Induction Agents Flashcards
Low dose IV anesthetics produce ____ and high doses produce ___
low dose = sedation
high dose = unconsunessness
T/F
We do not witness stage 2 with IV induction.
True
No outward presentation of stage 2; goes thru stage 2 in ~2 seconds
EEG can show tho
TIVA
total IV anesthesia
Uses for induction agents
Induction of anesthesia
TIVA (Total intravenous anesthesia)
MAC (Monitored anesthesia care)
Sedation during local and regional anesthesia
All IV anesthetics are ____ and produce…
sedative-hypnotics
dose-dependent CNS depression
Ideal induction agent criteria
-Hypnosis and amnesia
-Rapid onset (time of one arm–brain circulation)
-Rapid metabolism to inactive metabolites
-Minimal CV and resp depression
-No histamine release/hypersensitivity reactions
-nonmutagenic, noncarcinogenic
-No untoward neurologic effects (seizures, myoclonus, neurotoxicity)
-beneficial effects: analgesia, antiemetic, neuroprotection, cardioprotection
-P.kinetic models for accurate dosing
-Ability to continuously monitor delivery
mutagenic
inducing or capable of inducing genetic mutation
we want our indxn agents to be nonmutagenic
ideal induction agent should be ___ soluble
water
however, a balance of water and lipid solubility is important
____ support microbial support
Lipids
Propofol has a preservative in it
also why we want water-soluble preparations for indxn agents
IV anesthetics have a ___ onset
rapid
IV anesthetics distribute rapidly to…
higher perfused and vessel-rich tissues
allows for rapid crossing of the blood-brain barrier
lipophilicity
Three-phase process that occurs after a bolus of propofol
-Rapid distribution phase(A): plasma –> peripheral tissues
-Slow distribution phase(B): into other tissues while the drug in rapid distribution tissue —> back to plasma
-Terminal phase or elimination phase(C): removed from the body
the branch of pharmacology concerned with the movement of drugs within the body
Pharmacokinetics
Used to describe the behavior in IV agents (propofol) during infusion via a pump
Three-Compartment Model
Central compartment
(CA1, blood)
Peripheral compartments
(CA2 and CA3)
Elimination
(G1)
Three compartment model steps
- Propofol is injected into the blood and fills the central compartment
- Redistributes to peripheral compartments (one rapid and one slow)
- Elimination
- Accumulation over time in peripheral compartments (infusion), less drug is removed from the central compartment by redistribution and less drug is needed to be infused
Elimination half-time (t1/2)
The time it takes for the plasma concentration of a drug to decrease to 50% of its original concentration (after one bolus dose)
1 compartment model
T/F
Context-sensitive half-time applies to IV boluses
false
applies to infusions!
In order to use Elimination half-time (t1/2), we must follow a ___ compartment model.
1
In order to use Elimination half-time (t1/2), the drug must be…
only in the blood phase or a drug administered only once (bolus)
Context-sensitive half-time
The time to achieve a 50% reduction in concentration after stopping a continuous infusion.
What does this graph tell us about fentanyl and propofol?
fentanyl has a much higher CSHT than propofol
will keep patient asleep for much longer
What does this graph tell us?
CSHT of opioids
note how remifent drops to 50% extremely quickly & how fentanyl takes very long
T/F
Remifentanil is distributed to tissue
False
broken down via ester hydrolysis rapidly
does not redistribute well
T/F
the ability to distribute into tissues and redistribute into the plasma compartment increases the half-life of a drug
True
Which opioid has a context-sensitive half-time that is essentially independent of the duration of the infusion?
remifentanil
Context-Sensitive half-time(3-compartment model)
Describes the transfer of drug:
plasma –> peripheral compartments –> (once the infusion is stopped) back into the central compartment
Propofol (Diprivan)
2,6-diisopropylphenol
Rapid onset, predictable context-sensitive half-time
Rapid emergence, rapid redistribution
Antiemetic properties
you must know this table in its entirety
How much of propofol is protein bound?
