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Anesthesia

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Triad of Anesthesia
Amnesia, relaxation, and Analgesia
Loss of perception of entire body
General Anesthesia
Loss of sensory perception over a specific part of the body
Regional Anesthesia
Loss of sensory perception over a small area of the body
Local Anesthesia
Three phases of anesthesia
induction, maintenance, emergence
4 components of anesthesia*
analgesia, unconsciousness, amnesia, and muscular relaxation
Analgesic regimens that employ a VARIETY OF AGENTS in small doses to block pain perception at different sites in the peripheral and central nervous system
multimodal (targeted) analgesia
Using multimodal analgesia in post op pain management results in ...
better analgesia with a concomitant reduction in adverse effects.

Also, faster recovery
Is rehab a component of multimodal therapy?
yes
All local anesthetics end in ...
-caine
First synthetic ester agent (local anesthetic)
procaine

tetracaine and chloroprocaine
First synthetic amide agent (local anesthetic)
Lidocaine - quickly replaced the esters due to being more stable, less toxic, less allergic potential

mepivacaine and bupivacaine
Local anesthetics are (weak/strong) (acid/base)
weak bases
What is the basis for classification of a local anesthetic as an ester or an amide?
Nature of the intermediate chain
The local anesthetic structure consists of a ..... separated from a ..... by an intermediate chain including either an ester of amide linkage
Aromatic benzene ring (lipophilic)

tertiary amine (hydrophilic)
local anesthetic amino amides*
Lidocaine, etidocaine, prilocaine, mepivacaine, ropivacaine, bupivacaine

notice the (i) in all of them
local anesthetic amino esters
procaine, 2-chloroprocaine, tetracaine
What is the MOA of local anesthetics?
They inhibit the action potential excitable cells (neurons and cardiac myocytes)

specifically, they work at the membrane bound voltage gated Na channels
.... forms of LAs block .... at the (alpha/beta) subunit on the (extracellular/intracellular) side*
charged/ protonated

Na channels

alpha subunit

intracellular

(notice the difference in pH)
Local anesthetics bind the alpha subunit on the intracellular membrane, thus inhibiting the .... influx associated with membrane depolarization*
Na+ influx
LAs have greatest affinity for Na channels in the (resting/open,active/inactivated) states*
open and inactivated
Binding of LAs is facilitated by ...
depolarization and frequency of depolarization
LAs bind more to neurons that fire (more/less) rapidly
more rapidly

membrane depolarization causes a conformational change in the Na channel, converting it to an open state. Na rush into the open pore. Then the channel goes into inactive state.
That LAs inhibition is both voltage and frequency dependent with greater binding occurring in nerve fibers that are firing more rapidly is known as*
Use Dependent Block
Resting membrane potential to depolarization in neuron
-70mV to +35mV
Does the Action Potential take place with a LA? Does binding alter the resting membrane potential?
No, AP is not met so there is no depolarization

No, LAs do not alter the resting membrane potential
What is sensitivity to local anesthetics determined by?

Comparing nerve fibers of the same type, does small or large diameter increase sensitivity to LAs?

with or without myelin?
axonal diameter and myelination

small

myelinated
Rank these for LAs inhibition:

autonomic, motor, sensory
A > S > M
Potency correlates with a LAs ability to do what?*
permeate lipid membranes (lipid solubility)
What factors affect potency?
fiber size, type, myelination, pH, frequency of nerve stimulation, electrolyte concentration
How does acidic pH affect potency?
Antagonizes
How does hypokalemia and hypercalcemia affect potency?
Antagonize
What is the most potent (most lipid soluble) LA?
Bupivacaine
What does duration correlate with?
Potency and Lipid Solubility
Highly lipid soluble LAs have a (longer/sorter) DOA secondary to slow diffusion from lipid rich environments to the bloodstream
longer
lipid solubility correlates with what?
plasma protein binding
Greater protein binding means that the LA will work (longer/shorter)
longer
What Plasma protein do LAs mainly bind?
alpha-1 acid glycoprotein
Degree of protein binding determines
Duration of action
Local anesthetics onset correlates with
lipid solubility and pKa
pH at which the fraction of ionized and non-ionized drug is equal
pKa
Clinically, what does bicarbonating LAs do? When is this important?
It speeds up onset.

