-
What happens to cause muscle contraction?
- -AP causes depolarization- Na+ enters neuron, causes Ca++ to go into nerve cytoplasm
- -Ca++ ions cause storage vesicles to fuse with terminal membrane and release Ach
- -Ach binds to nic. cholinergic receptors
- -muscle contraction occurs
-
Where does Ach bind to the nicotinic Ach receptor?
- -both alpha subunits
- -Ach must bind to both for the channel to open and Na+ to flow in
-
How does the amt of Ach released relate to the amount needed for muscle contraction?
-It exceeds the amount needed, it's a safety mechanism
-
How is Ach metabolized? Where is this located?
- -Metabolized by acetylcholinesterase
- -Acetylcholinesterase is embedded in the motor end plate
-
Where does Ach work?
all end organs, not just NMJ
-
What's the goal of muscle relaxant reversal?
Maximize nicotinic transmission while minimizing muscarinic side effects
-
3 types of cholinergic receptors
- 1) postjunctional nicotinic cholinergic receptors
- 2) extrajunctional cholinergic receptors
- 3) prejunctional nicotinic receptors
-
post-junctional nicotinic cholinergic receptors
concentrated at NMJ
-
extrajunctional cholinergic receptors
- -occur over enture postjunctional membrane (muscle cell) not just NMJ
- -develop in response to denervation injuries, disease, or trauma
- -highly responsive to Ach and succ
-
pre-junctional nicotinic receptors
interfere with mobilization of Ach from areas of synthesis to release
-
Succ MOA?
- -partial agonist at Ach receptor
- -succ on 1 alpha subunit causes blockade as Ach needs to be on both subunits for depolarization
- -generates an AP in muscle cell (fasciculations- it's a PARTIAL agonist)
- -mimics Ach
-
Why does succ have a longer DOA than Ach?
- -It is metabolized by plasma cholinesterase
- -Must diffuse away from receptor, into plasma, to be metabolized
-
How does the structure of Ach compare to succ?
- -succ = 2 Ach molecules joined together
- -resembles Ach
-
MOA of non depolarizing block
- -binds to Ach receptors but no conformational change in receptor so Na+ channel doesn't open
- -acts as a competitive antagonist at the Ach receptor
- -1 molecule of a non depolarizer prevents the effect of Ach
-
Type of block associated with succ?
Phase 1
-
Type of block associated with non depol?
Phase 2
-
Up regulation of nicotinic Ach receptor
- -due to decreased Ach release which causes a compensatory increase in the number of receptors
- -exaggerated response to agonists (succ) and decreased response to antagonists (depol)
-
How does succ affect plasma K levels?
K levels are increased by 0.5 mEq/L
-
Causes of nic Ach receptor upregulation
- -SC injury
- -CVA
- -trauma
- -thermal injury (burns)
- -prolonged immobility
- -prolonged exposure to NMBs
- -MS
- -Guillian-Barre
-
Why does nicotinic Ach receptor up regulation result in resistanace to non depol blockers?
-Non depolarizers are antagonists, so need more of the drug to get the same effect
-
How does the exaggerated response to depolarizers from upregulation manifest?
Increased K+ release
-
Down regulation of nicotinic Ach receptor
- -Decreased number of functional Ach receptors (due to antibody destruction in mystathenia gravis)
- -Resistance to depolarizers
- -Increased sensitivity to non depolarizers
-
Causes of down regulation of nicotinic Ach receptor
- -myasthenia gravis
- -Ach-esterase OD
- -organophosphate poisoning
-
Most frequently monitored peripheral nerves
ulnar and facial
-
What muscle are we assessing that's stimulated by the ulnar nerve ?
Adductor pollicis
-
What muscle are we assessing that's stimulated by the facial nerve
obicularis oculi
-
Should the electrodes be placed over the nerve or the muscle?
The nerve!
-
What are we looking at when we assess the adductor pollicis muscle?
- -Thumb ADDuction
- -Look at and feel strength
-
What electrode placement produces maximal twitch height when assessing the ulnar nerve?
