Chapter 11 Neuromuscular Blocking Agents

-NMJ – presynaptic motor neuron, postsynaptic muscle fiber, AChAse b/w the two.
-electrical signal  chemical signal release Ach)  electrical event (muscle membrane
depolarization)  mechanical event (muscle contraction).
-nicotinic muscle type ach receptors in folds of postsynaptic muscle membrane; not found
extrasynaptically
-more muscle fibers = more precision in muscle contraction
-nerve stimulation: depolarization of motor nerve reaches nerve terminal, Ca voltage gated
channels open  vesicles that contain Ach are released by exocytosis from nerve terminal into
cleft. K channels limit Ca entry – nerve membrane repolarization initiation. Release of Ach
antagonized by hypoCa, hyperMg.

Presynaptic events:
-Ach synthesized in presynaptic terminal: reserve pool vs active zone (adjacent membrane).
Once nerve depolarization occurs, Ca intracellular concentration INC, ach released into synaptic
cleft  binds to postsynaptic nAChR  muscle contraction  hydrolysis by AChAse. Choline
repuptake by presynaptic nerve terminal.

Postsynpatic:
-small quantities of ach released into cleft; when enough ach released into postjunctional
muscle membrane depolarization reaches end palte potential and excitation-contraction
activated.
-Na influx, K efflux – muscle cell depolarization. Voltage gated Na channels on muscle
membrane propagate action potential across membrane  muscle tesion.

Receptor up/downregulation:
-when frequency of NMJ stimulation decreases (burns, immobilization, infection, use of
neuromuscular blocking agents, CVA)  number of immature nAChRs increases (upregulation).
-immature nAChRs have inc sensitivity to agonists  Ach, SCh, and dec sensitivity to
nondepolarizers (NMBAs).
-downregulation of mature nAChRs during periods of sustained agonist stimulation – chronic
use in pts with myasthenia gravis or organophsphate poisoning (sensitivity to nondepoloarizing
NMBAs)

Neuromuscular Blocking Agents:

-Potency: dose required to produce effect (Depression of normal muscle contraction);
-ED95 – NMBA potencies expressed dose required for 95% depression of single twitch during
nerve stimulation.
-onset time inversely related to dose, can be affected by rate of delivery (blood flow, speed
injection), receptor affinity, mechanism of action (depolarizing, competitive), plasma clearance
-DUR 25% - time from drug administration until recovery of ST to 25% of baseline/normal
strength
-duration of action: time from drug administration until recovery of train of four to .90 (Directly
related to dose NMBA)
-depolarizing NMBA: produce muscle relaxation by directly depolarizing on nAChRs (ex:
succinylcholine – mimicks ach; fastest onset, shortest duration)
-nondepolarizing NMBA: compete with Ach for two subunit alpha subunit sites, preventing
normal nAChR fxn. Based on chemical structure (benzylisoquinolinium, steroidal)

Depolarizing Neuromuscular Blocking Drugs: Succinylcholine

-depolarizes postsynaptic and extrajunctional receptors. Potentiated by anticholinesterases.
-flaccid paralysis – fasciculations
-inc dose = progressive dec in force of muscle contraction
-response to repetitive stimulation (TOF) maintained (no fade) b/c SCh has no affinity for
presynaptic (neuronal) nAChRs
-fastest onset on peripheral muscles, slowest on diaphragm. Prevent gastroparesis in RSI.
-side effects: bradycardia, asystole, premature ventricular beat, fasciculation, myalgiaas
-can cause hyperK (in receptor upregulation – long immobilized. Be careful in renal failure),
esp in kids with pediatric myotonia/muscular dystrophies
-can trigger lethal malignant hyperthermia, esp in those with prior volatile anesthetic .

