Seizure Pharmacology Flashcards
What are the 4 ways in which neural inhibitory neurons can be opposed to cause a seizure?
- Increase in extracellular K+
- Increase in Ca2+ at presynaptic terminals (increased neurotransmitter release)
- Activation of NMDA excitatory neurons
- Cell swelling and changes in tissue osmolarity
What leads to the high frequency burst of APs in seizures?
influx of extracellular Ca2+ (depolarization) with activation of voltage-dependent Na+ channels
What leads to hypersynchronization in seizures?
hyperpolarizing after-potential via GABA receptors or K+ channels
What are the 3 major MOAs of AEDs?
- Blockage of voltage-gated sodium channels
- Enhancement of GABA
- Inhibition of voltage-gated clacium channels
Why does blockade of voltage gated sodium channels prevent seizures?
diminishes the effects of glutamate by promoting the inactivated state to limit the sustained, repetitive firing of neurons
What type of seizures do drugs that block voltage-gated sodium channels treat?
partial and secondary generalized tonic-clonic seizures
List the drugs that work through blocking voltage-gated sodium channels.
carbamazepine, oxcarbazepine, phenytoin, topiramate, lamotrigine, valproate, zonisamide, lacosamide
Why does enhancing GABA prevent seizures?
GABA is the principal inhibitory neurotransmitter int he CNS and enhancing it will prevent hypersynchronization
What type of seizures do drugs that enhance GABA treat?
partial and secondary generalized tonic-clonic seizures
What are the two places where drugs that enhance GABA can work?
Post-synaptically (increases Cl- influx in response to GABA)
Pre-synaptically (promote GABA release or prevent GABA metabolism)
What drugs bind separately at post-synaptic sites on the multimeric ion channel complex to modulate the activity of endogenous GABA
Benzodiazepines (clonazepam)
Barbiturates
What drug works presynaptically to promote GABA release (Inhibition of α-2 δ-1 subunit of Ca2+ channels)?
Gabapentin
Pregabalin
What drug works presynaptically to prevent GABA metabolism?
Valproate
How do drugs that inhibit voltage-gated calcium channels treat seizures?
diminish effects of glutamate by reducing pacemaker current that underlies thalamic rhythm in spikes and waves
What type of seizures do drugs that inhibit T-type Ca2+ channels treat?
generalized absence seizures
What drugs act by inhibition of voltage-gated calcium channels?
Ethosuximide
Oxcarbazepine (possible, along with increase in K+)
Zonisamide (with blockage of Na+)
True or false: most AEDs are administered orally
TRUE (though some are available for IV dosing)
Which AEDs have increased levels of protein binding compared to the others (with limited protein binding)?
phenytoin
valproate
Which AED accumulates in erythrocytes?
Zonisamide
Where are most AEDs metabolized?
hepatic metabolism
Which AEDs induce CYP 3A4?
Carbamazepine, felbamate, oxcarbazepine
Which AED induces CYP 3A4 and 3A5?
Oxcarbazepine
Which AED induces CYP 3A4, 2C9 and 2C19?
Phenytoin
Which AEDs induce UGT?
carbamazepine, lamotrigine
Which AEDs inhibit CYP2C19?
felbamate, lacosamide, oxcarbazepine, valproate
Which AED inhibits UGT?
Valproate
Which AEDs are NOT metabolized by CYPs?
Gabapentin, Lamotrigine, levetriacetam, pregabalin, topiramate
Which AEDs need to have routine drug monitoring of serum drug levels (because they alter their own T1/2 by altering the CYPs that metabolize them)?
carbamazepine, ehtosuximide, gabapentin, phenytoin, valproate
Which is the ONLY AED that is not eliminated in the urine? How is it eliminated?
Phenytoin (eliminated in stool)
True or false: you must immediately stop therapy if the patient feels like the drug is making them feel worse.
FALSE- abrupt termination of therapy can precipitate onset of status epilepticus, increase the frequency of seizures and lead to various neurologic issues. Where possible, termination should involve tapering of drug over a period of time.
What is unique about the pharmacokinetics of phenytoin?
one of the only drugs to have zero-order pharmacokinetic behavior (half-life varies with drug dose)
What are factors that can impact the metabolic processing of phenytoin?
highly variable CYP induction and protein binding displacement; age, smoking and hepatic status
What is the pro-drug of phenytoin?
