Lectures 48-49 - Pharmacotherapy of Seizure Disorders Flashcards
Lowering the seizure threshold: medications
usual doses: bupropion, clozapine, theophylline, varenicline, phenothiazine, antipsychotics, CNS stimulants (amphetamines)
high doses and impaired renal function: carbapenems, lithium, meperidine, penicillin, quinolones, tramadol
Quality of life monitoring
seizure frequency
functional status – evaluation of ability to continue employment, school, elderly living status; and role activities in everyday life
social functioning - driver’s license?
mental health status - depression is a common co-morbidity
Cognition – many antiseizure medications can have cognitive side effects
Number of doses of drug per day – streamline drug regimen cost of drug therapy - can the patient afford it?
Lifelong treatment?
not necessarily - long term studies have shown that successful antiseizure medicaiton withdrawal may occur after a seizure free period of 2-5 years
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
- 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
Drug-resistant epilepsy
defined as failure of at least two trials of antiseizure meds of adequate dose and duration
Possible reasons for treatment failure
failure to reach the CNS target
alteration of drug targets in the CNS
drugs missing the real target
Management of drug-resistant epilepsy
rule out pseudo-resistance - wrong drug or diagnosis
combination therapy
electrical/surgical intervention
Status epilepticus
continuous seizure activity lasting 5 (five) minutes or more, or two or more discrete seizures with incomplete recovery between seizures
■ Intravenous drug therapy commonly used in this situation
Possible drug therapy for status epilepticus
benzodiazepines, most commonly lorazepam or midazolam (IV)
initial tx phase (5-20 min): IV lorazepam or midazolam
2nd tx phase (20-40 min): IV fosphenytoin, IV valproic acid, IV levetiracetam
Phenytoin/fosphenytoin requires
cardiac monitoring, may also cause a local reaction called “purple glove syndrome”
Fosphenytoin equivalent to
20 mg PE (phenytoin equivalents)
Oral phenytoin dosing considerations
MUST obtain both phenytoin serum concentration and serum albumin in the same blood draw
Oral phenytoin therapeutic serum concentration
10-20 mcg/mL
Valproate IV to PO conversion
1:1 mg/mg
IV loading dose: 15-30 mg/kg
Valproate desired serum concentration
80 mcg/mL (range 50-125 mcg/mL)
1A2 inducer
carbamazepine
phenobarbital
phenytoin
2C9 inducer
carbamazepine
phenobarbital
phenytoin
3A4 inducer
carbamazepine
phenobarbital
phenytoin
lamotrigine
oxcarbazepine
topiramate
UGT inhibitor
valproate
Lamotrigine warning
Boxed warning for Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis – lamotrigine is a UGT substrate, high initial serum concentrations associated with SJS/TEN – specific dosing based on concomitant drug therapy with UGT inducers or inhibitors
Lamotrigine 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 w/o concomitant 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 with UGT inducers (carbamazepine, 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
Anticonvulsant hypersensitivity syndrome
Strong correlation for positive
HLA-B1502 allele and AHS
in patients of Asian descent
Positive HLA-A3101 in those of Northern European and Asian descent may confer similar risk
Black box warning - genetic screen for HLA-B*1502 allele prior to initiating carbamazepine or like derivatives (oxcarbazepine, eslicarbazepine)
Patients with positive allele should not be treated with carbamazepine or like derivatives unless benefit clearly outweighs risk
DRESS syndrome
Potentially life-threatening – estimated mortality rate of 10%
Generally, occurs 2 – 6 weeks after initiation of drug therapy
Associated with carbamazepine, cenobamate, lamotrigine, phenobarbital, phenytoin, valproate, zonisamide
Increased risk in patients who are positive for the HLA-A*3101 allele (usually of Asian or Northern European descent)
Antiseizure 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
Antiseizure drug therapy in pregnancy
Drug serum concentrations may be altered in pregnancy due to changes in volume of distribution
Valproate is not recommended in pregnancy; causes neural tube
defects and is associated with a decreased IQ in the offspring
Many antiseizure drugs are known teratogenic risks – carbamazepine, clonazepam, fosphenytoin, phenobarbital, phenytoin, primidone, topiramate – patient counseling for people of child-bearing age should include education about these risks and contraceptive use (keep in mind OC drug interactions)
Supplemental folic acid (5 mg daily) should be considered during pregnancy
infant should receive vitamin K 1 mg IM at birth to decrease risk of hemorrhagic disease
