NMBAs Flashcards
What is the resting membrane potential of a neuron? Threshold potential?
resting: -90mV
threshold: -45mV
What is the principle effect of NMBAs?
to interrupt transmission of nerve impulses at the NMJ in order to optimize surgical conditions and augment patient safety
What types of channels and receptors are found in the membrane of the presynaptic nerve terminal?
- voltage-gated Ca++ channels
- Nicotinic ACh receptors
Where are nicotinic ACh receptors located?
presynaptic and postsynaptic cell membranes
How and where is ACh synthesized?
how: acetyl-CoA and choline are catalyzed via choline acetyltransferase (ChAT)
where: cytoplasm
Describe the transportation of ACh throughout the cell:
transported from cytoplasm in synaptic vesicles (quanta) containing 1-50K molecules per vesicle. 5-10K ACh molecules are released per vesicle.
What prompts ACh quanta to fuse with the cell membrane?
- motor nerve AP enters, depolarizes nerve terminal
- voltage-sensitive Ca++ channels open
- Ca++ diffuses down conc. gradient within nerve terminal (enters the cell)
- ACh vesicles fuse with nerve cell membrane
What does release of ACh depend on?
Ca++ entry into the nerve terminal
How is the amount of ACh in the cell maintained?
positive feedback mechanism:
- ACh is released into the synaptic cleft
- ACh diffuses down conc. gradient from pre to postsynaptic cell
- presynaptic nicotinic ACh receptor responds to ACh by increasing synthesis and release
What type and how many subunits of the nicotinic ACh receptor must be activated before anything happens?
2 alpha subunits (5 subunits total) must be bound with 2 ACh molecules
Describe what happens when ACh is bound with a nicotinic ACh receptor:
- 2 ACh bind to 2 alpha subunits of nicotinic ACh receptor
- channels snap open
- Na+ and Ca++ INTO postsynaptic cell
- K+ OUT of postsynaptic cell
- ion shifts cause motor end plate to depolarize and trigger an action potential
How many postsynaptic nicotinic ACh receptors need to be occupied to generate an AP at the motor end plate?
250-500K of the 5 million postsynaptic receptors
What happens to ACh when it interacts with acetylcholinesterase?
- AChE splits ACh into choline and acetate
- choline transported back to nerve terminal for reconversion to ACh
- acetate diffuses away
- hydrolyzation happens rapidly d/t high conc of AChE at synapse
Where are nicotinic receptors located (3 places) and what are they responsible for in each location?
1) presynaptically: when combined with ACh, further augment ACh release
2) postsynaptically: play a role in initiating depolarization OR blockade by NDMAs
3) extrajunctionally: structurally different from nicotinic receptors @ synapse; proliferate in response to paralysis, dystrophies, motor neuron injury, burns; stay open 4x longer and upregulate K+
Describe the nicotinic receptor at the NMJ:
- ligand-gated ion channel
- 5 subunits (2 alpha, 1 beta, 1 delta, 1 episilon)
- both alpha subunits must be occupied by an agonist (ACh) for channel to open
- when open: Na+ & Ca++ enter; K+ exits
What happens what Na+ and Ca++ enter the cell, and K+ exits the cell?
depolarization
Describe how ACh is made:
AcetylCoA and choline are combined via choline acetyltransferase to produce ACh
occurs in the presynaptic neuron
Where is ACh stored?
vesicles until the neuron fires/depolarizes
Where is acetylcholinesterase stored?
synaptic cleft
Give 4 names for AChE:
true cholinesterase
specific ‘’
genuine ‘’
type I ‘’
Depolarizing muscle relaxants act as ACh receptor (agonists/antagonists).
agonists
NDMAs act as ACh receptor (agonists/antagonists)
competitive antagonists
What medication is the only short acting depolarizing muscle relaxant?
succinylcholine
Name the long acting NDMRs:
pancuronium
Name the intermediate acting NDMRs:
atracurium
cisatracurium
rocuronium
vecuronium
Name the short acting NDMRs:
mivacurium (no longer available)
How is succinylcholine related structurally to acetylcholine?
Succs is 2 ACh molecules bound together
What is the MOA of succinylcholine?