Nondepolarizing Neuromuscular Agents:

-bind to alpha subunits of nAChRs. Antagonized by anticholinesterases. Positively charged –
distributed in ECF (more required in hepatic failure – larger ECF).
-with repetitive stimulation – muscle contraction fatigue (fade) develops
-TOF: four stimuli delivered at 2hz. Degree of fade calculated: ratio of amplitude of fourth
response (T4) to amplitude of first response (T1).
-nondepolarizing block: transient amplification of responses that follows 5 second period of
tetanic stimulation
-benzylisoquinolinium (atracurium, cisatracurium, mivacurium) vs aminosteroid (pancuronium,
rocuronium, vencuronium)

-rocuronium LESS potent than vecuronium – have to give greater dose so concentration higher
of rocuronium. This will speed up onset but also cause greater duration of action.
-pancuronium: DUR 25 1-2 hours but prolonged in renal/hepatic failure
 High potency  slow onset of neuromuscular blockade (2 doses to intubate in <5 min)
 Vagolytic effects, direct sympathomimetic effects.
-vecuronium: intermediate duration NMBA, no cardio effects.
 More potent than rocuronium  slower onset of action
 Not recommended for RSI
 Accumulates with large/repeated doses, in ICU can cause persistent paralysis
-rocuronium:
 Low potency  high plasma concentration achieved rapidly, duration of action
determined by redistribution (not elimination)
 No metabolites, risk of accumulation minimal.
 Hemodynamically stable, no histamine release, rare allergies.
  Sugammadex – reversal
-atracurium:
 Can double dose to quicken onset, but then histamine release  skin flushing, tachy,
hypotension
 Duration 30-45 min
 Not affected by hepatic/renal failure
-cisatracurium:
 High potency  longer onset than atracurium. LESS concentration for this reason  no
histamine release
 Dual elimination similar to atracurium  not affected by renal/hepatic failure. HDS.
Preferred in ICU.

Drug interactions:
-two chemically similar drugs of same classes: additive potency, no effect on duration
-diff class drugs added (cisatracurium and rocuronium) – synergistic – more than additive.
-when two drugs added together – duration follows longer acting one
-adding depolarizing and nondepolarizing NMBA – antagonistic effect
-inhaled anesthetics POTENTIATE NMBA action (neuromuscular block). Propofol has NO
effect.
-local anesthetics – inc duration of action of NMBA, but doesn’t shorten onset
-anticonvulsants: acutely, NMBA block potentiated. Chronically, decreased.
-ephedrine – inc CO, hasten rocuronium onset
-steroids – when administered for immobility/ill pts, inc risk of myopathy
-rare allergic rxns, anaphylaxis

-hypothermia: prolongs duration of NMBA, dec receptor sensitivity/ach mobilization, reduce

renal/hepatic metabolism
-aging – dec total BW + serum albumin, reduce volume distribution. Dec rate of elimination.
-acid base/electrolyte imbalance – hypoK potentiates non depolarizing block. HyperMg
prolongs duration of action of NMBA (inhibit Ca channels). Hypercarbia/acidosis  interferes
with NMBA antagonism (Aka longer duration of action?).

-double burst stimulation – 2 intense stimuli separated by .75s, two fused responses evaluated
as direct comparison. Can detect fade at <.6 (normally <.4).

Reversal of NMBA:
-blocking breakdown of AChAse = inc in available Ach at synaptic cleft to compete with
nondepolarizing NMBA  normal transmission
-AChase inhibitors: neostigmine, edrophonium, pyridostigmine. Duration of action similar for
all, onset fastest for edrophonium > neostigmine > pyridostigmine. Edrophonium less effective
at reversing deep block.
-all cholinesterase inhibitors block AChAse at cholinergic synapses – PNS effect.
-glycopyrolate (with neo, no cross BBB) or atropine (faster tachy onset, similar to edrophonium,
crosses BBB). Glycopyrolate preferred in cardiac pts. Dec salivation that is good to counteract
neostigmine cholinergic effects.
-ceiling effect for neostigmine – at least TOF .6.

-more neostigmine = faster reversal, faster in kids.

-factors that potentiate effect of nondepolarizing NMBAs also prolong recovery: volatile
anesthestics, aminoglycoside abx, magnesium, opioids (induce hypercarbia, acidosis),
hypothermia
-.9 needed for safe extubation, .7 for reversal

-sugammadex – most affinity to reverse rocuronium

-excreted in kidneys
-still need to monitor neuromuscular monitoring to make sure no residual weakness