98%
⭐️
Propofol
primary mechanism
GABA-A receptor agonist
enhancement of GABA inhibition
⭐️
Propofol
CV effects
significant decreases in
SVR, SV, & CO
⭐️
Propofol
pulmonary effects
respiratory depressant
potent bronchodilator
⭐️
T/F
Unlike opioids, Propofol does not exhibit potential for addiction.
False
Addiction potential: may elicit feelings of well-being or euphoria during emergence
⭐️
Propofol
Key Clinical Uses
-General anesthesia: induction & maintenance
-TIVA
-Conscious & deep sedation
-ICU sedation
-PONV prophylaxis & rescue!
-Safe with malignant hyperthermia
⭐️
T/F
When used for surgical procedures, propofol can only be used in the OR.
False
Used for conscious and deep sedation, including out-of-operative-room settings
⭐️
Is propofol safe to use in malig.hyperthemia?
yes
⭐️
Propofol
CNS effects
-CNS depressant
-neuroprotective
-anticonvulsant
-decreases CerebPerfPrsr, CMRO2, CBF, & ICP
What happens when the GABA receptor allows Cl- to flow in?
-hyperpolarized
-does not allow electrical conductivity
Propofol is primarily metabolized by the ____. The kidneys excrete …
liver
inactive and water-soluble metabolites
Most common extrahepatic sites of propofol metabolism are ….
They account for ___% of metabolism.
kidneys and lungs
30%
Which model explains the elimination of propofol?
3 compartment
How does propofol induce an unconscious state
enhances GABA’s inhibitory pathways
~central cholinergic transmission, NMDA or alpha-adrenergic sites
paradoxical excitation
unpredictable movement, not easily arousable
T/F
Higher doses of propofol will always create deeper sedation/anesthesia
False
possible paradoxical excitation (unpredictable movement, not easily arousable) at higher doses
T/F
Propofol is an anticonvulsant and can treat status epilepticus
True
also shortens seizure duration
T/F
Propofol can be used for electroconvulsive therapy (ECT)
False
ECT requires inducing a seizure & propofol is an anticonvulsant
⭐️
Why are the CV effects of propofol more significant after induction than gtt?
CV effects are dose dependent
Smooth muscle relaxant & impair SNS
T/F
Propofol affects the SNS.
True
decreases sympathetic activity
indirect effects on arterial vasodilation and venodilation
With larger doses of propofol, what changes are you likely to see in the BP and HR?
Drop in SBP & DBP without the increased HR
(decreased CO, SV, SVR)
What makes propofol a good bronchodilator?
direct effect on intracellular calcium
Maintenance doses of propofol can result in which resp effects?
diminished tidal volume and increased RR
An induction dose of propofol will create apnea how quickly?
within 30 seconds
T/F
Propofol can only exhibit its antiemetic effects when used with certain adjuncts.
False
PONV is decreased with propofol administration regardless of the type of anesthetic
Propofol dose for PONV
10-15mg IV
Propofol infusion rate for PONV prophylaxis
Background infusions of 10 ug/kg/min
How does Propofol prevent PONV?
possible direct effect on the vomiting center (Chemoreceptor trigger zone)
Propofol dose for opioid-induced pruritus
10 mg IV
How does Propofol treat opioid-induced pruritus?
Mechanism is related to spinal cord suppression
What makes propofol the induction agent of choice?
rapid, predictable awakening
What makes propofol easily titratable?
quick recovery (very short elimination half-life)
predictable clearance
Induction dose of Propofol
1-2.5 mg/kg
(2 mg/kg)
IV sedation/MAC propofol dose
25-75 mcg/kg/min (variable)
Maintenance of anesthesia (GA) dose of propofol
100-200 mcg/kg/min (variable)
Propofol usual concentration
10mg/mL (200mg/20mL)
Which pt population typically requires lower doses of propofol?
old ppl
small ppl
(note: peds need more b/c high Vd & Cl)
What gives Propofol its allergic potential?
its phenyl nucleus and di-isopropyl side chain
egg LECITHIN
most egg allergies are actually to egg proteins; prop = lecithin (fatty part of yolk)
Generic contains sodium metabisulfite = contraindicated in patients with sulfite sensitivity
Why is propofol painful on injection?
thick, glycerol-based emulsion
How common in pain on injection from propofol?
