Lectures 48-49 - Pharmacotherapy of Seizure Disorders

Question 1

Lowering the seizure threshold: medications

Answer 1

usual doses: bupropion, clozapine, theophylline, varenicline, phenothiazine, antipsychotics, CNS stimulants (amphetamines)
high doses and impaired renal function: carbapenems, lithium, meperidine, penicillin, quinolones, tramadol

Question 2

Quality of life monitoring

Answer 2

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?

Question 3

Lifelong treatment?

Answer 3

not necessarily - long term studies have shown that successful antiseizure medicaiton withdrawal may occur after a seizure free period of 2-5 years

Question 4

Risk factors for seizure recurrence

Answer 4

• < 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

Question 5

Drug-resistant epilepsy

Answer 5

defined as failure of at least two trials of antiseizure meds of adequate dose and duration

Question 6

Possible reasons for treatment failure

Answer 6

failure to reach the CNS target
alteration of drug targets in the CNS
drugs missing the real target

Question 7

Management of drug-resistant epilepsy

Answer 7

rule out pseudo-resistance - wrong drug or diagnosis
combination therapy
electrical/surgical intervention

Question 8

Status epilepticus

Answer 8

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

Question 9

Possible drug therapy for status epilepticus

Answer 9

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

Question 10

Phenytoin/fosphenytoin requires

Answer 10

cardiac monitoring, may also cause a local reaction called “purple glove syndrome”

Question 11

Fosphenytoin equivalent to

Answer 11

20 mg PE (phenytoin equivalents)

Question 12

Oral phenytoin dosing considerations

Answer 12

MUST obtain both phenytoin serum concentration and serum albumin in the same blood draw

Question 13

Oral phenytoin therapeutic serum concentration

Answer 13

10-20 mcg/mL

Question 14

Valproate IV to PO conversion

Answer 14

1:1 mg/mg
IV loading dose: 15-30 mg/kg

Question 15

Valproate desired serum concentration

Answer 15

80 mcg/mL (range 50-125 mcg/mL)

Question 16

1A2 inducer

Answer 16

carbamazepine
phenobarbital
phenytoin

Question 17

2C9 inducer

Answer 17

carbamazepine
phenobarbital
phenytoin

Question 18

3A4 inducer

Answer 18

carbamazepine
phenobarbital
phenytoin
lamotrigine
oxcarbazepine
topiramate

Question 19

UGT inhibitor

Answer 19

valproate

Question 20

Lamotrigine warning

Answer 20

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

Question 21

Lamotrigine with UGT inhibitor (valproate)

Answer 21

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

Question 22

Lamotrigine w/o concomitant UGT drug interactions

Answer 22

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

Question 23

Lamotrigine with UGT inducers (carbamazepine, phenytoin)

Answer 23

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

Question 24

Anticonvulsant hypersensitivity syndrome

Answer 24

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

Question 25

DRESS syndrome

Answer 25

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)

Question 26

Antiseizure Drug Withdrawal Syndrome

Answer 26

Associated with abrupt discontinuation of antiseizure medication therapy May cause recurrence of seizures, doses of antiseizure medication should always be tapered for discontinuation

Question 27

Antiseizure drug therapy in pregnancy

Answer 27

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

Question 28

Contraceptive drug interactions

Answer 28

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

Question 29

Cardiovascular Adverse Effects

Answer 29

Arrhythmia: lamotrigine heart block: lacosamide arrhthmia: phenytoin/fosphenytoin valvular heart disease: fenfluramine PR interval changes: lacosamide, pregabalin

Question 30

Electrolyte abnormalities

Answer 30

Carbamazepine/eslicarbazepine/oxcarbazepine – hyponatremia, syndrome of inappropriate antidiuretic hormone (SIADH)

Question 31

Metabolic acidosis

Answer 31

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

Question 32

Mineral metabolism (bone loss)

Answer 32

Phenytoin – Altered vitamin D metabolism and decreased calcium concentrations leading to osteoporosis with long-term use

Question 33

Psychiatric Side Effects of Antiseizure Medications: perampanel

Answer 33

Boxed warning: dose-related serious and/or life-threatening neuropsychiatric events (use with caution with pre-existing psychosis)

Question 34

Psychiatric Side Effects of Antiseizure Medications: levetiracetam

Answer 34

Psychosis, suicidal thoughts/ behaviors, unusual mood changes, worsening depression (most often seen in children and adolescents)

Question 35

Psychiatric Side Effects of Antiseizure Medications: valproate

Answer 35

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

Question 36

Psychiatric Side Effects of Antiseizure Medications: topiramate

Answer 36

Associated with cognitive dysfunction if the dose is increased too rapidly, use a slow dose titration

Question 37

Visual Abnormalities: topiramate

Answer 37

post-marketing warning for vision loss, myopia, retinal detachment

Question 38

Visual Abnormalities: vigabatrin

Answer 38

is contraindicated in patients who have other risk factors for irreversible vision loss.

Question 39

FDA safety and warning: gabapentin and pregabalin respiratory depression

Answer 39

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

Question 40

Clinical pearls -mazepines

Answer 40

Carbamazepine: strong P450 (1A2, 2C9, 2C19, 3A4) and p-glycoprotein inducer (induces own metabolism) Oxcarbazepine induces 3A4 Carbamazepine, Oxcarbazepine, Eslicarbazepine: hyponatremia

Question 41

Clinical pearls: valproate

Answer 41

Valproate can cause thrombocytopenia – monitor CBC/platelets; can cause PCOS, weight gain, sedation

Question 42

Clinical pearls: topiramate and zonisamide

Answer 42

Topiramate and Zonisamide: weight loss, oligohydrosis, nephrolithiasis Zonisamide is contraindicated if there is a sulfa allergy

Question 43

Clinical pearls: phenytoin

Answer 43

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

Question 44

Clinical pearls: gabapentin and pregabalin

Answer 44

Gabapentin and pregabalin are renally eliminated, decrease dose in with renal impairment

Question 45

Clinical pearls: lamotrigine

Answer 45

Lamotrigine has been associated with arrhythmia in people with underlying cardiac conditions

Question 46

Medical marijuana cannabidiol

Answer 46

can help to control seizures, especially those refractory to current AED meds lennox-gastaut syndrome dravet syndrome

Question 47

Lennox-gastaut syndrome

Answer 47

multiple seizure types that develop in childhood, usually accompanied by intellectual disability, sometimes responsive to combination of some AEDs

Question 48

Dravet syndrome

Answer 48

rare genetic epileptic encephalopathy with normal childhood development until seizures begin in 1st year of life leading to multiple seizure types and developmental disability

Question 49

Epidiolex® - cannabidiol oral solution

Answer 49

Indicated for Dravet Syndrome and Lennox Gastaut Syndrome

Question 50

Everolimus only indicated for

Answer 50

tuberous sclerosis complex (TSC)-associated partial-onset seizures

Question 51

The ketogenic diet

Answer 51

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.

Question 52

Depression in epilepsy

Answer 52

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

Question 53

Depression is a common

Answer 53

co-morbidity