Fosphenytoin
What is the dose adjustment between fosphenytoina nd phenytoin?
150mg fosphenytoin = 100 mg phenytoin
TRUE or FALSE: ALL AEDs produce dose-related manifestations of CNS toxicity including nystagmus, ataxia, headache, etc.
TRUE
Which drugs carry NO risk for SJS?
clonazepam and lacosamide
Who has the highest risk of having a dermatologic toxicity to an AED?
Asians with HLA-B 1502 allele SNPs
Other than CNS and dermatologic toxicities, what is the rare but serious potential side effect of AEDs?
hematologic toxicity
What potential side effect of AEDs is usually observed 1-24 weeks after starting the drug?
suicidal ideation
What is the common and serious adverse effect seen in pregnant women taking phenobarbital and carbamazepine?
fetal hydantoin syndrome
What are the features of fetal hydantoin syndrome?
including upturned nose, mild midfacial hypoplasia, and long upper lip with thin vermilion border and distal digital hypoplasia
Which AED (teratogen) can lead to cleft lip and palate?
topiramate
Which AED (teratogen) can lead to neural tube defects, skeletal abnormalities and developmentl delay?
valproate
Which AED (teratogen) may lead to fetal hydantoin syndrome (but not as commonly as phenobarbital and carbamazepine)?
phenytoin
Which AED (teratogen) leads to inhibited dihydrofolate reductase (lowering fetal folate levels)?
lamotrigine
Name all of the AED teratogens?
Valproate Phenytoin Carbamazepine Phenobarbital Lamotrigine Topiramate
True or false: successful drug therapy for epilepsy is successful in around 25% of patients.
FALSE: 50%
MOA: Inhibition of NMDA receptors (glutamate) and increase in GABA receptor conductance
felbamate
MOA: Blockage of Na+ channels, enhancement of GABA mediated Cl- influx, increase K+ current, and decrease in glutamate activity
Topiramate
MOA: Increase GABA activity and inhibits Na+ channels
valproate
BBW: agranulocytosis
Carbamazepine
BBW: aplastic anemia, bone marrow suppression, hepatic disease
felbamate
BBW: SJS or TEN
lamotrigine
TOXICITY: Gingivial hyperplasia, hirsutism, derm toxicity, hematologic changes
phenytoin
TOXICITY: renal calculi
Topiramate and Zonisamide
Why do topiramate and zonisamide cause renal calculi?
weak carbonic anhydrase inhibitors (need to monitor serum bicarbonate levels)
TOXICITY: thrombocytopenia and increased bleeding time; hepatotoxicity in kids > adults
vlaproate
Which AED would be good for an obese patient?
zonisamide
Which AED would be good in a patient with bipolar disorder?
valproate
Which AEDs would you potentially want to check for HLA-B 1502 SNPs?
Phenytoi
Lamotrigine
Carbamazepine
Which AED would be good for a patient with depression and mood disorders?
lamotrigine
List the 1st line AEDs for partial seizures.
Carbamazepine
Lamotrigine
Levetiracetam
Oxcarbazepine
List the 1st line AEDs for generalized tonic-clonic seizures.
Valproate
Levetiracetam
Lamotrigine
List the 1st line AEDs for absence seizures.
Ethosuzimide
Valproate
List the 1st line AEDs for atypical absence, myclonic, and atonic seizures.
Valproate
Levetiracetam
Lamotrigine
List the AEDs used to treat status epilepticus.
Valproate
Phenytoin
What is status epilepticus?
prolonged seizure, or cluster of seizures, without a return to baseline, lasting longer than 30 minutes
What are the most common causes of SE in patients?
Up to 50% of cases of SE occur in patients with epilepsy due to recent changes in AEDs or non-adherence. The remainder of cases in adults are most often secondary to stroke.
What is the first drug given to treat SE?
Benzodiazepine (lorazepam or midazolam)
What is the second drug give (after benzodiazepine) for SE?
IV AED (valpraote > phenytoin > midazolam > levetriacetam > Phenobarbital)
Why are benzodiazepines used to treat SE?
because they can be given RAPIDLY and work on the GABA receptor (prolong opening time) to terminate the SE (but cannot maintain control alone)
What are the predictors of mortality for SE?
generalized seizure, increased patient age, anoxic brain injury, stroke, CNS infection or tumor, and long duration of SE
What is the prognosis of SE?
mortality ranges from 7-40%
