(3.11) Pharmacotherapy of seizure disorders Flashcards
What are risk factors for seizure reccurrence?
- <2 yrs seizure free
- Onset of seizure after age 12
- Hx of atypical febrile seizures
- 2-6 yrs before good seizure control in tx
- > 30 seizures before controlled
- Partial seizures (most common)
- Abnormal EEG
- Organic neurological disorder
- Withdrawal of phenytoin or valproate
What is drug resistant epilepsy?
Failure of at least 2 trials of antiseizure meds of adequate dose and duration
What are possible reasons for tx failure in drug resistant epilepsy?
- Failure to reach CNS target
- Alteration of drug targets in CNS
- Drugs missing the real target
What are management strategies of 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 w incomplete recovery between seizures
What dosage form is most commonly used for status epilepticus?
IV
What is the most common drug class used for status epilepticus?
Benzodiazepines, most commonly lorazepam or midazolam
When is fosphenytoin used?
In the second or third treatment phase of status epilepticus
What is an issue with phenytoin?
Contains propylene glycol - can cause hypotension and this limits infusion rate
What is fosphenytoin?
Prodrug of phenytoin, better IV tolerance of dosing
What is the loading dose of fosphenytoin?
- 20 mg PE (phenytoin equivalents)/kg IV, may give additional dose 10 minutes after load
- Up to 150 mg PE/min IV infusion
What is the monitoring parameter with phenytoin/fosphenytoin?
Cardiac monitoring required, may also cause local rxn called “purple glove syndrome”
What must be obtained in the same blood draw (oral phenytoin dosing considerations)?
MUST obtain both phenytoin serum conc and serum albumin
What is the equation for adjusted conc (oral phenytoin dosing considerations)?
What is the therapeutic serum conc range (oral phenytoin dosing considerations)?
10-20 mcg/ml
What does it mean if there the unadjusted conc falls within the therapeutic range?
There is unbound phenytoin within the therapeutic range of 1-2 mcg/ml
What is the IV to PO conversion of valproate?
1:1 mg/mg
What is the desired serum concentration of valproate?
80 mcg/ml (range 50-125 mcg/ml)
Which drugs are 1A2 inducers?
- Carbamazepine
- Phenobarbital
- Phenytoin
Which drugs are 2C9 inducers?
- Cabamazepine
- Phenobarbital
- Phenytoin
Which drugs are 3A4 inducers?
- Carbamazepine
- Lamotrigine
- Oxcarbazepine
- Phenobarbital
- Phenytoin
- Topiramate
Which drug is a UGT inhibitor?
Valproate
What is the dosing of lamotrigine?
What is the black box warning prior to initiating carbamazepine or derivatives?
Genetic screen for HLA-B*1502 allele due to anticonvulsant hypersensitivity syndrome
Can HLA-B*1502 allele positive pts be treated with carbamazepines or derivatives?
NO unless benefit clearly outweigh the risk
There is a strong correlation for positive HLA-B*1502 allele and anticonvulsant hypersensitivity syndrome in ppl of what descent?
Asian descent
What other allele may confer similar risk to HLA-B*1502 and anticonvulsant hypersensitivity syndrome?
Positive HLA-A*3101 in those of Northern European and Asian descent
What is the outlook and mortality rate of DRESS syndrome?
Potentially life threatening - estimated mortality rate of 10%
When does DRESS syndrome occur?
Generally, occurs 2-6 wks after initiation of drug therapy
What drugs are associated w DRESS syndrome?
Carbamazepine, cenobamate, lamotrigine, phenobarbital, phenytoin, valproate, zonisamide
Which pts have an increased risk for DRESS syndrome?
Pts who are positive for HLA-A*3101 allele
What can cause antiseizure drug withdrawal syndrome?
Associated w abrupt d/c of antiseizure med therapy
What can antiseizure drug withdrawal syndrome cause?
Recurrence of seizures, doses of antiseizure me should always be tapered for d/c
Drug serum concentrations may be altered in pregnancy due to what?
Volume of distribution
Which common antiseizure drugs are known teratogenic risks?
Carbamazepine, clonazepam, fosphenytoin, phenobarbital, phenytoin, primidone, topiramate
What should pt counseling consist for ppl of child bearing age?
