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What are the different mechanism of action of AED?
- - affects Na, K, Ca ions
- -augmentation in inhibitory neurotrasmission by increasing CNS concentrations of GABA
- -Decrease excitatory neurotransmission by decreasing glutamate and aspartate neurotransmission
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What are some adverse effects of AED?
- Acute effects can be dose/serum concentration related or idiosyncratic
- Concentration dependent effects are common but not life threatening
- Neurotoxic ADE common
- Idiosyncratic SDE
- ADE can occur despite being within therapeutic range
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What are examples of Neurotoxic ADE?
sedation, dizziness, blurred vision, difficulty with concentration, ataxia
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What are examples of Idiosyncratic SDE?
- Idiosyncratic SDE can range from allergic rxn or they can be more severe hypersensitivity reactions
- If acute organ failure occurs, it will occur within first 6 months of tx
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What are first line agents for Focal Seizures?
- Carbamazepine
- Phenytoin
- Lamotrigine
- Valproic Acid
- Oxcarbazepine
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What are first line agents for absence seizures?
Valproic acid, ethosuximide
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What are first line agents for myoclonic seizures?
Valproic acid, clonazepam
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What are first line agents for tonic-clonic seizures?
Phenytoin, carbamazepine, valproic acid
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What is carbamazepine first line agent for?
partial and tonic-clonic seizures
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What is the MOA of carbamazepine?
Inhibition of voltage gated sodium channels
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Where is carbamazepine metabolized?
- Metabolized primarily by CYP3A4 in the liver
- active metabolite is carbamazepine-10, 11-epoxide
- has anticonvulsant activity
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Which AED is an autoinducer?
Carbamazepine is an autoinducer (induces its own metabolism)
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What is special about carbamazepine being an autoinducer?
- decreased half-life after chronic tx
- begin 3 to 5 days of the initiation of tx
- takes 21 to 28 days to complete
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What is the therapeutic range for carbamazepine?
6 to 12 mcg/mL
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What may occur if there is the presence of the HLA-B*1502 allele?
- Increased risk for serious skin reactions (stevens johnson syndrome and toxic epidermal necrolysis)
- Seen in Asians
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What is the adult dose for carbamazepine?
- 400-1200 mg/day
- Critically ill patients need a loading dose
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What are some drug interactions with carbamazepine?
- interact with other meds by inducing their metabolism
- Valproic acid increases the 10-11epoxide concentrations w/o affecting the carbamazepine concentrations
- CYP3A4 metabolism
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What are some adverse effects of Carbamazepine?
Hyponatremia (increased in elderly), drowsiness, lethargy, diplopia, blurred vision, HA, ataxia, nystagmus, Stevens-Johnson Syndrome, agranulocytosis, aplastic anemia
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What is a potentially fatal blood cell abnormality with Carbamazepine?
- Leukopenia: most common
- rare reaction that responds to d/c
- Discontinue if WBC <2500/mm3 or ANC <1000/mm3
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What is the first line treatment for absence seizures?
Ethosuximide
Dosing: 500-1000 mg BID (max 1500 mg BID)
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What is the therapeutic range of Ethosuximide?
40-100 mcg/mL
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What is the MOA of Ethosuximide?
inhibition of T-type calcium channels
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What type of metabolism can Ethosuximide exhibit?
May exhibit nonlinear metabolism at high doses
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What is the MOA of phenobarbital?
elevate seizure threshold by decreasing post synaptic excitation by stimulating post synaptic GABA receptors
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What is the therapeutic range for Phenobarbital?
10-40 mcg/mL
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What is the dose for Phenobarbital?
- 1-3 mg/kg/day
- or 50-100 mg 2-3 times/day
- dosed once daily before bedtime to minimize sedation
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What are some side effects of phenobarbital?
rash, sedation, ataxia, depression, depenance
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What is phenobabital the drug of choice for?
neonatal seizures
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What is phenytoin first line AED for?
generalized seizures and partial seizures
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What is the MOA for phenytoin?
stabilizes neuronal membranes by decreasing sodium influx/increasing sodium efflux through voltage gated dep. sodium channel blockade
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Which CYP enzymes metabolize Phenytoin?
CYP2D9 and CYP2D19
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What type of pharmacokinetics does phenytoin exhibit?
Michaelis-Menten
-small dose changes results in large serum concentration changes
metabolism dec with age
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Is phenytoin highly protein bound?
Yes, >90%
- competes for albumin sites with other drugs
- know patient's albumin level with interpreting serum concentrations
- significant renal dysfunction alters protein binding
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What is the therapeutic range for phenytoin?
- total phenytoin 10-20 mcg/mL
- Free phenytoin 1-2 mcg/mL
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What is the inital phenytoin dose?
5 mg/kg/day divided 1-3 times/day
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What happens if there is the HLA-B*1502 allele present in patients taking phenytoin?
- increase risk for serious skin rxn
- steven johnsons syndrom
- seen in asian descent
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Drug interactions with phenytoin?
- potent CYP inducer
- other meds can inhibit or induce phenytoin metabolisn
- FOLIC ACID replacement enhances phenytoin clearance
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What are some ADE with phenytoin?
- vit D def
- confusion
- slurred speech
- ataxia
- rash
- nystagmus
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