Seizure Pharmacology

Question 1

What are the 4 ways in which neural inhibitory neurons can be opposed to cause a seizure?

Answer 1

• Increase in extracellular K+
• Increase in Ca2+ at presynaptic terminals (increased neurotransmitter release)
• Activation of NMDA excitatory neurons
• Cell swelling and changes in tissue osmolarity

Question 2

What leads to the high frequency burst of APs in seizures?

Answer 2

influx of extracellular Ca2+ (depolarization) with activation of voltage-dependent Na+ channels

Question 3

What leads to hypersynchronization in seizures?

Answer 3

hyperpolarizing after-potential via GABA receptors or K+ channels

Question 4

What are the 3 major MOAs of AEDs?

Answer 4

• Blockage of voltage-gated sodium channels
• Enhancement of GABA
• Inhibition of voltage-gated clacium channels

Question 5

Why does blockade of voltage gated sodium channels prevent seizures?

Answer 5

diminishes the effects of glutamate by promoting the inactivated state to limit the sustained, repetitive firing of neurons

Question 6

What type of seizures do drugs that block voltage-gated sodium channels treat?

Answer 6

partial and secondary generalized tonic-clonic seizures

Question 7

List the drugs that work through blocking voltage-gated sodium channels.

Answer 7

carbamazepine, oxcarbazepine, phenytoin, topiramate, lamotrigine, valproate, zonisamide, lacosamide

Question 8

Why does enhancing GABA prevent seizures?

Answer 8

GABA is the principal inhibitory neurotransmitter int he CNS and enhancing it will prevent hypersynchronization

Question 9

What type of seizures do drugs that enhance GABA treat?

Answer 9

partial and secondary generalized tonic-clonic seizures

Question 10

What are the two places where drugs that enhance GABA can work?

Answer 10

Post-synaptically (increases Cl- influx in response to GABA)

Pre-synaptically (promote GABA release or prevent GABA metabolism)

Question 11

What drugs bind separately at post-synaptic sites on the multimeric ion channel complex to modulate the activity of endogenous GABA

Answer 11

Benzodiazepines (clonazepam)

Barbiturates

Question 12

What drug works presynaptically to promote GABA release (Inhibition of α-2 δ-1 subunit of Ca2+ channels)?

Answer 12

Gabapentin

Pregabalin

Question 13

What drug works presynaptically to prevent GABA metabolism?

Answer 13

Valproate

Question 14

How do drugs that inhibit voltage-gated calcium channels treat seizures?

Answer 14

diminish effects of glutamate by reducing pacemaker current that underlies thalamic rhythm in spikes and waves

Question 15

What type of seizures do drugs that inhibit T-type Ca2+ channels treat?

Answer 15

generalized absence seizures

Question 16

What drugs act by inhibition of voltage-gated calcium channels?

Answer 16

Ethosuximide
Oxcarbazepine (possible, along with increase in K+)
Zonisamide (with blockage of Na+)

Question 17

True or false: most AEDs are administered orally

Answer 17

TRUE (though some are available for IV dosing)

Question 18

Which AEDs have increased levels of protein binding compared to the others (with limited protein binding)?

Answer 18

phenytoin

valproate

Question 19

Which AED accumulates in erythrocytes?

Answer 19

Zonisamide

Question 20

Where are most AEDs metabolized?

Answer 20

hepatic metabolism

Question 21

Which AEDs induce CYP 3A4?

Answer 21

Carbamazepine, felbamate, oxcarbazepine

Question 22

Which AED induces CYP 3A4 and 3A5?

Answer 22

Oxcarbazepine

Question 23

Which AED induces CYP 3A4, 2C9 and 2C19?

Answer 23

Phenytoin

Question 24

Which AEDs induce UGT?

Answer 24

carbamazepine, lamotrigine

Question 25

Which AEDs inhibit CYP2C19?

Answer 25

felbamate, lacosamide, oxcarbazepine, valproate

Question 26

Which AED inhibits UGT?

Answer 26

Valproate

Question 27

Which AEDs are NOT metabolized by CYPs?

Answer 27

Gabapentin, Lamotrigine, levetriacetam, pregabalin, topiramate

Question 28

Which AEDs need to have routine drug monitoring of serum drug levels (because they alter their own T1/2 by altering the CYPs that metabolize them)?

Answer 28

carbamazepine, ehtosuximide, gabapentin, phenytoin, valproate

Question 29

Which is the ONLY AED that is not eliminated in the urine? How is it eliminated?

Answer 29

Phenytoin (eliminated in stool)

Question 30

True or false: you must immediately stop therapy if the patient feels like the drug is making them feel worse.

Answer 30

FALSE- abrupt termination of therapy can precipitate onset of status epilepticus, increase the frequency of seizures and lead to various neurologic issues. Where possible, termination should involve tapering of drug over a period of time.

Question 31

What is unique about the pharmacokinetics of phenytoin?

Answer 31

one of the only drugs to have zero-order pharmacokinetic behavior (half-life varies with drug dose)

Question 32

What are factors that can impact the metabolic processing of phenytoin?

Answer 32

highly variable CYP induction and protein binding displacement; age, smoking and hepatic status

Question 33

What is the pro-drug of phenytoin?

Answer 33

Fosphenytoin

Question 34

What is the dose adjustment between fosphenytoina nd phenytoin?

