Neuromuscular Physiology & NMBDs

Question 1

muscle classifications

Answer 1

skeletal, smooth, cardiac

Muscle comprises 45-50% of body mass (Skeletal muscle 40%)

• Skeletal and cardiac share same basic contractile organization
• Skeletal multinucleated and tubular
• Cardiac mono-binucleated intercalated disks

Question 2

skeletal muscle innervated by

Answer 2

large myelinated alpha neurons
-Cell bodies located in brainstem or anterior spinal cord

A motor unit is the functional contractile unit

• Single alpha neuron
• All muscle fibers that receive innervation from it

Question 3

small versus large motor units

Answer 3

Small innervate “slow red” fibers

• Resistant to fatigue
• Small motor units innervate “red slow” fibers. These fibers appear red due to the high concentration of myoglobin, mitochondria and capillaries as compared to large motor units that innervate ”fast white” fibers

Large innervate “fast white” fibers
-In general, large motor nerves innervate more muscle fibers than smaller nerves.

Question 4

3 components of NMJ

Answer 4

• Presynaptic nerve terminal
• Synaptic cleft
• Postsynaptic muscle membrane
• Presynaptic motor nerve ending meets postsynaptic membranes of skeletal muscle
• Designed to transmit impulses from nerve terminal to muscle via acetylcholine (ACh)

Question 5

presynaptic nerve terminal contains

Answer 5

Synaptic vesicles (SV) filled with ACh, and Mitochondria
-SV are special secretory organelles that are synthesized in the endoplasmic reticulum, and transported to nerve terminal via microtubule system
-ACh is synthesized in the cytoplasm from:
Acetyl coenzyme A and choline, catalyzed by choline acetyltransferase

“Quantum” of transmitter = vesicle
-5,000-10,000 molecules of ACh in each vesicle

SV contain proteins with two basic functions:

• Uptake of neurotransmitters, Mediate SV membrane traffic
• Calcium plays pivotal role in exocytosis

Two “pools” of vesicles: active and reserve

Question 6

synaptic cleft

Answer 6

~20 – 50 nm wide. It separates nerve and muscle fiber plasma membranes and encompasses the synaptic basal lamina.

• Acetylcholinesterase attached to basal lamina at the cleft
• Responsible for hydrolysis of free ACh:
• 50% hydrolyzed before reaching nicotinic ACh receptor (nAChR), 4,000 ACh molecules hydrolyzed per active site per second
• ACh broken down to choline and acetate

Additional roles of acetylcholinesterase:
Promote nerve growth and nAChR modulation

Question 7

postsynaptic muscle membrane

Answer 7

• Highly infolded (secondary folds)
• Increase surface area
• nAChR located at the crests of folds (Each NMJ has several million receptors)

Pentameric compound comprised of:

• Two alpha, one beta, one delta and one sigma subunits
• Two alpha subunits have acetylcholine binding sites

Fetal vs. adult nAChR

• Fetal nAChR are low conductance channels when compared to adult nAChRs. Fetal receptors are found in states of denervation.
• Fetal more sensitive to succinylcholine and less sensitive to nondepolarizing neuromuscular blocking agents

Question 8

Succinylcholine

Answer 8

is a partial agonist of nAChR

• Binds to only one subunit
• Not hydrolyzed by acetylcholinesterase

Succinylcholine is structurally two molecules of acetylcholine bound together and is a partial agonist of nAChR. Because succ is not catalyzed by acetylcholinesterase, the channel remains open longer than it would when exposed to acetylcholine, resulting in a depolarizing block. It is possible that Succ will diffuse across and repeatedly bind to multiple nAChR until it is cleared from the area of the NMJ where it is exposed to plasma cholinesterase and hydrolyzed.

Question 9

Nondepolarizing agents

Answer 9

bind to one or both alpha subunits

• Lack agonist activity (competitive blockade)
• Channel remains closed
• Non-depolarizing NMB drugs will bind to one or both alpha subunits, but unlike ACh they lack agonist activity. Since a conformational change does not occur, the receptor remains closed and ions do not flow across the channel. If enough channels are closed, there is a blockade of neuromuscular transmission. Some non-depolarizing NMB drugs may show a preference for one of the alpha subunits and it is possible to see synergism if two separate Non-depolarizers are used.

