NMBA Flashcards
Clinical Use of NMBAs
- Eliminate laryngeal spasm, RSI, rapid control of airway
- Central, immobile eye position for ophthalmic sx
- Sx access; prevention of spontaneous movement for neurologic, cardiothoracic, ophthalmic sx
- Decreased resistance to controlled ventilation
- Reduction of SkM tone
NMJ
AKA motor end plate
= communication btw nervous system, m – NMBA interfere/block connection
Prejunctional motor nerve ending, postjunctional membrane of skeletal m
Main NT?
Acetylcholine
What is the ACh R?
Nicotonic ACh R - LG Na channels
Motor Unit
Uninterrupted large myelinated N from SC to NMJ/target m divides into many branches to contact many m fibers
Synpatic Cleft
Separates nerve from m
ACh in Presynaptic Nerve
o ACh synthesized in nerve terminal, stored in vesicles (quanta)
o Readily available ACh: at edge of presynaptic cell, available for exocytosis/release
o Reserve ACh: deeper in pre-synaptic cell, supply of ACh
Structure of the Postsynaptic M Cell
o Surface folded, secondary clefts within primary ones –> large surface area
o Shoulders = nAChRs (~5M/junction)
Safety feature, have far more than need
VG Na channels in clefts
o Proximity btw VG Na channels, LG Na channels helps to propagate AP
Change in endplate potential –> AP –> stimulation of m cell –> m ctx
Perijunctional Zone
o Immediately below NMJ, crucial for functioning
o Mixture of receptors –> enhances capacity of Na channels to propagate wave of depolarization created by nAChRs
NM Transmission
o Nerve synthesizes ACh – stored in small vesicles
o Arrival of AP through nerve activates VG Ca channels via AC, production of cAMP
o Increased intracellular Ca –> migration, discharge of vesicles
o Two molecules of ACh bind nAChR 2 molecules ACh required to activate R
o LG Na channels open, trigger opening of VG Na channels AP on m – all or none
o Depolarization of m cell (=ctx) occurs after Ca from t-tubules
o ACh immediately detaches, destroyed by AChEs
o Note: activation of process to initiate m ctx vs process of m ctx itself
High Margin of Safety
o Amt of quanta released = small fraction of that available
o Safety margin/factor = excess in amplitude of EEP over firing threshold
o AP endplate threshold depends on density, state of excitability of Na channels
o Key: release more ACh than need, have more nAChR than need
Amplitude of end-plate potential (EEP)
depends on # of quanta released, # of nAChRs
Excess of ACh released, nAChRs present several folds above what’s necessary
Sensitivity of postsynaptic membrane to ACh dependent on density of AChR, AChR conductance
Redundant: if function decreased, maintain NM transmission
Acetylcholinerase
very efficient, much of ACh hydrolyzed before reaches post-synaptic cell (~50%)
o Secreted by m cell
o High concentrations in cleft
nAChRs
o Synthesized in muscle cells, anchored to motor end plate membrane by rapsyn protein
o Electron microscopy: central pit (ion channel) surrounded by raised area (binding site)
o 5 subunits, passes through muscle membrane – protrudes in/out
Receptor Density in Junctional Folds
Receptor density in junctional folds: 10-20,000/microm2
Interaction btw ACh and nAChR
o ACh interacts with two a1 subunits – NEEDS TO INTERACT WITH BOTH
Protein rotates conformation –> ion channel opens –> ion flow
Small cations only: Na in, K/Ca out
Binding of ligand to R = competitive process, antagonists have advantage bc only need to occupy 1 R
What are the three types of ACh R?
- presynaptic
- Postsynaptic adult
- Postsynaptic fetal
Presynaptic nAChR
a3b2 subunits
- Mediates negative/positive FB loops – neg fb to block ACh release, pos fb to prepare nerve cell to release more ACh for next m ctx
- Development of fade when blocked by non-depolarizing
- Not inhibited by sux –> no fade during phase 1 block
- M1/M2 R (GPCR) also modulate pos/neg fb of ACh release from prejunctional cell via modulation Ca influx
Fetal nAChR
Sometimes called extrajunctional, located all over muscle cell surface
During first few weeks of life, gamma subunit replaced by episilon
See in disuse injury, trauma, burns, nerve injury, muscle atrophy
Humans: usually decreased within 48hr, can appreciate for up to 2yr
Different affinity for ACh, different opening times
Consequence of More fetal nAChR
decreased sensitivity to non-depolarizing/competitive but increased sensitivity to depol/non-compet (sux)
* ACh channels stay open longer –> more K+ efflux –> extreme hyper K+
* Low conductance channel
Causes of Increased Fetal nAChR?
-Spinal cord injury
-Stroke
-Burns
-Prolonged immobility
-MS
-Prolonged exposure to NMBAs
Causes of Downregulated nAChR?
-MG
-AChE Poisoning
-OP Poisining
Two Structures of Fetal nAChR?
fetal R a1a1b1delta-gamma and a7
Consequence of increased fetal nAChR?
