Pharm Chapter 24- Antiseizure Drugs

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oral bioavailability of phenytoin

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variable because of individual difference in first-pass metabolism

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phenytoin metabolism

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nonlinear: elimination kinetics shift from first-order to zero-order at moderate to high dose levels
-binds extensively to plasma proteins and are increased by drugs that compete

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drugs that compete for binding with phenytoin

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carbamazepine, sulfonamides, valproic acid

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metabolism of phenytoin is increased in the presence of

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inducers of liver metabolism
-phenobarbital, rifampin

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metabolism of phenytoin is inhibited by

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cimetidine, isoniazid

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phenytoin effect on liver

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induces hepatic drug metabolism, decreasing effects of other antiepileptic drugs including carbamazepine, clonazepam, and lamotrigine

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fosphenytoin

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water-soluble prodrug form of phenytoin that is use parenterally

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general desired effect of antiseizure drugs

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suppress repetitive action potentials in epileptic foci in the brain

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phenytoin MOA

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block voltage-gated sodium channels in neuronal membranes
-blocks high-frequency firing of neurons through action on VG Na+ channels
-decreases synaptic release of glutamate

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phenytoin elimination

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rate-dependent (dependent on the frequency of neuronal discharge)

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Clinical use of phenytoin

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generalized tonic-clonic seizure; partial seizures

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phenytoin tox

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diplopia, ataxia, gingival hyperplasia, hirsutism, neuropathy

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phenytoin interactions

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carbamazepine, isoniazid, febamate, oxcarbazepine, topiramate, fluoxetine, fluconazole, digoxin, quinidine, cyclosporine, steroids, oral contraceptives

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Carbamazepine MOA

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blocks high-frequency firing of neurons through action on VG Na+ channels
-decreases synaptic release of glutamate

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Pharmacokinetics of carbamazepine

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well absorbed orally with peak levels 6-8h, no significant protein binding

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metabolism of carbamazepine

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induces formation of liver drug-metabolizing enzymes that increase metabolism of the drug itself and may increase the clearance of many other anticonvulsant drugs

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carbamazepine interactions

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phenytoin, carbamazepine, valproate, fluoxetine, verapamil, macrolides, isoniazid, propoxphene, danazol, phenobarbital, primidone

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clinical use of carbamazepine

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generalized tonic-clonic seizures, partial seizures

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carbamazepine toxicity

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nausea, diplopia, ataxia, hyponatremia, headache

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carbamazepine blood toxicity

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blood dyscrasias (aplastic anemia and agranulocytosis)
-most in elderly patients with trigeminal neuralgia

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carbamazepine teratogenicity

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craniofacial abnormalities and spina bifida

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phenytoin teratogenicity

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IUGR, microcephaly, craniofacial abnormalities, limb defects

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other clinical uses of carbamazepine

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trigeminal neuralgia
-oxcarbazepine= similar analgesia with fewer adverse effects

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valproic acid MOA

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-causes neuronal membrane hyperpolarization
-inhibits low-threshold (T type) Ca2+ currents, especially in thalamic neurons that act as pacemakers to generate rhythmic cortical discharge

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valproic acid pharmacokinetics

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-well absorbed from several formulations
-highly bound to plasma proteins
-extensively metabolized

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valproic acid metabolism

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competes with phenytoin
-inhibits metabolism of carbamazepine, ethosuximide, phenytoin, phenobarbital, and lamotrigine

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clinical use of valproic acid

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generalized tonic-clonic seizures, partial seizures, generalized seizures, absence seizures, myoclonic seizures

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valproic acid toxicity

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nausea, tremor, weight gain, hair loss, teratogenic, hepatotoxic

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valproic acid teratogenicity

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neural tube defects (spina bifida)

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vigabatrin relation to GABA and benzos

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irreversibly inactivates GABA aminotransferase (GABA-T) which is necessary to terminate action of GABA
-valproic acid can do this at high doses

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drugs that may facilitate inhibitory actions of GABA

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felbamate, topiramate, and valproic acid

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Ethosuximide MOA

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reduces low threshold Ca 2+ currents (T-type)
-especially in thalamic neurons that act as pacemakers to generate rhythmic cortical discharge

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ethosuximide pharmacokinetics

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-no significant protein binding
-metabolized in part to active epoxide
-long half life

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ethosuximide clinical uses

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absence seizures

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ethosuximide toxicity

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GI distress, dizziness, headache

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phenobarbital MOA

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-enhances GABAa receptor responses
-reduces excitatory synaptic responses

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phenobarbital clinical use

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generalized tonic-clonic seizures, partial seizures

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phenobarbital pharmacokinetics

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-long half life, inducer of P450
- sedation, cognitive issues, hyperactivity, ataxia

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benzodiazepines for seizures

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diazepam (enhance GABAa receptor response): used for status epilepticus
clonazepam (same): used for absence and myoclonic seizures, infantile spasms

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Gabapentin MOA

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blocks Ca channels

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gabapentin pharmacokinetics

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variable; renal elimination

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all GABA derivatives used for seizures pharmacokinetics

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gabapentin, pregabalin, vigabatrin= renal elimination

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lamotrigine MOA

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blocks Na and Ca channels, decreases glutamate

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first-line drug treatment of mania

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valproic acid

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bipolar disorder alternative drugs

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carbamazepine and lamotrigine

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pain of neuropathic origin treatment including post-herpetic neuralgia

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gabapentin

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migraine

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topiramate

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drugs of choice for generalized tonic-clonic seizure

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valproic acid and carbamazepine

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DOC for partial seizures

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carbamazepine or lamotrigine or phenytoin

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DOC for absence seizures

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ethosuximide or valproic acid because minimal sedation

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DOC myoclonic and atypical absence syndromes

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valproic acid; lamotrigine approved but monotherapy

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DOC status epilepticus

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IV diazepam or lorazepam effective in terminating attacks and providing short-term control
-prolonged therapy, IV phenytoin

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fatal toxicity of valproic acid

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hepatotoxicity

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lamotrigine tox

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stevens-johnson syndrome or toxic epidermal necrolysis

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felbamate toxicity

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aplastic anemia and acute hepatic failure