Question 10

neuromuscular transmission

Answer 10

1. Depolarization of the nerve opens calcium channels
   - Mobilizes SV and release of ACh
   - Potassium channels present in the nerve terminal limit the amount of calcium release.
2. ACh binds to nAChR
   - Two molecules work together
   - Channel opens allowing: Sodium to flow into the cell, Potassium to exit the cell
3. Depolarization mediates and propagates action potentials across the surface of the muscle into the transverse tubules

There are two types of calcium channels

• Dihydropyridine receptor (DHPR) in the T-tubule (Activated by membrane depolarization)
• In turn, activate ryanodine receptors
• Ryanodine receptor (RyR1) in the sarcoplasmic reticulum (SR)

Question 11

excitation-coupling

Answer 11

DHPR-RyR1 interaction releases a large amounts of calcium from the SR

• Binds to troponin C
• Initiates movement of tropomyosin on thin filament
• Allows cross-bridging between myosin and actin
• After release of calcium, SR begins to reaccumulate by active transport (ATP provides energy for “calcium pump”)
• Once level decreases sufficiently, cross-bridging ceases

Question 12

malignant hyperthermia

Answer 12

Failure to of the calcium pump results in:

• Sustained muscle contraction
• Marked increase in temperature

The gene for this calcium ion channel is on chromosome 19
-Mutation of this gene is associated with malignant hyperthermia susceptibility

Question 13

smooth muscle categorization

Answer 13

(lacks visible cross-striations and lack T-tubules)

Categorized as
1. Multiunit:
-Controlled almost completely by nerve signals
-Spontaneous contractions are rare
(Ex: ciliary eye muscles, iris, many large blood vessels)
2. Visceral:
-Cell membranes adjacent to cell membranes
-Often undergo spontaneous contractions as a single unit without nerve stimulation

Question 14

smooth muscle

Answer 14

-In addition, smooth muscle is unique in that: it’s sensitive to hormones and tissue factor

Mechanism of contraction

• Contain actin and myosin, but lack troponin
• Calcium-calmodulin complex activation
• Smooth muscles do not atrophy when denervated
• Do become hyperresponsive to neurotransmitters

Smooth muscles do not have a NMJ like skeletal muscles

• Neurotransmitters are secreted into the interstitial fluid
• Acetylcholine and norepinephrine
• Norepi acts to reverse the effects of ACh. Specific excitatory or inhibitory receptors determine the response to the neurotransmitters.

Question 15

Vd of NMBDs

Answer 15

0.3 – 0.4

So far: remifentanil, NSAIDs, and now NMBDs

Question 16

Choline Hydrolysis

Answer 16

1. Acetylcholinesterase (“True” cholinesterase)
   - Present at the NMJ
   - Rapid hydrolysis of ACh
2. Butyrylcholinesterase (“plasma cholinesterase”)
   - Aka “pseudocholinesterase” (PChE)
   - Synthesized in the liver
   - Hydrolysis of succinylcholine in the plasma
   - This is what is going to metab esters (ester amides - local anesthetics), remifentanil
   - Doesn’t really affect ACh

Question 17

monitoring (nerves) and mechanism of NMBDs

Answer 17

• Contraction of the adductor muscle of the thumb (ulnar nerve) is the preferred method of determining level of blockade
• Facial nerve monitoring generally involves stimulation of the orbicularis oculi muscle (facial nerve)
• Face is highly vascular – will relax first. Just bc eye stops twitching, doesn’t mean your diaphragm/trunk/extremities are relaxed

Order of Onset of relaxation
Eye muscles > extremities > trunk > abdominal muscles > diaphragm
-Blood flow is greatest to the head neck and diaphragm
-More drug distributed to these areas
(Onset measured in facial nerves, Recovery best measured in the hand)

There are five clinical tests of neuromuscular function:

• Single twitch
• Train-of-four (TOF)
• Double-burst suppression (DBS)
• Tetanus
• Posttetanic count

Question 18

TOF

Answer 18

most widely used means of stimulation

• Four separate stimuli every 0.5 seconds at 2Hz
• Comparison made between the four twitches; T1-T4
• Awake, nonmedicated person, should get 4 equal twitches of equal amplitude
• With TOF we talk about 1) strength of twitch and 2) fade
• With onset of paralysis in non-depolarizing agent there is a successive decrease in twitch response between T1-T4 (fade)

Question 19

fade versus amplitude

Answer 19

• 4 full twitches = no fade
• can have 4 weak twitches (person with 4 weak twitches has more neuromuscular blockade than the person with 4 full, duh). This is the amplitude of the twitch.

Fade = strength from the first twitch to the last twitch

• decreasing twitch for each twitch - progressively weaker
• In general fade/phase II block – bolus injections of nondepolarizers. If talking about nondepolarizers, think of FADE.