Increased sensitivity to sux, increased risk hyperkalemia
Decreased sensitivity to non-depor NMBA
Adult nAChR
(a1a1b1delta-episilon): mainly responsible for NMB effects – twitch depression
How weaker/slower muscular twitch becomes
High affinity binding site btw alpha and episilon, low affinity btw alpha + beta
High conductance channel
Two Main Hypotheses Assoc with NMBA
- Desensitized State Hypothesis
- Channel Blockade Hypothesis
Desensitized State Hypothesis
o Disruption of NM transmission by NMBA
o R bind ACh to alpha subunits but conformational changes, channel opening does not occur
R said to be “desensitized”
o Agonists, antag, inhalants appear able to switch to desensitized state
Explains synergistic actions btw inhalants + NMBAs
o Sux, thiopental, Ca channel blockers, LAs, phenothiazines, cyclohexamines, some ABX
Channel Blockade Hypothesis
o Cholinergic R binds agonist to each of alpha subunits –> ion channel opens –> molecule becomes stuck within channel
o Mouth of ion channel much wider than TM-spanning region, permits entrance of ions but not crossing
Entrapped molecules act like plugs
Interfere with normal passage of ions IRT binding of ACh
o Blocks normal NM transmission by interfering with depolarization process IRT binding of agonist
Why is the channel blockade hypothesis important?
paralysis not antagonized by admin of AChE-I
AChE-I may increase intensity blockade –> opening of more ion channels IRT greater concentration of ACh may provide increase opportunity for offending molecules to become trapped within channel
o Caused by many drugs, including NMBA
Partial explanation: admin of AChE-I to antagonize profound NMB may intensify paralysis
CV Effects of NMBAS
o Similarly in structure btw ACh, NMBA – positively charged nitrogen atom
o Stimulation, blocking of cardiac muscarinic R or of sympathetic ganglia = increase/decrease in HR, development of cardiac dysrhythmias
Effect of rapid IV injection of d-Tubocurarine
blocked action of ACh at sympathetic ganglia –> decrease in sympathetic tone, hypotension
Effect of rapid IV inj pancuronium:
increase HR DT blockade of cardiac muscarinic R –> decrease PNS activity, +/- release of NE from sympathetic nerves
Effect = inconsistent btw species: dogs, pigs, ponies yes; horses, calves no
Histamine Release
o DT quaternary ammonium structure, cross-bridging with IgE in mast cells
See quaternary ammonium in foods, household chemical products
o Leading cause of hypersensitivity rxn in ax in people
o Vasodilation, decrease BP, +/- increase HR
o Benzylisoquinolines > steroids with low potency
Biggest offender = d-Tubocurarine
Atra, but at 2.5x ED50 to cause clinically significant histamine release
o Pretreat with H1/H2 R antagonists, slow IV inj, no more than recommended doses
CNS Effects
o Large, polar, hydrophilic molecules – do not readily cross cell membranes BUT most gain access to CSF, may be assoc with resultant CNS effects
o No effect on MAC of halothane reduction in people (panc, atra, vec)
o Accidental admin in CSF: myotonia, autonomic effects, sz
What metabolite of NMBA does have CNS effects?
Laudanosine easily crosses BBB in dogs, does not reach clinically applicable doses to cause CNS stimulation with clinically used doses of atracurium
What effect does NMBA have on the urethra?
- Unblocking in male cats: urethra contains skeletal muscle, two papers
o Galluzzi et al JSAP 2012 – Effects of intraurethral administration of atracurium in male cats with urethral plugs
NMBA Protein Binding
o ~50%, All = protein bound, unclear clinical significance
o Only unbound fraction available to interact with AChR
o Potentially decreased renal elimination, bc only free/unbound drug filtered at glomerulus
o Amt of NMBA protein-bound in hypoproteinemic patients seems unchanged (human studies)
General MOA of NMBA
o Occupation of only one ACh site required for blockade
o Pre-synaptic R responsible for fade –> only sensitive to non-depolarizing
Binding of non-depolarizing NMBA to pre-synaptic R blocks the feedback loops so that no mobilization of stored/reserve ACh to periphery
When keep stimulating nerve, runs out of ACh – hence fade on TOF
What is true about NMBA use in birds?
WILL CAUSE MYDRIASIS IN BIRDS DT SKELETAL M IN PUPIL
Important Clinical Features of NMBA
o Muscles of respiration = paralyzed must control ventilation
Diaphragm less sensitive to NMBA than limbs
Lower density of ACh R in slow muscle fibers in peripheral m vs faster m fibers in laryngeal muscles, etc
Horses: dose required to abolish hoof twitch, facial twitch remains at decreased strength
o Upper airway m very sensitive to NMB
Humans: if not reversed, 2x as likely to develop pneumonia
Onset/Offset of NMBAs
related to blood flow, rate of drug delivery to tissues
Greater blood flow per g of m: higher peak plasma concentration of drug, rapid redistribution
General Features of NMBAs
No sedative, analgesia, or anesthetic properties
Assessment of Ax Depth with NMBAs
Assessment of ax depth = more challenging; palpebral reflex, jaw tone, spontaneous movement to assess depth not usable
Speed of Onset of NMBA
Inversely proportional to potency
Charge of NMBAs
PK markedly different from other agents (propofol, etc): rapid onset, rapid termination DT rapid metabolism, redistribution to skeletal m/adipose tissue
Hepatic metabolism, redistribution to sites other than skeletal m not major mechanisms of action termination
Do NMBAs cross blood brain barrier or blood placental barrier?