Contraceptive drug interactions
mediated by P450 3A4 induction
■ This interaction can be minimized by using higher-dose estrogen contraceptives – warning for increased thromboembolism
■ Can use progestin-only contraceptives – depot formulation
– IUDs are also recommended
■ Estrogen can significantly decrease lamotrigine serum concentration (50%) and lamotrigine decreases estrogen concentrations
Cardiovascular Adverse Effects
Arrhythmia: lamotrigine
heart block: lacosamide
arrhthmia: phenytoin/fosphenytoin
valvular heart disease: fenfluramine
PR interval changes: lacosamide, pregabalin
Electrolyte abnormalities
Carbamazepine/eslicarbazepine/oxcarbazepine – hyponatremia, syndrome of inappropriate antidiuretic hormone (SIADH)
Metabolic acidosis
zonisamide - metabolic acidosis, renal caniculi
Topiramate – decreased serum bicarbonate leading to metabolic acidosis; nephrolithiasis – monitor serum bicarbonate (is also a carbonic anhydrase inhibitor); also associated with decreased sweating, heat intolerance, and oligohydrosis
Mineral metabolism (bone loss)
Phenytoin – Altered vitamin D metabolism and decreased calcium concentrations leading to osteoporosis with long-term use
Psychiatric Side Effects of Antiseizure Medications: perampanel
Boxed warning: dose-related serious and/or life-threatening neuropsychiatric events (use with caution with pre-existing psychosis)
Psychiatric Side Effects of Antiseizure Medications: levetiracetam
Psychosis, suicidal thoughts/
behaviors, unusual mood
changes, worsening depression (most often seen in children and adolescents)
Psychiatric Side Effects of Antiseizure Medications: valproate
Acute mental status changes related to hyperammonemia; differentiate from sedation side effect
valproate interferes with Kreb’s cycle, causes elevated blood ammonia, carnitine supplementation needed
Psychiatric Side Effects of Antiseizure Medications: topiramate
Associated with cognitive dysfunction if the dose is increased too rapidly, use a slow dose titration
Visual Abnormalities: topiramate
post-marketing warning for vision loss, myopia, retinal detachment
Visual Abnormalities: vigabatrin
is contraindicated in patients who have other risk factors for irreversible vision loss.
FDA safety and warning: gabapentin and pregabalin respiratory depression
Take-away: Evaluate the appropriateness of gabapentin or pregabalin use and risk for respiratory depression in a patient who is taking other CNS depressants, has pulmonary disease, or is elderly
can increase risk of overdose with other CNS depressant
Clinical pearls -mazepines
Carbamazepine: strong
P450 (1A2, 2C9, 2C19,
3A4) and p-glycoprotein inducer (induces own metabolism)
Oxcarbazepine induces 3A4
Carbamazepine, Oxcarbazepine, Eslicarbazepine: hyponatremia
Clinical pearls: valproate
Valproate can cause thrombocytopenia – monitor CBC/platelets; can cause PCOS, weight gain, sedation
Clinical pearls: topiramate and zonisamide
Topiramate and Zonisamide:
weight loss, oligohydrosis, nephrolithiasis
Zonisamide is contraindicated if there is a sulfa allergy
Clinical pearls: phenytoin
Phenytoin can cause
gingival hyperplasia and
hirsutism
Phenytoin absorption is decreased when given with enteral feedings, hold feedings 1 – 2 hours before and after administration
Clinical pearls: gabapentin and pregabalin
Gabapentin and pregabalin are renally eliminated, decrease dose in with renal impairment
Clinical pearls: lamotrigine
Lamotrigine has been
associated with
arrhythmia in people with
underlying cardiac
conditions
Medical marijuana cannabidiol
can help to control seizures, especially those refractory to current AED meds
lennox-gastaut syndrome
dravet syndrome
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 seizures begin in 1st year of life leading to multiple seizure types and developmental disability
Epidiolex® - cannabidiol oral solution
Indicated for Dravet Syndrome and Lennox
Gastaut Syndrome
Everolimus only indicated for
tuberous sclerosis complex (TSC)-associated partial-onset seizures
The ketogenic diet
3:1 or 4:1 fats:carbs/proteins
Side Effects: hyperlipidemia (reversible upon d/c of diet), weight loss, constipation, kidney stones, decreased bone mass/growth
Adults seem to respond only while on the diet, the effects in children may continue after the diet is discontinued.
Depression in epilepsy
All antiseizure drugs carry a warning for increased risk of suicidal thinking and/or behaviors during treatment
Antidepressants also carry a warning for increased risk of suicidal thinking and behaviors during treatment in patients < 24 years of age
Use of bupropion should be avoided in patients with uncontrolled seizure disorders, as it can increase the risk of seizures and seizure frequency
Depression is a common
co-morbidity
