Epilepsy II PDF

PCOL 825B Drugs for Epilepsy II Alison K. Veltri, PhD 1 Contents First-line drugs DDIs/things to consider Carbamazepine Oxcarbazepine Eslicarbazepine Ethosuximide Felbamate Gabapentin Lacosamide Lamotrigine Levetiracetam Brivaracetam Perampanel 2 First-Line Drugs Phenytoin Carbamazepine Ethosuxamide...

PCOL 825B Drugs for Epilepsy II Alison K. Veltri, PhD 1 Contents First-line drugs DDIs/things to consider Carbamazepine Oxcarbazepine Eslicarbazepine Ethosuximide Felbamate Gabapentin Lacosamide Lamotrigine Levetiracetam Brivaracetam Perampanel 2 First-Line Drugs Phenytoin Carbamazepine Ethosuxamide Lamotrigine Oxcarbazepine Topiramate Valproic acid Goals: 1. Eliminate or reduce seizure frequency 2. Avoid adverse effects 3. Normalize lifestyle 3 DDIs Can be inducers or inhibitors of other drugs Watch for DDIs Consider monotherapy when appropriate 4 DDIs Inducers: carbamazepine (autoinduction), phenytoin, phenobarbital, primidone Inhibitors: felbamate, valproate Watch for other drugs that lower the seizure threshold! 5 Drugs that Lower Seizure Threshold In known epilepsy, consider alternative drugs for other conditions when appropriate 6 7 Antiepileptic Drugs Suicidal behavior/ideation risk Multiorgan hypersensitivity reactions Rash, fever, systemic organ involvement Typically consider initiating medication therapy following second seizure Gradual dose titration for tolerance and seizure control 8 Carbamazepine (Tegretol) MOA: Inhibits the generation of repetitive action potentials by blocking sodium channels Indications: simple and complex partial seizures (first line), generalized tonic-clonic seizures NOT for absence seizures Note: induces its own metabolism Result is lower total drug blood concentrations at high doses 9 Carbamazepine (Tegretol) Adverse Effects Dose and non-dose related adverse effects Dose related: Diplopia Ataxia GI upset Hyponatremia Non-dose related: Skin rashes Aplastic anemia and agranulocytosis (rare, fatal) Other considerations: Elderly: hyponatremia especially common Pregnancy: can cause spina bifida and craniofacial abnormalities in fetus 10 Carbamazepine (Tegretol) PK Notes Metabolized to carbamazepine-10,11-epoxide (active metabolite) Known potent inducer of liver microsomal enzymes FDA classified as strong inducer (AUC decrease of victim drug ≥ 80%) Increases metabolism of many other antiepileptic drugs Counseling point: interacts with grapefruit juice 11 Oxcarbazepine (Trileptal) Prodrug Metabolized into 10-monohydroxy (MHD) MOA: similar to carbamazepine Indicated for partial seizures and generalized tonic-clonic seizures 12 Eslicarbazepine (Aptiom) MOA: voltage-gated sodium channel blocker Indications: approved for adult partial-onset seizures Eslicarbazepine acetate converted by hydrolysis to active eslicarbazepine Adverse effects: dizziness, somnolence, diplopia, headache Serious (rare) adverse effects: psychiatric changes 13 Ethosuximide (Zarontin) MOA: T-type calcium channel inhibition Results in abnormal seizure discharge reduction Indication: absence seizure (first line) Caution: can worsen other seizure types Not for use in tonic-clonic or partial seizures Adverse effects: GI distress, fatigue, headache 14 Felbamate (Felbatol) MOA: calcium channel inhibition, competitive NMDA glutamate receptor binding, GABA modulation Indication: partial seizures (alternative medication) Adverse effects: aplastic anemia, liver failure Known inhibitor of drugs metabolized through CYP2C19 Induces drugs metabolized by CYP3A4 15 Gabapentin (Neurontin) MOA: Decreases glutamate Indication: Adjunct therapy for focal seizures Adverse effects: drowsiness, dizziness, ataxia Unusual PK: no plasma protein binding, no liver metabolism 16 Lacosamide (Vimpat) MOA: stabilizes voltage-gated sodium channels, binds to collapsing response mediator protein-2 (CRMP-2) Stabilizes hyperexcitable neuronal membranes Prevents repetitive neuronal firing Indication: adjunct for focal seizure Fun fact: available in injectable formulations Adverse effects: dizziness, headache, fatigue 17 Lamotrigine (Lamictal) MOA: blocks sodium channels and high voltage-dependent calcium channels Dihydrofolate reductase inhibitor Indications: effective for wide variety of seizure types (first line for general tonic-clonic seizure) Alternative for absence seizures if first-line medications fail Adverse effects: dizziness, headache, ataxia, rash Caution: Divalproex significantly decreases lamotrigine clearance (higher concentration of drug) 18 Levetiracetam (Keppra) MOA: unknown; involves inhibition of synaptic vesicle protein (SV2A) Indications: adjunct therapy for focal, myoclonic, and primary generalized tonic-clonic seizures (adults and children) Few DDIs Caution: can cause mood changes (titrate dose) 19 Brivaracetam (Briviact) MOA: SV2A analog Higher affinity for SV2A than levetiracetam Indications: monotherapy for partial seizure Slightly more favorable neuropsychiatric safety profile than levetiracetam 20 Perampanel (Fycompa) MOA: ⍺-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist Indications: partial seizures, generalized tonic-clonic seizures Long half-life Caution: may cause serious psychiatric, behavioral reactions 21 Coming Up Drugs for Epilepsy III 22