NO!
* Also DT quaternary ammonium moieties
* No effects on neonates when used in C sections
Other differences with NMBAs vs most other anesthetic agents?
o Limited Vd, esp compared to most other ax agents – poor lipid solubility
o Easily excreted by glomerular filtration into urine DT water solubility, generally not reabsorbed by renal tubules
o Neonates: require higher doses —> higher percentage body water, higher vol for water-soluble drugs to distribute into
Two Main Types of NMBA
- Competitive/Non-depolarizing
- Non-competitive/Depolarizing
Two Subcategories of the Non-Depolarizing NMBAs
Aminosteroids
* Vecuronium, pancuronium, rocuronium, pipercuronium
Benzylisoquinolinium
* Atracurium, cis-atracurium, mivacurium, doxacurium
MOA: bind to a subunit
Succinylcholine
o 2 ACh molecules
Binds to ACh R –> opens channel, prolonged depolarization of EP = m fasciculations
o Biphasic action: first produces stimulation (m fasciculations), drug stays bound to R, then block
R unavailable vs refractory period
SE of Succinylcholine
Causes changes in HR, BP
All else normal: increase K by 0.5mEq/dL
Movement of Na into cells, K out of cells
BAD if metabolic acidosis, hypovolemic – source of K = GI
Use of Sux
o Rapid-sequence induction (RSI) in people bc fastest acting, not short acting in some species
Horses, cats, humans: PChE high, sux broken down quickly
Dogs: PChE activity mediocre, sux broken down more slowly
Sux Metabolism
Broken down by pseudocholinesterases/plasma cholinesterase
Hydrolysis rapid: only 10% of original injected dose survives degradation in plasma to reach site of action
Termination/Accumulation of Sux
Termination of sux depends on diffusion of drug away from NMJ, into ECF
* DOA depends on plasma clearance
Minimal accumulation following large or repeated doses
* Metabolite succinylmonocholine much weaker, slower metabolism
PChE
Synthesized in liver
Very little PChE present in synaptic cleft
Drugs that Will Prolong Succinylcholine Activity
Inhibit PChE
esmolol, MAOi, chemotherapeutic agents/cytotoxic drugs, metoclopramide, OP insecticides in horses, bambuterol (prodrug of terbutaline)
* Also liver dz, chronic anemia, malnutrition, burns, pregnancy, old age
* NOT clinically significant: large decreases in PChE activity –> modest increases sux DOA
Do you see fade with Sux?
Pre-synaptic ACh R not sensitive to succinylcholine – DO NOT SEE FADE!
Phase I Block
end plate depolarization initially stimulates m ctx but sux not degraded by AChE –> remains in NMJ to cause continuous end plate depol/m relax
Phase II Block
IV infusion, large dose, repeated doses
* Continuous activation of AChR: ongoing shifts in Na into cell, K out
* Post-junctional membrane potential eventually moves in direction of normal even in presence of sux DT Na-K ATPase pump (K in, Na out)
* R does not respond appropriately to ACh, NMB prolonged
Dibucaine Test
- Test for PCheE function in humans
-If normal PChE, admin of dibucaine (LA) will interfere with function of normal PChE, abN PChE less inhibited
Single aa substitution/sequencing error at or near active site of enzyme
Normal Genotype for PChE:
70-80% PChE inhibition
Heterozygous for PChE:
50-60% inhibition, 1-2x prolongation of succ
Homozygous for PChE:
- Homozygous: 20-30% PChE inhibition, up to 8hr prolongation of sux
Dibucaine #
% Inhibited
Atypical Cholinesterase
won’t break down sux, require plasma transfusion
Cardiac Effects of Sux
mimics effect of ACh at cardiac muscarinic R sinus bradycardia, junctional rhythms, sinus arrest
Decreases threshold of ventricle to catecholamine-induced dysrhythmias in monkeys, dogs
Effects of Other Autonomic Stimuli on Sux
ET intubation, hypoxia, hypercarbia, sx – additive effects
Effects of Sux on other NMBA
increase duration of atra, roc if given first but not panc
o Admin of AChE-I following sux will PROLONG DURATION
Non-NM Effects of Sux
- Hyperkalemia
- Increased IOP
- Increased intragastric pressure
- Increased ICP
- Increased m pains
MOA Hyperkalemia with Sux
- Binds to nAChR, not degraded by AChE vs ACh –> persistent state of depolarization + open ion channels
o K: muscle fibers –> extracellular space - Transient increase in K concentrations following sux dose (0.5mEq/mL)
- Increased density fetal nAChR following nerve injury, etc: increase intracellular K released
o Risk: 48hr post injury, persists 2-3mo up to 2yr
MOA Increased IOP with Sux
- Transient, peaks 2-4’, remains increased for 6’
- MOA unknown – dilation of choroidal BV, ctx tonic myofibrils
- Avoid in veterinary patients with penetrating eye injuries
