NONVOLATILE
ANESTHETICS
PRESENTED BY JACOB HUMMEL, M.D.
TULANE ANESTHESIOLOGY
OBJECTIVES
An overview of the nonvolatile anesthetics
- Kinetics/Dynamics
- Organ system effects
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-Effects of Propofol on the cardiovascular system
-Pharmacological differences between fospropofol &
propofol
-Effects of Barbiturates on CBF and CMRO2
-How Benzodiazepines affect ventilation
-Ketamine effects on CBF and CMRO2
-Dexmedetomidine, effects of bolus vs. infusion
GOALS
-It is my desire to have you walking away from this lecture
feeling well versed in all topics related to nonvolatile
anesthetics
-It is also my desire for everyone to find this lecture
enjoyable and entertaining and serve as a catalyst to our
collective PLD session this afternoon
DISCLOSURES
All opinions expressed today are those of a licensed
physician, however, some CRNAs still claim that CA-1s, like
myself, are still only students
GENERAL OVERVIEW
Nonvolatile anesthetics have several uses, but primarily are
used for
1. INDUCTION
2. MAC/ICU SEDATION
Several of these drugs can be administered via various
routes, but their use in anesthesiology is primarily via the
intravenous route
Most of the anesthetics described are lipophilic in nature
which means RAPID ONSET and RAPID TERMINATION of
their anesthetic effects
PHARMACOKINETICS
What the body does to the drug…
-The drugs in this class are primarily administered
intravenously and therefore bypass absorption
-The initial termination of their effects leading to waking up
from anesthesia is the result of re-distribution into less
perfused tissues
-Biotransformation is primarily completed by the liver
Phase I: oxidation (P450), reduction, hydrolysis
Phase II: conjugation with glucuronides
KINETICS (CONT.)
-Kidneys are the prinicipal
organ of excretion
-The kinetics for most drugs
can be described by a twocomparment model, central
and peripheral
-The kinetics for some drugs
are better explained by a
three-compartment model,
central and 2 peripherals
PHARMACODYNAMICS
What the drug does to the body…
-The mechanism of action of most drugs depends on the
interaction with a receptor
-The receptors are likely tied to either the function of ion
channel or the production of a second messenger
-Most of our anesthetics act at the synapse of neurons and
affect GABAa chloride channels or NMDA cation channels
PROPOFOL
Most frequently administered drug for induction of anesthesia and
also used for ICU sedation, procedure sedation, rapid sequence
induction and PONV
Formulations support bacterial growth
and there are cases of SEPSIS and
DEATH related to propofol
contamination
Egg allergy not necessarily a
contraindication to its use
PROPOFOL-KINETICS
Initial distribution half-life of 2-8 minutes,
typically 8-10 minute wake-up from
induction dose
Clearance of propofol exceeds hepatic
blood flow, suggesting extrahepatic
metabolism
Moderate cirrhosis and chronic renal failure
do not affect clearance
…however, being a pop icon does affect
how your body clears the drug…
PROPOFOL (CONT.)
Decrease in arterial blood pressure due to drop
in SVR
Hypotension is more pronounced than
thiopental and more likely to occur with:
Large doses!, Rapid Injection!, Old Age!
Also impairs normal baroreflex response (no
inc. HR)
PROPOFOL (CONT.)
Profound respiratory depressant as many patients will
become apneic after induction dose
Inhibits response to hypoxia and hypercarbia
Positives include depression of upper airway reflexes and
less incidence of wheezing
According to the 2009
autopsy report, "the cause
of death is acute propofol
intoxication," which
caused the singer to stop
breathing
PROPOFOL (CONT.)
Decreases cerebral blood flow and intracranial pressure
Provides neuroprotection against focal ischemia (not global)
Induction accompanied by twitching/spontaneous movement
easy to be confused as seizure activity but appears to have
anticonvulsant properties
And when it comes to antiemetic effects, you can’t BEAT IT!