60-70% of pts complain
Children need (higher/lower) doses of prop bc…
higher doses
higher Vd and faster clearance
Why do elderly people need lower doses of prop?
prolonged effects and increased sensitivity due to decreased cardiac output and clearance
Would prop be okay to use in a pt with CV Dz?
probably not
decreases CO, SV, SVR and BP
Opened propofol vials are good for ____ & ___ for syringes.
vial (infusion) = 12 H
syringe = 6 H
Propofol Infusion Syndrome (PRIS)
-Doses of 4 mg/kg/hr for > 48 hours (67 ucg/kg/min)
-brady; possible into asystole
-unexplained: metabolic acidosis, hyperkalemia, rhabdomyolysis, hyperlipidemia, and/or enlarged liver, renal failure, EKG changes, arrhythmias
Green urine with prop use is a sign of…
Increased extrahepatic metabolism
excretion of these metabolites in urine
Which conditions may contribute to Propofol Infusion Syndrome (PRIS)?
cardiomyopathies, skeletal myopathy, or hyperkalemia
Highly dependent on infusion dose and duration
with longer propofol infusions urine may become…
milky colored
Etomidate (Amidate)
GABA-A receptor agonist
A carboxylated imidazole derivative
T/F
Avoid use of etomidate in patients prone to hypotension.
False
Etomidate is hemodynamically stable
Etomidate
adverse effects
Adrenocortical suppression (critically ill)
Postoperative nausea and vomiting possible
Etomidate is good for which pts?
cardiac, trauma, and elderly
⭐️
Why do we not use etomidate infusions?
Continuous infusion limited due to possible adrenal suppression
Etomidate follows with compartment model?
3
Etomidate metabolism
liver & plasma esterases
excreted by kidneys (80%) and in bile (20%)
Is Etomidate highly protein bound?
Yes
75%
Etomidate has a (fast/slow) onset. This is due to…
fast
redistribution
Is etomidate irritating to veins? Why or why not?
yes
Solvent (propylene glycol) contribute to veno-irritation and phlebitis
⭐️
How long does etomidate’s adrenal suppression last?
up to 72 H
Etomidate Induction dose:
0.2-0.3 mg/kg
T/F
Etomidate is considered a proconvulsant
true
lowers seizure threshold
Etomidate MoA
GABA-A agonist
Etomidate
CNS effects
potent vasoconstrictor that reduces CBF, ICP and CMRO2
When giving etomidate as an induction agent, we should watch for ____. If that happens, we give ____.
seizure-like, myoclonic movements
versed/opioids
Etomidate
CV effects
Minimal/no effect on MAP, PA pressure, PCWP, CVP, SV, CI, SVR and PVR
How does etomidate cause adrenocortical suppression?
Inhibits 11β- hydroxylase
prevents conversion of cholesterol –> cortisol
If prolonged, adrenocortical suppression will cause…
hypoTN
Ketamine (Ketalar) is a derivative of…
Phencyclidine (PCP)
-chiral compound
-racemic: S and R enantiomers
When emerging from Ketamine, what may the pt experience?
Emergence delirium & hallucinations
⭐️
T/F
The Ketamine compound is achiral.
False
-PCP analog
-chiral compound
-racemic mix: S and R enantiomers
Of all induction agents, which is metabolized into a clinically significant metabolite?
Ketamine
Liver: demethylation = norketamine (biologically active, 1/3 - 1/5 as active)
What is Ketamine’s metabolite?
