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Anesthetics and adjuvants
Tom Archer, MD, MBA
UCSD Anesthesia
Many Ways to Skin A Cat
• No “best anesthetic” by
outcome measures.
• We want to achieve
hypnosis, amnesia,
analgesia, immobility and
autonomic stability.
• “Synergy” takes
advantage of multiple
agents.
• So: “Garbage anesthesia”
is OK!
Drugs vs. the human touch
• The best “tranquilizer” or “sedative” may be your
calm, reassuring and informative presence!
• Don’t forget the power you have to set the
patient at ease.
• Take the time, and don’t be afraid to make
human contact with your patients.
• The “solution” is not always a drug.
Broad Themes (1)
• Tailor the anesthetic to the patient’s needs,
preferences and co-morbidities. Make use of
“side effects” of our drugs.
• Regional vs. general
• Pre-emptive analgesia
• Synergy (“garbage anesthesia”)
Broad Themes (2)
• Receptor model of drug action: NMDA, GABA,
Ach, opioid, norepinephrine, dopamine,
glycine…
• Receptors open ion channels (Na+ or Cl-),
thereby promoting or inhibiting action potential
formation.
• Agonists, modulators and antagonists at
receptors (NMDA, GABA, alpha, beta, Ach,
Broad Themes (3)
• Direct vs. indirect drug actions.
– Example:
• N2O, ketamine and desflurane are DIRECT
myocardial depressants, but…
• They usually cause cardiovascular stimulation
because of sympathetic stimulation.
Regional Anesthesia
• Many people would like to believe that
regional is “safer” or “better” than GA, but
there is no evidence for this in terms of
mortality and major morbidity (except in
OB?).
• So: Tailor anesthesia to individual needs,
preferences and clinical situation, and do
what you do best!
“Preemptive Analgesia”
• Can we prevent “sensitization” to pain, via
regional, ketamine or methadone, and
thus diminish post-op pain?
• Controversial area with some evidence in
favor of regional, and ketamine and
methadone, both of which block NMDA
receptors.
Synergy
• Use two or more agents to avoid large doses
(and significant undesired side effects) of any
single agent.
• Examples:
–
–
–
–
propofol and fentanyl
opioid and NSAIDs
volatile agent and non-depolarizing NMB agent
benzodiazepine, barbiturate and ethanol
Synergy– How does it work?
Synergy means that agonist effects are multiplicative.
Effect of propofol and fentanyl depends on the product of
the concentrations.
“Fentanyl Neuron”
Pain Response:
Inhibition
Movement
“Pain Neuron”
Inhibition
“Propofol Neuron”
“Ouch!!”
Hypertension,
Tachycardia
"Isobologram": Propofol and Fentanyl Concentrations Which
Prevent 50% of Rats From Moving in Response to Tail Clamp
14
Fentanyl Concentration
12
10
8
Series1
6
4
2
0
0
2
4
6
8
Propofol Concentration
10
12
14
Synergy
• Drug Effect = [Drug A] X [Drug B]
• Mathematically this is a hyperbola.
So, let’s rejoice in the diversity of
our pharmacology!
• Multiple drugs imply danger and / or
benefit of drug interactions.
• Anesthesiologists routinely use drugs
synergistically– on purpose.
Using synergy and the concentration– response curve to
get the effects we want– sedation, paralysis, analgesia, etc.
Surfing the Concentration-- Response Curve
Response (paralysis, respiratory rate, sleepiness, etc.)
120
100
80
60
Series1
40
20
0
0
2
4
6
8
Drug Concentration
10
12
14
16
How do receptors influence nerve
activity?
• A nerve cell integrates the input of the
cells which impinge upon it.
• Nerve cell responds to its “constituents.”
• Drugs “stuff the ballot box” by
predisposing nerve cells to fire (EPSP) or
not fire (IPSP).
Fig. 48.12
Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings
“Ligand- gated ion channels”: opened by GABA,
NMDA, acetylcholine, glycine or serotonin binding
to their receptors.
• Summation: graded potentials (EPSPs and
IPSPs) are summed to either depolarize or
hyperpolarize a postsynaptic neuron.
Fig. 48.14
Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings
Example: Ligand NMDA opens Na+ channels, depolarizing the
nerve cell body and promoting action potential formation:
the vote is “pain!” or “awaken!”
NMDA Receptors
• When activated, they open and allow Na+ to
depolarize the nerve cell membrane, promoting
pain perception.
• Ketamine, phencyclidine (“Angel Dust”) and
Mg++ block these Na+ channels in the NMDA
receptor.
• Clinically ketamine blocks pain transmission and
Mg++ is an anticonvulsant.
Example: GABA receptor opens an inhibitory Cl- channel.
Benzodiazepines, barbiturates and ETOH
“turn up the gain” (modulate) the GABA receptor’s function.
GABA Opens Cl- Channels, Hyperpolarizing the Nerve Cell
Body and Inhibiting Action Potential Formation: The Vote is
“No Pain!” or “Sleep!”
