Benzodiazepines Flashcards
what receptor do benzodiazepines bind to
GABA-A ligand-gated chloride channel complex
what is the mechanism of action of benzodiazepines
binds to GABA-A–> enhances the inhibitory effects of GABA-regulated channels
INHIBITS neuronal activity presumably in AMYGDALA-centered fear circuits to provide therapeutic benefits in anxiety disorders
inhibitory actions in CEREBRAL CORTEX may provide therapeutic benefits in seizure disorders
how many GABA receptor subtypes are there
3–> A, B, C
what is the function of the GABA-A receptor subtype
gatekeeper for the chloride channel–> chloride goes into the cell, polarizing the action potential AWAY from activation
action is inihibitory in the amygdala and frontal cortex
the GABA-A receptor is allosterically modulated by which compounds
benzos
alcohol
Z drugs
barbiturates
list the four MAIN indications for benzodiazepines
anxiety disorder
anxiety disorder associated with depressive symptoms
initial treatment of status epilepticus (
preanesthetic
list other indications for benzodiazepines
insomnia
muscle spasm
alcohol withdrawal psychosis
headache
panic disorder
acute mania (adj)
acute psychosis (adj)
how quickly might someone notice benefit from benzodiazepines
some immediate relief with first dosing is common
can take several weeks for maximal therapeutic benefit with daily dosing
what is the usual starting dose and the typical range of the following benzodiazepine:
lorazepam
start–> 0.5mg
typical daily dosing–> 1-2mg /day
what is the usual starting dose and the typical range of the following benzodiazepine:
clonazepam
start–> 0.5mg
typical daily dosing–> 0.5-2mg /day
what is the usual starting dose and the typical range of the following benzodiazepine:
diazepam
start–> 2-10 mg
typical daily dosing –> 4-40mg/day
can you use benzodiazepines if kidney/liver function is present
monitor functioning if impairment is present
list common side effects of benzodiazepines
sedation
fatigue
depression
decreased cognitive processing
anterograde amnesia
dizziness
ataxia/visuospatial and visuomotor deficits
slurred speech
weakness
tolerance/dependence
rebound anxiety
in which patients should you not prescribe benzodiazepines (non-psychiatric reason)
those with occupational risks i.e truck drivers, pilots–> higher likelihood of crashes (OR 1.6 on any benzo)
list rare side effects from benzodiazepines
hallucinations
hypotension
paradoxical agitation
respiratory depression (esp. when Rx along with CNS depressants)
what medication can counter benzodiazepine overdose
flumazenil
what does benzodiazepine overdose look like
hypotension
rare respiratory depression
in which patients is the risk of tolerance/dependence to benzodiazepines higher
treatment periods over 12 weeks
those with polysubstance abuse
what CYP interactions does the following medication have:
lorazepam
none
what CYP interactions does the following medication have:
clonazepam
3A4 (major substrate)
what CYP interactions does the following medication have:
diazepam
3A4 (major substrate), 2C19 (major substrate)
is lorazepam safe in end stage kidney disease
no–> not recommended
which benzo should be used with caution in liver impairment
diazepam
what is the half life of lorazepam
10-20 hours
what is the half life of clonazepam
30-40 hours
what is the half life of diazepam
20-50 hours
what determines duration of action in benzodiazepines
distribution (not as much by elimination half life)
–> ie diazepam has long half life but is highly lipid soluble so actually has relatively SHORT duration of action as will distribute fairly quickly
marked inter-individual variation
how are benzos metabolized
hepatic oxidation, reduction and conjugation
how long will someone notice benefits for insomnia from benzos
about 14 days
what is the risk of rapid withdrawal of benzodiazepines
seizure
what is the recommended tapering protocol to get someone off benzos if they have been on them a long time
rec. taper length is 6-12 months (10% per month)
first half of taper usually much easier than second half
list 3 of the strongest predictors of benzo withdrawal severity
- high baseline neuroticism
- female sex
- mild to mod alcohol use
*these are more predictive than daily dose or half life of the benzo
you should evaluate patient for what medical disorder before prescribign benzos
OSA–> benzos can worsen OSA
how might you reconsider benzo use in the pediatric population
lower dosing range
higher risk of SEs
(same for geri)
which benzo is NOT recommended for use during pregnancy
lorazepam–> especially during first trimester
what are some of the considerations for benzo use during pregnancy
possible increased risk of birth defects when benzos taken during pregnancy
infants whose mothers received benzos late in pregnancy may experience withdrawal effects
neonatal FLACCIDITY has been reported in mothers who took benzo during pregnancy
some drug found in mother’s breast milk
effects on infant that have been observed: feeding difficulties, sedation, weight loss
*risk category D–> positive evidence of risk to human fetus/ benefits may still justify use
list indications for clonazepam
REM sleep behaviour disorder
akathesia
2nd line panic disorder and GAD
how quickly does clonazepam act
slow onset
list indications for lorazepam
EtOH/benzo withdrawal
akathesia
agitation
seizure
catatonia
2nd line panic disorder and GAD
which benzos can be given IM
lorazepam and midazolam
how is lorazepam excreted
renally–> so does not accumulate in liver failure
(same as oxazepam and temazepam)
how quickly does lorazepam act
intermediate onset
indications for alprazolam
2nd line panic disorder and GAD
how quickly does alprazolam act
intermediate onset
what is the max dose for lorazepam
10mg/day
30mg/day in catatonia
what is the max dose of alprazolam per day
8mg/day
what is the max dose of diazepam per day
40m /day
what is the max dose of clonazepam per day
4mg/day
indications for diazepam
EtOH/benzo withdrawal
2nd line panic disorder
how quickly does diazepam work
rapid onset
*careful in liver failure (increases half life from 50 hours to 500 hours)
what is the starting dose of midazolam
0.2mg/kg
indications for midazolam
anesthesia
palliative sedation
seizure
how quickly does midazolam work? what is its half life?
