Anticonvulsants Flashcards
Note that fosphenytoin is a pro-drug for phenytoin
What are the types of partial seizures?
simple partial
complex partial
partial seizures secondarily generalized
What are the types of generalized seizures?
generalzed tonic-clonic (grand mal)
absence (petit mal)
tonic
atonic
clonic and myoclonic
How do seizures arise?
they begin discretely with depolarization of neurons via influx of Ca2+ and activation of voltage dependent Na+ channels, resulting in high-frequency bursts of action potentials
These APs are then carried forward through GABA and K+-mediated actions, where activation of NMDA excitatory neurons, cell swelling, and changes in tissue osmolarity prevent inactivation
How do AEDs work?
- limit the sustained firing of neurons by promoting/prolonging the inactivated state of voltage-gated Na+ channels (partial and 2ndarily generalized tonic-clonic seizures)
- pre- or post-synaptic enhancement of GABA-mediated synaptic inhbition, an effect mediated by either a presynaptic or postsynaptic action (partial and 2ndarily generalized tonic-clonic seizures)
- Inhibition of voltage-gated Ca2+ channels responsible for T-type Ca2+ currents (absence seizures)
What AEDs work by limiting the sustained firing of neurons by promoting/prolonging the inactivated state of voltage-gated Na+ channels?
Carbamazepine
Phenytoin
Topiramate
Lamotrigine
Valproate
Zonisamide
Note that GABA works primarily via chloride gated channels, to inhibit transmission. How do benzodiapines and barbiturates promote this?
They bind seperately at sites on the multimeric ion channel complex to enhance the inhibitory effect of GABA
Note that GABA works primarily via chloride gated channels, to inhibit transmission. How does gabapentin promote this?
It acts presynaptically to promote GABA release
What drugs work via the blockade the T-type calcium channels, which reduce the activity of pacemaker currents (thus, both sodium and calcium blockers diminish the effects of glutamate)?
Valproate and Ethosuximide
What are the main Na+ channel inhibitor AEDs?
Carbamazepine
Lacosamide
Lamotrigine
Oxcarbazepine (+ possible increased K+ and decreased Ca2+ effects)
Phenyotin
Zonisamide (and decreased T-type Ca2+ actions)
What are the main Ca2+ channel inhibitor AEDs?
Ethosuximide (t-type)
Pregabalin and Gabapentin (a2 delta-1 subunit of Ca channel)
What is the MOA of Felbamate?
decreased NMDA and increased GABA
What is the MOA of Clonazepam?
GABA allosteric agonist
What is the MOA of Topiramate?
decreased Na channels and glutamate activity
increased K+ current and GABA activity
Describe the ADME of AEDs
- Most administered PO
- limited plasma protein binding except phenyotin and valproate
- long half lives
- predominantly hepatic metabolism with urine output
slow release (facilitates adherence- fewer doses/day)
CYP interactions
Routine monitoring of serum drug levels is required with what AEDs?
carbamazepine
Ethosuzimide
Gabpentin
Phenytoin
Valproate
What is ano important thing to note about topiramate and zonisamide?
they are both weak carbonic anhydrase inhibitors, which cause of loss renal HCO3- and promote renal stones by reduing urinary citrate excretion and by icnreasing urinary pH
monitor serum HCO3-
What can occur with abrupt termination of AED therapy?
It can precipitae the onset of status epilepticus, increase the frequency of seizures, and cause anxiety
Taper down termination over time
Important points about Phenytoin
- shows 0-order pharmacokinetic behavior (thus, the half-life varies with drug dose)
- metabolism highly variable
- CYP DDIs (confounding effects- age, cigs, and hepatic smoking all affect)
- fosphenytoin pro-drug (dose adjustment needed when switching)
What are the AEs of Phenytoin?
CNS effects (nystagmus, HA, atacia; drowsiness not common)
- Gingival hyperplasia
- Derm effects are rare (rash to SJS, TEN, and DRESS; hypertrichosis or hirsutism)
- Heme changes
What are the AEs of Carbamazepine?
-CNS effects during initial tx phase (Dizziness, drowsiness, ataxia)
Heme changes- agranulocytosis or aplastic anemia
Derm effects are rare (rash to SJS, TEN, etc.)
-Constipation or dry mouth, N/V
Who is at a higher risk of developing SJS and TEN when using AEDs?
Asians with a SNP mutation in their human leukocyte antigen-B 1502 allele (most common with carbamazepine, phenytoin, and fosphenytoin). Whole blood EDTA testing is available
What are the AEs of Valproic Acid?
-CNS effects related to infusion rate (somnolence, dizziness, asthenia, HA)
Heme changes- thrombocytopenia, prlonged bleeding time
Derm effects are rare (rash to SJS, TEN)
Nausea, diarrhea
Hepatotoxicity in children rarely
What are the main AEs of Felbamate?
asplastic anemia, bone marrow suppression, hepatic disease
What are the main AEs of Lamotrigine?
serious rash (TEN/SJS)
dizziness, diplopia, ataxia
What AEDs are contraindicated in pregnancy (teratogenic)?
Valproate (worst)- Cat X
Lamotrigine- C
Carbamazepine- D
Phenytoin- D
Phenobarbital- D
How does fetal hydrantoin syndrome present (similar effects seen with phenobarbital and carbamazepine)?
upper facial features including upturned nose, mild midface hypoplasia, and long upper lip with thin vermillion vorder
lower distal digital hypoplasia
What drugs should be used to tx partial, including 2ndarily generalized seizures?
lamotrigine
carbamazepine
levetiracetam
oxcarbazapine
What drugs should be used to tx primary, generalized tonic-clonic seizures?
Valproate
Lamotrigine
Levetriacetam
What drugs should be used to tx absence seizures?
ethosuximide
valproate
These are equally effective (50-75% of pts experience complete control)
What drugs should be used to tx atypical absence, myoclonic, and atonic seizures?
valproate
lamotrigine
levatiracetam
What is status epilepticus?
A prolonged seizure, or cluster, without a return to baseline, lasting 30+ minutes
These seizures can be generalzied tonic-clonic, complex or simplex partial, absence, or subclinical
Up to 50% of cases of SE occur in pts with epilepsy due to what?
recent changes in AEDs or non-adherence
The remainder of cases in adults are most often due to strokes
T or F. SE is a medical emergency
T. With a 7-40% mortality rate. predictors of mortality include generalized seizure, increased pt age, anoxic brain injury, stroke, CNS infection or tumor, and long duration of SE.
Successful outcomes require early and aggressive tx
How should SE be handled?
Benzodiazepines are the DOA
Backups: IV lorazapam, IM midazolam, or rectal diazepam, followed by:
IV valproate, phenytoin, midazolam, levetiracetam, or phenobarbital
Compare and contrast Phenobarbital and Benzodiazepine
Both work on GABA receptors, but at different site
Barburates prolong the opening time of Cl- channels
Benzodiazepines shift the dose-response curve of GABA
BOTH have issues of dependence and withdrawal, develop tolerance, will produce dose-related sedation, and can be given rapid IV, unlike phenyotin or valproate
Only phenobarbital will induce CYP2B6 and 3A4 levels
Why are benzodiazepines first line for tx of SE?
They can be given rapidly IV, where the admin of other drugs is limited. Thus, the benzodiazepine can rapidly terminate the SE< but short BNZ half-lives mean that additional drugs must be given to provide more drug control