FOSPROPOFOL
The water-based prodrug of propofol and was approved by
the FDA for use as a sedation agent for MAC procedures
Metabolized by alk phos in a reaction that produces propofol,
phosphate and formaldehyde
Kinetics have been difficult to establish
Dynamics similar to propofol but onset and recovery are
prolonged
FOSPROPOFOL-SAFETY
ASPF newsletter:
http://www.apsf.org/newsletters/html/2010/summer/07_Fospropofol.htm
Fospropofol has the advantage of less pain on injection, less risk of
hyperlipidemia and less bacterial contamination
High incidence of perineal paresthesias and pruritus…awkward
Frustrating pharmacokinetics but serves as an alternative during
propofol shortages
BARBITURATES
Derived from barbituric acid, this class has varying degrees of
hypnotic, sedative and anticonvulsive effects
Substitutions at Carbon #5 determines hypnotic potency and
anticonvulsant effect
Substitutions at Carbon #2 alter the lipid solubility
BARBITURATES (CONT.)
Even though they are derived from acid, the ultimate
formulations are alkaline with a pH of 10 therefore they
cannot mix with acids (NMBDs) or it will precipitate
Precipitates will block IV lines and cause tissue necrosis if
accidentally injected into an artery
The formulations are also racemic mixtures and the
potencies reflect the ratio of the different isomers
BARBITURATESKINETICS
Duration of action determined by
re-distribution, not metabolism
All of the barbiturates, except for
phenobarbital are metabolized by
oxidation in the liver and excreted
into the urine after conjugation
Chronic administration of
barbiturates or other drugs that
induce oxidative enzymes (P450)
enhance its metabolism
BARBITURATES (CONT.)
Thiopental is highly protein bound (80%), but its great lipid
solubility and high nonionized fraction (60%) account for
maximal brain uptake within 30 sec.
Induction dose affected by:
AGE, SERUM ALBUMIN, BLOOD ACIDITY and VOLUME
STATUS
Methohexital and thiopental have similar distribution
patterns, but methohexital is cleared quicker than thiopental
which accounts for the slightly faster recovery after
anesthesia
QUESTION
Which of the patients described below will require the
smallest induction dose of thiopental?
A. 45 year-old hyperventilating and anxious with
questionable drug abuse history
B. 65 year-old with hx of liver disease who was involved in a
trauma with lots of blood loss
C. 65 year-old with hx of CAD currently on a high protein
diet
D. 22 year-old sickle cell patient who has crackles on exam
after transfusion of 2 units of PRBCs
ANSWER
A. 45 year-old hyperventilating and anxious with
questionable drug abuse history
B. 65 year-old with hx of liver disease who was involved in a
trauma with lots of blood loss
C. 65 year-old with hx of CAD currently on a high protein diet
D. 22 year-old sickle cell patient who has crackles on exam
after transfusion of 2 units of PRBCs
Increased age, Decreased albumin, Hypovolemic and
Acidotic
BARBITURATES PHARMACODYNAMICS
The sedation for anesthesia is achieved through the action at
the reticular activating system
Suppress transmission of excitatory neurotransmitters and
enhance transmission of inhibitory transmitters
They work at the synapse by either limiting neurotransmitter
release or stereoselectively interacting with postsynaptic
receptors
BARBITURATES (CONT.)
CARDIAC – smaller depressant effects than propofol,
depress the medullary vasomotor center and decrease
sympathetic outflow
Negative ionotropic effects are usually masked by
baroreceptor-mediated reflexes like increased heart rate
RESP – decrease tidal volumes and decrease rate
Blunt response to hypercarbia and hypoxia
Induction doses will cause apnea
Not as good as propofol for facilitating airway
instrumentation
BARBITURATES (CONT.)
CEREBRAL – A good choice for neurosurgical cases
because they are potent cerebral vasoconstrictors and
decrease CBF, CMRO2 and ICP
Provide neuroprotection from focal cerebral ischemia (not
global)
Increasing doses decrease CMRO2 to a point where there is a
flat line on the EEG
Methohexital does not have this isoelectric effect, in fact, it
activates epileptic foci and is used in surgery aimed to ablate
epileptic foci
NO ANALGESIC PROPERTIES! In fact, it may lower the pain
threshold
QUESTION
In which scenario would a barbiturate not offer
neuroprotection for the patient?
