Neuromuscular Relaxants Sungai Buluh 2017

Neuromuscular Relaxants
Lim TC
Department of Anaesthesia
Hospital Melaka
2017 Neuromuscular Relaxants
• Neuromuscular relaxants are drugs which

are used to produce striated muscle
relaxation during surgical anaesthesia and
act via a reversible inhibition of the
interaction between acetylcholine and the
postjunctional nicotinic receptors
Structure of Neuromuscular
Junction (NMJ)
• Typical neuromuscular junction (NMJ)
consists of
• Prejunctional motor nerve ending
• Highly folded postjunctional membrane of
skeletal muscle fibre
• Separated by synaptic cleft (20-60 nm) filled with
extracellular fluid
Cleft on postsynaptic
membrane
Synapse containing
basement membrane
Synaptic vesicles at
active zone
Terminal
nerve branch
• Prejunctional Motor Ending

– Motor neuron runs without interruption from ventral
horn of spinal cord to NMJ as a large myelinated
axon
– As motor nerve approaches skeletal muscle, myelin
sheath disappears to form a spray of terminal
branches against muscle surface and this terminal is
covered by Schwann cells cytoplasm
– NMJ commences at the unmyelinated nerve ending
which is distal to the last node of Ranvier
– These terminals form expansions known as

synaptic boutons from which motor neuron
releases neurotransmitter
• Each bouton is positioned over a junctional fold in
sarcolemmal membrane which is a deep
depression in surface of motor endplate
• Axon terminals contain numerous mitochondria
and synaptic vesicles
– Active zone (AZ)

• Site at presynaptic terminal where synaptic vesicular
docking and exocytosis occurs
• Possesses high density of voltage-gated calcium
channels and other molecules that mediate the
docking, fusion and clearance of synaptic vesicles
• Located opposite to the crests of synaptic folds to
minimize the distance between the release site and
postjunctional receptor
• Synaptic cleft
– Approximately 50 nm
– Consists of a basal lamina which is mainly
formed by mucopolysaccharides
– Basal lamina contains molecular components
important to synapse formation,
maintenance, and function
– Acetylcholinesterase is anchored to the basal

lamina in the synaptic cleft where it rapidly
hydrolyzes ACh
– Consequences of this thin gap:
• Neurotransmitter, acetylcholine crosses synaptic
cleft rapidly
• Local concentrations of acetylcholinesterase
active sites and acetylcholine receptor can be very
high
• Postjunctional membrane
– Consists of a membrane covering the muscle
fibre, sarcolemma
– Corrugated heavily with deep invaginations of
junctional cleft (synaptic folds)  very large
total surface area of motor endplate
– Nicotinic acetylcholine receptors (nAChR) are

densely packed at motor endplate (especially at
shoulder or crest of synaptic folds) with density
of 10,000/m2  safety factor in neuromuscular
transmission
– Density of nAChR drops drastically at sites away
from motor endplate
– nAChR is anchored into cell membrane by a
complex system of cytoskeletal proteins like
dystroglycans
• Perijunctional zone
– Area of muscle immediately beyond the
junctional area
– Critical to function of NMJ
– Contains nAChR and voltage-gated sodium
channels
– Responsible to transduce the motor endplate
depolarization into wave of depolarization
travelling along the muscle
Acetylcholine: Synthesis & Storage

• Choline is required for the synthesis of
acetylcholine (ACh) and it is derived from
– Dietary choline
contributes 50% of source of choline
– Plasma choline
– Hydrolysis of Ach contributes 50% of source of choline
• Choline is quarternary amine which is a

hydrophilic molecule and requires a carrier
mechanism for the transport into interior of nerve
terminal (Sodium-Dependent High Affinity Choline
Uptake System, SDHACU)
• Acetyl-Co-A (AcCoA) is also required in the

synthesis and this is formed in mitochondria of
axon terminals from decarboxylation of pyruvate
• Reaction between AcCoA and Choline
(acetylation) is catalyzed by Choline Acetyl-O-
Methyltransferase, ChAT): Choline + AcCoA 
ACh and CoA
• Activity of this enzyme is inhibited by ACh and
enhanced by nerve stimulation
• Approximately 50-80% of synthesized ACh is

transferred into synaptic vesicles
• Uptake of ACh into synaptic vesicles is
accomplished via the action of ACh/proton
antiport which utilizes ATP as energy source
• Each vesicle appears to contain 5,000–10,000
molecules of Ach
• Ach contained in a single vesicle is often referred
to as a quantum of transmitter
• Two pools of synaptic vesicles which release ACh:

reserve store, VP1 and readily releasable store,
VP2
– Majority of the vesicles (80%) are of larger size,
distributed throughout the axoplasm where they are
bound to a filamentous network composed of mainly
actin, synapsin (an actin-binding protein),
synaptotagmine and spectrin (Reserve store, VP1)
– Small number (20% of vesicles) are located at release
sites on axolemma of motor nerve terminal (Readily
releasable store, VP2)
Nicotinic Acetylcholine Receptors