Question 20

TOF and the degree of block

Answer 20

• Most sensitive between 70-100% paralysis
• T4 – 75-80%
• T3-4 – 80-85%
• T2-4 – 90-95%
• Zero twitches – 100%

**A pt can have 4 twitches and have 75% of receptors blocked!

Question 21

tetany

Answer 21

continuous electrical stimulation for 5 seconds at 50-100Hz – SUSTAINED CONTRACTION

• Think about this more in terms of you want to wake up your pt and need to determine amt/type of reversal you need.
• Reliable for detecting fade
• Sustained contraction without fade; significant paralysis unlikely
• Seeing a huge release in ACh- what’s your body’s ability to recover? If sustained, you can be fairly confident that they have no paralysis
• Contraction + fade = still some NMB that’s competing with the ACh

-If you release a FUCK TON of ACh and there’s no fade, that means that there’s really no NMBD that is competing with all that ACh. Conversely if you release a FUCK TON of ACh and the contraction starts to fade, then you know that there’s still NMBD on board that is causing that.

Question 22

posttetanic count

Answer 22

Tetany followed in 3 seconds by single twitch stimulations – tells you how intense the residual blockade is!

• The higher the count (> 8) the less intense the block
• You’ve flushed out all of the presynaptic ACh with the tetany → now you’re reset and want to see what is the ratio of ACh to neuromuscular blocking drug
• What is your ratio of agonist to antagonist? That will show up in what effect you see when you do the posttetanic count

Question 23

single twitch

Answer 23

single twitch at 0.1-1 Hz for 0.1-0.2 milliseconds

• Determine whether 100% paralysis is present
• Example of anesthesiologist who would turn on single twitch and NOT let you intubate the pt until they stopped twitching
• Induction (30-45 seconds for prop to work, 1-2 minutes for narcotic to work, if fent) – establish ventilation – THEN push NMB/muscle relaxant. Bc if you can’t intubate a patient who can’t ventilate themselves then you’re fucked.

Question 24

double-burst suppression

Answer 24

• Seems to improve ability to detect residual paralysis

- Evaluating 2 rather than 4 twitches facilitates detection

Question 25

UNRELIABLE indicators for endotracheal intubation

Answer 25

• 5-second head lift (but pt needs to be awake to do this)
• TOF ratio < 0.60
• Generate peak negative inspiratory pressure - 20-30 cmH2O (big deep breath)

But pt needs to be awake to do all of this – there are better ways to do that

Question 26

NMB structure

Answer 26

-All neuromuscular blockers are quaternary ammoniums (whether depolarizers or nondepolarizers)
-Next to the N is a charge – ionized – low Vd
-Structurally related to ACh
-Majority are synthetic alkaloids
(Tubocurarine is the exception)

Question 27

nondepolarizing blockade

Answer 27

you’re still getting 4 twitches, but they’re decreasing (FADE)

Characterized by:

• Decrease in twitch tension
• Fade during repetitive stimulation
• Posttetanic potentiation
• They do NOT cause muscle contraction. Just sits right on top of receptor.
• Nondepolarizing muscular blockers act as antagonists at the POSTsynaptic receptors, and PREsynaptic receptors

Question 28

fade

Answer 28

concentration – nondepolarizers

• Twitch depression results from block of postsynaptic nicotinic acetylcholine receptors
• Posttetanic or TOF fade results from blocking presynaptic nicotinic acetylcholine receptors [Dr. Falyar to check on this wording]
• Amount of released ACh does not match the demand
• Nondepolarizers will be recirculated –> need to get to the liver to get metabolized.
• There’s only a certain amt of that drug being removed at a time, why we see a more gradual return of fn
• Don’t have to worry abt redistribution (Vd ~14L, so they’re limited to intravascular space)
• Remember where you’re monitoring: diaphragm comes back 1st, eye comes back last. (Ex: intraabdominal surgery, you have 2 twitches in the eye –> pt is probably pushing against surgeon)

YOUTUBE

• Presynaptic receptors: you have VG Ca++ channel receptors, AND ACh presynaptic receptors
• Nondepolarizing blockers bind to both presynaptic and postsynaptic nAChR’s
• 1st twitch – AP opens VG Ca++ channels, Ca++ into cytosol, releases quantum of ACh
• Could be enough ACh to displace some of the nondepolarizer, to get a full twitch
• 2nd twitch – competition at presynaptic nAChR, less release of ACh, less response from 2nd twitch (plus AChesterase is there chewing up what little was released)
• … might not even get 4th twitch.
• 0 twitches means that the ACh released, even on the 1st twitch, was not enough to displace the nondepolarizer at the motor endplate
• NOW if you have 0 twitches, you use posttetanic count to see just how much medication is still on board. You’ll release a FUCK TON of ACh, so if you’re not getting a lot of twitches, then you still have quite a bit of medication on board.