Cerebral Ischemia resulting from…
A. Acute cerebellar stroke
B. Clips used during aneurysmal surgery
C. Cardiac arrest
D. Surgical retraction
ANSWER
Cerebral Ischemia resulting from…
A. Acute cerebellar stroke
B. Clips used during aneurysmal surgery
C. Cardiac arrest
D. Surgical retraction
This is an example of global ischemia
THIOPENTAL VS PROPOFOL
“(Propofol)… resulted in a significantly quicker
recovery and an earlier return of psychomotor
function as compared with thiopentone and
midazolam irrespective of the agent used for
maintenance of anaesthesia.”
BENZODIAZEPINES
Benzodiazepines are used for premedication, IV sedation,
induction of anesthesia and suppression of seizure activity
The structures of commonly used benzodiazepines and their
antagonist flumazenil share a seven-member diazepine ring
The benzene ring adds to the lipophilicity
BENZODIAZEPINESKINETICS
Diazepam is quite lipid soluble and rapidly penetrates the
blood-brain barrier
Midazolam is water-soluble, but its imidazole ring closes at a
physiological pH making it highly lipophilic
Lorazepam is only moderately lipophilic, why it has slower
onset and recovery
Collectively they are slower in onset and recovery than
thiopental
BENZODIAZEPINESKINETICS
Benzodiazepines are metabolized in the liver into watersoluble glucuronides that are excreted by the kidneys
Midazolam and diazepam have similar distribution patterns,
but midazolam has a significantly shorter half-life (2 hrs) than
diazepam (30 hrs) because of its high hepatic extraction ratio
But the same holds true for the benzodiazepines as with the
other anesthetics, the termination of their action is
dependent on re-distribution and not metabolism
BENZODIAZEPINESDYNAMICS
Like barbiturates, benzodiazepines also
activate GABAa receptor complexes
and enhance Cl- current to
hyperpolarize neurons and effectively
reduce their excitability
Benzodiazepines have their own
specific binding site on GABA receptors
and midazolam has a twice greater
affinity for these receptors than
diazepam
GABA receptors responsive to
benzodiazepines are almost exclusively
located on post-synaptic nerve endings
in the cerebral cortex minimal
depressant effects on ventilation and
blood pressure
BENZODIAZEPINES (CONT.)
CARDIAC – minimal depressant effects, HR occasionally rises
RESP – usually minimal depressant, but can cause apnea but usually in
the presence of opiates
Produces decreased response to carbon dioxide
CEREBRAL – like barbiturates, they decrease CBF and CMRO2, but to a
smaller extent
Midazolam unable to produce isoelectric EEG, suggesting a ceiling effect
to their decreases in CMRO2
Minimal effect on ICP, no neuroprotective qualities
AS AN INDUCTION AGENT?
Rarely used for induction, but you can use a dose of 0.1-0.3
mg/kg
Onset of induction is slower than other induction agents
Appears on paper to have a better organ system profile with
less cardiac and respiratory affects, but it is unlikely it offers
any advantage over the other induction agents
OPIODS
Class of drugs known
for their analgesic
effects
Classified as
anesthetics because of
their sedative qualities
OPIODS - KINETICS
Fentanyl and Sufentanil have the highest lipid solubility leading
to quick onsets and quick recoveries (5-20 minutes)
Even though it has less lipid solubility, alfentanil is quicker in
onset than fentanyl and sufentanil
Redistribution terminates the action of all opiods, however large
doses must depend on biotransformation to adequately lower
plasma levels
Biotransformation takes place in the liver and since they all
have a high extraction ratio, clearance depends on hepatic
blood flow
OPIODS (CONT.)
Remifentanil has a unique ester structure makes it susceptible
to ester hydrolysis in the blood
This extrahepatic metabolism is so rapid and complete that the
duration of remifentanil infusion infusion has little effect on
wake-up times
Its context sensitive half time (time required for the plasma
concentration to decline by 50% after termination of infusion) is
3 minutes regardless of the duration of infusion
Remifentanil is therefore an excellent choice as a continuous
infusion
OPIODS
CARDIAC – minimal direct effects, but the release of
histamine leads to decreses in SVR and blood pressures
Meperidine is similar in structure to atropine and can cause
increased heart rate
RESP – decrease ventilation, particularly respiratory rate
Elevated apneic threshold (CO2 level at which they breathe)
Fentanyl, sufentanil and alfentanil increase chest wall rigidity
that is responsive to neuromuscular blocking agents
Histamine can also cause bronchospasm
OPIODS
CEREBRAL – variable effects on ICP and CPP, reduce
CMRO2 and ICP in general, but to a lesser extent than
barbiturates or benzodiazepines
Stimulation of the CTZ is responsible for the high incidence
of nausea/vomitting
G.I. – slows gastric emptying and sounds a lot like an internal
medicine problem
ENDOCRINE – block the hormones associated with the
stress response, may be beneficial to patients with heart
disease
QUESTION
Propofol:
a.Has a faster onset-time for hypnosis than thiopental.
