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a transient alteration of behavior due to the disordered, synchronous and rhythmic firing of population of brain neurons
Seizure
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A disorder of brain function characterized by the periodic and unpredictable occurrence of seizures
epilepsy
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non-epileptic seizures
occurred in a normal brain by treatments
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epileptic seizures
evoked without evident provocation
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repeated epileptic seizures persist for a long period of occur so frequently that there is no recovery between attacks
status epilepticus
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proposed mechanism for antiepileptic drugs
- blocking the ability of neuronal cells to fire at high frequency
- act on sodium or calcium channels
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antiepileptics acting on sodium channels
- phenytoin
- carbamazepine
- valproate
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antiepileptics acting on calcium channels
- low threshold (T-type) current reduction
- ethosuximide
- valproate
- diazepam
- barbiturates
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mechanisms to enhance inhibitory pathways
- activation of GABAa receptor
- inhibition of GABA transaminase (degrades GABA)
- inhibition of GABA transporter GAT-1 to reduce neuronal and glial uptake of GABA
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activation of GABA
BDZs and Barbiturates
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inhibition of GABA transaminase
vigabatrin
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inhibition of GABA transporter GAT 1
tiagabine
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block NMDA receptor
valproate
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pharmacological effects of phenytoin
- inhibits repetitive action potentials by alternating Na, K and Ca conductance
- decrease glutamate release
- enhances GABA release
- no CNS depression
- no elevation of seizure threshold
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Drug metabolism of phenytoin
- good GI absorption
- highly protein bound
- metabolized by CYP
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side effects and toxicity of phenytoin
- gingival hyperplasia
- gi disturbance
- cardiac arrhythmias
- hirsutism
- osteomalacia (abnormal vitamin D metabolism)
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isoniazid and cimetidine
inhibit phenytoin metabolism
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phenobarbiturate
increases phenytoin metabolism
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Diphenylhydantion. phenytoin (dilantin) uses
- effective against partial seizures and generalized tonic-clonic seizures (grand mal)
- alternative for status epilepticus
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Phenobarbital
oldest anti-epileptic drug
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pharmacological effects of phenobarb
- anticonvulsant effects at doses below hypnosis
- suppress spread of seizure activity, but raise seizure threshold
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Phenytoin pharmacological effects
glutamate release and AMPA receptor blockate
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metabolism of phenobarbital
- oral absorption is slow
- bound to plasma protein
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side effects and toxicity of phenobarbital
- sedation
- tolerance/dependance
- hepatic toxicity
- osteomalacia
- drug interactions
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phenobarb used for these types of seizures
- tonic-clonic
- myoclonic
- NOT petit mal
- used in neonates, infants and children
- not recommended in pregnancy
- used in status epilepticus as an alternative
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Primidone
- metabolized to phenobarbital
- similar action as phenytoin
- toxicity limits use
- used as monotherapy for grand mal patients who fail to respond to phenytoin or phenobarb
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Carbamazepine
- tricyclic structure
- similar mechanism as phenytoin (block Na channels and inhibits high frequency repetitive firing)
- acts presynaptically
- complete metabolism
- induction of CYP enzymes
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common side effects of carbamazepine
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clinical uses for carbamazepine
- monotherapy for grand mal and partial seizures
- primary drug for trigeminal neuralgia
- bipolar depression when lithium is not effective
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Ethosuximide
- raises threshold for seizures
- reduces low threshold Ca2+ currents (T Currents) in neurons
- GI disturbances
- Stevens-johnosn syndrome
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Clinical uses of ethosuximide
- monotherapy drug of choice for absence seizures (petit mal)
- highly effective and safe
- polytherapy with carbamazepine or phenytoin for mixed seizures
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Valproic acid or valproate
- blocks high frequency firing
- decreases Na current
- blocks NMDA mediated excitation
- GAT1 inhibition
- GAD facilitation
- inhibits GABA transaminase
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Drug interactions with valproic acid or valproate
- displaces phenytoin
- inhibits metabolism of phenytoin, carbamazepine and phenobarb
- decreases lamotrigine clearance
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Side effects with valproic acid and valproate
- n/v & gi distress
- weight gain
- alopecia
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anticonvulsant uses of valproic acid and valproate
- very effective for absence seizures
- generalized absence, tonic-clonic and myoclonic seizures
- monotherapy for mixed seizure
- used for bipolar depression if Li does not work
- migrane prophylaxis
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clonazepam used for these seizure types
- petit mal
- myoclonic
- one of the most potent antiseizure agents known
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diazepam used for these
- status epilepticus (iv)
- prophylaxis of febrile seizures
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lorazepam used for these
status epilepticus
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chlorazepate used for
- acute alcohol withdrawl
- adjunctive therapy for complex partial seizures
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Acetazolamide
- diuretic and carbonic anhydrase inhibitor
- all types of seizures, limited monotherapy use
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Gabapentin
- GABA analog but does not stimulate GABA receptors
- promotes release, reuptake and metabolism of endogenous GABA
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uses of Gabapentin
- ajunct for poly therapy of partial seizures and generalized tonic-clonic seizures
- neuropathic pain
- excreted in unchanged form in urine
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Lamotrigine
- blocks Na channels
- decreases glutamate release
- adjung therapy for partial seizures or bipolar
- life-threatening dermatitis
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Vigabatrin
- irreversibel GABA aminotransferase inhibitor
- partial seizures and infantile spasms
- irreversible visual field defect
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Tiagabine
- inhibits GABA transporter (reuptake)
- used as adjunct for partial seizures in adults
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Topiramate
- blocks NA channels
- potentiates inhibitory effects of GABA
- inhibits excitatory action of kainate on AMPA
- used for partial and primary generalized tonic-clonic adjunct
- teratogenic in animals
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Zonisamide
- sulfonamide derivative
- inhibits NA channels and T-type Ca++ channels
- adjucnt for partial seizures
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simple partial seizures
- carbamazepine
- phenytoin
- valproate
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complex partial seizures
- carbamazepine
- phenytoin
- valproate
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Partial seizures with secondary generalized
- carbamazepine
- phenobarbital
- phenytoin
- primidone
- valproate
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Absence seizures (petit mal)
- ethosuximide
- valproate
- clonazepam
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tonic-clonic seiszures (grand mal)
- carbamazepine
- phenobarb
- phenytoin
- primidone
- valproate
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