Exam 3: Seizure Flashcards
Seizure
paroxysmal disorder of the CNS characterized by abnormal cerebral neuronal discharges with or without loss of consciousness
Epilepsy
repeated seizures due to damage, irritation, and/or chemical imbalance in the brain which leads to a sudden, excessive, synchronous electrical discharge
Seizures are a result of what?
disordered, synchronous, and rhythmic firing of a population of brain neurons (synchronized hyperexcitiability)
Focal Onset
classified to either aware or impaired awareness
motor or non-motor onset
and may progress to focal to bilateral tonic-clonic (generalized seizure) (with aura)
Generalized Onset
Classified to either motor (tonic clonic or other motor) or non-motor (absence seizure)
Unknown Onset
Classified to either motor (tonic clonic or other motor) or non-motor
Where do focal seizures begin
temporal lobe
What are generalized seizures presumed to be
genetic
Partial Seizure Spread
seizure activity spreads from a focus in one part of the brain (focal seizure)
Partial Seizure Secondary Generalized
focal seizures frquently progress to secondary generalized seizures via projections to the thalamus (focal to bilateral)
primary generalized seizure
propagate via diffuse interconections between the thalamus and cortex (no discrete focus)
earliest clinical signs show involvement of both brain hemispheres
AWARE type of seizure
simple partial
no loss of consciousness
subjective experiences (auras) also occur (sense of fear, unpleasant smell, abdominal discomfort)
Impaired Awareness seizure
complex partial
most common among focal seizures
clouding of consciousness
staring
repetitive motor behaviors (swallowing, chewing, lip smacking)
disturbances of visceral, emotional, and autonomic systems
seizure followed by confusion, fatigue, and throbbing headache
aura is common
postictal state due to impaired awareness
postictal state
after a seizure, a pt will not recover a normal level of consciousness immediatlely
may last seconds to hours
confusion, disorientation, anterograde amnesia
absence seizure
typical: petit mal
- brief loss of consciousness (10-45 seconds)
- staring or eye flickering
- begin abruptly
- often repetitive
- may not realize it after the seizures
- no convulsions, aura, or postictal period
Atypical
- slower onset than typical
more difficult to control
First phase generalized seizure
tonic phase
begins abruptly, often with diaphragm contraction (no aura)
Second phase generalized seizure
clonic phase
begins as relaxation periods become more prolonged
involves violent jerking of the body that lasts 1-2 minutes
Therapeutic Goal
bring seizures under control within 60 minutes
does one seizure define epilepsy?
no
Drug therapy withdrawal
gradually withdrawn in patients who have been clinically free of seizures for 2-5 years
depolarization
involves the activation of AMPA and NMDA channels by the excitatory neurotransmitter glutamate and voltage gated calcium channels
influx of cation Ca2+
Hyperpolarization
activation of GABA receptors
influx of chloride ions
efflux of potassium
homeostasis
neuronal signaling (depolarization) is normally dampened by feed-forward and feedback inhibition involving GABAergic neurons
disrupted E/I balance
Tonic Phase Mechanism
GABA mediated inhibition disappears
Glutamate-mediated AMPA and NMDA receptor activity increases
Clonic Phase Mechanism
GABA mediated inhibition gradually returns, leading to a period of oscillations
drugs that aggravate or increase risk of seizure
alcohol
theophylline
bupropion
oral contraceptives
withdrawal from depressants
CNS stimulants
Clozapine (1A2)
Drugs that decrease sodium influx, prolong the inactivation of Na channels
carbamexepine
oxcarbazepine
phenytoin
lacosamide
lamotrigine
valproate
drugs that reduce calcium influx (absence)
ethosuximide
lamotrigine
valproate
drugs that enhance GABA mediated neuronal inhibition
Barbiturates (activate GABA receptor)
Benzos (activate GABA receptor)
valproate (increases GABA levels)
gabapentin (increases GABA release)
vigabatrin (inhibits GABA transaminase)
tiagabine (inhibits GAT-1)
antagonism of excitatory transmitters (glutamate)
felbamate (antagonist of NMDA)
topiramate (antagonist of kainate/AMPA receptors)
Presynaptic targets of drugs at the excitatory synapse