MOA Increased Intragastric Pressure
- Abdominal skeletal m fasciculations from initial depolarization of motor end plate abdominal compression, increased intragastric pressure
- +/- worsen incidence of regurg, may worsen outcome in GDV
- Variable, patient dependent
MOA Increased ICP with Sux
- Proposed MOA: m fasciculations
- Humans: prevented by prior admin of d-tubocurarine or another non-depol
- Avoid in patients with increased ICP
M Soreness Following Sux
- Humans: post ax m soreness»_space;> veterinary patients
- Proposed MOA m fasciculations during initial depolarization of motor endplate, good correlation btw intensity of fasciculations + intensity of pain
o Reduced by pre-tx with prostaglandin inhibitor - Increased CK in humans + myoglobinuria, animals following sux admin
- Also see masseter m rigidity
Pancuronium
–Steroid structure
–Onset 5’, DOA 40-60’ in dogs
–Repeated doses = cumulative effect
–Renal»_space;> hepatic metabolism, prolongation of effects in patients with renal insufficiency
Removal of one methyl group/one positive charge = vec
Cardiac Effects of Pancuronium
o Blocks cardiac muscarinic receptors
Vagolytic properties DT presence of second positive charges within steroid molecule
Increased HR
Varies among species, not always clinically relevant
Atracurium
o Onset ~5’, DOA 30’ in dogs – noncumulative with repeated doses
o Racemic mixture of ten optical isomers
o Metabolism: Hoffman elimination, plasma esterases
Metabolism of Atracurium
Metabolism: Hoffman elimination, plasma esterases
–HE not a biologic process, does not require enzyme activity - temp, pH dependent
–Remaining fraction degraded by unknown routes
–Not prolonged in people with renal, hepatic failure
Plasma esterases not related to PChE, DOA not prolonged in presence of AChE-I
Storage of Atracurium
Refrigerated, pH 3.25-3.65 to slow degradation
Effects of Atracurium Metabolism
o Following IV admin at physiologic pH/temp, spontaneously decomposes into laudanosine, quarternary monoacrylate
Laudanosine = known CNS stimulant, potential to induce sz
Hepatic clearance –> concentrations may be elevated in patients with hepatic dz
Effects unlikely to be problematic unless used for prolonged periods
Other Features of Atracurium
o Hypothermia: prolong duration, decrease infusion rate needed to maintain NMB
o Risk of histamine release present, less vs d-Tubocurarine
–Several times ED95 required for NMB before appreciable amounts of histamine released
Cisatratracurium
o 1R-cis, 1R-cis’isomer of atracurium
o 15% racemic atracurium, 4x potency (smaller dose required vs atracurium), decreased histamine release, similar onset/DOA
o Hoffman elimination >50%
Laudanosine production, less than atracurium
No ester hydrolysis
Vecuronium
w/o significant CV effects – no tachycardia, histamine release
o Removal of single methyl group from pancuronium = vec
o Dogs: does not change arterial BP
o Dose-dependent onset of action of ~5’, intermediate duration ~30’
Don’t see cumulative effect with subsequent doses
DOA of Vec
o Dose-dependent onset of action of ~5’, intermediate duration ~30’
Don’t see cumulative effect with subsequent doses
Storage/Formulation of Vec
Unstable when prepared in solution —> lyophilized powder, add sterile water prior to admin
Stable for 24hr at room temp once reconstituted
Metabolism of Vec
o More than half drug metabolized by hepatic microsomes, excreted in bile – significant fraction undergoes renal elimination
o Humans: duration slightly prolonged/normal in patients with renal insufficiency; hepatic failure prolongs DOA only if increased doses administered
Rocuronium
o Derivative of vecuronium, 1/8 potency of vec – similar MWs
o Larger dose greater # of molecules near NMJ more rapid onset of NMB
Optimal conditions for intubation not as rapid as succinylcholine
o DOA: similar to vec, atracurium
o Virtually without CV AEs, no histamine release
o Primary route of admin: hepatic, small fraction eliminated via kidney
Pipercuronium
o Steroid, derived from pancuronium
o Greatly decreased antimuscarinic effects – free of tachycardiac effects while retaining long DOA
o Hypotension in dogs
o Eliminated primarily by renal route, smaller fraction = biliary excretion
Doxacurium
o Very potent benzolisoquinolinium
o Long DOA
o No vagolytic properties, no ganglion blockade, no appreciable histamine release
o Minimally metabolized –> excreted unchanged into urine, bile
Mivacurium
o Not currently available
o Rapid-acting, short-duration – human tracheal intubation
