Antiseizure Drugs

Question 1

Goals of therapy

Answer 1

Eliminate seizures

Avoid side effects

Achieve best possible psychosocial function

Question 2

Principles of AED therapy

Answer 2

Verify a diagnosis of epilepsy

Acute symptomatic seizures (e.g. hyponatremic seizure or seizure related to drug intoxication) is not epilepsy and does not require initiation of an AED.

Many other things can mimic an epileptic seizure, such as psychogenic non-epileptic seizures and syncope.

Select an AED based on seizure-type, other medications and co-morbidities, and potential adverse effects.

Manage adverse effects

Attempt to get seizure-freedom with monotherapy.

Monitory therapy with serum drug levels, if available.

Question 3

Drugs for Focal-onset seizures:

Answer 3

ALL AEDs except ethosuxamide (based on FDA approval)

There is no clear front-runner to choose from based on efficacy alone. You must make a selection based on other things, like drug interractions and side effects.

Question 4

Drugs for absence seizures

Answer 4

Ethosuxamide (works for nothing else)

Valproic acid

Zonisamide

Question 5

Drugs for Primary generalized seizures

Answer 5

Valproic acid

Lamotrigine

Topiramate

Zonisamide

Levetiracetam

Perampanel

Question 6

Drugs for myoclonus

Answer 6

Valproic acid

Levetiracetame

Zonisamide

Question 7

Criteria for surgery

Answer 7

Some patients with epilepsy need to have surgery to reduce seizure frequency. One criteria commonly used to recommend epilepsy surgery is the use of at least two AEDs over at least two years, which fail to achieve seizure freedom.

Question 8

Efficacy of first AED

Answer 8

The first drug you choose has about a 60% chance of seizure freedom. Each drug you choose after that has diminishing returns unless use is limited by side effects (in which case you get a do-over).

Question 9

What are complex partial seizures and drugs of choice

Answer 9

Complex Partial Seizures

Focal onset seizures with altered awareness

ALL AEDs are useful except for ethosuxamide

“classic” drugs of choice:

carbamazepine

phenytoin

valproic acid

oxcarbazepine

lamotrigine

lacosamide

Question 10

Side effects of Pheytoin

Answer 10

Gum hypertrophy

Facial coarsening and hirsutism

Osteopenia

Teratogenesis

Ataxia with cerebellar atrophy

Question 11

Side effects of Valproic acid

Answer 11

Weight gain

Tremor

Alopecia

Question 12

Side effects of topiramate

Answer 12

Nausea and weight loss

Nephrolithiasis

Glaucoma exacerbation

Question 13

Side effects of Levetiracetam

Answer 13

Irritability and mood disorder exacerbation

Question 14

Drugs that interact with Broad spectrum CYP inducers

Answer 14

Carbamazepine

Phenytoin

Phenobarbital

Primidone

Question 15

Drugs that interact with CYP3A inducers

Answer 15

Oxcarbazepine

Topiramate

Felbamate

Question 16

Drugs that interact with CYP450 inhibitors

Answer 16

Valproic acid

Question 17

Drugs that have NO effects on the CYP system

Answer 17

Levetirecetam

Gabapentin

Lamotrigine

Tiagabine

Zonisamide

Question 18

Drugs that carry a risk of stevens johnson syndrome

Answer 18

Carbamazepine

Oxcarbazepine

Valproic acid

Phenytoin

Phenobarbital

Ethosuxamide

Lamotrigine

Zonisamide

Question 19

Drugs with hepatotoxicity

Answer 19

Carbamazepine

Oxcarbazepine

Valproic acid

Phenytoin

Phenobarbital

Felbamate

Question 20

Drugs that cause Leukopenia/aplastic anemia

Answer 20

Carbamazepine

Oxcarbazepine

Valproic acid

Phenobarbital

Ethosuxamide

Zonisamide

Felbamate

Question 21

How does Voltage-gated sodium channel modulation work

Answer 21

The most important known AED mechanism of action is modulation of sustained repetitive firing, usually through modulation of voltage-gated sodium channel function.

Question 22

Benzodiazapenes MOA

Answer 22

GABA receptor modulation

The second most important AED mechanism of action is enhancement of GABAA receptor function and therefore, enhancement of synaptic inhibition.

Question 23

AED used for tremor

Answer 23

Primidone

Question 24

AED used for pain

Answer 24

gabapentin, pregabalin

Question 25

AED used for migraine

Answer 25

topiramate, valproic acid

Question 26

AED used for mood disorder

Answer 26

lamotirigine, valproic acid, topiramate

Question 27

Phenytoin MOA and indication

Answer 27

Mechanism of action: Sodium channel modulator Indication: FDA approved for focal onset seizures

Question 28

Phenytoin pharmokinetics

Answer 28

Liver metabolism, which is nonlinear Phenytoin switches from first-order to zero-order kinetics in the middle of its therapeutic dose range. Interracts with mutliple drugs (broad spectrum CYP inducer) Twice daily dosing, half-life of ~22 hours (good if you miss a dose)

Question 29

Carbamazepine MOA, indications, pharmacokinetics, adverse effects

Answer 29

**Mechanism of action: Sodium channel modulator** **Indication: FDA approved for patrial onset seizures** **Phamacokinetics:** Liver metabolism Broad spectrum CYP inducer TID dosing, half life 8-22 hours **Adverse effects:** Hyponatremia Hepatitis Aplastic anemia Ataxia

Question 30

Gabapentin indication and pharmacokinetics

Answer 30

**Indication: FDA approved for focal onset seizures** **Pharmacokinetics: very favorable** No active metabolites or protein binding 93% excreted unchanged in urine Does not induce hepatic enzymes Low interraction with other AEDs TID or QID dosing, half life 5-7 hours

Question 31

Lamotrigine indication, pharmacokinetics, side effects

Answer 31

**Indication: FDA approved for focal onset seizures but commonly used also in generalized seizures** **Pharmacokinetics:** Metabolized in the liver but not CYP450 daily or BID dosing, half life 12-60 hours **High rate of rash, including Stevens Johnson syndrome**

Question 32

Levetiracetam MOA, indication, pharmacokinetics, side effects

Answer 32

**Mechanism of action:** not entirely clear **Indication:** FDA approved for focal onset seizures but also frequently used in generalized seizures **Pharmacokinetics:** 2/3 excreted unchanged and 1/3 metabolized in the liver BID dosing, half-life 6-8 hours **Adverse effects:** irritability and aggressiveness

Question 33

Fetal malformations associated with each drug

Answer 33

—Structural teratogenesis with 1st trimester exposure and cognitive teratogenesis is with exposure throughout pregnancy **—Valproate**- Associated with spina bifida, hypospadias, lower verbal IQ and autism, may be dose dependent **—Phenobarbital** is associated with cardiac malformations **—Topiramate**- Associated with facial clefts **—Carbamazepine**- Spina bifida **—Phenytoin**- hypospadias and cardiac defects **—Levetiracetam**- Only 2 major malformations occurred (inguinal hernia and reflux requiring surgery) **—Folic acid** decreases the risk of neural tube defects, lower verbal IQ and the risk of spontaneous miscarriage (1-4 mg)