- ACh nicotinic receptor agonist
- mimics the action of ACh in both presynaptic and postsynaptic neurons
- presynaptic: mobilizes supplies of ACh in nerve terminal
postsynaptic: causes ion channels top open, generating a prolonged depolarization of muscle end plate
What does “absolutely refractory period” mean?
action potentials cannot be initiated in the skeletal muscle cell until the cell repolarizes; voltage-gated Na+ channels in the membrane adjacent to the motor end plate snap into the inactivated state
What is the dose, onset, and duration of succinylcholine?
dose: 0.5-1 mg/kg
onset: 30 seconds
duration: 3-5 minutes
What is the ED95 of succinycholine?
0.3mg/kg
Why does succinylcholine have a short DOA?
rapid hydrolysis by plasma cholinesterase
What is the metabolite of succinylcholine?
succinylmonocholine
List the alternative names for plasma cholinesterase:
pseudocholinesterase
butyrylocholinesterase
false cholinesterase
non-specific ‘’
type II ‘’
How much of an injected dose of succinylcholine reaches the NMJ?
10%
Where is plasma cholinesterase primarily located?
plasma
Give 3 reasons for a prolonged blockade by succinylcholine:
1) liver disease (decreased hepatic production of plasma cholinesterase
2) drug-induced decreases in plasma cholinesterase
3) genetically determined presence of atypical plasma cholinesterase
What drugs lower plasma cholinesterase?
metoclopramide
esmolol
neostigmine, pyridostigmine
echothiophate
oral contraceptives/estrogen
cyclophosphamide
N2 mustart
MAOIs
What co-existing conditions can lower plasma cholinesterase?
atypical plasma cholinesterase
liver disease
renal disease
burns
elderly
organophosphate poisoning
neoplasm
malnutrition
pregnancy
Atypical plasma cholinesterase is a (quantitative/qualitative) defect.
qualitative
(pseudocholinesterase produced in sufficient quantity, but it is not functional)
What is the anesthetic implication of atypical plasma cholinesterase?
- cannot hydrolyze succinylcholine
- prolonged neuromuscular blockade (1-3 hours instead of 3-5 minutes) after normal dose
How is atypical plasma cholinesterase dianosed?
Dibucaine test (measures the percentage of inhibition of pseudocholinesterase activity)
Describe dibucaine and its relevance to plasma cholinesterase:
local anesthetic that inhibits normal plasma cholinesterase activity (NO effect on atypical)
Give the range of results of a dibucaine test and their implications:
80+= normal response to succs (recover 8-10 minutes)
40-60= response to succs prolonged 50-100% (20-30 minutes)
20 and below= response to succs prolonged by 4-8 hours
A patient who is heterozygous for atypical plasma cholinesterase will have what response to succs? What about homozygous for atypical?
heterozygous = dibucaine # 50-60, 20-30 mins recovery
homozygous atypical = dibucaine # 20-30, 4-8 hour recovery
Describe succinylcholine-induced postoperative myalgias:
- typically in neck, back, abdomen
- last for 24-48 hours
- common in young muscular adults, women > men
- minimized with NDMR pretreatment?
- prevention is to avoid succs, deep intubation
List the potential side effects of succinylcholine:
- bradycardia (esp peds)
- tachycardia and HTN
- hyperkalemia
- myalgias
- myo-globinuria
- incr intra-gastric pressure, ICP, IOP
- MH
- masseter spasm
- prolonged respiratory paralysis
In which population is routine administration of succs contraindicated?
peds - risk of cardiac arrest and sudden death d/t hyperkalemia in children with undiagnosed skeletal muscle myopathy
List the factors that can alter the depolarizing blockade with succinylcholine:
- antibiotics (esp aminoglycosides)
- local anesthetics
- anticholinesterase agents
- increased extracellular K+
- increased extracellular Mg+
- inherited pseudocholinesterase defect
- lithium
Succs can increased K+ in the body - list the potential conditions that can accentuate this side effect:
- muscular dystrophy
- burns
- conditions with upregulation of extrajunctional ACh receptors (paraplegia, Guillain-Barre, CVA, spinal cord injury, etc)
- severe sepsis
Describe how extrajunctional nicotinic receptors differ from presynaptic and postsynaptic receptors:
- subunits differ (gamma subunit instead of epsilon, or 5 alphas)
- response to ACh and succs:
*increased sensitivity
*stay open 4x longer
*increased efflux of K+
What is the MOA of non-depolarizing muscle relaxants?