• Nicotinic Acetylcholine Receptors (nAChR)
– Common architecture with 5 subunits
surrounding a central pore
– Activation of nAChR by ACh causes an influx of
cations (Na+ and Ca2+) which ultimately leads to
membrane depolarization (ligand-gated non-
selective transmembrane cation channels)
– Subdivided into muscle and neuronal subtypes
based on the classical major site of expression
– At least 17 nicotinic subunits have been cloned
recently:
• Muscle α1, β1, δ,  and ε subunits
• Neuronal α2 to α10 and β2 to β4 subunits
– Muscle type nAChRs are composed of 2 1 subunits

along with one each of 1 and -subunits and either an -
subunit (adult receptors) or a -subunit (foetal receptors)
– Neuronal type nAChRs are composed of either
• 2 -subunits (2-6) and 3 -subunits (2-4) (heteromeric neuronal-
type receptors), or
• 5 identical subunits of 7, 8, 9 and 10 (homomeric neuronal-
type receptors)  7 is found postsynaptically at muscle
membrane during development and denervation
Muscle
nAChR
Neuronal
nAChR
• Prejunctional nAChR
– Functions not fully understood and may have the
following actions:
• Regulation and mobilization of ACh release
– Presynaptic nAChR acts as an autoreceptor, a receptor located on
presynaptic nerve cell membranes and serves as a part of a
feedback loop in transmitter release
– Neuronal AChR (inhibitory) and muscle AChR (facilitatory) on
motor nerve terminals which regulates ACh supply and release at
low and high frequencies of stimulation respectively
– However other authors believed that the nAChR responsible for
the increased release of ACh during high frequency stimulation is
the neuronal nAChR α3β2 subtype
– Facilitatory process enhances further mobilization of

ACh to readily releasable sites  enable sustained ACh
mobilization and release in presence of continuous
stimulation (tetanic stimulation)
– Inhibition of these receptors by non-depolarizing
neuromuscular relaxants  fade but depolarizing
neuromuscular relaxants like suxamethonium does not
have action on these receptors  No fade
• Postjunctional nAChR
– Muscle nAChR
– 1-10 millions at endplate with concentration of
approximately 10- 30,000/m2
– Synthesized in muscle cells and are anchored to endplate
by special 43-KD protein, rapsyn and agrin
– Funnel shaped with relatively large extension into
extracellular space
– Traverse postsynaptic membrane and surrounding an
ionophore
– Integral membrane protein consists up 5 subunits with
molecular weight of about 250 kD
– Each subunit consists of approximately 400-

500 amino acids and has four membrane-
spanning regions (M1-M4)
– Amino terminal domains of various subunits
form extracellular portion of receptor and
contain binding sites for Ach
– Ordering for subunits around the pore is α-ε-
α-β-δ (clockwise when viewed from
extracellular side)
– Two  subunits are noncontiguous

• Each must bind simultaneously to an ACh
molecule to induce conformational changes and
open the ion channel
• Occupation of one subunit will not open the
channel  sufficient for one molecule of
nondepolarizing neuromuscular relaxant to bind to
one subunit to produce a block
• Immature/ Extrajunctional Receptors

– Foetal, immature or extrajunctional muscle
nicotinic ACh receptor consists of 2 1 and
one of each 1,  and  subunit
– Innervation of muscles in foetus progresses
slowly during foetal life and infancy but with
time, immature receptors reduce in
concentration and disappear from peripheral
part of muscle
– With innervation,  subunit is replaced by ε

subunit which creates adult, mature or
junctional muscle nAChR present through
healthy life
– Although difference in amino acid homology
is small in ε and  subunit, these differences
are significant to affect its function
– Found in various situations

