantin)
Carbamazepine (Tegretol)
Zonisamide (Zonegran)
Lamotrigine (Banzel)
8
Q
Phenytoin (Dilantin)
Indications
A
Focalized and Generalized (motor)
No activity against absence seizures
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*
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:
- Dose dependent (Michaelis Mentin also known as _______ kinetics)
A
- 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*
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*
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)
- ____ ______ (<_._ mg/dL)
A
- 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*
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*
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*
15
Q
Carbamazepine (Tegretol)
Indications
A
Focal and Generalized (Motor) Seizures
16
Q
Carbamazepine (Tegretol)
Routes
A
PO only
Give with food to avoid GI upset
17
Q
Carbamazepine Pharmacokinetics
- Highy ______ bound (~75%)
- Does it require serum concentration levels?
A
- Protein
- Yes (goal 6-10mcg/mL)
18
Q
Carbamazepine Metabolism
(2)
A
-
Inducer*
- AUTOINDUCTION: Up regulates and induces its own metabolism
- Substrate*
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*
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
21
Q
Poll
Which drug is most at risk for causing hypotension?
A
IV Phenytoin
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
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
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
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
