Benzodiazepines (2) Exam 1 Flashcards
Differentiate sedatives and hypnotics.
- Sedatives: induce calm/sleep
- Hypnotics: induce hypnosis/sleep
When is anesthesia awareness most common?
- During sedation cases and during emergence.
- 1:1000 (or 1:10,000 per some studies)
What is the mechanism for less EEG activity seen during anesthesia/sedation?
Less cerebral blood flow (CBF) and cerebral metabolic requirement of oxygen (CMRO₂) = less metabolism = less EEG activity.
What was the first compressed EEG?
- Bispectral analysis
- 1500 subjects w/ 5000 hours of EEG signaling
What drugs were utilized in the bispectral analysis study?
- Isoflurane/ O₂
- Propofol/nitrous
- Propofol/alfentanil
Which drug exhibited a strong correlation between BIS change and patient movement?
Which drug had less correlation?
- Hypnotic drugs strong correlation
- Narcotics less correlation
In the BIS study, what reading indicated that a patient was for sure unconscious?
<58
In the BIS study, a reading of <65 indicated a ___% of return to consciousness within the minute.
5%
What is a normal BIS range?
40-60
What are the four parameters (other than the BIS itself) noted on a BIS monitor?
- SQI (signal quality index)
- EMG (electromyogram)
- EEG (electroencephalogram)
- SR (suppression ratio)
What is the SR noted on a BIS monitor?
Suppression Ratio (percentage of time that the EEG is flat)
Name drugs that could suppress EEG activity.
Hypnotics, volatiles, NMBDs, Opioids
β-blockers
Name drugs that could enhance EEG activity.
Ketamine, epinephrine
What are the five main functions of a benzodiazepine?
- Anxiolysis
- Sedation
- Anterograde amnesia
- Anticonvulsant
- Spinal-cord mediated muscle relaxation
What is the only “thing” that can cause retrograde amnesia?
ECT (electroconvulsive therapy)
Why are written instructions given to a patient after waking up from benzodiazepine sedation?
Anterograde amnesia effects last longer than sedative effects.
Can benzodiazepines be substituted for NMBs due to their spinal-cord mediated skeletal muscle relaxation?
No; not adequate for true paralysis
__________ drugs can induce CYP450’s.
Barbiturates
What is the mechanism of action of benzodiazepines?
Enhancement of GABA affinity to GABA-A receptor. Allows for greater Cl⁻ influx and thus hyperpolarization.
Which GABA site do benzodiazepines bind to?
Trick question. Benzo’s do not bind directly to GABA sites, they bind to BZD sites which activate GABA sites.
How many subunits are present in a GABA receptor?
Five
In-between the α1 & β2 subunits
What subunits do Benzodiazepines bind to on the GABA receptor?
In-between α1 & γ2
GABA receptors with α1 subunits exhibit what properties when bound?
- Sedation, amnesia, & anticonvulsion
- Most abundant: cerebral cortex, cerebellar cortex, & thalamus.
GABA receptors with α2 subunits exhibit what properties when bound?
Anxiolysis & skeletal muscle relaxation
Less abundant: hippocampus & amygdala
What other drugs bind to GABA receptors besides benzodiazepines? (4)
Barbiturates, Etomidate, Propofol, & EtOH
Risk of overdose & cross-tolerance
Benzodiazepines are highly _____ soluble and highly _______ bound.
Lipid; protein
What factors cause differing effects amongst benzodiazepines?
- Potency
- Lipid solubility
- Redistribution (to peripheral tissues)
- Pharmacokinetics
List EEG waves from greatest activity to least activity.
Gamma → Βeta → Αlpha → Theta → Delta
What general effect(s) do benzodiazepines have on EEG activity?
Decreased αlpha activity
What platelet effects do benzodiazepines have?
Inhibitory towards platelet aggregation (very slight, only in vitro studies)
What structural characteristic of midazolam stabilizes structure and allows for rapid metabolism?
Imidazole Ring (lots of nitrogens)
What two situations is midazolam primarily used for?
Preop anxiolysis & conscious sedation
How much more/less potent is midazolam than diazepam? Why is this?
2-3x more potent due to greater receptor affinity.
What facilitates water solubility of midazolam?
- pH dependent ring opening
- pH < 3.5 = open ring = water soluble & protonated.
- pH > 4 = closed ring = lipid soluble & unprotonated.
Why is midazolam non-irritating upon injection?
No propylene glycol needed for stabilization
What is the onset and peak of midazolam (versed)?
Onset: 1-2 minutes.
Peak: 5 minutes
Why is midazolam’s duration of action short?
Short due to rapid redistribution.
What is the Elimination ½-time of midazolam?
2 hours
Doubled in elderly patients (4 hours-ish)
What is the Vd (volume of distribution) of midazolam?