• Reduced activity in muscle as seen in foetus
before innervation
• Following upper or lower motor neuron injury
• After burns or sepsis
• After other events which cause increased muscle
protein catabolism including sepsis or generalized
inflammation
– Synthesis of immature extrajunctional
receptors is initiated within hours of inactivity
but takes several days for whole muscle
membrane to be fully populated with
receptors
– Degraded soon after the return of neural
influence
– As the ion channel of immature extrajunctional

receptors tend to open for longer time, amount of K+
moving from muscle to blood can be very large and
leading to larger extent of hyperkalaemia
– This is not prevented by prior administration of non-
depolarizing neuromuscular relaxants as these
receptors are not very sensitive to non-depolarizing
neuromuscular relaxants
Prejunctional Events
• Generation of action potential
• Depolarization of nerve terminal
• Vesicle mobilization, docking, priming, fusion &
exocytosis
• Quantal release of ACh
• Cycling of synaptic vesicles
• Generation of Action Potential and

Depolarization of Motor Nerve
– Changes in potential (electrical potential inside of
motor nerve is made less negative,
depolarization), Na+ channels open and allow Na+
to enter the motor nerve
– Action potential activates adenyl cyclase and
converts ATP to cAMP
– cAMP acts on a protein kinase to open up P-type
Ca2+ channels
– cAMP is then degraded by a phosphodiesterase
to become AMP
– Ca2+ enters axoplasm and combines with
calmodulin
– Number of quanta released by a stimulated nerve
is affected by concentration of ionized Ca2+ in
extracellular fluid
• Vesicle mobilization, docking, fusion &

exocytosis
– Following Ca2+ influx after the action potential,
phosphorylation of synapsin is activated by
• cAMP-dependent protein kinase
• Ca2+-calmodulin activated protein kinases I and II
– This weakens binding between synaptic vesicles
and the cytoskeleton  mobilization of vesicles
from reserve pool into active pool
– Vesicles are then attached to active zone of

presynaptic membrane in a process called
docking
– Synaptotagmin (p65), Synaptic Vesicle
Associated Membrane Protein (VAMP) or
synaptobrevin and synaptophysin are integral
vesicular membrane protein involved in
docking
– Synaptotagmin may act as Ca2+ binding protein, localizes
the vesicles to synaptic zones rich in voltage-gated Ca2+
channels and stabilizes them in docked state at
presynaptic membrane
– Subsequently, a complex consists of 3 synaptic proteins
(SNARE* complex) is formed and these proteins include
• Synaptosomal-associated protein of 25 kDa (SNAP25*) Integral protein of motor
nerve terminal plasma
• Syntaxin membrane
• Synaptobrevin (Integral protein of synaptic vesicle membrane)

– This complex forms an anchor for a cascade of protein-
protein interactions required for exocytosis to occur
*SNARE= Soluble N-
ethylmaleimide-sensitive-
factor Attachment Receptor
– Further priming is required to convert a docked

vesicle into a fusion-competent, readily
releasable vesicle
– Fusion is a Ca2+-dependent process and is
mediated by two proteins with opposite actions
• Synaptotagmin: Ca2+ sensor which is responsible for
transmitter release
• rab3: limits number of vesicles which can be fused
– After the vesicle fusion, fusion pore is formed

between vesicle membrane and plasma
membrane at active zones which then dilates
to release vesicular content into synaptic cleft
via exocytosis
– After fusion and exocytosis, synaptic vesicle
membrane is recovered via endocytosis
(recycling of vesicle membrane)
– A nerve impulse causes the release of

approximately 20-200 quanta depending on
the species within a fraction of milisecond
– A quantum represents contents of one vesicle
which amounts to 5-12,000 molecules
– Fate of released ACh
• Diffusion into synaptic cleft
• Binding to acetylcholinesterase (degradation)
• Binding to postsynaptic AChR (activation of
muscle endplate)
Postjunctional Events
• nAChR activation
• ACh hydrolysis
• Excitation-contraction coupling
• nAChR activation
– Two ACh bind to α-subunits simultaneously induces
conformational changes allowing ion channels to open
permitting influx of Na+ and efflux of K+ following
concentration gradient
– Ion-channel opening is an extremely rapid all-or-one
phenomenon lasting for 5-10 msecs
– With endplate depolarization, transmembrane potential
changes and if the endplate is depolarized above a critical
threshold (-50 mV), voltage-gated Na+ channels on
sarcolemma open and allow flow of Na+ into muscle 
action potential passes around sarcolemma causing
muscle to contract
• ACh hydrolysis
– Acetylcholinesterase (AChE)
• True or specific cholinesterase
• Type B carboxylesterase
• Was given systematic name acetylcholine
acetylhydrolase (EC 3.1.1.7) by Enzyme
Commission in 1964
• Encoded by a single gene localized to
chromosome 7q22 in humans
• Not found in plasma but in other tissues:
– All excitable tissues, whether nerve or muscle, central or
peripheral, cholinergic or adrenergic, motor or sensory
– Most erythrocytes
– Placental tissue
– Structure of AChE Choline