Question 29

depolarizing blockade

Answer 29

ONLY SUCCINYLCHOLINE

• Constant, but diminished. So succ will cause some of the muscle to contract and then they’re done. So when you do the TOF, you get twitches at decreased amplitude. Fade is talking about [ ]. You’ll see less fade as the drug is wearing off.
• Aka “phase I block” is often preceded by muscle fasciculation

Depolarizing block is characterized by:

• Decrease in twitch tension
• No fade during repetitive stimulation
• No posttetanic potentiation

(St) In the case of administration of a depolarizing neuromuscular blocking agent, such as succinylcholine, the muscle response that has been “classically” described is quite different. Depolarizing block (also called phase I block) is often preceded by muscle fasciculation. During partial neuromuscular block, depolarizing block is characterized by (a) decrease in twitch tension, (b) no fade during repetitive stimulation (tetanic or TOF), and (c) no posttetanic potentiation

”Phase II block” seen in repeated or long-term administration

• Doses > 6 mg/kg
• Inhibit pre-synaptic AChR
• YOU SHOULD NOT SEE FADE or posttetanic potentiation– fade is more related to [ ] of ACh released

Question 30

succinylcholine

Answer 30

• Only depolarizing NMBD
• Two ACh molecules linked by acetate methyl groups

-Takes 30-60 seconds to achieve paralysis
(unless the pt has a pseudoplasmacholinesterase deficiency) you know that the drug is going to be metabolized in the bloodstream
-ACh causes a muscle contraction, then disassociates –> taken up by true AChesterase and is taken back up into the presynaptic terminal
-Succinylcholine causes a muscle contraction, then dissociates 4-5 minutes later (how long you stay paralyzed) –> disassociates –> goes into the bloodstream, where it is metabolized by pseudocholinesterase

3-4 minutes, drug released, then metabolized by same enzymes as remifentanil, then it will be eliminated
-(versus nondepolarizing agents can work for 30+ minutes, drug slowly metab, but they’re released into circulation. Then they can either be eliminated or can reattach to another receptor)

If you run someone on a succinylcholine gtt, it will act like a non-depolarizer

Usually won’t give 2nd dose of succinylcholine bc:

• Attaches to ACh receptor, causes muscle contraction and then stuck there, then disassociates after 4-5 minutes. Then floats back into bloodstream
• Wouldn’t use TOF unless single-twitch
• Won’t get 0 twitch, will just have lower amplitude **

Question 31

succinylcholine dosing and PK

Answer 31

• Dose for tracheal intubation 1.0 mg/kg (low Vd – based on IBW)
• Creates intubating conditions in approximately 60 seconds
• Larynx approximately 34 seconds
• Recovery to 90% muscle strength 9-13 minutes

Usually use TOF to see if they’re ready to wake up.

• Short action due to rapid hydrolysis by butyrylcholinesterase
• Succinylmonocholine and choline
• Succinylmonocholine is weak NMBD
• Succinic acid and choline – whole process done in minutes, succ has gone into bloodstream to get metabolized unlike ACh which is metab right in synaptic cleft
• Recovery from succinylcholine motor blockade occurs as it drifts away from the NMJ down a concentration gradient

Fasciculation – usually see it in extremities. You will see a difference in ventilation while they’re contracting, but that’s like 1 sec.

T1/2 – 47 seconds (St)

Question 32

butyrylcholinesterase (PChE)

Answer 32

Metabolized in the liver and found in the plasma

Responsible for the metabolism of:
-Succinylcholine, mivacurium, procaine, chloroprocaine, tetracaine, cocaine and heroin

Factors decreasing PChE activity include:

• Advanced liver disease, age, malnutrition, pregnancy, burns, oral contraceptives, MAO inhibitors, echothiophate, cytotoxic drugs, neoplastic disease and anticholinesterase drugs
• Beta blockers cause a mild prolongation of succinylcholine (you prob wouldn’t notice it)
• Genetic variations can cause significant prolongation of succinylcholine effects
• Dibucaine number

-Does that mean liver failure patients would have higher than normal amounts of this enzyme, and therefore have an even shorter half-life and effect time of succinylcholine and the other drugs that are metabolized by them? Prob

Question 33

Dibucaine number

Answer 33

• Dibucaine – local anesthetic that inhibits typical PChE
• Dibucaine number reflects the quality of cholinesterase not quantity (e.g. – Dibucaine of 80 infers 80% of enzyme inhibited)