Diffuse epidurals for vaginal births (have sensory/pain relief, but can still push) that have to go to C-section. For emergency C section, time is critical, if you add bicarbonate to the LA, you can have the perfect block and have a C section without having to put the patient to sleep and without having to worry about intubating
What does adding epinephrine to an LA do?
It can double the DOA (more so with lidocaine and not with bupivacaine due to different MOAs)
Epinephrine added to LA block given on finger or penis can cause what complication?
ischemia or other injury due to epi causing vasoconstriction
Do moist mucus membranes or intact skin cause more rapid absorption of LA when placed directly on the skin?
mucus membranes (intact skin will require a higher concentration)
EMLA cream contains what?
1:1 5% Lidocaine 5% prilocaine in an oil in water emulsion
How long does EMLA take to achieve anesthesia for peripheral line placement?
1 hour
What are the contraindications of EMLA?
mucus membranes, broken skin, infants younger than 1 month, patients with predisposition for methemoglobinemia
What is absorption of injected LAs dependent on?
blood flow
What factors will affect the absorption of injects LAs?
site of injection, presence of vasoconstrictors, and local anesthetic agent
Site of injection: Which has the highest to lowest levels of blood flow?*
Intravenous, trachea, intercostal, caudal, epidural

Remember: IT ICE
Presence of Vasoconstrictors: Addition of Epinephrine to LAs causes what?
Vasoconstriction, which causes the decreased systemic absorption (has more pronounced effect on shorter acting agents)
local anesthetic agent: more lipid soluble agents are more (slowly/quickly) absorbed when injected
slowly
Distribution depends on
organ uptake
Factors that affect organ uptake (distribution)
Tissue perfusion, tissue/lipid partition coefficient, tissue mass
Tissue Perfusion:

Highly perfused tissues are (alpha/beta) phase

Moderately perfused tissues are (alpha/beta) phase
alpha (rapid uptake) -brain, lung, liver, kidney, heart

beta (slower uptake) - muscle and gut
Tissue/lipid partition coefficient:

Lipid solubility is associate with what?
greater plasma protein binding and tissue uptake
Tissue mass:

What provides the greatest reservoir for the distribution of LAs?
muscle
Biotransformation and Excretion of LAs are defined by
their chemical structure
What metabolizes LA amides and where does it take place?
P450 in the liver (prilocaine is the fastest and bupivacaine the slowest)
What is prilocaine metabolized to?* What can this lead to?
metabolized to o-toluidine, and can lead to methemoglobinemia
The metabolism of benzocaine can also lead to methemoglobinemia. What is it treated with?
intravenous methylene blue, which reduces methemoglbin Fe+++ to Hemoglobin Fe++
Is metabolism of LA amides slower or faster than metabolism of LA esters?
slower
LA esters metabolized by
pseudocholinesterase
Procaine and bezocaine are metabolized to
p-aminobenzoic acid (PABA)

associated with rare anaphylactic reactions

Ester hydrolysis is very rapid and metabolites are excreted in the urine
Does CSF have esterase enzymes?
no, have to wait till redistribution into blood stream
How is cocaine metabolism different from other ester anesthetics?
Partially metabolized in the liver and partially excreted unchanged in the urine
LAs have toxicity for the
CNS and Cardiovascular
Symptoms of LA toxicity lead to
cardiac arrest

the main reason we don't want LA to be intravascular (we use much safer LAs now, so if the drug does go Intravasuclar, the PT won't be injured)
What is a life saving treatement for LA toxicity and how does it work?
Lipid Emulsion Therapy lowers the levels of LAs by drawing lipophilic substances into "lipid sink" which develops a concentration gradient between tissue and blood
Ropivacaine is what type of enantiomer?
S (-)