interaction
binding:
with
charged quaternary
Earlier evidence Recent evidence group of the choline
moiety of ACh
Anionic Site Catalytic Anionic Site
Esteratic Site Catalytic Triad Catalytic machinery:
consists of triad of
Peripheral Anionic Site
hydroxyl group of
serine, imidazole
group of histidine and
glutamate
– Anionic subsite of the active site is negatively charged

and probably consists of indole group of tryptophan and
phenylalanine to form electrostatic (ionic) bond with
quaternary N of choline moiety in Ach
– Active catalytic esteratic subsite is located at the bottom
of a deep and narrow cleft, named as active-site gorge,
lined with hydrophobic amino-acid side chains
– Esteratic site consists of a catalytic triad: hydroxyl group
of serine, imidazole group of histidine and glutamate
– AChE was later shown to possess one or more
additional binding sites, peripheral anionic sites (PAS) for
ACh and for other quaternary ligands
• Quaternary structure
– In NMJ, it is found in folds of endplate and embedded in
basement membrane of synaptic cleft
– Principal form of AChE in NMJ is an asymmetric A12
species in which 3 groups of 4 catalytic subunits each
are anchored by disulfide bonds to filamentous,
collagen-containing structural subunits
– Collagen-containing tail of the macromolecular complex
is associated with basement membrane of
postjunctional membrane
– Appearance of a bunch of flowers sprouting from
postjunctional motor endplate
– Approximately 3 millions AChE molecules per

endplate: very efficient hydrolysis and AChE
ranks as one of the highest catalytic
efficiencies known
– Approximately 50% of released ACh is
immediately hydrolyzed before reaching the
endplate
– Any one ACh survives long enough to open
only one receptor ion channel at the most
– Reaction involved is extremely rapid: 4,000
molecules of ACh can be hydrolyzed per
active site of the enzyme per sec and
hydrolysis is completed within 15 msec
• Excitation-Contraction Coupling
– Describes the sequence of physiological and biochemical
changes between depolarization of T-tubular system and
muscle contraction
– Propagated muscle action potential is conducted along
electrically excitable muscle membrane and enters
transverse tubular system (T-tubular system) at end of
sarcomere
– Depolarization of T-tubular system  release of Ca2+ from
sarcoplasmic reticulum via the interaction of voltage-
gated channels (DHP Receptor) and Ryonidine Receptor
– Released Ca2+ are bound by troponin C

producing conformational changes in other
troponins and tropomyosin
– Simultaneously myosin ATPase is activated
and ATP is hydrolyzed to ADP providing
supply of intracellular energy
– Cross bridges are formed between actin and
myosin resulting in muscle contraction
Summary
Margin of Safety of Neuromuscular

Transmission
 Structure and function of NMJ are designed
such that successful neuromuscular
transmission is virtually guaranteed
 In healthy subjects, even under most extreme
limits of muscular exertion, NMJ functions
satisfactorily
 Neuromuscular transmission has a substantial
margin of safety and reserve capacity to
improve the margin of safety of neuromuscular
transmission
– Number of nAChR opened is in excess of those

required to produce an action potential
• Approximately 50-100,000 nAChR are activated during
the peak of an evoked response
At least 3-6 fold
of safety factor
• Approximately 13,000 of activated nAChR are required

to depolarize a muscle fibre from resting potential to
threshold for action potential generation
– Large amount of nAChR must be occupied by
antagonist to inhibit neuromuscular transmission
• 75% nAChR blockade: fade
• 95% nAChR blockade: complete suppression of twitch
– Amount of ACh released is in excess of those

required to produce an action potential
• Action potential is generated by more ACh molecules
(10 times) than are required  10-fold safety margin to
protect a normal neuromuscular transmission
– Magnitude of the end-plate potential is greater than the
threshold required for triggering action potentials
– At prolonged high-frequency stimulation of muscle
contraction, neurotransmission is still reliable
– NMJ has substantial capacity of ACh in reserve
and only a small fraction of available vesicles are
used upon stimulation
– Structural features which may contribute to

improved margin of safety:
• Pre-synaptic Ca2+ entry occurs mainly at active
zones where voltage-gated Ca2+ channels are
clustered near vesicles
• Active zones are positioned opposite clusters of
post-synaptic nAChR to minimize distance ACh
must travel in order to bind to receptors
• Voltage-gated Na+ channels are clustered in
depths of post-synaptic folds where membrane
depolarization is greatest following nAChR
activation
Drugs Affecting Neuromuscular