b.Has a longer context-sensitive half-time than fentanyl after a 1 h
infusion.
c.Has a higher clearance than alfentanil.
d.Is suitable for infusions of long duration because it has a large
volume of distribution at steady state.
e.Has a clearance that is greater than hepatic plasma flow.
QUESTION
. Alfentanil:
a.Reaches steady-state more rapidly than fentanyl using a constant
infusion rate.
b.Is less lipid soluble than fentanyl.
c.Has a faster onset-time than propofol because it has a lower pKa.
d.Has the same context-sensitive half-time after an infusion of 2 h as
after an infusion of 6 h.
e.Administration can be through a commercially available targetcontrolled delivery device.
KETAMINE
A derivative of PCP and 10 times less potent, it differs from
other anesthetics in it stimulating effects on the organ
systems and the analgesia it provides
The R-(-) isomer is the most potent stereoisomer and all
formulations in the U.S. are only available as racemic
mixtures
KETAMINE-KINETICS
High lipid solubility ensures
rapid onset
Termination of effects occur
first as the result of
redistribution to other
inactive tissues and then
metabolized in the liver by
P450
Ketamine has very low
protein binding (12%)
KETAMINE-DYNAMICS
Major effect of ketamine is through the inhibition of the
NMDA receptor complex
After induction of ketamine, patients go into a cataleptic state
where their eyes are open and a slow, nystagmic gaze is
present
Frequently increases lacrimation and salivation, should pretreat with an anticholinergic like glycopyrrolate
No amnestic qualities, will need to supplement with
midazolam if used as sole anesthetic
KETAMINE-DYNAMICS
Significant analgesic properties
Emergence from ketamine may include vivid dreams,
hallucinations, out of body experiences along with an array
of distorted senses (visual, auditory, tactile)
Patients can either experience fear or euphoria
Children have a decreased incidence of these emergent
reactions
KETAMINE (CONT.)
CARDIAC – produces transient increases in systemic blood
pressure and heart rate through sympathetic stimulation
However, it also is a direct myocardial depressant…only
shows in a critically ill patient
RESP – does not produce respiratory depression
Response to hypercarbia remains intact
Protective airway reflexes remain intact
Relaxes bronchial smooth muscle
Beware, kids can still get laryngospasm on ketamine
KETAMINE (CONT.)
CEREBRAL – Ketamine is not to be used for someone with
intracranial pathology as it increases CBF, increases CMRO2
and increases ICP
However, it can be used as an anticonvulsant
…Ultimately, ketamine is an important alternative because of
its desirable cardio and respiratory effects while also
providing analgesia by different routes, but its regular use is
prohibited by emergence reactions
ETOMIDATE
Etomidate is a hypnotic with no analgesic properties and
minimal hemodynamic effects
Structurally unrelated to other anesthetics, but behaves very
similar to barbiturates
Etomidate contains a carboxylated imidazole ring
Prepared in propylene glycol, causes pain on injection
ETOMIDATE-KINETICS
Only available as IV, bypasses absorption
Highly protein-bound, but still characterized as a very rapid
onset of action due to its high lipid solubility and large
nonionized fraction at physiological pH
Redistribution is responsible for decreasing the plasma
concentration to awakening levels
Shorter half-life than thiopental because of its clearance
ETOMIDATE-DYNAMICS
Depresses the reticular activating system and mimics the
inhibitory effects of GABA
Unlike barbiturates, it has disinhibitory effects in the
extrapyramidal motor area leading to myoclonus at a rate of
30-60%
PONV more than common than seen with a barbiturate
induction
ETOMIDATE (CONT.)
CARDIAC – Produces minimal, if any, changes in heart rate
and cardiac output with a slight decrease in systemic blood
pressure
Contractility remains the same
No histamine release
ETOMIDATE (CONT.)