This enantomer shows a significant reduction in CNS and Cardiac Toxicity
What was ropivacaine developed to replace?
bupivacaine, which contains an R(+) enantiomer (and is a racemic mixture of S(-) and R(+)), has high CNS and Cardiac toxicity

Ropivacaine is what is used in the hospital
Long acting bupivacaine (EXPAREL), has prolonged analgesic effects for up to*
72 hours (as opposed to 8)

Commerically called
What drug is a pure S (-) enantiomer?
naropin
What are the indications for Neuromuscular Blockade (NMBD) aka muscle relaxant drugs in the clinic?*
facilitates intubation, provides muscular relaxation during surgery, facilitates artificial ventilation
Do NMBDs produce analgesia? amnesia? anesthesia?
no, they produce paralysis
Describe the neuromuscular transmission process
Neuromuscular junction is between the motor neuron and muscle cell

AP depolarizes the terminal causing and influx of Ca ions through voltage gated channels that causes the release of ACh which diffuses along the synaptic cleft

Binds to nicotinic cholinergic receptors on the motor end place which causes change in the membrane permeability to ions (Na+ in and K+ out)
Cholinergic receptors are either
nicotinic or muscarinic
Interruption of nerve impulses at the neuromuscular junction is produced in one of two ways, what are they?*
Preventing the action of acetylcholine (D-tubocurarine, metocurine, pancurioium, vecuronium, gallamine - nondepolarizers are competitive antagonists)

depolarizing the receptor (succinylcholine, decamethonium)
What is the only depolarizer used clinically?*
Succinylcholine
Do you need to reverse succinylcholine activity? What hydrolyzes it?
No, it is rapidly hydrolyzed in the plamsa by pseudocholinesterase.

(You only have to reverse non-depolarizers which can sit and work from 20 mins to hours)
What is the NT at the neuromuscular junction?*
Acetylcholine, a quaternary ammonium ester
What are the nicotinic effects of Ach?*
autonomic ganglia and SK stimulation
What are the muscarinic effects of Ach?*

Why is this important?
Myocardium causes heartbeat to slow (bradycardia), bronchioles become constricted

Important clinically because when we give reversal of non-depolarizers, we give AchEI, we also give an antimuscarinic drug
What are some of the complications of Succinylcholine?*
fasciculations, low levels of plasma pseudocholinesterase (pregnancy and liver disease), raised intraocular pressue, bradycardia, increase in serum K, TRIGGERING AGENT IN MALIGNANT HYPERTHERMIA
How is Malignant Hyperthermia passed on?
AD inherited myopathy
Malignant Hyperthermia is caused by a defect in what receptor?
Ryanodine receptor, calcium release channel
What does the defect in the ryanodine receptor in Malignant Hyperthermia cause? symptoms?
massive release of Ca2+ from the Sarcoplasmic Reticulum

Hypermetabolic state, muscle rigidity, and acute severe rhabdomyolysis (produce rapidly increasing temp and extreme acidosis)
Early diagnosis and the use of .... have reduced mortality from Malignant Hyperthermia from 70% to < 5%*
dantrolene
Are opioids, non-depolarizing muscle relaxants, propofol, anxiolytics, and NO triggering agents for MH?
no
Are Halothane, Sevoflurane, Isoflurane, desflurane, and succinycholine triggering agents for MH?
yes
What is the main clinical feature of MH?
Marked temperature elevation
How does dantrolene work?*
Inhibits SR calcium release without affecting reuptake
Binds to the post-synaptic cholinergic receptor of the motor endplate and competitively prevent acetylcholine transfer to acetylcholine receptors*
nondepolarizers
How do you reverse a nondepolarizer?*
AchEI (NEOSTIGMINE) with an antimuscarinic (ie GLYCOPYROLATE or atropine)