sodium (phenytoin, carbamazepine, lacosamide)
calcium (ethosuximide)
postsynaptic targets of drugs at the excitatory synapse
NMDA (felbamate)
AMPA (topiramate)
presynaptic targets of drugs at the inhibitory synapse
GABA transporter (GAT-1) (tiagabine)
GABA transaminase (GABA-T) (vigabatrin)
postsynaptic targets of drugs at the inhibitory synapse
GABA a and b (phenobarbital, benzos)
phenytoin MOA
binds and stabilizes the inactivated state of sodium channels (not isoform selective thus can target sodium channels in the brain as well as other parts of the body)
fosphenytoin
injectable phosphate prodrug
phenytoin elimination kinetics
dose dependent
non linear pharmacokinetics
drug interactions: phenytoin
displaced from plasma proteins by other drugs (valproate) leading to an increase in its plasma concentrations
phenytoin induces liver cytochrome P450 enzymes
Side effects: phenytoin
arrhythmia
visual
ataxia
gi symptoms
gingival hyperplasia, hirsutism
hypersensitivity reactions
Carbamazepine MOA
binds and stabilizes the inactivated state of Na channels
carbamezepien drug interactions
induces liver cyp P450 increasing the metabolism of itself and other drugs
carbamezepine toxicity
blurred vision, ataxia, gi disturbances, sedation at high doses, serious skin rash, DRESS
oxcarbazepine reduced toxicity
lacosamide moa
enhances inactivation of voltage gated sodium channels
lacosamide toxicitiy
dermatologic rxn
cardiac risks
visual disturbances
Barbiturates moa
binds to allosteric regulatory site on the GABA receptor, increases duration of the chloride channel opening events (enhances GABA inhibitory signaling)
barbiturates drug interactiosn
liver cyp P450 enzymesb
barbituates toxicity
sedation, physical dependence
drug of choice in inhants up to 2 months old
phenobarbital
primidone moa
may be more similar to that of phenytoin than phenobarbital
Diazepam use
especially useful for tonic-clonic status epilepticus
diazepam moa
binds to an allosteric regulatory site on the GABA receptor
increases the frequency of CL channel opening events (enhances GABA inhibitory signaling)
diazepam toxicity
sedation
physical dependence
not useful for chronic treatments
clonazepam use
useful for acute treatment and absence seizures
Gabapentin MOA
increases GABA release
decreases presynaptic calciuim influx, thereby reducing glutamate release
gabapentin toxicity
sedation, ataxia
vigabatrin and tiagabine use
adjunct therapy for refractory patient
vigabatrin MOA
irreversible inhibitor of GABA-T (enzyme that degrades GABA)
vigabatrin toxicity
sedation, depression, visual field disturbancest
tiagabine MOA
inhibits gaba transporter (GAT-1)
Tiagabine toxicity
sedation, ataxia
NMDA receptor
glutamate binding triggers an influx of Na and Ca and an efflux of K
AMPA receptor
glutamate binding triggers an influx of sodium and an efflux of potassium. this is also true of a 3rd type of ionotropic glutamate receptor, the kainate receptor
Felbamate MOA
NMDA recepotr antagonist
Felbamate toxicity
severe hepatitis (which is why its a 3rd line drug)
Topiramate MOA
AMPA and kainate receptor antagonist
Topiramate Toxicity
nervousness, confusion, cognitive dysfunction, sedation, vision loss
ethosuximide MOA
blocks T-type Ca2+ channels (low-threshold current) in thalamic neurons
T-type calcium channels are thought to be involved in generating the rhythmic discharge of an absence attack
ethosuximide toxicity
GI distress, sedation
Lamotrigine use
for focal and primary generalized seizures, include absence; also used for bipolar disorder
Lamotrigine MOA
inhibits sodium and voltage-gated Ca channels
Lamotrigine toxicity
sedation, ataxia, serious skin rash (stevens johnson syndrome/toxic epidermal necrolysis)
Valproate MOA
inhibits sodium and calcium channels
valproate drug interactions
displaces phenytoin from plasma proteins
inhibits the metabolism of phenytoin, carbamazepine, phenobarbital, lamotrigine
valproate toxicity
GI distress, hyperammmonemia, hepatotoxicity (can be fatal, careful monitoring)
levetiracetam MOA
binds to the synaptic vesicular protein SV2A, and thus interferes with synaptic vesicle release and neurotransmission
also appears to interfere with calcium entry through calcium channels and with intraneuronal calcium signaling