- -Negative electrode closest to nerve (near wrist)
- -Positive electrode proximal and less than 2 cm away
-
Do we monitor twitch height?
No, only done in research
-
What are the different modalities of NMB monitoring? Which is most commonly used?
- -twitch
- -TOF (most commonly used)
- -Tetany
- -Double-burst stimulation
-
What are clinical indications of recovery? Which is most useful?
- -Sustained head lift
- -Inspiratory effort of -25 cm water
- -Forceful hand grip (most useful)
-
twitch
single impulse delivered from every second to q10 secs
-
TOF
4 successive 0.2 msec stimuli in 2 seconds
-
With TOF, disappearance of the 4th twitch = ____ % block?
75
-
With TOF, disappearance of the 3rd twitch = ____ % block?
80
-
With TOF, disappearance of the 2nd twitch = ____ % block?
90
-
What percent block is desired clinically?
75-90%
-
Tetany
- -50-100 Hz
- -sensitive test of NM function
- -a sustained contraction for 5 seconds indicates adequate (not necessarily complete) reversal
- -better suited to assess reversal
-
Double burst stimulation
- -variations of tetany
- -more sensitive than TOF
- -less painful
-
Can you reverse a pt with no twitches?
No, they are not reversible!!
-
T or F, all muscles paralyze and regain function simultaneously?
F
-
What's the last muscle to become paralyzed and the first to come back?
The diaphragm, however, the pt may be able to spont breath, but unable to clear and maintain their airway!!
-
Phase 1 characteristics
- -4 twitches but all diminished
- -all of same ht
- -succ
-
phase 2 block characteristic twitches
- -fade
- -twitches get progressively weaker
-
can succ produce a phase 2 block? What else is this called?
- -Yes, if excess succ is given (rpt doses or single large dose, > 2 mg/kg IV)
- -AKA "dual block"
-
How can testing tetany be useful?
- -tell us if the pt can be reversed
- -if TOF produces a weak twitch, then do tetanus, then TOF again, should get stronger twitch; this means the pt can be reversed
- -called post tetanic potentiation / fasciculations
-
Which location is best to monitor readiness for intubation?
- -adductor pollicis
- -extremity nerves have longer onset, so when start to get fade here, pt probably ready for intubation
- -orbicularis oculi- no twitches
-
Which location is best to monitor readiness for reversal?
- -adductor pollicis
- -again extremities have longer onset time
- -so if have good twitches here, you will have good neuromuscular transmission of respiratory muscles
- -won't overestimate spontaneous reversal
-
What muscle movement should be seen with facial nerve stimulation?
- -orbicularis oculi- eye closes and forehead wrinkles
- -corrugator supercilli- medial end eyebrow down and forehead wrinkles
-
What's a possible danger of monitoring only the facial nerve?
- -Possible overdose of relaxant or overestimation of recovery
- -When no twitches at adductor pollicis, those of orbicularis oculi showed only minor fade
-
If you can't monitor the ulnar or facial nerve what other locations can be used?
- -Posterial tibial nerve, look for big toe flexion
- -Response is similar to adductor pollicis
- -also peroneal nerve, look for foot dorsiflexion
-
How do the facial and ulnar nerve compare in terms of onset?
-Facial nerve has more rapid onset than ulnar
-
Intubating conditions occur when there are no twitches at the adductor pollicis, T or F?
F, ulnar nerve has longer onset. Intubating conditions occur when there's 2-3 twitches or fade begins
-
Which muscles are most resistant to NMB?
- Most rx to least:
- VC, diaphragm, orbicularis oculi, abdominus rectus, adductor pollicis, masseter, pharyngeal, extraocular (ppl can get blurred vision)
-
When should the first TOF be checked?
After induction and before administration of NMB
-
If succ is used for intubation when should the next muscle relaxant be given?
- -Once the pt has demonstrated some degree of reversal
- -Avoid unrecognized pseudocholinesterase deficiency
-
How many twitches would indicate adequate surgical relaxation?
- -1-2
- -Don't want to obliterate all twitches
- -Want pt to be reversible at all times
-
How does hypothermia affect blockade?
-DOA is prolonged
-
How does nerve damage affect blockade?
