RE Ch 9 Flashcards
The time to awakening following a single dose of propofol is generally how long?
5-15 minutes
An open vial of propofol is good for how long?
12 hours, or 6 hours if transferred from its original container- like in a syringe
True or False: Metabolism of propofol plays the biggest role in initial awakening of the patient, but little in the eventual clearance of the drug.
FALSE
Metabolism plays little role in the initial awakening
Metabolism IS important in the eventual clearance of the drug
True or False. Propofol has rapid metabolic clearance which actually exceeds hepatic blood flow.
TRUE
Why might you see no change in elimination for patients with severe cirrhosis?
Likely due to extrahepatic sites of metabolism
What percent of propofol is excreted unchanged?
1%
which enzyme is not responsible for the metabolism of propofol CYP2B6 UGTHP4 CYP2C6 CYP450
CYP450
While the dose of propofol is decreased for the elderly, why is it increased for children?
they have an increased volume of distribution based on body weight and their rate of clearance is also higher
The elimination half life of propofol is how long
1-2 hours
Propofol reversibly binds to _____________ (50%) and _________ (48%) which makes the free concentration less than 2%.
erythrocytes plasma proteins (most commonly plasma albumin)
Define decrement time
time from the end of the infusion to 50% recovery and includes pharmacokinetic data related to concentration decrease and pharmacodynamic data correlating with recovery.
Three scenarios that may increase the level of free active fraction
third trimester pregnancy
kidney failure
liver failure
all cause decreased plasma protein levels
The GABAa receptor where propofol works is what type of receptor
Ligand-gated ion channel receptor is activated by binding of the neurotransmitter GABA
The binding of GABA to GABAa receptors initiates the movement of what ion through ion channels into the cell?
chloride
The movement of chloride into the cell results in what?
hypopolarization of postsynaptic cell membrane and the inhibition of neuronal cell excitation.
True or false: propofol both directly stimulates GABAa receptors AND potentiates the actions of endogenous GABA.
TRUE
Name 4 dose dependent physiologic reductions that occur with propofol infusions.
CBF
CMRO2
ICP
CPP
True or False: Cerebral auto-regulation and reactivity to changes in CO2 are preserved with propofol.
True
propofol causes cerebral vasodilation or constriction?
vasoconstriction (pg 107)
Propofol may cause insignificant hypotension in healthy adults and children. Predictors of hypotension with propofol induction are….
age greater than 50
ASA class 3 or 4
baseline MAP less than 70
coadministration with high dose fentanyl
List the factors from table 9-3 that alter protein binding
Increase binding:
Decrease binding:
Increase: increased pH >8.0, Increased protein concentration
Decrease: Decreased lipid solubility, Increased drug concentration, Increased competition for binding sites with other drugs
Propofol induced hypotension results from a combination of….
WHAT ARE THE PRIMARY REASONS?
a combination of CNS,cardiac, and baroreceptor depression, as well as decreases in sympathetic tone and systemic vasodilation
PRIMARY- DECREASED SYMPATHETIC TONE AND VASODILATION
Can propofol be used in cardiac anesthesia?
Yes, but with a decreased dose
With propfol administration- which is greater….decrease in tidal volume or decrease in resp rate?
Tidal volume. although apnea is common with initial or induction dose
Does propofol cause histamine release?
No
which anesthetic agent is NOT a preferred induction agent for a patient with asthma?
Propofol
Ketamine
Etomidate
Etomidate
Does propofol cross the placenta in pregnant women? give rationale
Yes, propofol is highly lipid soluble and therefore DOES cross the placenta often leading to neonate sedation and lower apgar scores
what is the ph and pka of etomidate
8.1 and 4.2
advantages and disadvantages of etomidate
no cardiac or respiratory effects
nausea, vomiting, pain with injection, no analgesia, adrenocortical suppression, myoclonia
Induction dose of etomidate
0.2-0.3 mg/kg
How is etomidate metabolized?
rapidly metabolized by the liver by hepatic microsomal enzymes and plasma esterases
what is the primary mode of metabolism of etomidate
ester hydrolysis in liver and plasma
etomidate is eliminated where?
10% bile
13% feces
remainder kidneys
T or F rapid metabolism accounts for etomidates extremely short duration of action?
F- Rapid Redistribution accounts for extremely short DOA
etomidate is or is not lipid soluble?
it IS lipid soluble so within a minute of administration brain levels rise rapidly.