candidate for treatment of status epilepticus cases that are refractory to other therapies
levetiracetam use
focal and generalized seizures, myoclonic seizures, status epilepticus
Drugs used for any seizure
lamotrigine
levetiracetam
valproate
zonisamide
Drugs that Lower the Seizure Threshold at Usual Doses
Bupropion
Clozapine
Theophylline
Varenicline
Phenothiazine Antipsychs
CNS Stimulants (amphetamines)
Drugs that Lower the Seizure Threshold at High Doses or Impaired Renal Functions
carbapenems (imipenem)
lithium
meperidine
penicillin
quinolones
tramadol
Quality of LIfe Monitoring
Seizure Frequency
Functional Status
Social Functioning (drivers license)
Mental Health Status (depression)
Cognition
Number of doses of drug per day
cost of drug therapy
Risk Factors for Seizure Recurrence
<2 years seizure free
onset of seizure after age 12
history of atypical febrile seizures
2-6 years before good seizure control in treatment
signficant number of seizures (>30) before control acheived
partial seizures (most common type)
abnormal EEG throughout treatment
organic neurological disorder (TBI, dementia)
Withdrawal of phenytoin or valproate
Possible reason for treatment failure
failure to reach the CNS target
alteration of drug targets in the CNS
drugs missing the real target
Management of treatment failure
rule out pseudo-resistance (wrong drug or diagnosis)
combination therapy
electrical/surgical intervention
Status epilepticus
defined as continuous seizure activity lasting 5 minutes or more, or two or more discrete seizure with incomplete recovery between seizures
Possible Drug Therapy for Status epilepticus
benzos, most commonly lorazepam or midazolam
Status Epilepticus Treatment (5-20 minutes)
if seizure continues, give IV lorazepam or IV midazolam
Phenytoin loading dose adverse effect
hypotension (propylene glycol, limits infusion rate)
Fosphenytoin vs Phenytoin loading dose
prodrgu of phenytoin
better IV tolerance of dosing
Fosphenytoin Loading Dose
20 mg PE/kg IV, may give additional dose 10 minutes after load
What is required when giving phenytoin/fosphenytoin loading dose
cardiac monitoring
purple glove syndrome
Oral phenytoin dosing considerations
must obtain both phenytoin serum concentration and serum albumin in the same blood draw
therapeutic serum concentration range: 10-20 mcg/mL
Valproate IV to PO conversion
1:1 mg/mg
Valproate desired serum concentration
80 mcg/mL
range (50-125 mcg)
1A2 inducers
carbamezepine
phenobarbital
phenytoin
2C9 inducers
Carbamezepine
phenobarbital
phenytoin
3A4 inducers
carbamezepine
lamotrigine
oxcarbazepine
phenobarbital
phenytoin
topiramate
UGT inhibitor
valproate
Lamotrigine dosing with UGT inhibitor (valproate)
25 mg every other day x 14 days
25 mg once daily x 14 days
50 mg once daily x 7 days
100 mg once daily
lamotrigine dosing without UGT drug interactions
25 mg once daily x 14 days
50 mg once daily x 14 days
100 mg once daily x 7 days
200 mg once daily
lamotrigine dosing with UGT inducers (carbamezepine, phenytoin)
50 mg once daily x 14 days
100 mg once daily x 14 days
200 mg once daily x 7 days
400 mg once daily
lamotrigine boxed warning
Stevens-Johnson/Toxic Epidermal Necrolysis
Anticonvulsant Hypersensitivity Syndrome Black box warning
genetic screen for HLA-B*1502 allele prior to initiation carbamazepine or like derivatives (oxcarbazepine, eliscarbazepine)
patients with positive HLA-B*1502 allele should/should not be treated with carbamazepine or like derivatives unless benefit clearly outweighs risk
should not
Strong correlation for positive HLA-B*1502 in what populations
patients of asian descent
HLA-A*3101
norhtern europeans
may confer similar risk of anticonvulsant hypersensitivity syndrome
DRESS Syndrome
potentially life threatening 10%
generally occurs 2-6 weeks after initiation of drug therapy
increased risk in patients who are psoitive for HLA-A*3101 allele
drugs associated with DRESS
carbamazepine
cenobamate
lamotrigine
phenobarbital
phenytoin
valproate
zonisamide
anti-seizure drug withdrawal syndrome
associated with abrupt discontinuation of antiseizure medication therapy
may cause recurrence of seizures, doses of antiseizure medication should always be tapered for discontinuation
drug serum concentrations in pregnancy