Function
• Generally drugs that modify

neuromuscular transmission may affect:
– ACh release
– ACh action
– ACh breakdown (hydrolysis)
– Excitation-Contraction Coupling
• Drugs affecting ACh Release

– Release of ACh from motor nerve terminal
may be affected by
• Drugs affecting Ca2+ transport
• Local and General Anaesthetics
• Neurotoxins
• Guanidine & Aminopyridine
• Miscellaneous
– Drugs affecting Ca2+ transport

• Drugs that prevent Ca2+ entry into motor nerve
terminal reduce the release of ACh and prolongs
non-depolarizing neuromuscular blockade:
– Bivalent inorganic cations: Mg2+, Cd2+, Mn2+
– Antibiotics: aminoglycosides, polymyxins, colistin,
tetracyclines, lincomycin
• Bivalent inorganic cations compete with Ca2+ for
transport into motor nerve terminal and reduce
ACh release  parenteral MgSO4 , Mg-containing
antacids
• Although primary action of antibiotics is
prejunctional, effects on motor endplate and
voluntary muscle may also occur
• Therapeutic doses of verapamil, diltiazem and

nifedipine usually have no significant effect on
ACh release as they act mainly on the slower L
channels in cardiovascular system and not the P
channels in the neuromuscular junction
– Local & General Anaesthetics

• Local Anaesthetics
– Reduce ACh release from motor nerve terminal
– After systemic absorption, they affect conduction in
unmyelinated nerve endings
• General Anaesthetics
– Reduce ACh release from motor nerve terminal
– Depression of CNS and reduce generation of nerve
impulses by anterior horn cells
– Some fluorinated agents may have direct effects on
muscle cell membrane  profoundly affect degree of
non-depolarizing neuromuscular blockade
– Diethylether and fluorinated ethers may potentiate
effects of muscle relaxants
– Neurotoxins
• Clostridial toxins including botulinum toxin and
tetanus neurotoxins selectively damage one or all of
the SNARE proteins and this blocks vesicular
exocytosis causing paralysis
• Botulinum toxin is used to treat spasticity and
spasm in several neurological and surgical diseases
(blepharospasm, cerebral palsy, torticolis), reduce
excessive swelling and correction of wrinkles in
cosmetic medicine
• Botulinum toxin
– Botulinum toxin binds to the neuronal cell
membrane at the nerve terminus and enters the
neuron by endocytosis
– Acts as endopeptidase that cleaves specific
sites on the SNARE proteins, preventing
complete assembly of the synaptic fusion
complex and thereby blocking acetylcholine
release
• α-latrotoxin
– Black widow spider venom contains -latrotoxin
which affects transmitter release in NMJ
– Mechanism:
 -latrotoxin specifically binds to its receptors on
presynaptic nerve terminals, neurexin and/or
latrophilin, LPH1 and forms Ca2+-permeable
channels (pores)
 Massive influx of Ca2+ through large, permanently
open α-latrotoxin pores causes prolific fusion of
synaptic vesicles with plasma membrane
 This toxin-induced exocytotic activity is so
strong that terminals soon lose all their vesicles
and transmitter secretion seizes entirely
• Guanidine & Aminopyridine

– Both drugs prolong duration of action potential and
increase Ca2+ entry and facilitate ACh release
– Used to increase ACh release in botulism and Eaton-
Lambert Syndrome
– Readily cross blood-brain-barrier causing convulsions
– Drugs Affecting Acetylcholine Action

• Neuromuscular relaxants
• Non-depolarizing neuromuscular relaxants act as
competitive antagonist to prevent binding of ACh
to the binding sites within the nAChR  paralysis
– Drugs Affecting Acetylcholine Hydrolysis
• Anticholinesterase (Anti ChE) prevent hydrolysis of
ACh via inhibition of this enzyme  accumulation
of ACh
– Drugs Affecting Excitation-Contraction
Coupling
• Normal muscle contraction depends on release
of Ca2+ from sarcoplasmic reticulum and
subsequent binding by troponin C
• Binding of Ca2+ causes conformational changes
in troponin-tropomyosin complex resulting in
activation of myosin ATPase and muscle
contraction
• Dantrolene
– Prevents release of Ca2+ from sarcoplasmic
reticulum (SR)
– Mechanism of action is unclear
– Proposed mechanisms:
 Acts on connections between t-tubules and SR
or SR directly or both to inhibit excitation-
contraction coupling in order to attenuate Ca2+
release from SR to myoplasm
 Acts on RYR1 but not on RYR2 isoform as there
is absence of major effects of dantrolene on SR
Ca2+ release in the heart
Depolarizing Block
• Depolarization of motor endplate
immediately before onset of
neuromuscular block
• Possible mechanisms
– Inactivation of voltage gated sodium channels
present immediately adjacent to end plate on
muscle membrane
– nAChR desensitization
 Inactivation of Na+ channel