-Normal genotype = Dibucaine number > 70
-Heterogenous for atypical gene = Dibucaine number 40-60 (Prolongs block 1.5-2 times longer)
 Homogeneous for atypical gene = Dibucaine number < 30 (Block prolonged for 4-8 hours)
They can’t metabolize the drug –> just have to wait for the drug to wear off

Question 34

succinylcholine SEs (cardiac, stim of autonomic ganglia, hyperkalemia, myoglobinuria)

Answer 34

Cardiac

• Bradycardia, junctional rhythm or sinus arrest
• Actions of succinylcholine on cardiac muscarinic receptors
• More likely to occur if
  1. Second dose given within 5 minutes of first dose (don’t do it!)
  2. Pediatric patients (are more PSNS motivated than adults – some of them you won’t even give a paralytic, just give prop and narcotic)

Stimulation of autonomic ganglia may cause:
Ventricular dysrhythmias, Tachycardia, Increased blood pressure
-(could be succ or it could be something else, like stimulation of intubation, anesthetic gases cause dysrhythmias, etc.) great.

Hyperkalemia

• 0.5 mEq/dL increase in plasma concentration in healthy individuals (bc of Na+ influx)
• May be severe in:
  1. Anyone who already has a high K+ level
  2. Burn patients, abdominal infections, metabolic acidosis, closed head injury and conditions associated with upregulation of nAChR (paraplegia, muscular dystrophy, Guillain-Barre’)
  3. Should be avoided in children except for emergency intubation

Myoglobinuria

• Damage to skeletal muscle; especially pediatric patients
• Most found to have DUCHENE muscular dystrophy or be malignant hyperthermia susceptible
• Remember that malignant hyperthermia is a failure to of the calcium pump that results in:
  1. Sustained muscle contraction
  2. Marked increase in temperature
  3. The gene for this calcium ion channel is on chromosome 19
• Mutation of this gene is associated with malignant hyperthermia susceptibility

Nowadays bc of sugammadex, ppl are just giving intubating doses of rocuronium and then just reversing them, to avoid the whole possibility of malignant hyperthermia

Question 35

succinylcholine SEs (increased intraocular pressure, increased intragastric/esophageal prssures, increased ICP, masseter spasm, myalgias)

Answer 35

Increased intraocular pressure

• Peaks at 2-4 minutes; pressure returns to normal by 6 minutes
• Not widely accepted in open eye injury
• (Avoid in head injury - don’t want to give them anything that will increase ICP)

Increased intragastric and lower esophageal pressures

• Related to intensity of fasciculations of abdominal muscles
• Prevented by prior administration of non-depolarizing drug
• Does not increase risk of regurgitation: (might need to decompress stomach to avoid aspiration)

Increased intracranial pressure
-Can be attenuated with pretreatment of non-depolarizing drug

Masseter spasm

• Succinylcholine = known MH trigger
• Masseter spasm may be an early indicator of MH, however not consistently seen
• Possibly due to inadequate dosing

Myalgias

• Massive muscle contraction – pts can say they ached for a week. Could also be if underdosing, part of the muscles contract and part of them don’t, which causes shearing, which causes myalgias
• Prominent in skeletal muscle of the neck, back and abdomen
• Greater in young adults, females and ambulatory surgery patients (young ppl have healthy muscles and will contract A LOT)
• Not well understood; possible muscle injury due to fasciculations
• Pretreatment with non-depolarizing drug, lidocaine or NSAIDs (defasciculation dose)

Myalgias occur even in absence of succinylcholine “some ppl will just wake up from surgery sore, whether they had succ or not”

Question 36

What is a defasciculation dose?

Answer 36

subtherapeutic nondepolarizing dose → not enough for them to be paralyzed, but some receptors blocked → then you give succinylcholine and some of the receptors are blocked so you won’t have as big of a contraction with your succ dose

Question 37

succinylcholine in special populations

Answer 37

Elderly:

• Onset slower due to decreased circulation
• Reduced levels of PChE
• Certain Alzheimer medications may prolong actions

Pediatrics

• Avoided in pediatric patients < 5 years-old
• Duchene muscular dystrophy (DMD) – malignant hyperthermia
• ***(bradycardia) d/t hyperK+ - more at risk for this than cardiac arrest d/t hyperK+
• Cardiac arrest from hyperkalemic rhabdomyolysis

Would just use ↑ dose of propofol and narcotic. It’s common to avoid paralytics in pediatrics.