Is it active or inactive?
norketamine
active (1/3-1/5 as active)
Ketamine metabolism
-mostly liver
-cytochrome P-450 enzymes
-demethylation to norketamine
Ketamine has (high/low) lipid solubility & (high/low) protein binding.
high lipid sol.
low protein binding
T/F
Ketamine can only be given IV.
False
Bioavailable by multiple routes: IM (93%)
transnasal (25-50%)
rectal/oral (16%)
T/F
Ketamine rapidly redistributes
True
Ketamine
induction dose
0.5-2 mg/kg IV
4-5 mg/kg IM
Ketamine onset (IV)
30-60 seconds
Ketamine duration
10-20 mins
Ketamine MoA
It produces a functional dissociation between thalamocortical & limbic systems
NMDA antagonist
What’s the benefit of using Ketamine with opioids/propofol?
Inhibit 2 different pain pathways
Ketamine acts as a (agonist/antagonist) at the ___ receptor
antagonist
NMDA
T/F
SNS stimulation is expected with Ketamine.
True
MAP, CO, SVR, and myocardial oxygen requirements increase
Aside from the NMDA receptor, where does Ketamine act?
-Non-NMDA glutamate receptors
-Nicotinic receptors
-Cholinergic receptors
-Monoaminergic receptors
-Mu, delta and kappa-opioid receptors
-inhibits neuronal Na+ channels (Local anesthetic action)
& Ca+ channels (Cerebral vasodil8)
T/F
Ketamine exerts effects similar to local anesthetics.
True
ketamine inhibits neuronal Na+ channels (Local anesthetic action)
Ketamine’s antagonist activity at the NMDA receptor causes…
pain relief
Ketamine is a NMDA receptor (agonist/antagonist).
antagonist
Dissociative amnestic state
is seen with which drug?
Ketamine
Dissociative amnestic state
(ketamine)
-unconscious; eyes open (nystagmus)
-spontaneous respiration
-do not react to painful stimuli
Induction doses of ____ are associated with increased HR and BP
Ketamine
Can we give ketamine to a hemodynamically unstable pt?
Yes!
T/F
Ketamine can be given to OB pts
True
Ketamine should be used with caution in pts with which cardiac condition?
severe right heart dysfunction (Ketamine increases PVR)
T/F
Ketamine can be used for depression
True
What causes Ketamine’s profound analgesia?
probably due to prevention of developing hyperalgesia
T/F
It’s okay to give ketamine to opioid abuse patients.
True
Emergence
Benefits of using ketamine
Using less opioid and adding ketamine can produce faster wake up.
T/F
Ketamine is not indicated for use in chronic pain.
False
treats acute and chronic pain
T/F
Ketamine causes significant respiratory depression.
False
Ketamine (increases/decreases) ICP. This is due to…
-increases ICP
-Potent cerebral vasodilator
-increases CBF of 60-80% during normocapnia
How can we can attenuate ketamine’s effect on ICP?
raises ICP
attenuate with hyperventilation
T/F
Increased ICP is an absolute contraindication to ketamine.
False
relatively contraindicated
research in progress
Due to its effect on muscarinic receptors, ketamine increases _____ _____.
airway secretions
How does Ketamine affect the airways (2)?
good bronchodilator
maintains protective airway reflexes
Ketamine’s CV effects resemble…
SNS stimulation
MAP, CO, SVR, & myocardial oxygen requirements increase
The mechanism for ketamine-induced CV effects
direct SNS stimulation
T/F
Ketamine can be used in pts w/ mild to severe hypovolemia.
False
ideal for induction in a hypovolemic patient
HOWEVER, use in critically-ill or shock-like patient = profound hypoTN
d/t catecholamine depletion in these patients, leading to unopposed direct myocardial depression
Emergence Delirium
phenomenon associated w/ postop ketamine anesthesia
-Visual, auditory illusions
-Confusion
-Delirium
Ketamine
Emergence Delirium usually occurs at doses higher than…
> 2 mg/kg
dose-dependent occurrence
Emergence Delirium Prevention
-preop midazolam
-Recover in calm/quiet environment
Dexmedetomidine (Precedex)
alpha 2-adrenergic agonist
highly selective, specific, and potent
Which is more selective of alpha 2 receptors?
