Benzodiazepines (Test 1) Flashcards
Sedatives:
a drug that induces calm or sleep
Hypnotics:
a drug that induces hypnosis or sleep
What are the commonalities between sleep and anesthesia?
Commonalities in the reticular activating system and CNS
Inhibits thalmic and mid-brain RAS
Reversibly inhibit CNS
How is unconsciousness measured?
Range of how deeply unconscious you are
When did EEG monitoring come about?
1937 EEG could be used to measure effects
1952 depth of anesthesia correlates with concentration of ether
What do electroencephalograms measure?
Continuous monitoring of cerebral function
Locations are related to location of the brain
Impractical to put these into the OR
What does BIS monitor stand for?
Bispectral Analysis: condensed processed EEG
1996
What is the BIS monitor used for?
Gage depth of anesthesia
Rapid change in BIS correlated with increase awareness
What level of BIS is the patient unconscious?
BIS <58
What level of BIS is associated with longer time to wake up?
<65
BIS change with hypnotic drugs:
BIS change correlated to patient movement
BIS changes with high dose narcotics:
Less correlation between BIS and movement
What is on all BIS monitors?
Signal quality Index (SQI)
EMG (no movement when paralyzed unless paralytic has worn off)
EEG (processed signals)
Suppression Rate (SR)–never has a number
What does a BIS of 0 mean vs a BIS of 100?
0= dead
100= aware
What is the ideal BIS to range for no recall?
40-60
What are some synergistic effects that also reduce BIS readings?
GABA effect, Muscle relaxers
What sedative medication can make BIS look higher?
Ketamine (sympathomimetic)–increases brain activity
What meds can make BIS more depressed?
Beta blockers
Volatile anesthetics
Narcotics
What is the main thing we use the BIS for?
Trending
What are the pharmacologic effects of benzodiazepines?
Anxiolytics-helpful to chronic anxiety
Sedation
Anterograde Amnesia-lasts longer than sedative effects
Anticonvulsant actions-valium
Spinal-cord mediated skeletal muscle relaxation
What is the only thing that can cause retrograde amnesia?
Electro convulsant therapy
How do Benzos compared to barbiturates?
-Less tolerance
-Less potential for abuse
-Fewer and less serious SE
-Do not induce hepatic enzymes
Benzos have replaces bariturates for preop sedation
How are all benzos similar?
Structurally similar
Same antagonist
What is the most common used benzo in perioperative period?
Midazolam–quick on quick off
How do diazepam/lorazepam compare to midazolam?
Much greater 1/2 time than midazolam
these are better for sedation post op
What is the principal inhibitory neurotransmitter in the CNS?
Gamma-aminobutyric acid (GABA)
What is the mechanism of action for benzos?
Facilitates action of GABA at GABA(A) chloride ionophore
Cl- hyperpolarization of post synaptic membrane–enhanced opening of Cl- channels
What is the most abundant GABA subunit and where is it located?
Alpha-1: sedative, amnestic, anticonvulsant
cerebral cortex, cerebellar cortex, thalamus
What happens at alpha 2 receptors?
Anxiolytic, skeletal muscle relaxation
hippocampus, amygdala
T/F? Benzos get effects of both alpha 2 and alpha 1
True
Future BZD design would want one that gives sedative, anxiolytic (parts from both sites)
What other drugs bind to GABA(A) receptor binding sites?
Barbiturates
Etomidate
Propofol
Alcohol
Volatiles
How do different benzos have different MOA?
Differences in onset and duration
-potency (receptor binding affinity)
-lipid solubility (crossing BBB)
-redistribution (peripheral tissue)
-pharmacokinetics (ADME)
Which benzo is unable to produce isoelectric state (flat line)?
Versed
What are general effects of benzos on an EEG?
Decreased alpha activity
What drugs are synergistic with benzos?