– Voltage-gated Na+ channel present immediately
adjacent to end plate on muscle membrane
(perijunctional zone)
• Upper voltage-dependent gate and lower time-
dependent gate
• Resting: upper gate close while lower gate opens
• With depolarization, upper gate opens and as bottom
gate still open  Na+ influx
• Shortly after upper voltage-dependent gate opens,

the bottom gate closes  Na+ influx terminated
• Lower time-dependent gate can’t open until the
upper voltage-dependent gate closes
• When depolarization of endplate stops, upper
voltage-dependent gate closes and lower time-
dependent gate opens and channel is reverted to
resting state
– As suxamethonium is not hydrolyzed rapidly,

persistent depolarization causes the persistent
closure of lower time-dependent gate  no
Na+ influx occurs through closed channels in
the perijunctional zone
– This form a zone of inexcitability and action
potential may not be able to be propagated
• Desensitization block
– nAChR exist in various states:
• Resting (free of agonist and ion channel closed)
• Two molecules of agonists bound to α subunit 
conformational change and ion channel opened
• Desensitized (receptors bind avidly to agonist
without conformational change and probably is a
physiologic response of AChR to prevent muscle
response to extreme neural stimulation)
– Increase in desensitized receptors can be

induced by an unphysiologically high
concentration of agonist:
• High ACh levels due to inhibition of Anti ChE
• High suxamethonium concentrations
• Nicotine
– Suxamethonium is not cleared by acetyl
cholinesterase, they react repeatedly with
nAChR and this prolonged contact causes
nAChR to cease responding to agonist
– Unknown mechanism but some evidence
suggests that desensitization is accompanied
by phosphorylation of tyrosine unit in
receptor protein
• Features of Depolarizing Block

– Paralysis is preceded by fasciculations
• Incoordinated contractions of muscles due to
repetitive firing of muscle fibres and are
associated with increased electromyographic
activity in voluntary muscles
• Unlikely related to depolarization of motor
endplate
• Proposed mechanisms:
– Stimulation of prejunctional ACh Receptors leading to
repetitive firing and release of ACh, and hence drugs act
on prejunctional site (tubocurarine) is able to abolish the
fasciculations induced by suxamethonium
– May be due to reflex effects mediated by AChRs in
muscle spindles
– Absence of fade
• ACh output is possibly maintained due to effects
of activation of prejunctional receptors which then
preserve ACh output at high rates of impulse
conduction
– No post-tetanic potentiation
– Potentiation by anticholinesterase drugs due
to inhibition of serum cholinesterase
– Antagonism by non-depolarizing
neuromuscular relaxants as they compete
with suxamethonium for nAChR on
postsynaptic membrane  endplate
depolarization reduces and depolarizing
block is minimized
– Possibility of Phase II block
• Commonly seen when large doses or prolonged
infusions of suxamethonium are used or when
drug elimination is compromised by enzyme
abnormalities or other drugs
Phase II Block
• Complex phenomenon occurs at NMJ
continuously exposed to depolarizing
neuromuscular relaxant
• Features consistent with non-depolarizing
blockade
• Onset of phase II block is often manifested
initially as tachyphylaxis
• Seen after
– High single or cumulative doses
– Normal doses during lack or functional
inefficiency of plasma ChE
• Reversal of response of phase II block by
anti ChE is difficult to predict
• Exact mechanism unclear and possible

explanations include:
– Changes caused by neuromuscular relaxants
(postjunctional mechanism)
• As long as depolarizer is present, receptor
channels remain open and ion flux through them
remains high
– Repeated opening of channels allows continuous efflux
of K+ and influx of Na+ and the resulting electrolyte
imbalance distorts function of junctional membrane
– Ca2+ entering muscle via opened channels causes
disruption of receptor
• Activation of the sodium–potassium ATPase pump
by initial depolarization of the postsynaptic
membrane, which attempts to restore ionic
balance and membrane potential towards normal
and repolarizes it
– Changes caused by inhalational anaesthetics