- competitive antagonists at nicotinic ACh receptors
- presynaptic: inhibit mobilization of ACh to be ready for exocytosis
- postsynaptic: combine with ACh receptors, competitively block ACh from attaching; channels stay closed, no electrolyte movement
- no DIRECT effect on the channel (unlike depolarizing agents)
Describe the pharmacokinetics of NDMRs:
- highly ionized
- water soluble
- limited lipid solubility (do not cross BBB or placenta)
- renal and hepatic elimination
- 50% bound to plasma protein
What are the steroidal NDMRs?
pancuronium (L)
vecuronium (I)
rocuronium (I)
What are the benzylisoquinolinium NDMRs?
atracurium (I)
cisatracurium (I)
mivacurium (S) - no longer available
Which class of NDMRs is not dependent on hepatic or renal function for metabolism/elimination? What happens to them instead?
benzylisoquinoliniums (atracuritum & cisatracurium)
instead, they undergo spontaneous degradation in the plasma
Describe the metabolism and elimination of atracurium:
metabolism: 66% ester hydrolysis, 33% Hoffman
liver elim: NONE
renal elim: 10-40%
metabolite: laudanosine (can cause seizures)
Describe the metabolism and elimination of cisatracurium:
metab: 77% Hoffman, no ester hydrolysis
liver elim: NONE
renal elim: 16% of total clearance
metabolite: laudanosine (5x less than atracurium)
Which class of NDMRs is dependent on hepatic/renal function for metabolism/elimination?
aminosteroids
Describe the metabolism and elimination of rocuronium:
metab: NONE
liver elim: 70%
renal elim: 10-25%
metabolite: NONE
Describe the metabolism and elimination of vecuronium:
metab: liver 30-40%
liver elim: 40-50% (cleared in bile)
renal elim: 25-30%
metabolite: 3-OH vecuronium (1/2 the potency)
Describe the metabolism and elimination of pancuronium:
metab: liver 10-20%
liver elim: 15%
renal elim: 85%
metabolite: 3-OH pancuronium (1/2 the potency)
Which NDMRs produce a vagal blockade?
pancuronium (blocks vagal muscarinic receptors in SA node)
rocuronium (slight effect)
List each NDMR’s primary means of elimination:
atracurium: ester hydrolysis
cisatracurium: Hoffman
rocuronium: liver
vecuronium: liver
pancuronium: renal
Which NDMR is associated with histamine release? What effect can it have?
atracurium – may lead to hypotension and tachycardia; dependent on dose and speed of injection
((succs is also associated with histamine release, but is a depolarizing NMBA))
List the NMBAs with active metabolites:
succs - succinylmonocholine
atracurium - laudanosine
cisatracurium - laudanosine
vecuronium - 3OH vec
pancuronium - 3-OH pan
rocuronium does not have a metabolite
Which paralytics are most associated with anaphylaxis?
succ > roc > atracurium > cisatracurium > vec
Describe how paralytics cause anaphylaxis:
chemical structure has an antigenic quaternary NH4+1 group that interacts with IgE causing mast cell and basophil degradation and increasing tryptase
What is the dose/onset/duration of pancuronium?
- dose: 0.067 mg/kg
(intubating 0.1 mg/kg)
(maintenance 0.01 mg/kg) - onset: 3-5 mins
- duration: 45-90 mins
When considering NDMRs, think ______ when you hear “renal elimination”.
pancuronium
What is the dose/onset/duration of vecuronium?
- dose: 0.043 mg/kg
(intubating: 0.1 mg/kg)
(maintenance: 0.01 mg/kg) - onset: <3 mins
- duration: 25-30 mins
What is the dose/onset/duration of rocuronium?
- dose: 0.305 mg/kg (LEAST potent)
(intubating: 1 mg/kg)
(maintenance: 0.1 mg/kg) - onset: 45-90 sec
- duration: 15-30 mins
Which NDMR is ideal for RSI?
rocuronium
What is the dose/onset/duration of atracurium?