What is the hepatic extraction ratio of etomidate?
what is the terminal half life
67%
2-5 hours
describe etomidates protein binding
76% protein bound, mostly to albumin
two factors that may compensate for changes in protein binding of etomidate?
metabolism and elimination
What is the MOA of etomidate?
GABA modulation
Cerebral blood flow and CMRO2 are increased or decreased by etomidate?
decreased
etomidate will increase or decrease intraocular pressure
decrease
pretreatment with which drugs may reduce the incidence of etomidate induced myclonia?
precedex, roc, lidocaine, midaz, or a small dose of etomidate prior to the induction dose.
which population is likely to have a significant decrease in sbp, pap, and pcwp following etomidate administration.
pts with aortic and mitral valve disease
describe the dose dependent changes seen with etomidate in regards to minute ventilation and respiratory rate
Ve decreases
RR increases
The ventilatory response to CO2 following etomidate administration is increased, decreased, or unchanged?
decreased
Enzymes inhibited responsible for the adrenocortical suppression seen with etomidate induction
The P450 dependent enzymes and 11B-hydroxylase
The inhibition of those enzymes results in an increase in _______ and decrease in ________.
cortisol precursors
cortisol, aldosterone, and corticosterone levels
solvent that causes pain and phlebitis on injection of etomidate
propylene glycol
3 contraindications of etomidate
known sensitivity
adrenal suppression
acute porphyrias
induction agents safe to use with patients with acute porphyria
propofol
ketamine
MOA of etomidate appears to be
GABA-mimetic
Due to the inhibition of 11B-hydroxylase which is required for the production of both corticosteroids and mineralocorticoids clinically significant reduction in ___________ may result from using etomidate both single dose and infusion
steroid production
Etomidate increases or decreases PONV
INCREASES
Name a drug that can be very useful in anesthesia and sedation of high risk, pediatric, and asthmatic patients
ketamine
pH and PKA of ketamine
pH 3.5-5.5
pka 7.5
MOA of ketamine
antagonism of the NMDA receptors in the brain.
antagonism of NMDA receptors on the brain results in…..
selective depressant effect on the medial thalamic nuclei that is responsible for blocking afferent signals of pain perception to the thalamus and cortex
Where is the primary site of analgesic action of ketamine
thalamoneocortical system
How does the NMDA receptor work?
NMDA receptor is a ligand-gated ion channel where Ca+ and Na+ are voltage dependent.
Name the amino acid that is probably the most important excitatory neurotransmitter in the CNS
L-glutamate
Is ketamine a competitive or noncompetitive antagonist at the NMDA receptor?
noncompetitive
T or F Ketamine induced analgesia has a spinal cord component.
True
describe the metabolism of ketamine
metabolism by the cytochrome P450 system is demethylation to form norketamine
elimination of ketamine is primarily
renal
T or F. The distribution kinetics of ketamine follows a two compartment model?
true
The onset of a standard 2-2.5 mg/kg dose of ketamine has a faster or slower onset than propofol or etomidate
slower. 3-5 mins
Why does ketamine have a slow elimination half life?
hepatic metabolism and excretion. A large amount of ketamine remains in the peripheral tissues as active drug and may be responsible for prolonged cumulative effects.
what is the elimination half life of ketamine
2-3 hours
Ketamine elimination is dependent or independent of hepatic blood flow?
dependent- the mean total body clearance is approximately the same as the hepatic blood flow
Is distribution of ketamine dose dependent?
No (pg 114)
So that implies zero order kinetics????
Which routes are available for ketamine administration? Which route has 93% bioavailability?
Oral
IM
IV
IM is 93% bioavailable
Skeletal muscle tone increases or decreases with ketamine administration?
increases. muscle movements may occur unrelated to painful stimulus
T or F. As with other IV induction agents, ketamine causes a decrease in CBF, CMRO2, and ICP
False, Increased
Describe EEG changes you would expect when a pt loses consciousness as a result of Ketamine
transition from alpha to theta waves
T or F Ketamine does not alter auditory evoked potentials
True
Describe Ketamines effects on bp, hr, contractility, CO, CVP
all increased
Injection of ketamine into the CNS causes an enhancement or inhibition of norepi uptake?
inhibits neuronal and extraneuronal uptake of norepi
who may experience negative inotropic effects from ketamine?
critically ill with depleted catecholamine stores
T or F- inhaled anesthetics may cause Ketamine to lower bp and CO
true- due to the decreasing sympathetic responses
What ophthalmic changes are seen with ketamine?
increased IOP and nystagmus
ketamine causes bronchodilation or constriction?
potent bronchodilator
T or F. With ketamine administration central response to CO2 is maintained.
