Unit 5 - Neuromuscular Blockers Flashcards
what are the 2 types of nicotinic AChRs at NMJ
- prejunctional Nn receptor: regulates ACh release
- postsynaptic Nm receptor: responds to ACh (depolarizes muscle)
enzyme in synaptic cleft
AChE
5 subunits of postsynaptic nicotinic receptor
- 2 alpha
- 1 beta
- 1 delta
- 1 epsilon
what causes postsynaptic nicotinic receptor to open
when 2 ACh molecules simultaneously occupy both alpha subinits
Na+ and Ca2+ enter cell, K+ exits
what causes postsynaptic nicotinic receptor to open
when 2 ACh molecules simultaneously occupy both alpha subinits
Na+ and Ca2+ enter cell, K+ exits
electrolyte movement when ACh activates Nm
Na+ flows down concentration gradient and enters cell
how is muscle contraction initiated after ACh binds to Nm receptor
- Na+ enters cell
- muscle cell depolarization instructs SR to release Ca2+ into cytoplasm
- engages in myofilaments, initiates muscle contraction
why don’t anions pass through Nm
repelled by negative charge
what is acetylcholinesterase metabolized to
choline + acetate
what terminates action of ACh
metabolism and diffusion away from receptor
what allows extrajunctional receptors to return later in life
denervation
prolonged immobility
where are EJRs distributed
NMJ & sarcolemma
conditions that increase EJRs
(avoid succs)
- Upper or lower motor neuron injury
- Spinal cord injury
- Burns
- Skeletal muscle trauma
- Cerebrovascular accident
- Tetanus
- Severe sepsis
- Muscular dystrophy
- Prolonged chemical denervation (Mg, long term NMB infusion, clostridial toxin)
how does succs affect serum K+
can transiently increase serum K+ by 0.5-1.0 mEq/L for up to 10-15 minutes
why can conditions that increase EJR cause life-threatening hyperkalemia
EJRs remain open longer than postjunctional receptors - allows more Na+ to enter & augments K+ leak
how is alpha 7 subunit (pathologic variant of nicotinic receptor) depolarized
succs and choline
general rule for avoiding succs with denervation injuries
- avoid for 24-48 hours after injury
- at least 1 year after
exception - burns (risk can exist for several years)
Primary treatment of succs-induced hyperkalemia
- IV CaCl
- hyperventilation
- sodium bicarbonate
- glucose + insulin
patient response to NDNMBs with increased EJRs
resistant
More receptors = more NMB needed to effectively antagonize Nm at NMJ
patient response to NDNMBs with increased EJRs
resistant
More receptors = more NMB needed to effectively antagonize Nm at NMJ
what causes fade with TOF
- when a NDNMB competitively antagonizes the presynaptic nicotinic receptor (Nn), ACh mobilization is impaired so only vesciles for immediate release can be used
- nerve stimulation can quickly exhaust this supply
- less ACh released with each successive stimulus
2 supplies of ACh at NMJ
1) some available for immediate release
2) some that must be mobilized before available for immediate release
what propagates AP along nerve axon
Na+ channels
how do ACh vesicles exit nerve
via exocytosis
each vesicle releases 5,000-10,000 ACh molecules into synaptic cleft
structure of
structure of postsynaptic nicotinic receptor at NMJ
- pentameric ligand-gated Na+ channel in motor endplate at NMJ
- 5 subunits that align circumferentially around an ion-conducting pore
what happens when ACh activates post-synaptic nicotinic receptor at NMJ
- ACh binds to alpha subunits, which prompts channel to open
- Na+ and Ca2+ enter cell, K+ leaves
- Na+ flows down concentration gradient and enters muscle cell
- voltage-gated Na+ channels activated, muscle cell depolarizes & generates AP
- myocyte depolarization instructs ER to release Ca2+ into cytoplasm to engage with myofilaments and cause muscle contraction
how is the ACh signal “turned off” at NMJ?