Answer 34

150mg fosphenytoin = 100 mg phenytoin

Question 35

TRUE or FALSE: ALL AEDs produce dose-related manifestations of CNS toxicity including nystagmus, ataxia, headache, etc.

Answer 35

TRUE

Question 36

Which drugs carry NO risk for SJS?

Answer 36

clonazepam and lacosamide

Question 37

Who has the highest risk of having a dermatologic toxicity to an AED?

Answer 37

Asians with HLA-B 1502 allele SNPs

Question 38

Other than CNS and dermatologic toxicities, what is the rare but serious potential side effect of AEDs?

Answer 38

hematologic toxicity

Question 39

What potential side effect of AEDs is usually observed 1-24 weeks after starting the drug?

Answer 39

suicidal ideation

Question 40

What is the common and serious adverse effect seen in pregnant women taking phenobarbital and carbamazepine?

Answer 40

fetal hydantoin syndrome

Question 41

What are the features of fetal hydantoin syndrome?

Answer 41

including upturned nose, mild midfacial hypoplasia, and long upper lip with thin vermilion border and distal digital hypoplasia

Question 42

Which AED (teratogen) can lead to cleft lip and palate?

Answer 42

topiramate

Question 43

Which AED (teratogen) can lead to neural tube defects, skeletal abnormalities and developmentl delay?

Answer 43

valproate

Question 44

Which AED (teratogen) may lead to fetal hydantoin syndrome (but not as commonly as phenobarbital and carbamazepine)?

Answer 44

phenytoin

Question 45

Which AED (teratogen) leads to inhibited dihydrofolate reductase (lowering fetal folate levels)?

Answer 45

lamotrigine

Question 46

Name all of the AED teratogens?

Answer 46

``` Valproate Phenytoin Carbamazepine Phenobarbital Lamotrigine Topiramate ```

Question 47

True or false: successful drug therapy for epilepsy is successful in around 25% of patients.

Answer 47

FALSE: 50%

Question 48

MOA: Inhibition of NMDA receptors (glutamate) and increase in GABA receptor conductance

Answer 48

felbamate

Question 49

MOA: Blockage of Na+ channels, enhancement of GABA mediated Cl- influx, increase K+ current, and decrease in glutamate activity

Answer 49

Topiramate

Question 50

MOA: Increase GABA activity and inhibits Na+ channels

Answer 50

valproate

Question 51

BBW: agranulocytosis

Answer 51

Carbamazepine

Question 52

BBW: aplastic anemia, bone marrow suppression, hepatic disease

Answer 52

felbamate

Question 53

BBW: SJS or TEN

Answer 53

lamotrigine

Question 54

TOXICITY: Gingivial hyperplasia, hirsutism, derm toxicity, hematologic changes

Answer 54

phenytoin

Question 55

TOXICITY: renal calculi

Answer 55

Topiramate and Zonisamide

Question 56

Why do topiramate and zonisamide cause renal calculi?

Answer 56

weak carbonic anhydrase inhibitors (need to monitor serum bicarbonate levels)

Question 57

TOXICITY: thrombocytopenia and increased bleeding time; hepatotoxicity in kids > adults

Answer 57

vlaproate

Question 58

Which AED would be good for an obese patient?

Answer 58

zonisamide

Question 59

Which AED would be good in a patient with bipolar disorder?

Answer 59

valproate

Question 60

Which AEDs would you potentially want to check for HLA-B 1502 SNPs?

Answer 60

Phenytoi Lamotrigine Carbamazepine

Question 61

Which AED would be good for a patient with depression and mood disorders?

Answer 61

lamotrigine

Question 62

List the 1st line AEDs for partial seizures.

Answer 62

Carbamazepine Lamotrigine Levetiracetam Oxcarbazepine

Question 63

List the 1st line AEDs for generalized tonic-clonic seizures.

Answer 63

Valproate Levetiracetam Lamotrigine

Question 64

List the 1st line AEDs for absence seizures.

Answer 64

Ethosuzimide | Valproate

Question 65

List the 1st line AEDs for atypical absence, myclonic, and atonic seizures.

Answer 65

Valproate Levetiracetam Lamotrigine

Question 66

List the AEDs used to treat status epilepticus.

Answer 66

Valproate | Phenytoin

Question 67

What is status epilepticus?

Answer 67

prolonged seizure, or cluster of seizures, without a return to baseline, lasting longer than 30 minutes

Question 68

What are the most common causes of SE in patients?

Answer 68

Up to 50% of cases of SE occur in patients with epilepsy due to recent changes in AEDs or non-adherence. The remainder of cases in adults are most often secondary to stroke.

Question 69

What is the first drug given to treat SE?

Answer 69

Benzodiazepine (lorazepam or midazolam)

Question 70

What is the second drug give (after benzodiazepine) for SE?

Answer 70

IV AED (valpraote > phenytoin > midazolam > levetriacetam > Phenobarbital)

Question 71

Why are benzodiazepines used to treat SE?

Answer 71

because they can be given RAPIDLY and work on the GABA receptor (prolong opening time) to terminate the SE (but cannot maintain control alone)

Question 72

What are the predictors of mortality for SE?

Answer 72

generalized seizure, increased patient age, anoxic brain injury, stroke, CNS infection or tumor, and long duration of SE

Question 73

What is the prognosis of SE?

Answer 73

mortality ranges from 7-40%