Anticonvulsants and BZDs Flashcards
Differentiate seizures and epilepsy.
seizure:
-sudden, uncontrolled burst of electrical activity in the brain
-changes in behavior, movements, feelings, consciousness
-most last 30s-2min (>5min=emergency)
epilepsy:
-two or more seizures at least 24 h apart that dont have a known cause
Differentiate generalized and focal seizures.
generalized:
-happen in both sides (hemispheres) of the brain
-more severe effects and symptoms
focal:
-only happen in one hemisphere
-symptoms only happen on one side or specific part of the body
-can spread and become generalized seizures
What are the types of generalized seizures?
absence seizures
myoclonic seizures
tonic seizures
tonic-clonic seizures
atonic seizures
Which class of medications is used to treat epilepsy and other seizure disorders?
anticonvulsants
Provide a recap of seizure mechanism.
imbalance of inhibitory and excitatory activity
-more excitatory activity
-glutamate > GABA
What is the MOA of carbamazepine and phenytoin?
block voltage gated Na+ channel
-stop glutamate release/binding
What is the MOA of barbiturates and BZDs?
behave like GABA
-enhancement of inhibitory transmission
Describe the absorption of CBZ.
slow, unpredictable
tmax: 4-8 hours
delay owing to anticholinergic effects
some evidence of enterohepatic recirculation
Describe the distribution of CBZ.
Vd = 0.8-2 L/kg
plasma protein binding: 76%
-not suitable for dialysis
Describe the metabolism of CBZ.
CBZ –> CBZ 10,11 epoxide (via 3A4)
-CBZ 10,11 epoxide is active and toxic
CBZ 10,11 epoxide –> trans-CBZ-diol (via epoxide hydrolase)
Describe the elimination of CBZ.
autoinduction
-t1/2 initial: 25-65h
-t1/2 after multiple doses: 12-17h
-t1/2 CBZ 10,11 epoxide: 5-10h
*drug as well as toxic metabolite induce CYPs
What is the therapeutic range of CBZ?
20-50 umol/L (narrow therapeutic window)
-toxicity develops within TR
What are the systems affected by CBZ toxicity?
neurologic (nystagmus, ataxia)
respiratory
cardiovascular
What are symptoms of toxicity from chronic use of CBZ?
headache
diplopia
ataxia
ECG abnormalities
hyponatremia due to SIADH
What kind of impacts can VPA and lamotrigine have on CBZ?
enzyme inhibitors of epoxide hydrolase
-therefore accumulation of the 10,11 epoxide active metabolite
What is the antidote to CBZ?
no antidote
How is CBZ toxicity managed?
supportive/symptomatic care
-hydration, airway, electrolytes, ABCs
-BZDs for refractory seizures due to CBZ
What is the decontamination method for CBZ?
SDAC
-binds
-1 to 2 hr window
What are the elimination methods for CBZ?
MDAC
-if severe
hemodialysis
-if theres lots of drug in the body, free proportion increases
Is death common due to phenytoin toxicity?
rare if good supportive care
What is the problem if IV phenytoin is released too quickly?
local tissue damage
cardiotoxicity
Describe absorption of phenytoin.
erratic absorption following PO administration
tmax: 3-12h after a single oral dose
-bezoar would increase time to tmax
Describe distribution of phenytoin.
rapidly distributed to all tissues
extensive PPB (88-93%)
-serum levels may not represent total drug
-TR but patient may exhibit signs of toxicity
Describe metabolism of phenytoin.
95% hepatically metabolized to inactive metabolite
polymorphism
-2C9, 2C19 poor metabolizers may experience toxicity at therapeutic levels
What happens to elimination of phenytoin as the concentration increases?
1st to zero order kinetics
What are therapeutic levels of phenytoin?
40-80 umol/L
What level do toxic effects of phenytoin start showing up?
after 80 umol/L
What is nystagmus?
rapid eye movement
Which systems are impacted by phenytoin toxicity?
neurologic
CV
GI/hepatic
What is the antidote for phenytoin?
no antidote
What is the management of phenytoin toxicity?
ABCs
supportive/symptomatic care
mainstay:
-if hypotension from IV = reduce infusion rate, IV fluids, vasopressors
-airway protection
What is a decontamination method for phenytoin?
SDAC
-binds; consider but no evidence of any change in clinical course
What are the elimination methods for phenytoin?
MDAC
-generally not necessary
hemodialyis
-current toxicology resources do not recommend hemodialysis for phenytoin toxicity
What are examples of barbiturates?
phenobarbitone
butobarbitone
pentobarbitone
thiopentone
methohexitone
What do most BZDs end in?
pam
-except chloradiazepoxide
Why did BZDs replace barbiturates?
safer profile in terms of respiratory depression
-however they can still cause some respiratory depression
What is the MOA of BZDs?
stimulating GABA-a receptor
-thereby opening Cl channel
lower the potential difference between the interior and exterior of the cell, blocking ability of cell to conduct nerve impulses
What is the antidote to BZDs?
flumazenil
Describe absorption of BZDs.
rapid and complete orally
tmax: 1-3h
relative lipophilic
-more lipophilic means faster onset and longer duration
half-life ranges from 2-50h
Describe distribution of BZDs.
Vd 0.75-1.5 L/kg
highly protein bound
How are BZDs eliminated?
hepatically metabolized
metabolites excreted renally
Describe BZD toxicity.
mortality from pure BZD overdose is rare
toxicity depends on:
-coingestants especially CNS depressants
-shorter acting BZD = more toxicity
-IV more likely to cause significant toxicity
-tolerance skews the course
What is a very important piece of information to gather when someone presents with BZD toxicity?
co-ingestants
What happens with chronic use of BZDs?
tolerance
What do urine levels test for in regards to BZDs?
substances metabolized to oxazepam and nordiazepam
false-negative if not metabolized to oxazepam/nordiazepam
What are decontamination methods for BZD toxicity?
SDAC (maybe)
-if within 1h of ingestion
gastric lavage (no)
What are elimination methods for BZD toxicity?
MDAC (no)
hemodialysis (ineffective)
What is the MOA of flumazenil?
selective competitive antagonist of GABA receptor
out competes BZD at recognition site on receptor complex thereby reversing BZD effect on CNS
What is the onset of flumazenil?
1-2 min
effect is short lived
What are safety concerns with flumazenil?
seizures
dysrhythmias possible when mixed overdose
re-sedation
What are the pros and cons of flumazenil?
pros:
-adverse effects minimal
cons:
-seizure risk
-withdrawal risk
Is flumazenil effective at reversing respiratory depression?
effective at reversing CNS depression but not respiratory depression
Which patients is it ideal to use flumazenil in?
BZD-naive and single BZD-ingested patients
When is flumazenil a poor option?
unknown overdoses because of life threatening seizures and dysrhythmias
can also precipitate seizure and withdrawal in BZD-dependent patients
safer to prioritize ABC in unknown overdose
What are the indications for flumazenil?
pure BZD OD
non-tolerant AND CNS depression, normal vital signs, normal ECG, normal neurological exam
Differentiate the MOA of barbiturates and BZDs.
barbiturates:
-enhance binding of GABA to GABA-a receptor
-prolong duration of channel opening
-narrow therapeutic index
BZD:
-enhance binding of GABA to GABA-a receptor
-increase frequency of channel opening
-wider therapeutic index than barbiturates