o Potential for histamine release, esp if high dose
o Degraded by plasma PChE, metabolites do not have appreciable NMB activity
Mivacurium Metabolism, DOA
o Degraded by plasma PChE, metabolites do not have appreciable NMB activity
Canine PChE enzyme: differing affinity for three primary isomers of mivacurium found in proprietary formulation
Cats: much shorter DOA than in dogs
Mivacurium vs Humans
o DOA in humans: 25’
Marked differences in potency, in duration of action among species
Potency in dogs»_space;> humans
1/3 dose in dogs 5x longer than in humans potentially DT differences in circulating quantities of PChE (normal in dogs 19-76% vs humans)
Gantacurium
o Fumarate
o Rapid-acting, ultra-short duration non-depolarizing NMBA
o Not stable in aqueous solution, provided as lyophilized powder – requires reconstitution
Gantacurium Metabolites
o Metabolites: CW002 (short acting, 5’), CW011 (intermediate acting, 40’)
CW bc developed at Cornell Weill
Use/Effects of Gentacurium
IV bolus 0.45-0.54mg/kg (2.5-3x ED95): optimal conditions for intubation in 90s
Short DOA: 14’ at 0.4mg/kg IV
Histamine release >2.5x ED95 – clinically significant decrease in BP, increase in HR/facial redness
Not observed in dogs at 25x ED95
Metabolism of Gentacurium
- pH-sensitive hydrolysis in plasma
- Inactivation
–Binding of non-essential amino acid cysteine to gantacurium ring structure –> endogenous or exogenous cysteine replaces chlorine atom, saturates double bond of fumarate moiety –> inactive, NM transmission resumes
Reversal for Depolarizing NMBA
o Recovery from Phase I block rapid, spontaneous – sux hydrolysis by plasma esterases
o Potentially delayed recovery in patients with decreased PChE activity
o Admin of AChE-I would prolong NMB
o Phase II block: antagonized similarly to non-depolarizing muscle relaxant, emphasizing importance of determining type of block
Role of AChE and Admin of AChE-I in NMJ
AChE hydrolyzes ACh into choline, acetic acid
Admin of AChE-I increases concentration of ACh molecules at NMJ –> competes with NMBA for same postsynaptic binding sites
AChE-I is NOT NMBA antagonist - reversal (recovery) is accelerated/enhanced
Limitations of reversal
Indirect MOA
Ceiling Effect
Cannot reverse deep block with traditional means
AChE-I + Anticholinergic Reversal
Goal: increase amt of ACh in synaptic cleft, compete with NMBA for binding site
Competition based in favor of relaxant bc binds 1 alpha subunit vs 2
Reversal not instantaneous, usually within 5’
Onset of action: edrophonium < neostigmine < pyridostigmine
Edrophonium
reversible inhibition by electrostatic attachment to anionic site, hydrogen bonding at esteratic site on AChE
Give anticholinergic first bc onset of action faster than atropine
DOA brief, no covalent bonds formed
ACh can easily compete with edrophonium for access to enzyme
Human patients: neostig 5.7x more potent than edrophonium
Neostigmine, pyridostigmine
Bond lasts longer than ACh+AChE –> prevents AChE from degrading ACh
Neostigmine = more potent, more severe muscarinic effects
Neostigmine metabolism
50% hepatic
Edrophonium Metabolism
30% hepatic
Pyridostigmine Metabolism
25% Hepatic
What happens to AChE-I not metabolized by liver?
Renal excretion of remainder, prolonged elimination in renal failure patients
DOA of AChE-I
o edrophonium ~ neostigmine, pyridostigmine 40% longer
o Cats: neostigmine 12x more potent than edrophonium
Problem with AChE-Is
increases ACh accumulation everywhere muscarinic effects on heart
Bradycardia, bronchospasm, salivation, lacrimation, miosis, intestinal hyperplasia
Give atropine or glyco immediately prior to AChE-I
* Humans: usually give as mixed
Atropine: more rapid onset, glyco onset of action ~ neostigmine
Paradoxical Block with Neostigmine
When given alone in non-relaxed patients, can induce NMB
Mixed evidence: if admin too late during recovery (TOF >0.8), could induce weakness
Romano, dogs: transient decerease in TOF ratio when neostigmine given at TOF ratio >0.9
* Twitches stronger, but 4th strength increased less than 1st twitch strength
Sugammadex
SRBA = selective relaxant binding agent
o STEROIDS ONLY
o Primarily used for rocuronium > vecuronium (potency 1:6 – check this)
o Binding efficacy: roc > vec (slightly lower binding affinity)
o gamma-monocyclodextran
MOA Sugammadex
o Selectively binds roc by encapsulation in plasma –> creates concentration gradient –> pulls roc from NMJ into plasma, increases plasma concentration of roc (free roc + encapsulated roc)
o Can reverse deep block quickly: dogs, ponies 4mg/kg
Reversal Agent for Fumarates?