Precedex
Clonidine
Precedex (7-8x more)
How does Precedex induce sedation?
activation of α2-receptors in the locus coeruleus
& induces a state mimicking natural sleep.
T/F
Precedex has analgesic properties.
True
T/F
Precedex does not cause respiratory depression.
False
can produce mild resp. depression
How does Precedex affect norepinephrine?
Inhibits Norepi release in locus coeruleus
How does Precedex affect opioid metabolism?
Dexmedetomidine: weakly inhibits CYP-450 system
could cause increased plasma [ ] of opioids administered during anesthesia
What % of Precedex is protein bound?
94%
Precedex faces (rapid/slow) (hepatic/renal) metabolism involving which reactions?
rapid
hepatic
conjugation
N-methylation
hydroxylation
Precedex CNS effects
-sedative, anxiolytic, & analgesic effects (spinal cord and brain)
T/F
Analgesic effects of Precedex do not alter the amount of opioid needed.
False
decreases opioid requirement
Precedex respiratory effects
-less ventilatory depression vs. other sedative-hypnotic/opioid anesthetics
-Bolus will reduce minute ventilation
If we give a bolus of Precedex, we should expect a decrease in which respiratory parameter?
minute ventilation
(amount of air that enters the lungs per minute)
How does Precedex cause hypoTN and bradycardia?
high alpha-2-adrenereceptor activity
Which pt population is esp at risk for bradycardia from precedex?
Children
Benefits of using Precedex as anesthetic adjuvant
blunt the hemodynamic effects of direct laryngoscopy
improves hemodynamic stability
Precedex uses
-sedation: procedural, postop, ICU, when controlled ventilation is required
-extubation: breathe spontaneously and appear calm (pediatrics)
-IV adjuvant: induction or maintenance of GA, local/regional
-blunt acute SNS response to laryngoscopy
Precedex sedation dose (initial)
0.5 - 1 mcg/kg given over 10 minutes
Precedex sedation dose (drip)
0.2-.7 mcg/kg/hr
Treating Precedex bradycardia
atropine, ephedrine or volume
Omitting the loading dose
Precedex side effects
hypoTN
bradycardia
dry mouth
nausea
hyperTN
The CV and resp effects of benzos are considered to be…
minimal
but be cautious
benzos produce…
amnesia
Benzos relax which muscles?
skeletal (centrally)
Benzos MoA
- bind to alpha subunits of GABA receptor
- increasing Cl- conductance
- hyperpolarization of the membrane
- nerve resists stimulation
Effects of Benzos are primarily d/t…
their effect on the central inhibitory neurotransmitter, GABA-A
GABA is an (excitatory/inhibitory) ____.
inhibitory neurotransmitter
Which benzo usually doesn’t burn on injection?
versed
other benzos typically burn
Which benzo is water soluble in its bottle?
versed
Versed’s first pass extraction is over ___%
50%
Which benzo has shortest duration of action?
Versed/midazolam
What contributes to Versed’s short duration?
rapid redistribution, hepatic metabolism and renal clearance
T/F
Versed dosage should be adjusted in pts with renal/liver Dz
true
Versed = hepatic metabolism and renal clearance
Benzos
CNS effects
Can decrease CMRO2, CBF with little effect on ICP
Benzos
Resp effects
may decrease upper airway reflexes & central respiratory drive
Benzos
CV effects
Can decrease the SVR and BP
Do Benzos cross the placenta?
yes
avoid in OB if possible
Benzos create amnesia in which timeframe?
remember everything up until the point you gave them versed
What type of amnesia do benzos create?