Question 38

malignant hyperthermia (triggers and s/sx)

Answer 38

Pharmacogenetic disorder triggered by:

• Volatile anesthetics
• Succinylcholine
• Stress
• Ryanodine receptor gene mutation (chromosome 19)

Signs and symptoms include:

• Increase in carbon dioxide production – 1st ↑ ETCO2
• Muscle rigidity – 2nd (↑ Peak pressures, ↓ Vt, surgeon might notice field is tighter)
• Metabolic acidosis
• High temperature (late sign) – by the time you get to the temp part of the dz, you’re probably too late

Question 39

classes of non-depolarizing NMBDs

Answer 39

• Steroidal (mostly use these)

- Benzylisoquinolinium (atricurium, cisatricurium)

Question 40

atricurium

Answer 40

(Rarely see this used. Racemic mixture of 10 stereoisomers separated into three geometrical isomer groups: cis-cis, cis-trans, trans-trans)

Intermediate-acting and onset

• Intubating dose 0.5 mg/kg
• Undergoes ester hydrolysis and spontaneous degradation (0% metab by kidney- all done in the blood)
• Hoffmann elimination – spontaneously degrade
• In theory we wouldn’t have to reverse them (just wait a certain pd of time. But if you’ve waited and you’re only getting 2 twitches, probably just give a little reversal)

**Laudanosine (tertiary amine) metabolite implicated in convulsions – tertiary amines are lipophilic and can cross the BBB (Doses given in anesthesia not capable of producing this)

Then why would you give it? Maybe you have a pt who is has liver issues who you don’t want that to affect the metabolization of your NMBD

Question 41

cisatricurium

Answer 41

(benefits without histamine release)

• The cis isomer of atracurium
• Intermediate onset and action
• Intubating dose 0.1 mg/kg
• Metabolized by Hoffman elimination - there is no ester hydrolysis (basically falls apart on its own)
• Good for renal/liver failure.
• T1/2 ~ 1 hr?
• Unlike atracurium, it does not cause histamine release

Question 42

mivacurium

Answer 42

-Only available short-acting non-depolarizer available… Not used in the United States

• Intubating dose 0.15 mg/kg
• Metabolized by butyrylcholinesterase
• 70-88% rate of succinylcholine (not metabolized as efficiently as succ - lasts longer!)
• Monoester, dicarboxylic acid

(Not really any histamine release, no malignant hyperthermia)

Question 43

steroidal compounds in general

Answer 43

type of nondepolarizer

• Acetyl ester thought to facilitate interaction with nAChR
• Essential that one of two nitrogen atoms are quaternized

Steroidal compounds include:

1. Pancuronium (cardiac anesthesia – longggg acting paralytic)
2. Vecuronium (most reliable)
3. Rocuronium (most commonly used)

Question 44

pancuronium

Answer 44

LONG
Potent long-acting neuromuscular blocking drug
-Intubating dose – 0.08 mg/kg
-Onset time to maximum block – 2.9 minutes (not good for high r/f aspiration)
-(remember succ – 30-60sec) in the olden days you could give succ for a difficult airway, and then give nondepolarizer for the rest of the case

*Vagolytic and butyrylcholinesterase-inhibiting properties  maintenance or ↑ of HR
Vagolytic- think anticholinergic [inhibit the action of vagus nerve on the heart, GI tract, and other organs]
-Use high narcotic induction dose for cardiac surgery –> cause bradycardia
-Can counter-act that bradycardia with pancuronium, has some sympathomimetic properties that we’ll want

• *Majority cleared by the kidney
• Small amount deacetylated by the liver
• Accumulation of 3-OH metabolite responsible for block prolongation

Most potent – slowest onset time

Question 45

vecuronium

Answer 45

-Intermediate-acting (compared to pancuronium, but still long-acting) neuromuscular blocking drug

• Intubating dose – 0.1 mg/kg
• Onset time to maximum block – 2.4 minutes
• Lasts about 1 hr before you could give a reversal agent

Essentially Pancuronium without quaternized methyl group

• Slight decrease in potency
• Loss of vagolytic properties (less stable CV profile than with pancuronium)
• Molecular instability (shorter duration of action)
• Increased lipid solubility – quicker than panc

Metabolized principally by the liver
-3-OH metabolite has 80% of neuromuscular potency

Question 46

rocuronium

Answer 46

(most commonly used. Most inconsistent)

• Intermediate-acting neuromuscular blocker
• Intubating dose – 0.6 mg/kg
• Time to maximum block – 1.7 minutes
• If you need to rapidly intubate someone, you could double that dose to 1.2 mg/kg and create intubating conditions in 60 seconds. In the olden days, you had no way to reverse this.