L-cysteine
Calabadion
o Harvard – similar to sugammadex, chelate agents and render useless
o Can use with ANY NMBA
o Problem: can also bind to other substances, might take away other important things (abx)
Impaired Metabolism, Excretion
- Hepatic insufficient: potential to alter initial effects DT increased Vd (decreased effect), decreased elimination if hepatic metabolism
-BDO: decreased clearance
-Decreased esterase activity slows biotransformation
-Renal insufficiency
Role of Ax Drugs
o Inhalants: time, dose dependent enhancement of intensity/duration of NMBA
Suppression of motor-evoked potentials IRT SC, transcranial stimulation
Alteration of m contractility
Variation in regional blood flow: greater fraction of NMBA reaches site of action
Potentiation of NMBA by Inhalants
o Potentiation: diethyl ether > enflurane > desflurane > sevoflurane > isoflurane > halothane > N2O/barbiturate/opioid or propofol ax
Greater clinical muscle-relaxing effects produced by less potent ax DT larger aqueous concentrations
Proposed MOA of Effect of Inhalants on NMBA
Des, sevo = low blood-gas, low tissue-gas solubility – equilibrium btw end tidal concentration and NMJ reached more rapidly with new ax than older ones
Proposed MOA: central effect on motoneurons, inhibition of postsynaptic nAChR, augmentation of antagonist’s affinity at R site
o Can also delay antagonism esp if inhalant ax continued after admin of reversal agent
o Injectables: +/- minimal enhancement – propofol, ketamine, thiopental
Effect of AB Disturbances
o Resp acidosis - increases intensity of NMB
o Resp alkalosis – decreases intensity of NMB
o Metabolic acidosis, alkalosis – potentiate effects, more difficult to antagonize
Effect of Potassium on NMBA
Hypokalemia: hyper polarization of end plate, resistant to ACh-induced depolarization
Hyperkalemia: lowered RMP, opposes effects
Role of Magnesium on NMBA
Increased serum Mg compete with iCa, increased ACh release
Patients admin mag sulfate: DOA of m relaxants increases
Effect of Calcium on NMBA
Hypocalcemia: increased effect DT decreased ACh
Hypercalcemia: decreased
Role of Hypothermia on NMBA
o Slows drug elimination, decreases nerve conduction, decreases m ctx
o Hoffman elimination = pH/temp dependent, more dramatic effect of benzylisoquinolones
o 10-15% decrease for every degree <36
NMBA in Pediatrics
o Youth: receptor immaturity, decreased clearance - increased potency in young
o Very young animals: decreased ECF, larger Vd vs adults – may require higher doses
Faster onset, faster recovery of NM function
Lower dose of antagonist required
NMBA in Geriatrics
o Old age: assoc with increased effect, lower Vd/impaired clearance
Higher doses for reversal often needed, slower spontaneous recovery
NMBA and NM Disorders
o Unpredictable responses to depol, non-depol NMBA
o Peripheral neuropathies: increased effect of depol DT proliferation of fetal nAChR, increased risk of sux-induced hyperkalemia
Tick Paralysis, Botulism
impaired presynaptic release of ACh, increased sensitivity to NMBA
Myasthenia gravis
autoimmune dz, generalized m weakness from decreased nAChR on motor end plate so ACh released normally but effect on postsynaptic membrane decreased
Resistant to NMB with sux
Extremely sensitive to non-depol NMBA, phase II block with sux
No increased sensitivity to sux induced hyperkalemia, MH
Polymixin
depress postsynaptic activity to ACh, enhance channel block
Antagonism with neostigmine, calcium = unreliable
Aminoglycosides
(gent, neomycin, tobramycin, amikacin, etc): presynaptic site of action, depressed ACh release
Decreased twitch tension but no change in recovery times in dogs, cats, horses
Tetracyclines
decreased ACh release via Ca chelation
Enhanced blockade usually reversible with Ca, not neostigmine
Lincosamines
o Lincomycin: direct inhibitory effect on muscle, +/- pre/post synaptic activity
Partially reversed with 4-aminopyridine
Clindamycin»_space;> lincomycin
Lithium
increased NMB, competes with Na, decreased ACh release
Effect of LAs
Enhance NMB by both non-depolarizing, depolarizing NMBAs
Effect of Steroids
prolong, antagonize effects of non-depolarizing agents
Monitoring of NMBA
- PNS + way to measure response
o Check how well nerve able to communicate with muscle, NOT a check of muscle function
o Observation of spontaneous movements, resp movements or even measurements of respiratory variables not good surrogates
MOA of NMBA Monitoring
- Stimulate peripheral motor nerve – fibular/peroneal, ulnar, radial N
o Short stimulus so that stimulates nerves without stimulating muscle, current such that will stimulate all muscle fibers
Duration of NMBA - affected by lot of things
o MMF 2014 Recovery from Neuromuscular Block and Spontaneous Ventilation in Dogs
o Parameters of ventilation returned several minutes prior to return of NM function
o Different muscles have different sensitivities to NMBA
Diaphragm: insensitive to NMBA, returns first (curare cleft on ETCO2)
In people, larynx btw diaphragm and adductor pollis (thumb) m – what used to monitor NMBA
Can’t monitor NM function in whole animal, pick group and extrapolate so pick group that most sensitive to monitor
Why Should We Monitor NMB?
