lectures 48/49 Flashcards
ott - pharmacotherapy of seizure disorders
how was epilepsy classified in 2011?
seizure can either be partial or generalized
a partial seizure can either be simple or complex
how was epilepsy classified in 2017?
focal onset
generalized onset
unknown onset
what medications lower the seizure threshold?
require usual dose –> bupropion, clozapine, theophylline, varenicline, phenothiazine antipsychotics, and CNS stimulants (amphetamines)
require higher/renal dosing –> carbapenems, lithium, meperidine, penicillin, quinolones, tramadol
what type of seizure is most common?
partial, doesn’t matter if its simple or complex
do patients respond better to mono or polytherapy?
mono –> around 50% of pts will have good control with one drug
poly –> most will have good control with 2 drugs
what are risk factors for seizure recurrence?
under 2 years seizure free
onset of seizure after age 12
hx of atypical febrile seizures
2-6 years before good seizure control in treatment
significant number of seizures (>30) before control achieved
partial seizures (which is the most common type)
abnormal EEG throughout treatment
organic neurological disorder - traumatic brain injury, dementia
withdrawal of phenytoin or valproate
what are possible reason for treatment failure?
failure to reach the CNS target
alteration of drug targets in the CNS
drugs missing the real target
what are management strategies to drug-resistant epilepsy?
rule out pseudo-resistance - wrong drug or diagnosis
combination therapy
electrical/surgical intervention
what is status epilepticus?
continuous seizure activity lasting 5 minutes or more, or two or more discrete seizures with incomplete recovery between seizures
what is the first line agent for status epilepticus?
benzodiazepines, most commonly lorazepam or midazolam
what are the phases of status epilepticus treatment?
stabilization 0-5 minutes
initial treatment 5-20
second treatment 20-40
third 40-60
if a person is being treated for status epilepticus, how should they be treated based on phase
stabilization –> no drug therapy
initial if seizure continues –> IV lorazepam and IV midazolam
second if seizure continues –> IV fosphenytoin, IV valproic acid, IV levetiracetam
what limits the infusion rate of phenytoin?
containing propylene glycol which can lead to hypotension
what is fosphenytoin?
prodrug of phenytoin
better IV tolerance of dosing
20 mg PE (phenytoin equivalents)/kg IV
for phenytoin/fosphenytoin loading dose, why is cardiac monitoring required?
due to local reaction called purple glove syndrome
for oral phenytoin, what should be collected in the SAME blood draw?
serum concentration and serum albumin
what is the therapeutic serum concentration range for phenytoin?
10-20 mcg/mL
what is dosing conversion of valproate loading dose?
1:1 mg/mg
IV to PO
what is the desired serum concentration range for valproate?
80 mcg/mL with a range of 50 - 125 mcg/mL
what is the dosing of lamotrigine with a UGT inhibitor (like valproate)?
25 mg QOD x 14d
25 mg QD x14d
50 mg QD x7d
100 mg QD
what is the dosing of lamotrigine without concomitant UGT Drug interactions?
25 mg QD x 14d
50 mg QD x 14d
100 mg QD x7d
200 mg QD
what is the dosing of lamotrigine with UGT inducers (like carbamazepine, phenytoin)?
50 mg QD x 14d
100 mg QD x14d
200 mg QD x7d
400 mg QD
what is an important drug interaction with lamotrigine?
lamotrigine is a UGT substrate, high initial serum concentrations are associated with Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN)
concomitant drug therapy with UGT inducers (carbamazepine, phenytoin) and inhibitors (valproate) need specific dosing
what is the black box warning of carbamazepine or like derivatives (oxcarbazepine, eslicarbazepine)?
anticonvulsant hypersensitivity syndrome so genetic screen for HLA-B*1502 allele PRIOR to initiating
if positive –> DO NOT USE, unless benefit clearly outweighs risk
what patient population is more likely to be positive for the HLA-B*1502 allele?
strong correlation for positive allele and AHS in patients of Asian descent
what patient population is more likely to be positive for HLA-A*3101?
those of Northern European and asian descent may have similar risk
what is DRESS syndrome?
drug reaction with eosinophilia and systemic symptoms
potentially life threatening with a mortality rate of around 10%
what drugs are associated with DRESS syndrome?
carbamezepine
cenobamate
lamotrigine
phenobarbital
phenytoin
valproate
zonisamide
generally occurs 2-6 weeks after initiation of drug therapy
what alleles correlate with what syndrome?
