Benzodiazepines (Exam I) Flashcards
Differentiate sedatives and hypnotics.
- Sedatives: induce calm/sleep
- Hypnotics: induce hypnosis/sleep
When is anesthesia awareness most common?
What are the rates of this occurring?
- 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?
Give the details of the study exploring its use.
- 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 drugs exhibit a strong correlation between BIS change and patient movement?
Which drugs do not exhibit this correlation?
- Hypnotic drugs
- Narcotics
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
- EMG
- EEG
- SR
What is the SR noted on a BIS monitor?
What would an SR of 60 indicate?
- Suppression Ratio (how many seconds per minute that the EEG is flat)
- SR of 60 means EEG is completely flat (could be brain death).
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 binding by changing receptor affinity. 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.
How many subunits are present in a GABA receptor?
Where do GABA molecules bind on said 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?
How abundant are these specific receptors and where are they found?
- Sedation, amnesia, & anticonvulsion
- Most abundant: cerebral cortex, cerebellar cortex, & thalamus.
GABA receptors with α2 subunits exhibit what properties when bound?
How abundant are these specific receptors and where are they found?
- Anxiolysis & skeletal muscle relaxation
- Less abundant: hippocampus & amygdala
What other drugs bind to GABA receptors besides benzodiazepines?
What is the result if one of these drugs is given in conjunction with benzodiazepines?
- 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
Onset of midazolam occurs in ____ _______.
Peak effect occurs in ___ _______
- 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?
How does this change in elderly patients?
- 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?
What is the primary metabolite and it’s significance?
- 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
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 2-3 minutes prior to this?
- 0.1-0.2 mg/kg IV over 30-60seconds
- 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 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 it’s 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
When is flumazenil contraindicated?
- When needed antiepileptics are being given
- If it precipitates acute EtOH withdrawal.