o Redose if need be (1 twitch)
o Determine whether CAN reverse +/- attempt reversal with neostigmine
o Check of residual blockade
Hertz
1 cycle per second
1 Hz = 1 stimulus per second
0.1 Hz = 1 stimuli per 10s
Constant Current Stimulator
Charge = voltage x duration
Stimuli
constant – changes attributed to transmission, not stimulus
Set current constant even if impedance through skin changes (temp, desiccation)
o Usually supramaximal (20-30% higher than maximal)
Ensures all nerve fibers depolarized, all muscle fibers recruited
Type of stimulus and why?
o Square wave stimulus, duration: 0.1-0.3msec
Avoids direct muscle stimulation
Want NERVE to stimulate the muscle
Single Twitch
o 0.1Hz (Q10s)
o Not used clinically anymore, used in potency studies
o Baseline needed (Tc) – all subsequent measures expressed as Tw/Tc
Measure height, force (MMG), AP (EMG) or velocity (AMG)
Limitations of Single Twitch
o Insensitive to detect residual block
Could have residual block even if baseline returns to normal
o Does not discriminate btw depolarizing, non-depolarizing
o ACh release decreased by prejunctional effects of relaxant frequency of single-twitch stimulation should be no greater than Q7-10s
Stimulus too frequent, resultant twitch response artificially low
Single Twitch: Depressed Response
not depressed until 75-80% receptors occupied, twitch response abolished when ~90-95% R blocked
Train of Four
o 4 (supramaximal) stimuli at 2Hz, each TOF separated by 10-20s
1 stimuli Q0.5s, 2x per second
Can separate TOF > 10-20s – if <10-20s, will have refractory period
Advantages of TOF
o No control needed: measurements not expressed in reference to baseline
Subjective TOF
count (TOFc)
Fade cannot be subjectively evaluated once TOF >0.5
Observing or palpating twitches is not sensitive way to determine residual block
Objective TOF
o If objective, TOF ratio (T4/T1) – compare intensity of fourth twitch to first twitch
o TOF ratio >1.0 (100%) without relaxants
Following admin of non-depolarizing NMBA, twitches begin to fade when 70% R occupied (4th 3rd 2nd 1st)
If T4:T1 > 100% following NMBA reversal, know no residual blockade
If T4:T1 <100%, have some degree of NMB/dysfunction
NMBA Recovery per ACVAA Consensus Statement
o LJ, ACVAA Consensus Statement (2009): T4:T1 >0.7 assoc with adequate signs of recovery from NMBA; human medicine/MMF >0.9
Phase I vs Phase II Block with TOF
o Phase I block from depolarizing NMBA: fade absent
Repeat admin or CRI of sux –> phase II block, will see fade following TOF stimulus
Double Burst
2 mini tetanic sequences of 3 stimuli at 50Hz (Q0.02), separated by 750msec
LJ: 2 minitetanic bursts, 2-4x each
Can see or measure fade
o Produces two large twitches, ratio of 2nd burst to 1st burst: D2:D1
Why use Double Burst?
o Attempt for easier observation of fade
o LJ: possibly superior to TOF, correlates highly to TOF when assessed via MMG – fade more readily seen with DBS using both visual, tactile means
Humans: able to subjectively identify when NMBA at 0.7 vs 0.4-0.5 for TOF
o MMF: Virtually same issues as TOF in dogs, no better than TOF to identify partial blockade
Tetanic Stimulation
–Sustained m contraction
–o Most common: 5sec at 50-100Hz ie stimulus Q0.01-0.022s for duration of 5 seconds
Lot of stimuli given very close together
No more frequently than Q2-3min bc produces potentiation
Insufficient ACh released, contraction starts to get weaker - decrease tetanic height
Physiological Principles of Tetanic Stimulation
Massive influx of Ca into presynapatic cell –> massive immobilization of ACh to periphery –> ACh competes with NMBA –> for short period of time, ACh can displace NMBA from nAChR
Use of Tetanic Stimulation
o No fade without NMBA, fade with partial NMB from non-depolarizing relaxant admin
o Helpful for detecting residual NMB
o Only with nondepolarizing (or phase 2)
o IT HURTS in lightly anesthetized or conscious patients
Post-Tetanic Fasciculation/Post Tetanic Count
o When have no twitches on TOF, allows you to monitor depth of blockade and predict return to function
Applied when TOFc is zero
Monitor deep blockade
MOA PTC
Usually consists of 15 single twitches (ST) [not going to produce response bc patient paralyzed BUT will mobilize large amt ACh], then TET, then 15ST – last 15ST represents PTC
Bc so much ACh, will have twitches with second set of single twitches
# of ST observed after TET inversely related w/ time to return of T1 (TOFc T1)
How Interpret PTC
# of ST observed after TET inversely related w/ time to return of T1 (TOFc T1)
* If only few single twitches, LOT of NMB
* If have many single twitches, not as much NMB
* Ex: if have 12 ST, will get first twitch on TOF back sooner vs if have 3 ST, going to be awhile before first twitch on TOF
Why is PTC Beneficial?