Benzodiazepines, barbiturates
and ethanol work synergistically
on the GABA receptor to cause
sleep and amnesia.
IV anesthetics– broad themes
• Pain on injection (propofol, etomidate).
• Excitement / movement as patient falls
asleep (etomidate, methohexital).
• Hemodynamic effects (direct and indirect,
on stroke volume, contractility, heart rate
and systemic vascular resistance).
• Tailor induction agent to the situation: eg,
What do you use in a hypovolemic,
hypertensive or asthmatic patient?
IV anesthetics– broad themes
• In general– watch your dose to avoid problems.
Use– and be afraid of-- synergy.
• IV induction agents can affect stroke volume,
heart rate, contractility and systemic vascular
resistance.
• We don’t usually measure CO, SVR (except with
LIDCO!).
• BP knocked down by:
– Propofol > Pentothal > Midazolam > Etomidate >
Ketamine.
Opioids– themes
• Very common drugs and very complex
mechanisms of analgesic action.
• Close the “gate” in spinal cord, both by
direct action in the substantia gelatinosa of
dorsal horn and by activating inhibitory,
descending pathways.
Opioids work within dorsal horn of spinal cord and
by activating descending inhibitory pathways
Opioid activates
descending,
inhibitory
pathways
Opioid directly closes
gate in dorsal horn
Painful
stimulus
The “gate”
Opioids-- themes
• Analgesia without (much) sedation.
• Respiratory “depression”– rate decreased
>> tidal volume (TV is maintained). Slow,
deep, “narcotized” respiration.
• Decreased cough reflex (tolerance to
ETT). “Eight is great” for analgesia and
tolerating ETT.
Opioids-- themes
• Nausea, urinary retention, itching and
constipation. Memorize these.
• Histamine release: Demerol / MS >>> fentanyl /
remifentanil / alfentanil / sufentanil. Histamine
can cause decrease in BP due to vasodilation.
Histamine also causes itching.
• Narcotics (except meperidine) can increase
vagal tone --->
– bradycardia
Opioids-- themes
• “Multi-modal analgesia”: other words for
“synergy”: opioid, NSAID or
acetaminophen, and local. Patient is
comfortable (until she gets home!)
Opioids
• No effect on myocardial contractility.
Hence, MS used for high risk cardiac
surgery beginning in the late 1960’s.
• Fentanyl (and congeners) have largely
replaced MS as primary “anesthetic”
narcotic.
Opioid Antagonists
• Titrate Naloxone to Effect. 20-40
micrograms at a time. Amp has 400 mcg.
Other antagonists
• Atropine (Ach antagonist) blocks Ach effect on muscarinic receptors
(heart) without affecting Ach effect at nicotinic receptors
(neuromuscular junction and sympathetic ganglia). Atropine (and
scopalomine) enter CNS, but, IMHO, danger of delirium from
modest doses of atropine is over-rated. For severe bradycardia,
please use atropine– and fast!
• Neostigmine (anticholinesterase) increases Ach present at
muscarinic and nicotinic receptors. Does not enter CNS.
• Physostigmine (anticholinesterase which enters CNS) will reverse
“central anticholinergic syndrome” due to atropine or scopalomine.
• Flumazenil will reverse benzodiazepine effect on GABA receptor.
Remember: benzo “receptor” is part of GABA receptor.
PONV
• “Multi-modal” approach– SYNERGY!
• 5HT blocker, dexamethasone and droperidol.
Danger of droperidol is VASTLY overrated!
VERY little risk at doses equal or less than
1.25mg.
• Hydration
• Oxygen? (effect on gut?)
PONV
• Propofol
• Limit Opioids.
• Avoid N2O? I use N20 a lot.
• I am liberal with antiemetics.
Local Anesthetics
Structure of LAs: Lipophilic, Linkage and
Hydrophilic Parts of Molecules:
Ester
Amide
Amides and Ester LAs,
Ionized (BH+) and Unionized (B) Forms
B Form Crosses Membrane,
BH+ Forms Plugs Na+ Channel
LA Speed of Onset
• Quantity of B (non-ionized form).
• Adding bicarbonate takes H+ away from
BH+, forming B. B crosses cell membrane
faster than BH+.
• BH+ blocks Na+ channels from the inside
of the nerve axon.
Toxicity to LAs
• LAs block Na+ channels in inhibitory nerves in the brain  CNS excitement.
• Seizures occur before cardiac depression.
• LAs block Na+ channels and depolarization (conduction)
in heart muscle and electrical tissue- reduced
contractility and SA and AV heart blocks.
• Also block Na+ channels in smooth muscle arteriolar
tissue - vasodilation.
Susceptibility to Blockade with LAs
• Sympathetic > Pain / Temperature >
Proprioception > Touch and Pressure >
Motor. My opinion: test block with ice, not
pin.