AChE positioned around pre- and postsynaptic nicotinic receptors hydrolyzes ACh almost immediately
where are EJRs distributed
at NMJ and also throughout sarcolemma
receptors stimulated by succs
prejunctional receptors
MOA of nondepolarizing NMBs
competitvely antagonize presynaptic Nn receptors
why is there no fade with succs
- succs facilitates mobilization of ACh when it binds to presynaptic Nn receptor
- there’s always ACh available for immediate release
what distinguishes between a phase 1 and phase 2 block
presence or absence of fade
phase 2 - ACh mobilization impaired, nerve terminal can only release imm
NMBs that cause phase 1 block
depolarizing NMBs
succs
NMBs that cause phase 2 block
nondepolarizers
succs in certain situations
2 situations that can create phase 2 block with succs
- dose > 7-10 mg/kg
- IV gtt
how is phase 2 block characterized
fade with tetany, prolonged duration
why can high dose succs cause phase 2 block
likely inhibits presynaptic nicotinic receptor, impairs ACh mobilization/release from presynaptic terminal, and/or creates conformational change in postsynaptic receptor
how many twitches will a patient have with succs
either 1 or 4
how to reverse a phase 2 block with succs
wait it out
(don’t give reversal)
best site to measure NMB onset with TOF
orbicularis oculi (closes eyelid) or corrugator supercilia (eyebrow twitch)
CN 7
Relying on flexion of the 5th finger over- or underestimates NMB recovery
over
best site to measure NMB recovery
adductor pollicis (thumb adduction) or flexor hallucis (big toe flexion)
Nerve = ulnar n. or posterior tibial n.
when is full recovery from NMB assumed
TOF ratio is > 0.9 at adductor pollicis
what is residual blockade
defined as TOF ratio <0.9
what Vt value suggests NMB recovery
5+ mL/kg
max receptors occupied when pt Vt 5+ mL/kg
80%
max % receptors occupied when pt reaches no fade with TOF
70
vital capacity that suggests NMB recovery & max receptors blocked
20+ mL/kg
70%
max % receptors blocked when pt has no fade with 50 Hz tetanus
60
inspiratory force that suggests NMB recovery
max % receptors blocked
better than -40 (more negative is better)
50%
max % receptors blocked with 5 second headlift
50
clinical endpoints of NMB evaluation that suggest max 50% receptors blocked
- head lift > 5 seconds
- hand grip same as preinduction
- holding tongue blade in mouth against force
best qualitative test of neuromuscular function
holding a tongue blade in the mouth against force
Limitation: can’t be performed with oral ETT in place
structure of succs
2 ACh molecules joined together
how can succs cause bradycardia
by stimulating M2 receptor in SA node
increases risk of bradycardia with succs admin
2nd dose
probably r/t primary metabolite succinylmonocholine
how can succs cause tachycardia
by mimicking ACh at sympathetic ganglia
how do adults vs. kids typically respond to succs in terms of HR
- Adults: tachycardia more common than bradycardia
- Kids: more susceptible to bradycardia d/t higher baseline vagal tone
how does succs affect IOP
Transiently ↑ IOP by 5-15 mmHg for up to 10 minutes
how to prevent increased ICP with succs
defasciculating dose
how does succs affect intragastric pressure
temporarily increases
prevent or minimize with defasciculating dose
how does succs affect barrier pressure
net unchanged (increases intragastric pressure, decreases LES tone)
does not increase risk of aspiration
how does succs affect barrier pressure
net unchanged (increases intragastric pressure, decreases LES tone)
does not increase risk of aspiration
side effect of succs that may or may not be related to an MH reaction
massetter spasm
black box warning of succs
risk of cardiac arrest and sudden death 2/2 hyperkalemia in children with undiagnosed skeletal muscle myopathy
function of dystrophin
(absence of protein in DMD)
- critical for structure of cytoskeletal on skeletal & cardiac muscle cells