very rapid onset
half life 3 hours
what is the max daily dose of chlordiazepoxide
300mg/day (start at 25mg)
indications for chlordiazepoxide
mild to mod EtOH benzo withdrawal
what receptor does zopiclone/zolpidem act on
GABA-A receptor
what is the starting dose and max dose of zopiclone
start 3.75mg
max 7.5 mg
what are the starting and max doses of zolpidem
start 5-6.25mg
max 10mg
side effects for zolpidem
complex sleep behaviours
sedation
nausea
headache
side effects for zopiclone
sedation
headache
nausea
how do the Z drugs affect sleep
reduce sleep latency
what is sodium oxybate
a GHB and GABA-B receptor agonist
what are indications for sodium oxybate
daytime sleepiness and cataplexy caused by narcolepsy
indications for Z drugs
insomnia
side effects of sodium oxybate
confusion
N/V
sedation
edema
respiratory depression
psychosis
suicidality
what general effects do benzodiazepines have
sedative-hypnotic
anxiolytic
anticonvulsant
muscle relaxant
describe benzodiazepine protein binding affinity
70-909% protein bound
*but distribute RAPIDLY to CNS
how do benzodiazepines cross the blood brain barrier
via passive diffusion
therefore, rate of CNS distribution correlates with lipophilicity
which are the two most lipophilic benzodiazepines
diazepam and midazolam
thus have fastest onset of action
list 3 benzodiazepines that do not go through CPY450 metabolism
lorazepam
oxazepam
temazepam
“the LOT benzos”
which benzos are metabolized through glucoronidation
the LOT benzodiazepines (loraz, oxaz, temaz)
we care because glucoronidation is better preserved in liver failure so these benzodiazepines are better for liver failure
are benzodiazepines agonists?
technically no–> they are positive allosteric modulators (PAMs) which act on GABA-A
apart from GABA-A, where else does clonazepam act
partial serotonin agonist
what are the “ATOM” benzos
Alprazolam
Triazolam
Oxazepam
Midazolam
what do the ATOM benzos have in common
all have rapid onset and are short acting
increases risk of abuse, misuse, addiction
how long does it take for tolerance and withdrawal to develop on benzos
minimum 4 weeks treatment
*psychological dependence can develop at any point during treatment
why should you be careful prescribing benzos to the elderly
significantly increases risk for confusion, delirium, cognitive impairment in the elderly
how do benzos cause respiratory depression
two actions:
- depress central respiratory drive and chemoreceptor responsiveness to hypercapnia
- midaz has been shown to depress the hypoxic ventilatory response
how do benzos affect REM sleep
decreases amount of REM sleep
what is the typical benzo taper
10-20% every 1-2 weeks
what common antidepressants affect metabolism of some benzos
fluoxetine, fluvoxamine, sertraline
decrease metabolism and increase plasma levels of benzos metabolized by the CYP system (i.e alprazolam… any of them but the LOT benzos)
how quickly does benzo withdrawal begin after cessation of the agent
depends on the agent
i.e short acting benzos like triazolam may precipitate withdrawal within hours after being stopped
how quickly might lorazepam withdrawal develop
can develop within 6-8 hours of med cessation
will peak in intensity on second day and improve by day 4-5
when might diazepam withdrawal syndrome start
has long acting metabolites and thus may not produce withdrawal symptoms for 1-2 days (or up to a week) and sx may not peak until the second week after med discontinuation
can benzo withdrawal be life threatening
yes–similar to EtOH withdrawal
can progress to a life threatening delirium
list risk factors for benzo withdrawal syndrome
longer substance use
higher dosages
—–> these factors increase risk for severe withdrawal
i.e doses of diazepam 40mg or more are more likely to produce withdrawal symptoms
doses of diazepam 100mg or above are more likely to be followed by withdrawal seizures or delirium
*note that withdrawal has also been reported with low doses when taken daily for several months
list symptoms of benzo withdrawal
autonomic hyperactivity (sweating, pulse above 100)
hand tremor
insomnia
N/V
transient visual/tactile/auditory hallucinations or illusions
psychomotor agitation
anxiety
grand mal seizures
what % of people undergoing UNtreated benzo withdrawal will have a grand mal seizure
20-30%
what tools can be used to monitor benzo withdrawal
CIWA-Ar or PAWSS (same as alcohol)
what is thought to be the pathophysiology behind benzo withdrawal symptoms
imbalance between GABA (decreased) and glutamate (increased)