Synergistic with other GABA related analogs:
Alcohol
Injected anesthetics
Opioids
Alpha 2 Agonists
Inhaled anesthetics
What are the most common alpha 2 agonists?
Precedex
Clonidine
Volatiles
How do benzos inhibit platelet aggregation?
BZDs may affect platelets–dont get “pseudopaws” to grab onto each other
surgical significance is unclear
What strcuture of midazolam allows it to be stable and allows rapid metabolism?
Imidazole ring
When is versed used?
Used in preop meds and conscious sedation
How does versed compare to valium in regards to potency?
Versed 2-3x as potent as valium
versed has greater affinity for receptor
How does versed influence amnesia?
Amnesia last longer than the sedation of versed
several hours–need someone to drive home
What makes versed active/inactive?
pH dependent ring opening–opening and shutting makes it active and inactive depending on pH
What is the ring position for versed when pH is <3.5?
Ring is open–water soluble (protenated)
What is the ring position for versed when pH >4.0?
Ring closes–lipid soluble
ACTIVE FORM (unprotonated)
What is the onset of versed?
1-2 minutes IV
Is versed plasma bound?
Extensively bound to plasma proteins (96-98%)
When is the peak effect of versed?
5 minutes (slow site equilibration)
Why does versed have a short duration?
d/t lipid solubility–rapidly moves from blood across lipid barrier to the brain to effect GABA sites
rapid redistribution
What is the 1/2 time of versed?
2 hours: 50% gone from plasma
How does half time of versed vary with elderly/ patients with liver/renal issues?
Doubled half time–hepatic flow/enzyme activity decreased
What is the Vd for versed? What about Vd in elderly/obese population?
1-1.5 L/kg (large)
Elderly: and Obese: Increase Vd (more fat to distribute in)
How is versed metabolized? Metabolites?
CYP3A4
metabolized into active and inactive metabolites
What is the active metabolite produces by versed? How is it cleared from the body?
1-hydroxymidazolam: 50% activity of versed
Conjugated and cleared by kidneys
Drugs that cause inhibition of P450 enzymes _________ benzo metabolism and _________ half life
decrease
delay
List some drugs that cause inhibition of P450 enzymes:
Cimetidine (tagamet)
Erythromycin
CCB
Anti-fungal
Fentanyl
How does versed clearance compare to ativan and valium?
Versed clearance is 5x faster than ativan
10x faster than valium
How does versed affect CNS?
Decreases CMRO2 (cerebral metabolic requirement of O2)
Decreases CBF
Unable to produce isoelectric EEG
Potent anticonvulsant (status)
Preserves vasomotor response to Co2
No changes in ICP (ok for neuro pts)
What is the vasomotor response to CO2?
Allows vessels to dilate and constrict as they would normally in response to CO2
-Increase CO2 dilates vessels
-Decrease CO2 constrict vessels
What is a concern if giving versed to patient with COPD?
Decreases hypoxic respiratory drive more so in patients with COPD
Versed can cause decreased ventilation depending on ______
Dose
What could happen if versed is given rapidly IV?
Transient apnea–increased when given with opioid
What makes versed increase risk for aspiration?
Depresses swallowing reflex and decreases upper airway activity
How does versed effect BP/HR/CO/SVR?
Decreases BP and SVR
Increases HR
CO unchanged d/t increase HR to compensate low BP
If a patient only received versed and was then intubated what would you expect from HR/BP?
Versed does not inhibit BP/HR response to intubation
would increases BP and decrease HR with intubation if no other meds onboard (never the case)
Versed dose for preop sedation in kids: what is the peak?
0.25-0.5 mg/kg oral syrup
peak 20-30 min (lose a lot through metabolism)
Versed dose for pre/intra op sedation in adults: what is the peak?
1-5mg IV
peak 5 minutes
decrease dose in elderly (greater CNS sensitivity)
What is the dose of versed for induction?
0.1-.2mg/kg IV over 30-60 seconds
Rare to use versed for induction today, common in 70s/80s
What isnt versed used for induction anymore?