-Rx to non-depolarizers
-
If a pt has hemiplegia, which side should be monitored?
The non paralyzed side
-
How do burns (affecting >30% of body) affect blockade?
- -Rx to non-depolarizers approx 10 days post injury, peaks at 40 days, and declines after 60 days
- -Altered affinity of Ach receptor for Ach and nondepolarizing drugs
-
How do abx affect blockade (both depol and non depol)?
Potentiate both
-
How do anti-convulsants affect blockade (both depol and non depol)?
- -Cause rx to non-depol (esp dilantin)
- -Need more frequent dosing
-
How do anti-dysrhythmics, anti-hypertensives, inh. and local anesthetics, magnesium sulfate, and abx affect blockade (both depol and non depol)?
-Potentiate both
-
How do cholinesterase inhibitors and lithium affect blockade?
-Potentiate depol only
-
How do ketamine and dantrolene affect blockade?
-Potentiate non depolarizing only
-
How does lasix affect NMB?
- -Doses <10 ug/kg potentiate both
- -Doses 1-4 mg/kg cause rx to both
-
How is succ metabolized?
-In the plasma by pseudocholinesterase to succinylmonocholine
-
Onset and duration of succ ?
- Onset 30-60 sec
- Duration < 10 mins
-
Why do we give a relative overdose of succ ?
-Because a lot of it gets metabolized in the plasma before it reaches the NMJ
-
Lipid solubility of all NMB? Why? Where do they distribute to?
- -Low lipid solubility
- -Due to quartenary ammonium structure
- -Distribute to ECF only
-
Quantitative pseudocholinesterase deficiency
- -Prolongs duration of succ
- -Decrease in number of enzymes
- -Due to pregnancy, liver disease, renal failure, malnutrition, certain drugs
-
Qualitative pseudocholinesterase deficiency
- -Prolonged duration of succ
- -slightly prolonged block, 20-30 mins (we may not notice), occurs in 1:50
- -or very prolonged block (6-8 hours), occurs in 1:3,000, due to homozygous atypical genetic enzyme abnormality
-
What drugs can cause a quantitative enzyme decrease?
- -cholinesterase inhibitors (organophosphates, neostigmine, echothiophate)
- -decrease in both acetylcholinesterase and pseudocholinesterease leading to prolonged block
-
dibucaine number
- -used to assess for qualitative enzyme decrease
- -80 confirms normal enzyme
- -20 confirms prolonged response to succ
- -dibucaine is a local anesthetic that inhibits activity of normal plasma cholinesterase by 80%
- -only detects certain variants
- -reflects quality NOT quantity of enzyme
-
succ indication
rapid sequence intubation
-
succ dose
- adult 1-1.5 mg/ kg
- if pretreating with non depol 1.5-2 mg / kg
-
How long does it take succ to produce intubating conditions ?
1 min
-
When pre-treating a pt with a non-depol prior to succ why is an increased succ dose needed?
-Non-depol are competitive antagonists, hence more succ is needed
-
Succ SE
- -Decrease HR (acts like Ach)
- -fasciculations (visible contractions)
- -hyperkalemia
- -myoglobinuria (due to skeletal muscle damage, uncommon)
- -myalgias
- -MH
- -increased intragastric pressure
- -incr .intraoccular pressure
- - incr ICP
-
Why would we want to pretreat a pt before giving succ ?
-To attenuate the fasciculations
-
In what type of pt are you likely to see fasciculations?
-Young, muscular pts
-
Does pre treatment with a non depol avoid K release?
NO
-
What can occur with rpt doses of succ? What type of drug would we want to have available?
- -Asystole
- -Anti-muscarinic
-
Succ can cause bradycardia, so should we give an anti-muscarinic at the same time?
- -In general no
- -Don't want to mask tachycardia from another source (like MH)
- -Might want to have ready if giving rpt succ doses
-
What's the most common SE with succ?
- -Myalgias
- -Most common in healthy outpt women
-
Masseter muscle spasm after succ
-Premonitory sign of MH
-
Cis-atrocurium claim to fame
not renally excreted so good for a pt in RF
-
What now obsolete drugs produced histamine?
metocurine and tubocurarine
-
What drug produces vagal blockade?