- helps anchor actin and myosin to cell membrane
patho of DMD that results from absence of dystrophin
- sarcomma destabilized
- allows creatine kinase and myoglobin to enter systemic circulation & cause inflammation, fibrosis, cell death
why are patients with DMD predisposed to hyperkalemia with succs
Absence of dystrophin alters type and number of postjunctional nicotinic receptors on muscle cell
s/s DMD assoc. with dystrophin absence
- skeletal muscle weakness
- conduction abnormalities
- cardiomyopathy
- sometimes cognitive impairment
marker of skeletal muscle breakdown
Creatine phosphokinase
EKG changes with mild hyperkalemia
peaked T waves, prolonged PR
treatment of cardiac arrest in a child after induction with succs
immediately start treating for hyperkalemia:
1. Stabilize myocardium: CaCl 20 mg/kg or CaGluc 60 mg/kg
2. Shift K+ into cells: hyperventilation, glucose + insulin, sodium bicarbonate, albuterol
3. Enhance K+ elimination: Lasix 1 mg/kg, volume resuscitation, dialysis, hemofiltration
elemental calcium in 10% CaCl vs. 10% CaGluc
10% CaCl = 27.2 mg/mL elemental calcium
10% CaGluc = 9 mg/mL
how much 10% glucose to use when treating cardiac arrest from succs
0.3-0.5 g/kg 10% glucose solution + 1 unit insulin per 4-5 g IV glucose
s/s postoperative myalgia assoc. with succs
muscle soreness in neck, shoulders, subcostal region, upper abd/trunk muscles
MOA of postop myalgia with succs
Believed to be r/t uncoordinated muscle contraction (fasciculations) before paralysis
pts at highest risk of postoperative myalgia with succs
young adults undergoing ambulatory surgery (women > men), those who don’t routinely engage in strenuous activity
do opioids decrease myalgia with succs
nope
pts with lowest incidence of postop myalgia with succs
Children, elderly, and pregnant pts seem to have lowest rates of occurrence
methods to decrease risk postop myalgia with succs
- NDNMB pretreatment
- NSAIDs
- lidocaine 1.5 mg/kg
- higher vs lower dose of succs
defasciculating dose
1/10th ED 95 dose of non-depolarizer
2mg roc, 1.5 mg atracurium, 0.3 vec 3-5 min before succs
why is a higher dose of succs needed if defasciculating dose of NDNMB used
- Nondepolarizer will competitively antagonize nicotinic receptor
- more succs needed to overwhelm effect
primary location of AChE
NMJ
synonyms for AChE
- Acetylcholinesterase
- Genuine cholinesterase
- Type 1 cholinesterase
- True cholinesterase
- Specific cholinesterase
primary location of pseudocholinesterase
plasma
synonyms for pseudocholinesterase
- Butyrylcholinesterase
- Pseudocholinesterase
- Type 2 cholinesterase
- False cholinesterase
- Plasma cholinesterase
enzyme that metabolizes succs, mivacurium, and ester LAs
pseudocholinesterase
where is pseudocholinesterase produced
liver
how does pseudocholinesterase activity serve as an indicator of hepatic function
produced in liver
reference concentration range of pseudocholinesterase
2900-7100 units/L in plasma
how does plasma concentration of Pseudocholinesterase affect symptoms
Neuromuscular symptoms begin at 60% of normal, prominent at 20% of normal
where is pseudocholinesterase located
liver, smooth muscle, intestines, white matter, heart, pancreas (not CSF)
drugs that reduce Pseudocholinesterase activity
- Metoclopramide
- Esmolol
- Neostigmine (not edrophonium)
- Echothiopate
- Oral contraceptives/estrogen
- Cyclophosphamide
- MAOIs
- Nitrogen mustard
diseases that decrease pseudocholinesterase activity
- Atypical PChE
- Severe liver disease
- Chronic renal disease
- Organophosphate poisoning
- Burns
- Neoplasm
- Advanced age
- Malnutrition
- Pregnancy (late stage)
definitive diagnosis of atypical acetylcholinesterase
dibucaine test
what is dibucaine
amide LA that inhibits normal plasma cholinesterase (no effect on atypical PChE)
what does dibucaine number reflect
% of normal enzyme inhibited by dibucaine
normal dibucaine no.