Not short acting–delayed wake ups
What med can be used to increase the induction speed when using versed?
Facilitated by giving opioid before (1-3 minutes)
What is the dose of versed for post op sedation?
1-7 mg/hr IV
Why is it uncommon to use versed gtt?
Markedly delayed wake up
active metabolite accumulate
Clearance depends on hepatic metabolism not redistribution
Versed may have suppression of healing through:
Immune/ T cell effects (unclear clinical significance)
Why is valium rarely used in anethesia?
Highly lipid soluble–more prolonged duration of action than versed
How is valium prepared?
Dissolved in organic solvents:
-insoluble in water
What is the onset of valium?
1-5 minutes
What is the half time of valium? Is valium protein bound?
20-40 hours–extensively protein bound
What is the Vd for valium?
similar to versed
lipid soluble–large Vd in women than men
How does the duration of valium compare to ativan?
Valium dissociates from GABA(a) faster than ativan
shorter duration of action, longer elimination half time
around in the system longer but not on the receptors for as long
How is valium metabolized? Does it form metabolites?
CYP3A pathway
2 active metabolites–almost as potent
What are the 2 active metabolites produced by diazepam?
Desmethyldiazepam (48-96 hours)
Oxazepam
nearly as potent as diazepam
What is the dose for valium as an anticonvulsant? What can it be used to treat?
Potent anticonvulsant
0.1mg/kg IV
Abolished DTs, status epilepticus, lidocaine toxicity related seizures
Which benzoscan produce isoelectric EEGs?
Valium
How does valium effect ventilation?
Slight decrease in Vt
After 0.2mg/kg IV increases in PaCO2
Exaggerated with opioids, alcohol, COPD
How can depressed ventilatory effects from diazepam be reversed?
with stimtulation
Does valium cause decrease in BP/CO/SVR?
Minimal decrease (even with induction dose)
BP changes can occur when given with synergistic drugs
How does valium effect neuromuscular system?
Decrease tonic effect on spinal neuron
Skeletal muscle decreased
Develop tolerance to skeletal muscle relaxant effects
What is the induction dose for valium? How do you change the dose for elderly, liver disease, presence of opioids?
0.5-1.0 mg/kg IV
Decrease dose by 25-50% for that population
Which benzo discussed in class is the most potent?
Ativan
more potent sedative and amnestic compared to midazolam and diazepam
What do bezos that are insoluble in water require?
Requires solvents: Polyethylene glycol
(ativan, valium)
Which benzo doesnt require solubilizing?
Versed
How does the onset of action of lorazepam differ from versed and valium?
Ativan has slower onset of action
lower lipid solubility–slower entrance to CNS
Slower metabolic clearance
What is the peak effect of ativan?
20-30 minutes with IV dose (1-4mg IV)
What are the uses for Ativan?
limited usefulness–induction, conscious sedation, anticonvulsant
not as useful for acute issues
What is the half time of Ativan?
14 hours
slower metabolism
Glucuronidation slower than oxidative hydroxylation
How is Ativan metabolized?
Not entirely dependent on hepatic enzymes
direct conjugation itself to be metabolized
good for liver patients
What is the non-specific reversal that works for all benzos?
Flumazenil (Romazicon)
What is the mechanism of action of flumazenil? What is it derived from?
Competitive antagonist: high affinity for BZD receptor
1,4 imidazobenzodiazepine derivate
What is the dosing for flumazenil?
0.2mg IV and titrated for consciousness
repeat 0.1mg q1 minute until conscious for max of 1mg total
What is the common dose of flumazenil to reverse sedation? what about to abolish therapeutic dose (people who chronically take BZDs)?
0.3-0.6mg to reverse sedation
0.5-1 mg for people who take BZDs chronically
When is flumazenil contraindicated?
Antiepileptic drugs
Precipitates acute withdrawal seizures