Education about these teratogenic risks in antiseizure meds and contraceptive use
Which drug is not recommended in pregnancy no matter what and why?
- Valproate
- Due to neural tube defects and is associated w a decreased IQ in offspring
Which supplement should be considered during pregnancy?
Folic acid 5 mg daily
What should infants receive at birth to decrease risk of hemorrhagic disease?
Vitamin K 1 mg IM
What are contraceptive drug interactions mediated by?
P450 3A4 induction - 3A4 inducer antiseizure meds will lower serum conc of estrogen contraceptives
How can contraceptive drug interaction be minimized?
By using higher-dose estrogen contraceptives but warning for increased thromboembolism
What contraceptives can be used to minimize contraceptive drug interaction?
Can use progestin only contraceptives:
- Depot formulation
- IUDs also recommended
What is an interaction between estrogen and lamotrigine?
Estrogen can decrease lamotrigine serum conc by 50% and lamotrigine decreases estrogen conc
What is a CV risk with lamotrigine?
Arrhythmia
What are CV risks w lacosamide and pregabalin?
PR interval changes
What is a CV risk w lacosamide?
Heart block
What is a CV risk w phenytoin/fosphenytoin?
Arrhythmia
What is a CV risk w fenfluramine?
Valvular heart disease
What can carbamazepine, eslicarbazepine, oxcarbazepine cause?
Hyponatremia (most caused by oxcarbazepine), syndrome of inappropriate antidiuretic hormone (SIADH)
What can phenytoin cause?
Altered vitamin D metabolism and decreased calcium conc leading to osteoporosis w long term use
What can topiramate and zonisamide cause?
- Decreased serum bicarb leading to metabolic acidosis
- Nephrolithiasis so monitor serum bicarb
- Also associated w decreased sweating, heat intolerance, oligohydrosis
What are the psychiatric SEs of levetiracetam?
Psychosis, suicidal thoughts/behaviors, unusual mood changes, worsening depression
What are the psychiatric SEs of perampanel?
Boxed warning: dose related serious and/or life threatening neuropsychiatric events
What are the psychiatric SEs of valproate?
Acute mental status changes related to hyperammonemia; differentiate from sedation SE
What are the psychiatric SEs of topiramate?
Associated w cognitive dysfunction if dose is increased too rapidly, use a slow dose titration
What are visual risks w topiramate?
Post marketing warning for vision loss, myopia, retinal detachment
What are visual risks w vigabatrin?
CI in pts who have other risk factors for irreversible vision loss
What is main evaluation points of gabapentin and pregabalin?
Risk for respiratory depression in pts who are taking other CNS depressants, has pulmonary disease, or is elderly
What can valproate cause?
- Thrombocytopenia - monitor CBC/platelets
- PCOS, weight gain, sedation
When is phenytoin absorption decreased and how can this be avoided?
- Decreased when given w enteral feedings
- Hold feedings 1-2 hours before and after administration
What are the main SEs of phenytoin?
Gingival hyperplasia and hirsutism
When is zonisamide CI?
CI if there is a sulfa allergy
How are gabapentin and pregabalin eliminated?
Renally eliminated, decrease dose in w renal impairment
What is Lennox-Gastaut Syndrome?
Multiple seizure types that develop in childhood, usually accompanied by intellectual disability, sometimes responsive to combination of some AEDs
What is Dravet Syndrome?
Rare genetic epileptic encephalopathy w normal childhood development until seizures begin in 1st year of life leading to multiple seizure types and developmental disability
What is Epidiolex?
Cannabidiol oral solution
What is Epidiolex used for?
Indicated for Dravet syndrome and lennox gastaut syndrome
What is the keto diet?
3:1 or 4:1 fats:carbs/proteins
What are SEs of keto diet?
Hyperlipidemia (reversible upon diet d/c), weight loss, constipation, kidney stones, decreased bone mass/growth
How do keto diet affect adults and children?
- Adults seem to respond only while on diet
- Children may continue to see effects after diet is d/c
What is a warning that all AEDs carry?
A warning for increased risk of suicidal thinking and/or behaviors during tx
What warning does antidepressants carry?
Increased risk of suicidal thinking and behaviors during tx in pts <24 yo
What is an absolute CI of bupropion?
Use of bupropion should be avoided in pts w uncontrolled seizure disorders, as it can increase risk of seizures and frequency