o Proposed MOA: increased ACh release from nerve terminal
This large mobilization of ACh is the post tetanic fasciculation
o First clinical indicator of recovery from NMB
o In humans, some procedures require profound blockade –> PTC allows estimation/prediction of time to return to function
Ways to Quantify Evoked Responses
- Mechanomyography
- Electromyography
- Acceleromyography
MMG = mechanomyography
Measurement of isometric force of contraction
Gold standard
Cats, horses, dogs, ponies, cows, llamas
Wire or suture connected to tendon to measure force, cumbersome
MOA MMG
Limb must be immobilized, no movement should occur
* Force transducer attached to paw or hoof at a right angle to direction of muscle contraction
* Maximum evoked muscle-twitch tension: resting tension 100-300g should be applied
* Resultant twitch tension can then be quantified
EMG = electromyography
Compound AP of muscle fibers contracting during supramaximal stimulus of peripheral motor nerve
Recording electrode: placed over innervation zone of m, midway btw origin and insertion
Reference electrode required – over insertion site
Ground electrode – btw other two electrodes
Advantages of EMG
requires less or no limb mobilization, no resting tension, more choices as to which muscles may be used
Disadvantages of EMG
difficult to obtain proper electrode placement for accurate results, particularly in smaller patients
Dogs and EMG
Dogs: no statistical difference btw MMG, EMG during TOF stimulation for either T1 or T4:T1
AMG = Acceleromyography
Most commonly used
Acceleration Newton’s Second Law, requires free moving limb
Piezoelectric crystal
Consequences of Post-Operative Residual Curarization
o Mild discomfort: diplopia
o Hypoxia: NMBAs interact at carotid bodies, blunt responses to [isocarbic] hypoxia
No changes IRT hypercarbia
People: TOFr 0.7-0.8 decreases response (LI Eriksson)
o Aspiration: awake volunteers fail to swallow at TOFr at 0.7-0.8 – without contribution of residual sedatives/hypnotics (LI Eriksson)
o Intraoperative AMG decreases postop negative respiratory events in people (GS Murphy)
PORC in Veterinary Medicine
almost no info in veterinary medicine
o In dogs, some laryngeal m recover SLOWER than limbs – opposite in people
o Sakai et al, Tseng et al: laryngeal m 5-15’ slower than limbs
o MMF: recover to TOF 1 (100%) + 15’
If TOF >0.7-0.8, atropine 0.02+neostig 0.02mg/kg
If TOF >1-2 twitches <0.7, atropine 0.02+neostig 0.04mg/kg (up to 0.07)
Horses and NMBA
residual NM dysfunction problematic during recovery, want NO degree of residual block but also don’t want to give atropine
Can give neostig to horses without atropine
MMF would use edrophonium, use smallest dose of NMBA (atra 0.08mg/kg for ophtho bc eyes so sensitive to NMBA), would use roc/Sugammedex
Guanifenesin
M relaxant in LA
Therapeutic doses: little effect on resp m or diaphragm
o No analgesia, no antagonist
o Does not produce unconsciousness
MOA GG
o Disrupt nerve impulse transmission at level of internuncial neurons of SC, BS, subcortical areas of brain
No analgesia, no antagonist, does not produce unconsciousness
Formulations of GG
powder + sterile water (5, 10, 15%), most commonly 5% in 5% dextrose
Keep warm - will precipitate out
SE of GG
o IV at high concentrations (>10%, in cows >5%) –> hemolysis, hemoglobinuria, venous thrombosis
Tissue damage if inadvertent perivascular injection
Dantrolene
Hydantoin derivative, interferes with E-C coupling –> relaxes skeletal m through decreases in amt of Ca released from SR into cytoplasm
Dosing of Dantrolene
o Therapeutic doses: do not depress respiration, do not adversely affect CaM or SmM
Under GA: decreased MV DT decreased VT/decreased RR
Doses:
Dogs, cats 1-5mg/kg IV, 5-6mg/kg PO SID for prophylaxis
Pigs 1-3mg/kg IV, 2-5mg/kg PO
Formulations of Dantrolene
o Solutions of reconstituted with 60mL sterile water to 0.33mg/mL = light sensitive, stable for 6h; also have 100mg capsules
20mg vials in powder + 3g mannitol to improve solubility
Prophylactic Use of Dantrolene
Does not guarantee effective blood levels
Horses: unwanted skeletal m weakness during recovery
Avoid volatiles, have injectable available if needed – can compound PO preparation for IV use
Metabolism of Dantrolene
liver through oxidative, reductive pathways
Metabolites, unchanged drug excreted in urine
SE Of Dantrolene
m weakness, nausea, diarrhea
Chronic tx in human patients = fatal hepatitis
Severe myocardial depression if given with verapamil, other Ca channel blockers
Delayed recovery of NMB with vecuronium