(postjunctional mechanism)
• Inclusion of inhaled anaesthetics changes the
postjunctional endplate membrane or acting on
prejunctional site to reduce transmitter output
– Desensitization block
– Presence of fade may indicate prejunctional
phenomenon: blockade of prejunctional
feedback receptors impairs the mobilization
of ACh to the immediately releasable site
Non-depolarizing Block
• Postjunctional action
– Competition of neuromuscular relaxants with ACh for receptor
sites on postsynaptic membrane (competitive antagonism)
Binding of a neuromuscular relaxant Amplitude of end plate potential reduces
molecule to one  subunit of a nAChR gradually and generation of action potential
produces NO change in membrane fails eventually causing neuromuscular
conductance and ionic permeability blockade
Activation of nAChR becomes impossible as

2  subunits within the receptor have to be AChE hydrolyzes ACh and removes it from
occupied by ACh to cause ion channel competition for nAChR
opening
Reduced number of effective ACh-nAChR

complexes formation as number of available
nAChR is reduced following occupation by
non-depolarizing neuromuscular relaxant
– Physical occlusion of ion channels on

postsynaptic membrane
• Most likely to occur when ion channel opening is
most frequent
• May occur at prejunctional sites as well
• Prejunctional action
– Competition between non-depolarizing
neuromuscular relaxant and ACh for
prejunctional AChR which are normally
responsible for mobilization and maintenance of
ACh output at high rates of stimulation
– Mobilization and release of ACh is inadequate to
maintain depolarization when motor nerve is
stimulated repetitively at frequencies of ≥ 2 Hz
• Features of Non-depolarizing Block

– Absence of fasciculations
• Occupation and antagonism of prejunctional
receptors
– Antagonism by anticholinesterase drugs
• Accumulation of ACh at motor endplate allows
neurotransmitter progressively to displace non-
depolarizing drugs from prejunctional and
postjunctional sites
– Presence of fade
• Pre-synaptic action to inhibit feedback control of
ACh leading to reduction in ACh output to sustain
muscle contraction during high-frequency (tetanus
or TOF) stimulation
– Post-tetanic facilitation
• Transient augmentation of response to
stimulation which follows a tetanic stimulus
• During tetanic stimulation, Ca2+ enters the motor
nerve ending but failed to be excreted as quickly
as the nerve is stimulated  Ca2+ accumulation
during tetanic period
• Intense tetanic stimulation induces increase in
mobilization and subsequent release of ACh
quanta and this continues for some time after
discontinuation of stimulation
• Abnormally large amount of ACh antagonizes
neuromuscular relaxant and causes increase in
size of twitch  generation of greater end plate
potential than obtained prior to tetanus
• Even though ACh release is increased, it is not
adequate to sustain response to tetanic
stimulation without fade
Structure-Activity Relationship
• Molecular size and Neuromuscular Block
– Bovet classified neuromuscular blocking agents into
pachycurares (thick, bulky and rigid molecules) and
leptocurares (slender, small and flexible molecules)
– Bulky molecules usually cause non-depolarizing block while
small molecules usually results in depolarizing block
– Methonium is a small onium head and succinic group is small
with flexible links suxamethonium is a depolarizing
– Steroid nucleus, benzylisoquinollinium and troponium heads are
rigid and bulky  non-depolarizing blockade
• Quaternary ammonium group and

neuromuscular blocking activity
– Analogous to ACh, neuromuscular relaxants have
at least one positively charged quaternary amine
group which is involved in binding to negatively
charged  subunit of nAChR
– Presence of ACh-like moiety in aminosteroids is
believed to facilitate their interaction with nAChR
• Number of quaternary ammonium group

and neuromuscular blocking potency
– General order of potency: tris- >bis-
>monoquaternary derivatives
– Number of quaternary ammonium groups in
various neuromuscular relaxants:
• Monoquaternary: tubocurarine, vecuronium,
rocuronium (one permanent quaternary cation and
one tertiary amine which present in uncharged
state at physiological pH)
• Bisquaternary: suxamethonium, decamethonium,
metocurine, pancuronium
• Trisquaternary: gallamine
• Interonium distance and Neuromuscular