Atropine is rarely used because it crosses the BRB
What are 3 examples of depolarizers*
Vecuronium, pancuronium, and rocuronium
Selection of muscle relaxant based on what 3 factors?*
Duration of action, cardiovascular effects, and class of muscle relaxant
Muscle relaxants with ultra short (5 min) DOA
succinylcholine
muscle relaxants with short (10 min) DOA
mivacurium
Muscle relaxants with intermediate (30 min) DOA
atracurium, rocuronium, vecuronium
Muscle relaxants with long (1 hour) DOA
tubocurarine, pancuronium, doxacurium, pipecuronium
For rapid intubation, which drug is often used because it can activate so quickly?*
succinylcholine

works in 45 seconds and breaks down in 7.

NOTE: The new drugs we have can inactivate steriodal NMBD in less than 1.5 mins
What is a new non-depolarizer? What are its benefits?
Cis-atracurium

Reduces histamine release, more cardiac stability, organ independent metabolism
What is a side effect of antimuscarinics?
increased HR
What is a new reversal agent that binds to rocuronium or vecuronium and inactivates it in 1.5 minutes?
Sugammadex (a new cyclodextrin)
Does sugammadex work on non-steroidal neuromuscular blockers?
no, only on steroidal
Onset of Blockade begins with (small/large) muscles?*
small: eyes and digits, then muscles of the trunk, then intercostals, and finally diaphragm
Reversal of neuromuscular blockade begins with (small/large) muscles?*
Opposite of onset: diaphragm, then intercostals, then muscles of the trunk and abdoment, then eyes and digits

NOTE: Consciousness and sensorium remain undisturbed
What is involved in the reversal of the neuromuscular blockade?
AchEI prevents breakdown of Ach, competitive inhibition of neuromuscular blockade, but this can cause unwanted side effects at muscarinic and nicotinic receptors so you have to use an antimuscarinic like atropine and glycopyrolate
How does an anesthesiologist measure clinically how paralyzed the patient is?
Electrical twitch monitors
How do anesthesiologists determine how much drug to give?*
Use dose in which 95% of receptors are blocked (ED95)
If you are not completely paralyzed, a typical twitch monitor, which uses 4 electrical pulses, will cause what to happen?
Thumb will move
What is the problem with the twitch monitor?
You can have 4/4 twitches and still have 2/3 receptors blocked
How do you determine if someone is completely recovered?
Sustained motor activity for 5-10 seconds (lift head, squeeze finger) - this is more sensitive than twitch
What are three methods for monitoring neuromuscular blockade?*
single twitch (determines degree), tetanus (adequacy), and train of four
What is the technical assessment of adequacy of neuromuscular blockade?*
Assessment of FADE with 50Hz stimulation over 5-10 seconds
What is the clinical assessment of adequacy of reversal of neuromuscular blockade?*
Ability to SUSTAIN motor activity for 5-10 seconds
What inhaled anesthetics do we use most often today?Why? Which is least pungent?*
Desflurane and Sevoflurane

Quick onset and recovery

Sevoflurane
What is stage 1 of anesthesia?*
Analgesia
What is stage 2 of anesthesia?*
Delirium
What is stage 3 of anesthesia?*
Surgical anesthesia
What is stage 4 of anesthesia?*
Medullary paralysis
- failure of ventilation and circulation
What inhaled anesthetic is used on children who don't have IVs due to being less pungent?
Sevoflurane
What IV induction of anesthesia agent is most often used for adults?
propofol
What are mitigating factors that change the dose of anesthetic?
Someone who is a chronic alcoholic is going to require more anesthesia.

