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Valproate
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
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
Valproate
Status Epilepticus Treatment Options:
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
Drug of choice in absence seizures
Ethosuximide
Ethosuximide
Adverse Drug Reactions – generally few side effects
Dose-related gastric distress most common (NV, pain)
Less common: transient lethargy-fatigue, dizziness, headache
Mechanism - Efficacy
Precise mechanism unknown - affects Ca++ channels
1st line in treatment of generalized tonic-clonic seizures
Levetiracetam
Levetiracetam ADRs
Somnolence, asthenia, dizziness
Low incidence of cognitive effects
No CYP450 metabolism - minimal DDIs
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
Lamotrigine
ADRs Lamotrigine
Similar to phenytoin (lower incidence): diplopia, ataxia, dizziness, skin rashes, sedation
Phenytoin
Very effective against partial and tonic-clonic seizures
Phenytoin Pharmacokinetics
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
Phenytoin Adverse Drug Reactions
Nystagmus-diplopia-ataxia-sedation –> dose-related
Rash; gingival hyperplasia-hirsutism develop gradually
Long-term use –> osteomalacia, peripheral neuropathy
Carbamazepine Efficacy
A drug of choice for partial seizures
Often tried first in tonic-clonic seizures
Carbamazepine Pharmacokinetics
**Strong inducer of CYP450 enzymes –> self-induction + drug-drug interactions
Carbamazepine Adverse Drug Reactions
Diplopia-ataxia-sedation –> dose-related
GI upset
Rare but serious
Aplastic anemia-agranulocytosis –> monitor CBC
Hepatotoxicity –> monitor liver function tests
________ and phenobarbital enhance the inhibitory effect of GABA (↑ opening of Cl- channels)
Benzodiazepines
Valproate appears to act partly by this mechanism
A drug of choice for partial seizures
Often tried first in tonic-clonic seizures
Carbamazepine
Diplopia-ataxia-sedation –> dose-related
GI upset
Rare but serious
Aplastic anemia-agranulocytosis –> monitor CBC
Hepatotoxicity –> monitor liver function tests
Carbamazepine
Strong inducer of CYP450 enzymes –>
self-induction + drug-drug interactions
Pharmacokinetics
Carbamazepine
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
Status Epilepticus
Neonatal status epilepticus
Adjunct for partial and tonic-clonic seizures
Phenobarbital
Metabolized slowly by P450 system - t1/2 of 4-5 days
Classic enzyme inducer
Phenobarbital
Irritability - overactivity in many children, sedative effects in others
Mild ataxia, nystagmus, skin rash, osteomalacia
May interfere with learning (cognitive deficits)
Phenobarbital
A drug of choice for partial seizures
Often tried first in tonic-clonic seizures
Carbamazepine