-
Main non depol used today
-
2 classes of non depol
examples of each
- steriods "-oniums"
- benzylquinolones "uriums"
-
Vd of non depol
- -Approximates ECF volume
- -200 ml / kg (14 L)
-
Non depol
-ionized or non
-water or lipid sol
-acid or base
- -ionized
- -water sol
- -never discussed from acid / base perspectice
- -all are quaternary ammoniums (no CNS effects)
-
Can non depols be given to a pregnant woman?
-Yes, they will not affect the fetus
-
Non depol onset time
2-7 mins
-
How do onset and potency of the non depols compare?
-Onset is fastest with low potency drugs as more needs to be given and the receptors are flooded
-
3 doses of non depols
- 1) intubating dose
- 2) 1st dose after giving succ for intubation= 1/2 of intubating dose
- 3) supplemental dosing to maintain 1-2 twitches, 20-25% of intubation dose
-
intubating dose of vec, panc, cis-atro
0.1
-
intubating dose of roc
0.6-1.2
-
intubating dose of atrocurium
0.4-0.5
-
How can the onset time of non depols be shortened?
-
priming
- -10-15% of intubating dose given 5 mins before induction to occupy enough receptors to speed onset
- -rarely done
-
priming risks / SE
- -dyspnea and desaturation
- -extraocular muscle is sensitive and pt may c/o double vision
-
pre-treatment dose
- -same as priming dose
- -10-15% of intubating dose
-
if a priming dose of a non depol is given, how does this effect the intubating dose?
-intubating dose = intubating dose minus priming dose
-
by what mechanism do the volatiles potentiate the non depols ?
postsynaptic augmentation
-
advantages of succ
- -fast on and off
- -no reversal needed
-
if a small amount of a non depol is given as succ pre-treatment, does it need to be reversed?
no, this is the only case where we don't reverse
-
factors that potentiate the non depols and cause increased duration
- -hypothermia
- -acidosis (also antagonizes reversal)
- -hypokalemia and hypocalcemia
- -hypermagnesemia
- -concurrent dz
- -drug interactions
- -age
-
how does age affect the non depols ?
- -neonates have increased sensitivity (immature NMJ)
- -but also have increased Vd (larger ECF)
- -so the dose is NOT decreased
-
How does Guillian-Barre affect response to non depols ?
-Varies from rx to hypersensitivity
-
What diseases can cause hypersensitivity to the non depols ?
ALS, autoimmune disorders, familial periodic paralysis, Gillian-Barre, MD, myasthenia gravis, myasthenic syndrome
-
What diseases can cause rx to the non depols ?
burn injury, CP, hemiplegia (rx on affected side), severe chronic infection (tetanus, botulism)
-
What does the RI (recovery index) tell you?
-how know when to check TOF and redose if needed
-
What does the T90 tell you?
-Time to 90% recovery
-
-
-
Suitable pt to use panc on
- -long case (it's long acting)
- -person who can handle the tachycardia
-
Why is tubocurarine obsolete?
- -extensive renal excretion
- -histamine release
-
Why is metacurine obsolete?
-preparations contain iodine
-
Metabolism of atrocurium
- -mostly ester hydrolysis
- -partly hoffman elimination
- -same as remi and esmolol, metabolized in the plasma by tissue esterases
-
Atrocurium SE
- -histamine release (minimized by slow administration)
- -active metabolite (laudanosine) causes CNS excitation, can occur at high concentrations in pt with liver dz
-
Cis-atro
- -atrocurium isomer (1 of 10)
- -metab by hoffman elimination
- -less laudanosine (more potent so used in lower doses)
- -no histamine
- -intermediate acting
-
Is atrocurium short, medium, or long acting?
intermediate
-
pancuronium
-duration
-structure
-metab and excretion
- -long acting
- -steroid ring with 2 modified Ach molecules attached
- -metab by liver
- -excreted by kidneys
-
panc SE
- -tachycardia (vagal blockade)
- -possible HTN (not usually seen)
-
vec
-structure
-metab
- -panc minus a quaternary methyl group
- -excreted in bile and 25% renally
-
vec SE
- -really none
- -prolonged blockade with long-term ICU administration may mimic chronic denervation
-
rocuronium
-structure
-elimination
- -steroid analog of vec designed for rapid onset
- -liver elimination
- -onset and duration are dose dependent
-
Problem with using rocuronium for RSI when succ contraind?