HLA-B1502 –> AHS
HLA-A3101 –> DRESS syndrome
what is antiseizure drug withdrawal syndrome?
associated with abrupt d/c
may cause recurrence of seizures, doses of antiseizure medications should always be tapered for d/c
how are drug serum concentrations affected by pregnancy?
may be altered due to changes in volume of distribution
what drugs pose a teratogenic risk?
carbamazepine
clonazepam
fosphenytoin
phenobarbital
phenytoin
primidone
topiramate
how should drugs with a teratogenic risk be counseled?
let people of child-bearing age should include education about these risk and contraceptive use
why is valproate not recommended in pregnancy?
due to causing neural tube defects and association with a decreased IQ in offspring
on top of antiseizure medications, what supplement should be considered in pregnancy?
folic acid (5mg daily)
and Vit K 10 mg daily during last month of pregnancy
what supplement should infants receive?
vit K 1mg IM at bird to decrease risk of hemorrhagic disease
what are important contraceptive drug interactions?
mediated by P450 3A4 induction (remember estrogen compounds are substrates of this)
interaction can be minimized by using higher-dose estrogen contraceptives, but pt can also use progestin-only contraceptives (depot formulation)
how do estrogen and lamotrigine influence each other?
estrogen significantly decrease lamotrigine serum concentrations (by 50%)
lamotrigine decreases estrogen concentrations
what is the recommended progestin-only concentration while on antiseizure?
IUDs
what is a warning about higher-dose estrogen contraceptives?
increased thromboembolism
what is CV AE of lamotrigine?
arrhythmia
what are the CV AE of lacosmide?
PR interval changes
heart block
what is the CV AE of pregabalin?
PR interval changes
may also cause peripheral edema, so caution in congestive HF
what is the CV AE of phenytoin/fosphenytoin?
arrhythmia
CI in heart block
what is the CV AE of fenfluramine?
valvular heart disease
what drugs cause hyponatremia/syndrome of inappropriate antidiuretic hormone (SIADH)?
carbamazepine
eslicarbazepine
oxcarbazepine
how does phenytoin affect mineral metabolism?
alters vit D metabolism –> decreased calcium concentrations –> osteoporosis with long-term use
what are the CP of topiramate?
decrease serum Bicarbonate –> metabolic acidosis
could cause nephrolithiasis so monitor serum bicarbonate
associated with decreased sweating, heat intolerance, and oligohydrosis
what are the psychiatric SE of levetiracetam?
psychosis
suicidal thoughts/behaviors
unusual mood changes
worsening depression (most often seen in children/adolescents)
what are the psychiatric SE of perampanel?
BOXED WARNING - dose related serious and/or life threatening neuropsychiatric events
in what pt population, should use of perampanel be cautioned?
pts with pre-existing psychosis due to BBW
what is the psychiatric SE of valproate?
acute mental status changes related to hyperammonemia
differentiate from sedation SE
what are psychiatric SE of topiramate?
associated with cognitive dysfunction if the dose is increased too rapidly, use a slow dose titration
what drugs are associated with visual abnormalities?
phenytoin
topiramate
vigabatrin
how does topiramate affect vision?
post-marketing warning for vision loss, myopia, retinal detachment
how does vigabatrin affect vision?
CI in pts who have other risk factors for irreversible vision loss
in what pt populations should pregabalin/gabapentin usage be evaluated for appropriateness?
in pts who are taking other CNS depressants, have pulmonary disease or is elderly due to risk for respiratory depression
what are the clinical pearls of carbamazepine?
strong P450 (so 1A2, 2C9, 2C19, 3A4) and p-glycoprotein inducer –> induces own metabolism
could lead to hyponatremia
what drugs could lead to hyponatremia?
carbamazepine
oxcarbazepine
eslicarbazepine
what CYP does oxcarbazepine affect?
induces 3A4
what are the clinical pearls of valproate?
can cause thrombocytopenia so monitor CBC/plateletes
can cause PCOS, weight gain, sedation
what are clinical pearls of topiramate and zonisamide?
weight loss
oligohydrosis
nephrolithiasis
what are the clinical pearls of phenytoin?
absorption is decreased when given with enteral feedings (hold feedings 1-2 hours before and after administration)
can cause gingival hyperplasia and hirsutism
what is a CI of zonisamide?
sulfa allergy
what are clinical pearls of gabapentin and pregabalin?
renal eliminated so decrease dose in renal impairment
cause peripheral edema and sedation
what are the clinical pearls of lamotrigine?
associated with arrhythmias in people with underlying cardiac conditions
what syndromes does medical marijuana help control?
lennox-gastaut syndrome
dravet syndrome
both occur in childhood development
what is epidiolex?
cannabidiol oral solution that is indicated for dravet syndrome and gastaut syndrome
what is the ketogenic diet?
3:1 or 4:1 fats:carbs/protein diet
adults seem to respond only while on the diet while the effects in children may continue after diet d/c
what are the SE of ketogenic diet?
hyperlipidemia (reversible upon d/c of diet)
weight loss
constipation
kidney stones
decreased bone mass/growth
what is key to note about antiseizure medications and depression?
all antiseizure drugs carry a warning for increased risk of suicidal thinking and/or behaviors during treatment
what is the warning associated with antidepressants and pts under 24 yo?
increased risk of suicidal thinking and behaviors in treatment
when should bupropion be used for seizures?
AVOID in pts with uncontrolled seizure disorders as it can increase the risk of seizures and seizure frequency
what is a common co-morbidity of seizure disorders?
depression
