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Question 1

Valproate

Answer 1

Efficacy

Broad spectrum agent with efficacy against the most common seizure types

Pharmacokinetics

Administered as enteric-coated and delayed-release formulations

Inhibits metabolism of other AEDs: phenytoin, lamotrigine, carbamazepine, phenobarbital, ethosuximide

Question 2

Dose-related GI upset (nausea-vomiting, pain)

Weight gain common

Black Box Warnings

• Hepatic failure
• Life-threatening pancreatitis – monitor symptoms
• Teratogenic effects (neural tube defects) – weigh benefit-risk

Answer 2

Valproate

Question 3

Status Epilepticus Treatment Options:

Answer 3

Initial therapy IV diazepam (lorazepam or midazolam) until seizures stop or 20 mg given

Then start phenytoin or fosphenytoin slow infusion

If seizures persist IV phenobarbital until seizures stop

If seizures still continue, pentobarbital or propofol infusion with pressor support

Question 4

Drug of choice in absence seizures

Answer 4

Ethosuximide

Question 5

Ethosuximide

Answer 5

Adverse Drug Reactions – generally few side effects

Dose-related gastric distress most common (NV, pain)

Less common: transient lethargy-fatigue, dizziness, headache

Question 6

Mechanism - Efficacy

Precise mechanism unknown - affects Ca++ channels

1st line in treatment of generalized tonic-clonic seizures

Answer 6

Levetiracetam

Question 7

Levetiracetam ADRs

Answer 7

Somnolence, asthenia, dizziness

Low incidence of cognitive effects

No CYP450 metabolism - minimal DDIs

Question 8

Effects on VSSCs (suppress repetitive APs) and VSCCs (↓ Glu release) - broad spectrum

1st line for partial or generalized seizures - better tolerated than phenytoin or carbamazepine

Answer 8

Lamotrigine

Question 9

ADRs Lamotrigine

Answer 9

Similar to phenytoin (lower incidence): diplopia, ataxia, dizziness, skin rashes, sedation

Question 10

Phenytoin

Answer 10

Very effective against partial and tonic-clonic seizures

Question 11

Phenytoin Pharmacokinetics

Answer 11

Oral absorption is formulation dependent – concern with generic switching

IM absorption erratic (better with prodrug Fosphenytoin)

Zero-order (saturation) metabolism in therapeutic range

**Strong inducer of CYP450 enzymes –> DDIs

Question 12

Phenytoin Adverse Drug Reactions

Answer 12

Nystagmus-diplopia-ataxia-sedation –> dose-related

Rash; gingival hyperplasia-hirsutism develop gradually

Long-term use –> osteomalacia, peripheral neuropathy

Question 13

Carbamazepine Efficacy

Answer 13

A drug of choice for partial seizures

Often tried first in tonic-clonic seizures

Question 14

Carbamazepine Pharmacokinetics

Answer 14

**Strong inducer of CYP450 enzymes –> self-induction + drug-drug interactions

Question 15

Carbamazepine Adverse Drug Reactions

Answer 15

Diplopia-ataxia-sedation –> dose-related

GI upset

Rare but serious

Aplastic anemia-agranulocytosis –> monitor CBC

Hepatotoxicity –> monitor liver function tests

Question 16

________ and phenobarbital enhance the inhibitory effect of GABA (↑ opening of Cl- channels)

Answer 16

Benzodiazepines

Valproate appears to act partly by this mechanism

Question 17

A drug of choice for partial seizures

Often tried first in tonic-clonic seizures

Answer 17

Carbamazepine

Question 18

Diplopia-ataxia-sedation –> dose-related

GI upset

Rare but serious

Aplastic anemia-agranulocytosis –> monitor CBC
Hepatotoxicity –> monitor liver function tests

Answer 18

Carbamazepine

Question 19

Strong inducer of CYP450 enzymes –>
self-induction + drug-drug interactions

Pharmacokinetics

Answer 19

Carbamazepine

Question 20

Initial therapy IV diazepam (lorazepam or midazolam) until seizures stop or 20 mg given

Then start phenytoin or fosphenytoin slow infusion

If seizures persist IV phenobarbital until seizures stop

If seizures still continue, pentobarbital or propofol infusion with pressor support

Answer 20

Status Epilepticus

Question 21

Neonatal status epilepticus

Adjunct for partial and tonic-clonic seizures

Answer 21

Phenobarbital

Question 22

Metabolized slowly by P450 system - t1/2 of 4-5 days

Classic enzyme inducer

Answer 22

Phenobarbital

Question 23

Irritability - overactivity in many children, sedative effects in others

Mild ataxia, nystagmus, skin rash, osteomalacia

May interfere with learning (cognitive deficits)

Answer 23

Phenobarbital

Question 24

A drug of choice for partial seizures

Often tried first in tonic-clonic seizures

Answer 24

Carbamazepine

Question 25

Decrease in low-threshold Ca++ (T-type) current

Answer 25

Oscillatory currents in thalamic neurons are abnormal in absence seizures - blocked by ethosuximide-valproate

Question 26

Inhibition of high-voltage activated Ca++-channels

Answer 26

VSCC (aka N-type) involved in regulation of glutamate neurotransmitter release - lamotrigine

Question 27

Inhibits function of synaptic vesicle protein SV2A

Answer 27

Impairs Ca++-mediated neurotransmitter release - levetiracetam

Question 28

________ –> block excitation of cells firing repetitively (epileptic foci) leaving low frequency firing neurons (normal) unaffected

Answer 28

Blockade is use-dependent

Phenytoin, carbamazepine, lamotrigine, valproate

Question 29

Inhibition of Sodium Channel Function

Answer 29

Block sustained high-frequency repetitive firing of APs that can initiate seizure formation

Phenytoin, carbamazepine, lamotrigine, valproate

Question 30

Impairs Ca++-mediated neurotransmitter release - levetiracetam

Answer 30

Inhibits function of synaptic vesicle protein SV2A