-A high dose is needed so it will last longer
-
How quickly can intubating conditions be obtained with roc?
1.5 mins
-
T or F, intubating conditions are dose dependent?
T
-
What drug class is used to reverse the non depols ?
- -cholinesterase inhibitors
- -AKA anti-cholinesterase
-
How do cholinesterase inhibitors work?
- -Inhibit Acetylcholinesterase by reversibly binding to the enzyme
- -Result is more Ach available at the NMJ
- -drug lines up with enzyme (at anionic and esteratic sites) to prevent Ach from contacting the enzyme
-
edrophonium
- -quartenary ammonium compound
- -short duration
- -main site of action is presynaptic
- -reversible inhibition of acetylcholinesterase
-
neostigmine, physostigmine, and pyridostigmine MOA
- -anti-cholinesterase agent
- -reversible inhibition
- -work by forming a carbamyl-ester complex on the enzyme
- -complex has a half-time of 15-30 mins
-
What are example of irreversible anti-cholinesterase agents?
- -Pesticides
- -Echothiopate (an eye drop!)
- -Nerve gases like Saran
- -New enzyme must be formed
- -Form a phosphorylate complex with the enzyme
-
Speed of onset, edrophonium vs. neostigmine
- edrophonium- rapid
- neostigmine- intermediate
-
SE of anti-cholinesterase agents
- -due to Ach accumulation
- -bradycardia, dysrhythmias
- - bronchospasm and secretions
- -intestinal spasm and increased peristalsis
- -increased bladder tone
- -pupillary constriction
-
Why is physostigmine the only anti-cholinesterase agent that causes CNS excitation?
-It's the only one that can cross the BBB as its a tertiary amine
-
How are the SE of the anti-cholinesterase agents attenuated?
By giving an anti-muscarinic simultaneously
-
When should neostigmine be given (how many twitches)?
- 1-3 (4) twitches
- <2 twitches- 0.07 mg / kg
- 3-4 twitches- 0.04 mg / kg
-
When should edrophonium be given (how many twitches)?
-4 twitches and decreased fade
-
Edrophonium dose
- -4 twitches moderate fade 0.5 mg / kg
- -4 twitches mild fade 0.25 mg / kg
-
What reversal drug should be given when no twitches are seen?
- -No drug!
- -Keep pt intubated, sedated, and ventilated until you get at least 1 twitch
-
Neostigmine max dose
5 mg
-
Dosing guidelines for glycopyrolate
-for each mg of neostigmine, you need to give 0.2 mg glyco
-
Which should be given first, the anti-cholinesterase agent or the anti-muscarinic? Can they be combined in 1 syringe?
-
Why is neostigmine used more often than edrophonium?
-Edrophonium is less effective than neostigmine in reversing dense blockade (where twitch height is less than 10% of control)
-
What inhibits anticholinesterase agents?
- -hypothermia
- -certain abx
- -resp or metab acidosis (PaCO2> 50 mmHg)
- -hypokalemia
-
anti-cholinergics
-AKA?
-3 or 4 amines?
- -AKA anti-muscarinics
- -tertiary- atropine, scopalomine; naturally occurs alkaloids of belladonna
- -quartenary- glycopryolate; semisynthetic
-
anti-muscarinics SE
- -increased HR (we give it to offset decreased HR of anti-cholinesterases)
- -decreased resp secretions
- -relaxation of bronchial smooth muscle
- -excitation, restlessness, hallucination (if crosses BBB)
- -decreased peristalsis
- -pupillary dilation
- -decreased ureter and bladder tone
-
What anti-muscarinic is recommended to use with neostigmine?
glyco
-
What anti-muscarinic is recommended to use with edrophonium?
-atropine
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