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Pcol II Antiepileptics


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Phenytoin is prototype drug
Effective against tonic-clonic seizures and all types of partial seizures.
NOT effective against ABSENCE SEIZURES.
Reduces sustained, repetitive firing of Na channels.
Weak acid that can be difficult to give IV. Minor problems with F.
Highly plasma protein bound.
Saturable metabolism. Range 10-20 mcg/mL
SE include CNS efx, cerebellum and vestibular problems, increase in facial hair, folic acid and vit D deficiencies and gingival hyperplasia.
Barbiturates (anti-seizure)
Phenobarbital is prototype drug.
Effective against tonic-clonic and all types of partial seizures.
NOT effective against ABSENCE SEIZURES.
Site of action brain stem(?). Enhancement of GABA-mediated inhibition.
10-35 mcg/mL, may take up to a week to reach steady state.
SE include drowsiness, paridoxical excitement in children, skin rxns, enzyme inhibition, and blood disorders (rare).
Primidone (Mysoline) is prototype drug.
Effective against tonic-clonic seizures and all types of partial seizures.
Metabolized to phenobarbital and PEMA. Phenobarbital blood levels are helpful for monitering.
SE include sedation/drowsiness (dose-related), blood & liver toxicity, hypersensitivity.
Ethosuximide is prototype drug.
Effective primarily for ABSENCE SEIZURES.
Site of action probably Thalamus, reduces Ca++ current (T current) to reduce 3/sec spike/wave rhythms of absence seizures.
40-100 mcg/mL, hydrolyzed to inactive metabolites.
SE are sedation/drowsiness (dose-related), blood & liver toxicities, and hypersensitivity (rare)
Trimethadione (Tridoine) and Paramethadione (Paradione) are prototype drugs.
Effective only for ABSENCE SEIZURES.
Possible mechanism of action related to Ca++ current.
700 mcg/mL
Problems are sedation (big), glare sensitivity, skin rash, blood toxicities, and hepatitis-like rxn.
Clonazepam (Klonopin)
Effective for myoclonal seizueres in children and absence seizures.
Problems are drowsiness/sedation/fatigue, tolerance (short holiday may help), behavioral effects (usually with chronic use), and a variety of non-life threatening effects like headache
Carbamazepine (Tegretol) is prototype drug
Effective against tonic-clonic and partial seizures.
Probably blocks Na+ channels in the cell membrane, may inhibit Ca++ channels.
6-12 mcg/mL.
Autoinduces metabolism.
Epoxide metabolite.
Problems include neurosensory problems, GI upset, water retention, skin rash, and blood dyscrasias.
Valproic acid (Depakene)
Effective against absence seizures and a wide variety of partial and generalized seizures (broad spectrum).
3 mechanisms of action may underlie its broad spectrum: Na channel blockade, T current inhibition (thalamus), and increased GABA.
Well absorbed orally, 30-100 mcg/mL.
Problems include GI upset, weight gain, blood dyscrasias, tremors or drowsiness,
Gabapentin (Neurontin)
Effective against refractory seizures with or without secondary generalization in adults.
Oral solution can be used for children as young as 3 years.
Mechanism of action: may release GABA, may interact with a protein of high-affinity Ca++ channels, may bind to amino acid transport.
Not metabolized, renally excreted unchanged.
Saturable absorption (safer in overdoses)
Adverse events are sleepiness, dizziness, fatigue, ataxia, skin rash.
Average dose 3600 mg qday or higher.
Also used for pain, restless leg syndrome, tremors, mood disorders, and anxiety.
Lamotrigine (Lamictal)
Indicated for refractory partial seizures in adults (but a broad spectrum drug).
MOA: Probably blocks Na+ influx through Na+ channels. May also inhibit Ca++ channels.
Advantages: (not many) Glucuronide conjugation, T1/2 = 25 h
AE: Dizziness, double/blurred vision, nausea & vomiting, delayed hypersensitivity skin rash (higher incidence <16 y)
Felbamate (Felbatol)
Indicated (initially) for partial and secondary generalized seizures and L-G syndrome in children. Changed to only seizures refractory to other drugs and L-G syndrome.
Mechanism of action: blocks glycine receptor, enhances GABA inhibition (?)
Advantages: 50% renal excretion, T1/2 20 h, use in L-G syndrome.
AE: insomnia, anemia, fatigue, headache/GI upset, aplastic anemia/hepatic failure.
gamma-Vinyl GABA: Vigabatrin (Sabril)
Indicated for partial or primary generalized seizures; NOT effective against ABSENCE SEIZURES.
MOA: Product of rational drug design; Inhibitor of GABA-T, increases GABA at nerve endings, inhibits a GABA transporter.
Advantages: renal excretion
AE: relatively safe, small # of pts got depression or psychotic rxn
Topiramate (Topamax)
Novel sulfamate compound.
Indicated for partial seizures in adults, add-on seizure control.
MOA: probably several; inhibit Na+ channels, increase GABA inhibition.
Advantages: 70% renal excretion, long T1/2.
AE: few, nausea/fatigue/weight loss, 1-2% kidney stones.
Levatiracetam (Keppra)
Indicated for partial seizures in adults. Initially approved for add-on seizure control.
MAO: ??
Advantages: renal excretion.
AE: somnolence, asthenia, dizziness
Oxcarbazepine (Trileptal)
Indicated for monotherapy in partial seizures (adults) or add-on therapy in adults/children as young as 4.
MOA: similar to carbamazepine & phenytoin.
Does not form epixode metabolite as does carbamazepine, less autoinduction.
Tiagabine (Gabitril)
Indicated for partial seizures in adults, add-on seizure control.
Probably blocks GABA reuptake.
Not many advantages: hepatic metabolism, T1/2 < 10 h
AE: dose-related CNS efx, dizziness, tremor, drowsiness
Zonisamide (Zonegran)
Indicated for partial seizures in adults, add-on seizure control.
MAO: may work on Na+ or Ca++ channels.
Too soon to tell advantages for sure.
AE: Drowsiness, loss of appetite, GI, ataxia, renal stones (not as bad as topamax)
Pregablin (Lyrica)
Approved in Europe
Indicated for add-on therapy for partial seizures, diabetic neuropathy, and postherpetic neuralgia.
Not metabolized extensively.
Decreases influx of Ca++ through Ca++ channels during high frequency sustained firing.
SE: dizziness, drowsiness, weight gain, incoordination, HE.
Dose can be changed quickly.
Fosphenytoin (Cerebyxl)
Water-soluble prodrug of phenytoin, 10-15x more expensive.

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