• Absorption rate: IV > Tracheal >
Intercostal > Caudal > Rest of Epidural
Space > Brachial Plexus > Leg Blocks >
Subcutaneous
LAs Don’t Work Well in Infected
Tissue– Why?
• Infected Tissue is Acidic.
• BH+ Form Predominates. Can’t Cross
Nerve Cell Membrane.
Allergy to LAs
• Very, very rare with amides. Amides have two
“i”s in their names, e.g. lidocaine.
• More common with esters, but still rare. Esters
have one “i” in their names, e.g. procaine.
• Preservatives can cause allergy– when in doubt,
use preservative free solutions.
• Epinephrine in dentist’s office is most common
cause of “allergy” (palpitations, fear, tinnitus).
Metabolism of LA’s
• Esters– plasma cholinesterase (just like
Sux and mivacurium).
• Amides-- liver
Plasma cholinesterase
• Metabolizes succinylcholine (Sch), mivacurium,
ester LA’s.
• Inhibited by neostigmine (anticholinesterase).
• If you give Sch after neostigmine– you can get
prolonged Sch block due to inhibition of plasma
cholinesterase by neostigmine.
Gaseous Anesthetics
What’s the difference between
“gaseous” and “volatile”
anesthetics?
“Gaseous” vs. “volatile”
• Ether, halothane, sevoflurane, desflurane,
isoflurane, etc. are gaseous and volatile. Volatile
agents are liquids which evaporate.
• N2O is gaseous but not volatile, since N2O is a
gas at room temperature.
• The gaseous form of a substance that is
primarily liquid at room temperature is a “vapor.”
We use the vapors of volatile agents.
MAC
(minimum alveolar concentration)
• MAC is a partial pressure (not a %!). MAC
as a % varies with atmospheric pressure.
• MAC = k x O/G. Site of GA action is
probably lipid.
• Lipid solubility also determines potency of
LAs. Site of LA action is probably lipid.
Solubility (blood-gas partition coefficient) of
inhaled agents in water inversely correlates
with rate of rise of alveolar concentration.
Low Blood / Gas Partition Coefficient (Low Solubility of Gas in Water)
Causes “Quick-On and Quick-Off” Effects of Desflurane and
Sevoflurane
Agent Relatively Insoluble in Water (Blood and Tissue)—Little Uptake by Tissues,
Rapid Rise of Fa- Fi. Examples: N2O, desflurane, sevoflurane,
Water (Blood or
Tissue)
Alveolar Gas
Desflurane
Desflurane
FA / FI (N2O and desflurane) at
UTHSCSA
FA / FI for N2O and desflurane
1.20
1.00
FA / FI
0.80
Fe/Fi N2O
0.60
Fe/Fi Des
0.40
0.20
0.00
0
2
4
6
8
10
Minutes
12
14
16
18
High Blood / Gas Partition Coefficient (High Solubility of Gas in Water)
Causes “Slow-On and Slow-Off” Effects of Isoflurane, Halothane and
Diethyl Ether.
Agent Highly Soluble in Water (Blood and Tissues)—Much Uptake by Tissues, Slow Rise of Fa - Fi.
Examples: Isoflurane or Halothane or Ether.
Alveolar Gas
Water (Blood or
Tissue)
Halothane
Halothane
FA / FI at UTHSCSA
(N2O and isoflurane)
FA / FI for N2O and isoflurane
1.2
1
FA / FI
0.8
Fe/Fi N2O
0.6
Fe/Fi Iso
0.4
0.2
0
0
2
4
6
8
Minutes
10
12
14
16
Volatile Anesthetics (Ethers)
• Isoflurane (I), Desflurane (D) and
Sevoflurane (S) all decrease SVR.
• Reflex (compensatory) increase in heart
rate and CO.
• BP falls, since SVR decreases more than
CO increases.
Volatile Anesthetic: Desflurane
• Desflurane causes sympathetic activation
at >6%. Tachycardia and hypertension.
• Irritates larynx (and bronchi?). Causes
cough at high concentration.
Volatile Anesthetic: Sevoflurane
• Non-irritating. Great for inhalation
induction (has replaced halothane).
Volatile Anesthetic-- Halothane
• Halothane (alkane) decreases HR, contractility
and SVR.
• Decreased CO and BP
• Sensitizes myocardium to arrythmogenic effect
of epinephrine.
Volatile Agents (not N2O)
• Act synergistically with (“potentiates”) NMB agents.
• This attribute is VERY useful clinically– we can use less
NMB agent and reverse it more easily.
• DON’T overdo the NMBs (especially when you go into
practice.)
• “Relaxation does not necessarily require relaxant.” Use
propofol, hyperventilation, deeper volatile agent, flex
table, etc. Please remember this! It will make your life
much more pleasant.
Neuromuscular blocking agents
(NMBs)
• Also potentiated by, Mg++, aminoglycosides,
cold, acidosis.
Parting thought
• Use synergy!
• Use your heart and your personality!
• Be careful out there.
• Vigilance!
The End
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