- dose: 0.21 mg/kg
(intubating: 0.5 mg/kg)
(maintenance: 0.1 mg/kg) - onset: <3 mins
- duration: 20-35 mins
Describe Hoffman elimination:
spontaneous non-enzymatic chemical breakdown that occurs at physiologic pH and temp
Describe ester hydrolysis:
catalyzed by nonspecific esterases (NOT AChE or pseudocholinesterase)
Which drug should be avoided in patients sensitive to histamine release? Why?
atracurium
- tachycardia, hypotension, and increased PIP can cause issues
What is the dose/onset/duration of cisatracurium?
- dose: 0.04 mg/kg
(intubating: 0.2 mg/kg)
(maintenance: 0.01 mg/kg) - onset: <3 mins
- duration: 30-60 mins
List the NDMRs in order of potency from least to greatest:
roc < atracurium < pan < vec < cisatracurium
What is ED95 when it comes to NDMRs?
dose where there is a 95% decrease in twitch height
- measure of potency (inversely related)
- dose required for optimal tracheal intubation is 2-3x the ED95
List the drugs that potentiate NDMR action:
- aminoglycoside abx
- antiarrhythmics
- local anesthetics
- volatiles (des>SEVO>iso>N2O)
- MgSO4
- lithium
- loop diuretics
List the patient factors that potentiate NDMRs:
- hypothermia
- gender (women are more sensitive)
List the electrolyte factors that potentiate NDMRs:
- HYPERmagnesemia
- HYPOcalcemia
- HYPOkalemia
What effect does chronic anticonvulsant therapy have on NDMRs?
decreases the effect of NDMRs; accelerated recovery and increased dosages required (block doesn’t last as long)
What electrolyte imbalances decrease the effect of NDMRs?
- hyperparathyroidism
- hypercalcemia
(more ACh to compete with NDMRs)
How do patients with myasthenia gravis respond to NDMRs?
- increased sensitivity to NDMRs
- resistant to succs
*fewer functional ACh receptors d/t degradation by antibodies
How do patients with muscle denervation injuries respond to NDMRs?
- resistant to NDMRs
- exaggerated response to succs
*chronic decrease in ACh release with upregulation of postsynaptic ACh receptors; more ACh receptors to be blocked and more being depolarized
Which PNS location is best to monitor recovery?
nerve: ulnar
muscle: adductor pollicis
Which PNS location is best to monitor onset?
nerve: facial
muscle: orbicularis oculi or corrugator supercilii
What is the pneumonic to list muscles in order from least to most sensitive to NDMRs?
Vocal cords
Die (diaphragm)
Out (orbicularis oculi)
After (abdominal rectus)
Adding (adductor pollicis)
Muscle (masseter)
Paralysis (pharyngeal)
Externally (extraocular)
What causes fade in PNS signals?
- antagonism of presynaptic nicotinic receptors by NDMRs
- blocked N receptors cause less release of ACh from vesicles
- limited supply of ACh in the synaptic cleft
What 2 situations may cause a phase II block?
1) succs dose > 7-10 mg/kg
2) 30-60 mins of continuous IV infusion of succs
Describe a phase I block:
- depolarizing
- typically preceded by fasciculation
- decrease in twitch tension
- NO FADE during repetitive stimulation
- NO post-tetanic potentiation
Describe a phase II block:
- non-depolarizing
- decrease in twitch tension
- FADE during repetitive stimulation
- post-tetanic potentiation
What does a TOF ratio indicate?
TOF 0.15-0.25 = adequate surgical relaxation
TOF <0.9 = increased aspiration and pharyngeal dysfxn
TOF <8 = impaired inspiratory flow and partial airway obstruction
TOF >0.9 = safe extubation
3 twitches corresponds to what percentage of neuromuscular block?
75%
Which 4 bedside tests indicate a maximum of 50% of receptors remain occupied?
- inspiratory force - better than -40cm H2O
- head lift >5sec - sustained x5sec
- handgrip same as preinduction - sustained x5sec
- sustained jaw clench on tongue blade - sustained x5sec
Sustained tetanus x5sec indicates what % of receptors are occupied?
60%
Vital capacity of >20mL/kg indicates what % of receptors remain occupied?
70%
4/4 TOF with no fade indicates what % of receptors remain occupied?
70-75%
A single twitch on the PNS indicates what % of receptors remain occupied?
75-80%
A tidal volume >5mL/kg indicates what % of receptors remain occupied?
80%