80 (dibucaine has inhibited 80% of pseudocholinesterase in sample)
genotype, dibucaine no., and succs duration assoc. with typical homozygous pseudocholinesterase
- genotype = UU
- dibucaine no = 70-80
- succs duration = 5-10 min
genotype, incidence, dibucaine no., and succs duration assoc. with typical heterozygous pseudocholinesterase
- genotype = UA
- incidence = 1/480
- dibucaine no = 50-60
- succs duration = 20-30 min
genotype, dibucaine no., and succs duration assoc. with atypical homozygous pseudocholinesterase
- genotype = AA
- incidence = 1/3200
- dibucaine no = 20-30
- succs duration = 4-8 hours
what is atypical plasma cholinesterase
Pseudocholinesterase is produced in sufficient quantity but not functional
qualitative defect
what is atypical plasma cholinesterase
Pseudocholinesterase is produced in sufficient quantity but not functional
qualitative defect
methods to restore levels in atypical pseudocholinesterase
Whole blood, FFP, or purified human cholinesterase
treatment of choice for atypical pseudocholinesterase
postop mechanical ventilation
diseases assoc. with hyperkalemia from succs
- DMD
- Guillain-Barre
- MS
- ALS
- Charcot-Marie-Tooth
- Hyperkalemic Periodic Paralysis
diseases assoc. with nondepolarizing NMB sensitivity
- DMD
- Guillain Barre
- MS
- ALS
- Huntingdon
- Myasthenia gravis
- myotonic dystrophy (may have normal response)
what is the ED95 of a non-depolarizing NMB
dose at which there’s a 95% decrease in twitch height
relationship between ED95 and NDNMB potency
inversely related
measure of potency
how can ED95 of NDNMB be used to predict onset
higher ED95 = lower potency = faster onset
mivacurium:
- ED95
- intubation dose
- onset
- duration
- ED95: 0.067 mg/kg
- intubation dose: 0.15 mg/kg
- onset: 3.3 min
- duration: 16.8 min
cisatracurium:
- ED95
- intubation dose
- onset
- duration
- ED95: 0.04 mg/kg
- intubation dose: 0.1 mg/kg
- onset: 5.2 min
- duration: 45 min
vecuronium:
- ED95
- intubation dose
- onset
- duration
- ED95: 0.043 mg/kg
- intubation dose: 0.1 mg/kg
- onset: 2.4 min
- duration: 45 min
atracurium:
- ED95
- intubation dose
- onset
- duration
- ED95: 0.21 mg/kg
- intubation dose: 0.5 mg/kg
- onset: 3.2 min
- duration: 45 min
rocuronium:
- ED95
- intubation dose
- onset
- duration
- ED95: 0.305 mg/kg
- intubation dose: 0.6 mg/kg
- onset: 1.7 min
- duration: 35 min
pancuronium:
- ED95
- intubation dose
- onset
- duration
- ED95: 0.067 mg/kg
- intubation dose: 0.08 mg/kg
- onset: 2.9 min
- duration: 85 min
short-acting NDNMB
mivacurium
intermediate-acting NDNMBs
cisatracurium, vecuronium, atracurium, rocuronium
NMBS in benzylisoquinolinium class
Atracurium
Cisatracurium
Mivacurium
-curium
NMBs in aminosteroid class
Rocuronium
Vecuronium
Pancuronium
-ronium
are NMBs ionized or unionized
ionized
which NDNMB class is more affected by renal failure
aminosteroids (may prolong duration)
metabolism of atracurium
Ester hydrolysis 66%
Hofmann 33%
elimination of atracurium
10-40% renally eliminated
(no liver)
metabolite of atracurium & cisatracurium
laudanosine
metabolism of cisatracurium
77% hoffman
elimination of cisatracurium
- mostly hofmann
- renal elim. is 16% of total clearance
- no liver
what is Hofmann elimination
base-catalyzed reaction dependent on normal blood pH and temperature
how do pH & temp affect Hofmann elimination
- Faster with alkalosis & hyperthermia
- Slower with acidosis & hypothermia
potential adverse effect of laudanosine accumulation
seizures
metabolism & elimination of roc
- metabolism: none
- > 70% liver elim
- 10-25% renal elim
- no metabolites
primarily eliminated via biliary excretion as unchanged molecule
metabolism & elimination of vec
- 30-40% liver metabolism
- 40-50% hepatic elim.