Anterograde amnesia
a loss of memory for events occurring forward in time
Benzo reversal
Flumazenil (Romazicon)
0.2 mg IV over 15 seconds
no reponse after 45 secs: give 0.2 mg
repeat at 1 min intervals (max: 4 doses)
Flumazenil (Romazicon)
dosing
0.2 mg IV over 15 seconds
no reponse after 45 secs: give 0.2 mg
repeat at 1 min intervals (max: 4 doses)
Benzo dosing
Versed
(Preop)
orally, nasally, rectally, IM, IV
peds preop: 0.5 mg/kg 30 mins b4 OR
adult preop: 1-2 mg
Which benzo(s) are not water soluble?
Lorazepam and Diazepam
“Don’t Like water”
Which benzo(s) usually cause injection pain? Why?
Lorazepam and Diazepam
propylene glycol (like etomidate!)
“Damn, Lady! That shit hurts!”
induction drugs that contain propylene glycol
Lorazepam
Diazepam
Etomidate
Versed
solubility changes upon administration
- water-soluble
- conformational change in bloodstream
- more lipophilic
Ring on its structure breaks once in blood and becomes lipophilic
Barbiturate Classes
Oxybarbiturates
O2 atom on the #2 carbon atom
Thiobarbiturates
Replacement O2 atom w/ sulfur on the #2 carbon atom
BOTH: pyrimidine center
Which barbiturate class contains sulfur?
Thiobarbiturates (pyrimidine center)
(O2 atom –> sulfur on carbon #2)
Oxybarbiturates
Methohexital (used in ECTs)
Phenobarbital
Pentobarbital
Secobarbital
Thiobarbiturates
Thiopental
Thiamylal
What do the two barbiturate classes have in common?
pyrimidine center
Barbiturate metabolism
Primary: hepatic
inactive metabolites excreted in urine and bile
Barbiturate redistribution
Rapid redistribution into highly perfused compartments
rapid termination after a single dose
Barbiturate extended infusion
(Thiopental)
accumulates in poorly perfused compartments
slow elimination (prolonged context-sensitive half-time and delayed recovery)
Barbiturate
Sites of action
cortical and brainstem GABA inhibitory pathways
Barbiturates will cause…
Loss of consciousness, respiratory and CV depression
Hypnotic effects of barbiturates are likely enhanced by…
inhibits central excitatory pathways
(glutamate via NMDA receptors & acetylcholine)
Thiopental elimination 1/2 life
12 H (long)
Does thiopental induce or treat seizures?
anticonvulsant
used to treat status epilepticus
How does thiopental affect ICP?
it decreases ICP!
-induction for pts with ↑ ICP
-treat ↑ ICP resistant to hyperventilation alone
Thiopental protects the brain by…(4)
-cerebrovascular vasoconstriction
↓ cerebral blood flow
↓ intracranial pressure
-Decreased cerebral metabolic O2 consumption
Thiopental stimulates the release of ___ from ___.
histamine
mast cells
Thiopental precipitates with…
succinylcholine
rocuronium
lidocaine
(Pharm class: pancuronium)
T/F
We cannot give succinylcholine, rocuronium, or lidocaine if we have already given the pt thiopental.
False
flush IV line thoroughly before giving after Thiopental
Acute Intermittent Porphyria (AIP)
disorder of porphyrin enzyme metabolism, either in the liver or the bone marrow
Porphyrins are involved in ___ production.
heme
_____ can precipitate an attack of AIP, and must be avoided in patients with a history of this disorder
all barbiturates
Acute Intermittent Porphyria (AIP)
5 P’s
Methohexital (Brevital)
Oxybarbiturate
Proconvulsant activity
Agent of choice in Electroconvulsive Therapy (ECT)
Methohexital (Brevital)
Methohexital
Induction dose
1-2 mg/kg (IV)
20-30 mg/kg (Rectal)
Thiopental
Induction dose
2.5-5 mg/kg (IV)
In the elderly reduce the dose by 30-35%