may be altered in pregnancy due to changes in volume of distribution
drugs with teratogenic risk
carbamazepine
clonazepam
fosphenytoin
phenobarbital
phenytoin
primidone
topiramate
Valproate and pregnancy
not recommended
neural tube defects and decreased IQ in offspring
What should be considered in pregnancy
supplemental folic acid (5 mg)
infant should receive vitamin K 1 mg IM at birth to decrease risk of hemorrhagic disease
Estrogen compounds drug interactions
3A4 substrates
use higher dose estrogen contraceptives (warning for increased thromboembolism)
IUD or progestin only contraceptives recommended
estrogen and lamotrigine
can significantly serum concentration by 50%
what drug causes arrhythmia
lamotrigine
phenytoin/fosphenytoin (contraindicated in heart block)
what drug causes PR interval changes
lacosemide, pregabalin
what drug causes heart block
lacosemide
what drug causes valvular heart disease
fenfluamine
electrolyte abnormalities: carbamazepine/eslicarbazepine/oxcarbazepine
hyponatremia
SIADH
zonisamide adverse effect
metabolic acidosis
renal calculi
phenytoin metabolic adverse effect
vitamin d metabolism altered
decreased calcium concentrations leading to osteoporosis with long term use
metabolic effect: topiramate
decreased serum bicarbonate leadingi to metabolic acidiosis
nephrolithiasis
decreased sweating, heat intolerance, oligohydrosis
Psych AEs: levetiracetam
psychosis
suicidal thoughts/behaviors
unusual mood
worsening depression
most often seen in children/adolescents
Psych AEs: perampanel
boxed warning: dose-related serious and /or lifethreatening neuropsychiatric events
Psych AEs: valproate
acute mental status changes
hyperammonemia
differentiate from sedation side effect
Psych AEs: topiramate
associated with cogntive dysfunction if the dose is increased too rapidly, use a slow dose titration
Visual abnormalities: topiramate
vision loss
myopia
retinal detachment
visual abnormalities: vigabatrin
contrainidcated in patients who have other risk factors for irreversible vision loss
Gabapentin and Pregabalin FDA warning
evaluate the appropriateness of gabapentin or pregabalin use and risk for respiratory depression in a patient who is takign other CNS depressants, has pulmonary disease, or is elderly
Clinical Pearls: Carbamazepine
strong P450(1A2, 2C9, 2C19, 3A4) and pgp inducer (induces own metabolism)
Clinical Pearls: oxcarbazepine
induces 3A4
Clinical Pearls: hyponatremia
carbamazepine
oxcarbazepine
eslicarbazepine
Clinical Pearls: carbamazepine serum concentration
4-12 mcg/mL
Clinical Pearls: valproate
can cause thrombocytopenia, monitor CBX/platelets
can cause PCOS, weight gain, sedation
Clinical Pearls: topiramate and zonisamide
weight loss
oligohydrosis
nephrolithiasis
Clinical Pearls: phenytoin absorpiton
decreased when given with enteral feeds
hold feedings 1-2 hours before and after administration
Clinical Pearls: pheytoin adverse effects
gingival hyperplasia
hirsutism
Clinical Pearls: zonisamide contraindication
sulfa allergy
Clinical Pearls: gabapentin and pregabalin elimination
renally
decrease dose in renal impairment
Clinical Pearls: lamotrigine
associated with arrhythmia with people with underlying cardiac conditions
Lennox Gastaut Syndrome
multiple seizure types that develop in childhood, usually accompanied by intellectual disability, sometimes responsive to combination of some AEDs
Dravet Syndrome
rare genetic epileptic encephalopathy with normal childhood development until seiuzres begin in 1st year of life leading ot multiple sizure types and developmental disability
Epidiolex (cannabidiol)
indicated for dravet and lennox gastaut syndrome
Ketogenic diet
3:1 or 4:1 fats:carbs/protein
adults seem to respond only while on the diet, effects in children may continue after diet is discontinued
ketogenic diet side effects
hyperlipidemia
weight loss
kidney stones
constipation
decreased bone mass/growth
depression in epilepsy
all antiseizure drugs carrry a warning for increased risk of suicidal thinking and/pr behaviors during treatment
antidepressents also carry warning in pts < 24 years of age
which drug should be avoided in pts with uncontrolled seizure disorders
bupropion
increases risk for seizure and seizure frequencyc
co-morbid conditions
depression