- 50-60% renal elim
- metabolite: 3-OH vecuronium
metabolism & elimination of pancuronium
- metabolism: 10-20% liver
- 15% hepatic elim
- 85% renal elim
- metabolite: 3-OH pancuronium
how can elim 1/2 times of aminosteroid NDNMBs be prolonged
- hepatic dysfunction
- renal failure
- age extremes
greatest to least NMB potentiation with volatiles
Des > Sevo > Iso > N2O > Propofol
antibiotics that potentiate NMB
Aminoglycosides, polymyxins, clindamycin, lincomycin, tetracycline
antidysrhythmics that potentiate NMBs
- Verapamil
- amlodipine
- lidocaine
- quinidine
how does lasix affect NMBs
potentiates
how does lithium potentiate NMB
↑ activates potassium channels
how do Mg, Ca, and K affect NMB
- Mg ↑ = ↓ ACh release from presynaptic nerve
- Ca ↓ = ↓ ACh release from presynaptic nerve
- K ↓ = ↓ RMP
how does hypothermia affect NMB
↓ metabolism & clearance
how does cyclosporin affect NMB
potentiates
NMBs that can cause histamine release & how to minimize
succinylcholine, atracurium, mivacurium
minimize with slow admin.
NMB that can stimulate autonomic ganglia
succs
not affected by rate of admin.
NMB with slight vagolytic effect
pancuronium
MOA of vagolytic effect with pancuronium
Inhibits M2 receptors in SA node, stimulates catecholamine release, inhibits catecholamine reuptake in adrenergic nerves
↑ HR & CO, minimal effect on SVR
MOA of vagolytic effect with pancuronium
Inhibits M2 receptors in SA node, stimulates catecholamine release, inhibits catecholamine reuptake in adrenergic nerves
↑ HR & CO, minimal effect on SVR
NMB pts with HCOM should not get and why
pancuronium - vagolytic effect can cause LVOTO
most common cause of periop allergic reactions
NMBs
1st - succs
2nd - roc
how do NMBs cause allergic reactions
- NMB structures contain 1 or more antigenic quaternary ammonium groups that interact w IgE
- Causes mast cell and basophil degranulation
lab value that reflects allergic reaction to NMB
elevated tryptase level (peaks at 15-120 min)
assoc. between exposure to soap/cosmetics and NMB allergy
- NMB structures contain 1 or more antigenic quaternary ammonium groups that interact w IgE
- Possible to develop following exposure to soap or cosmetics (contain quaternary ammonium)
What characterizes a phase II block following succs administration?
Inhibition of presynaptic nicotinic receptors
do NMBs treat bronchospasm
No - they relax skeletal muscle, NOT smooth muscle
possible explanations for why des potentiates NMB the most of volatiles
- central alpha effect on motor neurons
- inhibition of postjunctional nicotinic receptors at NMJ
- increased NMB affinity at postjunctional nicotinic receptors at NMJ