RESP – ventilation is affected less with etomidate than with
barbiturates or benzodiazepines
Induction doses do not result in apnea unless given with
opiods
CEREBRAL – decreases CBF, CMRO2 and ICP to SAME
EXTENT as thiopental
CPP remains constant because cardiac function is well
perserved
Changes on EEG resemble those of barbiturates, however,
the one difference is their enhancement of SSEPs
SO WHY IS IT NOT USED…?
First off, we never have it…
Second off, and probably more relevant, it causes
adrenocortical suppression
Induction doses transiently inhibit enzymes involved in
cortisol and aldosterone synthesis (11-beta hydroxylase)
The suppression only lasts 4-8 hours, difference in opinion
as to whether there is an increased mortality rate
DEXMEDETOMIDINE
Selective alpha-2 agonist and primarily used for ICU sedation
or as an adjunct during general anesthesia or for sedation
during awake fiberoptics
Observations of patients who took clonidine revealed the
decreased amounts of anesthetic that were required, so now
it is part of our anesthetic arsenal
DEXMEDETOMIDINEKINETICS
Very water soluble
Rapid hepatic metabolism
A relatively high context
sensitive half time,
surprisingly
DEXMEDETOMIDINEDYNAMICS
Hypnosis presumably results from stimulation of alpha-2
receptors located in the locus ceruleus
Analgesic effect results from alpha-2 stimulation in the spinal
cord
The sedation created by dexmedetomidine is a different
quality as it more resembles sleeping as it activates
endogenous sleep pathways
Tolerance and dependence develop as seen with clonidine
DEXMEDETOMIDINE (CONT).
CARDIAC – infusion produces moderate decreases in heart
rate and SVR with a subsequent decrease in blood pressure
However, when given as a bolus it will produce transient
increases in blood pressure and pronounced decreases in
heart rate
Bradycardia can be significant enough to require treatment
RESP – moderate decrease in tidal volumes
CEREBRAL – decrease CBF, no significant effects on CMRO2
or ICP
DROPERIDOL
A dopamine receptor antagonist, affecting the caudate
nucleus and chemoreceptor trigger zone (similar to haldol)
Commonly used for PONV, it garners classification as an
anesthetic for its activity in the CNS and its tranquilizing
effects
DROPERIDOL (CONT.)
CARDIAC – mild alpha adrenergic blocking effects lead to
vasodilation
Associated with prolongation of QT, must have an EKG
before administering (>440ms is contraindication)
Can induce catecholamine release, DO NOT USE WITH
PHEOCHROMOCYTOMA
CEREBRAL EFFECTS -Extrapyramidal reactions
-Makes them apprehensive and fearful
-Decrease CBF and ICP, but not CMRO2
COMPARISON OF PROFILES
Dose
Duration
Vd
Distribution Protein Clearance Elimination
Propofol
1-2.5
3-8
2-10
2-4
97
20-30
4-23
Thiopental
3-5
5-10
2.5
2-4
83
3.4
11
Methohexital
1-1.5
4-7
2.2
5-6
73
11
4
Midazolam
0.1-0.3
15-20
1.1-1.7
7-15
94
6.4-11
1.7-2.6
Diazepam
0.3-0.6
15-30
0.7-1.7
10-15
98
0.2-0.5
20-50
Lorazepam
0.03-0.1 60-120
0.8-1.3
3-10
98
0.8-1.8
11-22
Ketamine
1-2
5-10
3.1
11-16
12
12-17
2-4
Etomidate
0.2-0.3
3-8
2.5-4.5
2-4
77
18-25
2.9-5.3
N/A
2-3
6
94
10-30
2-3
Dexmedetomidine N/A
CONCLUSION
Quickest onset and recovery?
GABA? NMDA? Alpha 2? Opiod?
Biggest cardiac depressent?
Biggest respiratory depressant?
Most neuroprotective?
REFERENCES
Comparative Study Between Three Intravenous
Drugs:Thiopentone Sodium, Propofol and Midazolam:Study of
100 Cases and Critical Review. S K Mondol1, M A Rahim 2, TAJ
June 2007; Volume 20 Number 1
Ronald D. Miller 2000 5th edition Anaesthesia
Clinical Anesthesiology - G. Edward Morgan; Maged S. Mikhail;
Michael J Murray. 2005-08-26