True
Which antisalagogue is considered superior for administration with ketamine?
atropine (p116)
ketamine is/is not highly lipid soluble…does/does not cross placenta?
IS highly lipid soluble and therefore does cross the placenta
how do you use ketamine safely in obstetrics?
decreasing the dose to 0.2-1 mg/kg spares the neonate sedation issues
ketamine may be the agent of choice in which peds populations?
difficult airway and reactive airway
what structure is unique to midazolam vs other benzos
the imidazole ring
T or F. midazolam is lipid soluble at pH less than 4.0
False, water soluble and does not require a lipoidal vehicle such as propylene glycol
What happens to midaz in a physiologic pH greater than 4.0?
the diazepine ring closes and midaz becomes lipophilic which accounts for its rapid onset of action
benzo MOA
agonist action at benzo receptor binding sites on the GABAa receptors throughout the CNS
Of the three classes of ligands that bind to benzo receptors (agonists, antagonists, and inverse agonists)…midaz, diazepam, loraz would be considered ______?
agonists- increase binding affinity for GABA- resulting in opening of chloride channels, resulting in post synaptic membrane hyperpolarization- inhibiting neuronal transmission
Give an example of a ligand that would be an antagonist at the benzo receptor
Flumazenil- forms a reversible bond with the agonist receptor but produces no agonist activity.
Name an example of a long, intermediate, and short acting benzo
long diazepma
intermediate loraz
short midaz
what is the T1/2 of midaz
less than 6 hours
benzos are terminated by
redistribution out of the CNS
of the 3 IV benzos…which is less dependent on hepatic cytochrome enzymes for metabolism? why?
lorazepam. it undergoes phase 2 conjugation to a significant extent. liver disease as well as hepatic enzyme induction or inhibition does not influence loraz as much as other drugs
benzos- Volume of distribution- large or small?
protein binding- limited or extensive?
large
extensive
which benzo may be useful in preventing chemo induced nausea and vomiting?
loraz
benzos increase or decrease the threshold local anesthetic induced seizure activity
increase
EEG changes associated with benzos
alpha disappears, beta activity is seen
which benzo causes the most respiratory depression
midaz
which patient population should avoid benzos
acute porphyrias
flumazenil is a competitive or noncompetitive antagonist?
competitive
onset and duration of flumazenil
1-2 mins, 45-90 mins
flumazenil is contraindicated in whom?
pts with known history of seizures
pts who are benzo dependent and experience withdrawal
MOA for precedex
selective alpha 2 agonist
what accounts for the hypotensive side effects seen with precedeX
stimulation of imidazoline receptors
when alpha 2 receptors are stimulated by an agonist what results?
decreased catecholamine release
what is the main site of action for the sedative effects of precedex?
the pontine noradrenergic nucleus the locus coeruleus
The alpha 2 receptors are what type of receptor?
G-protein coupled receptors
When the G protein coupled receptors are activated….the result is activated or inhibited Ca+ channels, potassium channels?
inbibited Ca+, activated K, and direct modulation of exocytic release of proteins
state the loading dose and infusion rate of precedex
1 mcg/kg over 10 mins, then 0.2-0.7 mcg/kg/HR
T or F precedex is protein bound and undergoes almost complete biotransformation leaving very little unchanged in the urine and feces
True
biotransformation of precedex involves….
direct glucuronidation
cytochrome P450-mediated metabolism
Precedex causes increased, decreased, or unchanged CMRO2
unchanged
Precedex is a drug of choice for what specific procedures?
procedures requiring a wake up test
precedex does or does not interfere with electrophysiologic monitoring
does not. useful for brain mapping
Effects of precedex on CBF
decreased due to vasoconstriction
precedex analgesia and anesthetic effects work at what levels?
brain and spinal cord
precedex enhances the analgesic effect of _______
N2O
Main CV effects seen with precedex?
bradycardia and hypotension
why does precedex cause hypoTN and bradycardia?
CNS alpha receptor stimulation and systemic vasodilation
T or F- precedex does not interfere with neuro monitoring
true
T or F: precedex is an alpha 2 agonist that results in central sympatholysis
TRUE
Who should generic propofol be used in caution with?
Metabisulfite - allergy or asthma
Benzoyl alcohol - avoided in infants