Faster onset of action than pancuronium or vecuronium

• Six times less potent than vecuronium
• Won’t last as long! So with 1 dose of vec, you might not have to re-dose for an hour. This one you might have to!

Primarily metabolized in the liver
-Approximately 30% is excreted in the urine

Question 47

factors that increase NMBD potency

Answer 47

• Inhalational agents and length of inhalational anesthesia (but you also get relaxation at sufficient doses of inhalation agents)
• desflurane > sevoflurane > isoflurane > nitrous oxide > IV anesthesia
• (propofol – amnestic induction agent. No analgesia, no relaxation.)
• Antibiotics: Aminoglycosides and Clindamycin** (pts with PCN/cephalosporin allergy get this instead)
• Hypothermia
• Magnesium sulfate (calcium antagonist) – calcium tightens things up, mag loosens things up/slow to wake up
• Local anesthetics (block nerve transmission…)
• Quinidine
• (no narcotics, no benzos)

Question 48

factors that decrease NMBD potency

Answer 48

• Chronic anticonvulsant administration (dilantin, Keppra – might need more drug!)
• Hyperparathyroidism and hypercalcemia (anything that ↑s Ca++ will make your drug work less) –> Decreased atracurium sensitivity

Question 49

relationship b/w potency and onset

buffered diffusions

Answer 49

**Potency and onset of action have an inverse relationship
Low potency = fast onset

Rocuronium – fast – low potency
Pancuronium – slow – high potency

Buffered diffusion seen with high potency drugs

• Drug diffusion is impeded because it binds to high-density receptors in a confined space
• If you inject enough drug into a tight space, it’s going to take a while to leave. If you give a high potency drug, it’s more likely to hang out at the site, will work longer

Question 50

adverse effects of NMBDs

Answer 50

1. Autonomic effects:
   - May also block nicotinic receptors within sympathetic and parasympathetic nervous system
   - Bradycardia and hypotension – attaching all the nAChR’s in other places than just the motor endplate
   - Histamine release – flushing, hypotension, reflex tachycardia and bronchospasm (atricuriums, not steroidals)
   - Pancuronium has direct vagolytic effects
   - Block muscarinic (m2) receptors –>SNS override - ↑ HR, BP
   - (depolarizing blockers – succ – acts as an agonist to m2 muscarinic receptors – stimulate PSNS - ↓ HR)
   - Inhibition of negative feedback system where catecholamine release is modulated or prevented

Histamine release ≠ allergic rxn!!

• Urticaria, Skin flushing*, hypotension, decrease in systemic vascular resistance, increased heart rate (bc of vasodilation)
• Seen in benzylisoquinoliniums (Mivacurium, atracurium and tubocurarine)
• Usually short duration (1 to 5 minutes)
• Slow administration or pretreatment with H1 (loratadine, zyrtec) and H2 blockers (famotidine/Pepcid), to reduce cardiovascular effects, Or give the drug slowly
• Flushing goes away

Respiratory effects

• Related to histamine release in patients with reactive airway disease (maybe think about steroidal)
• Increased airway resistance and bronchospasm
• Allergic reactions

Question 51

NMBD allergy (and tx)

Answer 51

• NMBD are a common cause of perioperative allergic reactions
• Rocuronium and succinylcholine (remember that roc doesn’t cause a release in histamine!) We also give such a high dose of it to get effects.
• 1:1,000 – 25,000

Cross reactivity between NMBDs and:
Food, cosmetics, disinfectants and industrial materials

Treatment includes:
-100% oxygen, Intravenous epinephrine, Early tracheal intubation, Fluid administration (crystalloid vs. colloid), Colloid may be better for older ppl, pts with poor cardiac reserve, Sympathomimetic drug

Question 52

NMBD reversal (thought process)

Answer 52

When we reverse, we are NOT eliminating the NMBD. We are creating a higher [ ] of ACh than the NMB by giving AChE inhibitors. Problem is that ACh is used everywhere. Nerve agents = AChE inhibitors. Muscarinic – bradycardia/hypotension/salivate/defecate/lacrimate (atropine and robinul help with these SEs)

• SLUD – salivation, lacrimation, urination, defecation
• Anticholinergics – work at nAChRs, to block some of the effects of the AChEs
• Basically: AChE inhibitors cause bradycardia/hypotension, lacrimation - urination - salivation - defecation
• So we give anticholinergics to combat these sxs: remember the SEs of anticholinergics: “can’t see, can’t pee, can’t spit, can’t shit”
• Acetylcholinesterase (AChE) rapidly hydrolyzes ACh. Reversal of NMBD is predicated on creating build-up of ACh at NMJ