1-1.5 L/kg (large due to lipid-solubility)
What metabolizes midazolam?
CYP3A4
1-hydroxmidazolam (½ the activity of midazolam)
What clears the active metabolite of midazolam?
Kidneys
What drugs will inhibit CYP450’s?
- Cimetidine
- Erythromycin
- CCBs
- Antifungals
- Fentanyl
What is midazolam’s clearance in comparison to lorazepam and diazepam?
5x faster than lorazepam and 10x faster than diazepam.
How does midazolam produce an isoelectric EEG?
Trick question. No isoelectric EEG capabilities.
Midazolam inhibits/preserves the vasomotor response to CO₂. What does this mean?
Preserves: (↑CO₂ = vasodilation; ↓CO₂ = vasoconstriction)
Why is midazolam a good choice for neuro cases?
No change in ICP with administration.
What are the pulmonary effects of midazolam?
Dose-dependent respiratory depression (increased with COPD).
Swallow reflex depression (aspiration).
Upper airway depression (aspiration).
What are the cardiovascular effects of midazolam?
Dose-dependent ↑HR & ↓BP.
How much does midazolam depress cardiac output?
Trick Question. No CO depression;
↓SVR = ↓BP, hence the increased HR compensation
Significant hypotension can occur with midazolam administration in the presence of _____________.
hypovolemia.
What is the preop/intraop sedation dosing for midazolam in pediatric populations? When do effects peak and what is the consequence of this?
0.25 - 0.5 mg/kg PO route.
Peaks in 20-30 min (give 30 min prior to OR).
What is the preop/intraop dosing of midazolam in adult populations? When does the effect peak?
1-5mg IV.
Peaks in 5 minutes.
What is the induction dose for midazolam? What drug is usually 1-3 minutes prior to this?
0.1-0.2 mg/kg IV over 30-60 seconds.
Fentanyl 50-100mcg.
What is the postoperative sedation dose of midazolam? How long should midazolam be used for long-term sedation? Why is this?
1-7 mg/hr IV.
2-3 days due to unclear effects on T-cell response.
Why does diazepam (valium) burn on injection? Is there a better formulation?
insoluble in water so it’s dissolved in propylene glycol.
Soybean formulation available but more expensive.
What is the onset of diazepam? What is the E ½ time of diazepam? What is the Vd of diazepam?
- Onset: 1-5 minutes.
- E ½ = 20-40 hours (very protein-bound).
- Vd = 1-1.5 L/kg.
What metabolizes diazepam? What are its primary metabolites and what is its significance?
CYP3A4.
Desmethyldiazepam & oxazepam.
Metabolites are nearly as potent as diazepam and hit 6-8 hours after administration.
What is the seizure dosing for diazepam? What seizures is it utilized for?
0.1 mg/kg IV.
DT’s, status epilepticus, lidocaine toxicity seizures.
What are the EEG effects of diazepam?
Can produce isoelectric EEG.
What are the pulmonary effects of diazepam?
Minimal; any depressant effects are reversed by surgical stimulation.
What are diazepam’s effects on the cardiovascular system? What effects would be seen with adjunct opioids?
Minimal decreases in BP, CO, and SVR (used be agent for cardiac cases).
Additive BP changes when used with opioid.
What are diazepam’s effects on the musculoskeletal system?
Decreases skeletal muscle tone.
What is the induction dose of diazepam? When would one decrease the dose by 50%?
0.5-1 mg/kg IV.
50% cut with elderly, liver patients, and with concurrent opioid use.
Of midazolam, diazepam, and lorazepam, which is the most potent sedative/amnestic?
Lorazepam.
Which benzodiazepine has the slowest onset of action?
Lorazepam.
When is peak effect seen with lorazepam?
20-30 min with IV dose (1-4mg).
What is the E ½ time of lorazepam?
14 hours.
Which benzodiazepine’s metabolism is less dependent on CYP450’s?
Lorazepam (better drug for liver patients).
When is lorazepam most useful?
Post-operative sedation.
What is flumazenil (Romazicon)?
Competitive antagonist for benzodiazepine receptor. (preventative and reversal).
What metabolizes flumazenil? What are its metabolites?
CYP450’s.
No active metabolites.
What is the dosing of flumazenil?
0.2mg IV titrated to consciousness (repeat 0.1mg q1min til 1mg total).
What is the sedation reversal dose range of flumazenil?
0.3 - 0.6 mg.
What is the complete reversal dose range of flumazenil?
0.5 - 1 mg.
If the patient is still unconscious after 0.5 - 1mg of flumazenil has been given, what should be considered?
Other intoxicants (opioids, EtOH, etc).
What is the duration of flumazenil?
30 - 60 min.
May need repeated doses
When is flumazenil contraindicated?
When needed antiepileptics are being given.
If it precipitates acute withdrawal seizures