Elderly or pregnant woman will require less.
Higher MAC dose needed for
young, chronic alcoholic, hypernatremia, cocaine
Lower MAC dose needed for
pregnancy, elderly, hyponatremia, anemia, lithium
What is Nitrous Oxide not used much anymore?
Not potent and associated with nausea and vomiting

(only gas currently being used to aid general anesthesia)
Why don't we give halothane anymore?
Slow recovery and under certain conditions it can give PT hepatitis
All inhalation agents cause what?
malignant hyperthermia
If you want to know how much anesthetic to give scientifically, what do you use?
Brain wave monitor
What does the Bispectral Index Monitor (brain wave monitor) show you? What is the scale?*
Depth of anesthesia with a scale from 0-100

Processed EEG
What is the target dose on a brain wave monitor? What happens if it is below this number?*
40, no recall.

Above 40, say someone who came in and didn't tell you they were a chronic alcoholic would be above 40 and would have recall so you would have to increase the dose
What is the primary receptor that inhalation anesthetics work on?
GABAa
What are the general anesthesia characteristics of inhalation anesthetics?*
controllability and non-specific
Factors governing uptake of a volatile anesthetic?*
cardiac output, solubility, and uptake
Low blood solubility for a given volatile anesthetic would provide for a (quicker/slower) uptake and effect
quicker

and faster recovery
Which inhalation anesthetic has the quickest recovery?*
desflurane
A high cardiac output would provide more toward muscle and result in a (quicker/slower) onset
slower
Uptake formula*
What is MAC?*
Minimum Alveolar concentration. A measure of the potency.

MAC is a guide to dosing each agent
What does a MAC of 1 mean?
Dose that prevents movement of a patient 50% of the time to painful stimulus
What does a MAC of 1.3 mean?
Dose that prevents movement of a patient 100% of the time to painful stimulus or incision
As a person gets older what happens to the MAC dose?
It becomes less
What is the unitary hypothesis?
Proposes that all inhalation agents share a common MOA
What is our most common IV anesthetic?*
propofol

etomidate and Midazolam are also used
TIVA?*
Total IV Anesthesia

mostly lipophilic in nature - rapid onset, rapid termination
What is Etomidate used for?*
Good for elderly people with limited cardiopulmonary reserve (minimal CV and respiratory depressant effects)

doesnt have the depressant effects of propofol
What properties does etomidate have?
Hypnotic but not analgesic

MINIMAL HEMODYNAMIC EFFECTS

fast onset, fast recover, adrenocortical supression, pain at injection site
What do we use Midazolam, which is a Benzodiazepine, for?
before surgery for amnesia because people get scared.
Ketamine has (analgesia/amnesia)?
Potent analgesic, used for shock patients (increase HR, CO, BP)**** and chronic pain patients
What type of agonist is dexedetomidine?* What is it used for?
alpha 2 receptors, used for sedation

sedative medication used in the OR - relatively unique in its ability to provide sedation without causing respiratory depression
What drug is selective in its reversal of benzos?
flumazenil
What is the MOA of benzodiazepines?
Activate GABAs receptor complexes and enhance CL- current to hyperpolarize neurons and reduce their excitability
What is the specific binding site for benzos?
BZP binding site on GABAa

midazolam 2x greater affinity for receptors than diazepam
analgesics such as .... are given as a supplement to volatile anesthetic gases and contribute to the overall MAC*
Narcotics: morphine and fentanyl (sublimaze)

all have a degree of respiratory depression, which is increased when combined with anesthetics
Has poor CNS penetration and an onset of 15-30 mins
morphine
What opiate do we give today in the OR?
Fentanyl - 100x more potent. Contributes to analgesia

more lipid soluble than morphine
75% first pass pulmonary uptake
83% protein binding
What opiate has 1000x potency of morphine?
sufentanil
What is the treatment for post operative nausea and vomiting?
Anticholinergics - antimuscarinics (scopolamine)
5 HT antagonists (ondansetron)
Antihistamines
Nausea is a (parasympathetic/sympathetic)?
parasympathetic, lecturer stated that you can use alcohol pads up people's noses to overside the parasympathetics with a noxious smell. 2 pads each nostril, 4 breaths