AChE inhibitors:

• Antagonize residual effects of NMBD
• Accelerate recovery from non-depolarizing drugs

Question 53

AChE inhibitors

Answer 53

1. Neostigmine (AChE inhibitor) + glycopyrrolate (anticholinergic)
   - glycopyrrolate - less CV changes
   - Glycopyrrolate is a quaternary ammonium – doesn’t cross BBB – no CNS depression
2. Edrophonium (AChE inhibitor) + atropine (anticholinergic)
   - atropine: more CV change, crosses BBB –> some sedation effects
   - Pyridostigmine

-The reason we give anticholinergics is bc they only target nAChRs at the muscarinic sites. So we want to block AChE inhibitors at these specific sites.

Question 54

neostigmine

Answer 54

has a ceiling effect, once reached additional doses have no effect

• Maximum block depth that can be antagonized corresponds to return of fourth twitch in TOF
• Cannot antagonize profound or deep levels of blockade – should not be using this if the pt has 0 twitches
• Administering more inhibitor may be detrimental (start getting into the nerve agent area)
• Slower onset – sustained effect – glycopyrrolate/robinul

Question 55

Antagonism of NMBDs depends on

Answer 55

• Depth of blockade when reversal is attempted
• Inhibitor chosen
• Dose
• Rate of spontaneous clear of NMBD
• Choice and depth of anesthesia

Question 56

doses of AChE inhibitors and their anticholinergics

Answer 56

• Neostigmine – 0.04-0.08 mg/kg (~2-4mg in a 70 kg adult)
• Edrophonium – 1.0-1.5 mg/kg (“little higher”)
• Glycopyrrolate – 0.01-0.005 mg/kg – marry that with neostigmine specifically, give this 1st maybe
• Atropine – 0.007-0.01 mg/kg – with edrophonium

(AChE inhibitors are quasi-competitive….)

Question 57

AChE inhibitor SEs

Answer 57

Cardiovascular: Muscarinic effects must be blocked by anticholinergic

Pulmonary
-Bronchoconstriction: Increased airway resistance, Increased salivation

Gastrointestinal

• Increased bowel motility
• ?No effect on incidence of PONV?

Effects reduced by coadministration of anticholinergics

Question 58

“Qualitative” monitoring

Answer 58

Qualitative monitoring gives you a % of receptors

• Will see % of receptors – must be 4 twitches
• 4th twitch is x % of your 1st twitch
• Following administration of NMBD it is essential to ensure adequate reversal
• TOF > 0.9 *** the only true objective measure that the pt has had adequate reversal

Less than 0.9 is associated with:

• Difficulty speaking
• Difficulty swallowing
• Visual disturbances
• Aspiration risk

Question 59

sugammadex

Answer 59

CAN ONLY USE ON STEROIDALS!

-No more ratio, you’re just getting rid of the drug.
Modified gamma-cyclodextrin – circular sugar that encapsulates the drug inside of it. There’s no metabolism of anything. No gradual reversal of anything. Go from paralyzed → ready to go.
-Reversal of shallow and profound aminosteroid-induced blockade
-Rocuronium > vecuronium&raquo_space; pancuronium
(Van der Waals forces, hydrogen bonds and hydrophobic actions)
-Selective relaxant-binding (No effect on acetylcholinesterase)

Dosing
TOF > 2 – 2 mg/kg (based on IBW, not worried about redistribution)
TOF 1-2 – 4 mg/kg
TOF 0 – 8-16 mg/kg (can reverse a rapid-sequence dose of rocuronium with sugammadex faster than succ will wear off)

Ineffective against succinylcholine or benzylisoquinoliniums

Possible allergic reactions and bleeding

• Can interfere with PO contraceptives – encapsulates them, for about 1 week
• Have been using this in asia for a long time – articles on SEs/allergies
• Maybe has an effect on anesthetics?
• Encapsulates progesterone – inhibits PO contraceptives for a week

Kids/cath lab

• worsens pHTN if given as a fast IVP
• Some reported that even if they have no hx of pHTN
• Not FDA approved in peds yet

Question 60

sugammadex dosing

Answer 60

• TOF > 2 – 2 mg/kg (based on IBW, not worried about redistribution)
• TOF 1-2 – 4 mg/kg
• TOF 0 – 8-16 mg/kg (can reverse a rapid-sequence dose of rocuronium with sugammadex faster than succ will wear off)