Blocking Activity
– It was hypothesized that optimum biological
activity for neuromuscular blockade was
found with interonium distance of 14 Å (1.4
nm), which corresponds to chain length of 10
C atoms (10-atoms rule)
– Separation of two quaternary N atoms by
chain longer than 11 C atoms loses potency
in neuromuscular blockade
– Molecular length of decamethonium best fits

the space available between 2 receptive sites
of nAChR  5 times potent as tubocurarine
• Substitution on Quaternary Nitrogen and

Neuromuscular Blocking Potency
– Most potent neuromuscular relaxants have at
least one methyl group on the active quaternary
N atom
– In place of methyl group, rocuronium and
rapacuronium have a propenyl (-CH2CH=CH2) 
rocuronium and rapacuronium are much weaker
than vecuronium due to presence of 16-N
quaternizing group which is larger than methyl
group
– By having a bulkier group, potency is

reduced:
• Distance between functional groups and receptive
sites increases
• Electrostatic interactions reduced due to
increased lipophilicity
• Addition of Methoxy groups and

Neuromuscular Blocking Potency
– Addition of methoxy groups increases
potency of benzylisoquinolinium relaxants
and reduces the side effects
– Both hydroxyl groups of tubocurarine are
methylated in metocurine  metocurine is 2-
3 times more potent than tubocurarine
– Atracurium, mivacurium and doxacurium

have on each of their benzylisoquinolinium
heads 4, 5 and 6 methoxy groups  potency
increases and propensity to release histamine
reduces in that same order
• Chemical Structure & Side Effects

– Number of quaternary ammonium groups
• Monoquaternary drugs are more likely to produce
autonomic ganglionic blockade than bisquaternary
compounds
• Metocurine is 3 times less potent than
tubocurarine in blocking sympathetic and
parasympathetic ganglia
• Exception in vecuronium: monoquaternary
compound which is believed to be responsible for
lack of important autonomic side effects in
comparison with pancuronium
• Bisquaternary compounds favour block of

postganglionic mAChR leading to vagolysis
(pancuronium >vecuronium and rocuronium)
• Exception: pipecuronium is a bisquaternary
compound which causes 10 times less prominent
vagolysis in comparison to pancuronium, likely
related to changes in quaternary groups
(quaternary N are placed at distal 4-position of
2,16-substitutions)
• Trisquaternary compound (gallamine) has marked
vagolytic effect probably due to presence of 3
positively charged N atoms
– Interonium distance
• Interonium distance of approximately 10-14 Å is
associated with negligible ganglion blocking
potency
• Exception: tubocurarine as it has significant
ganglion blocking activity probably because of its
molecule is flexible to allow interaction with
ganglionic receptors
– Methoxy groups
• Increased methoxy groups is associated with less
histamine release and ganglionic blocking activity
which may be related to improved specificity and
reduction in dose requirement: atracurium
>mivacurium >doxacurium
• Chemical Structure & Metabolism

– Water solubility generally
• Reduces hepatic metabolism and/or elimination
• Easily excreted by glomerular filtration in urine
• Prevents passage across lipoid barriers like blood-
brain barriers and placenta
• Prevents passage across lipid membrane of most
cells like renal tubular cells, hepatocytes, nerve
and muscle cells and erythrocytes
– Water solubility in neuromuscular relaxants is

improved by
• Presence of quaternary groups
• Various oxygen-bearing groups:
– Ester linkages in suxamethonium, mivacurium, cis-
atracurium and atracurium
– Acetate groups in pancuronium, vecuronium, rocuronium
and rapacuronium
– Ether linkages in metocurine and tubocurarine
– Hydroxyl groups in alcuronium and tubocurarine
– Methoxy groups in tubocurarine, metocurine, doxacurium,
mivacurium, cis-atracurium and atracurium
– Exception of this general lack of hepatic
elimination: vecuronium, rocuronium and
rapacuronium
– Reversed ester linkages of atracurium and

cisatracurium are susceptible to Hoffman
degradation and/or non-specific esteratic
hydrolysis both in plasma
• Connecting diester is reversed (ester O and the
carbonyl groups, CO are transposed, -CO-O-(CH2)n-O-
OC- : Reversed ester arrangement was designed to for
the acyl group to break away under physiological pH
and temperature, leaving tertiary benzylisoquinoline
product laundanosine
– As reverse ester linkage is not found in the

structure of doxacurium and mivacurium,
Hofmann degradation is not a significant
pathway of metabolism
– Plasma ChE hydrolyzes suxamethonium and

mivacurium but not doxacurium
• Exception of doxacurium illustrates the incomplete
understanding of structural requirements for
hydrolysis by plasma ChE
– Ester structures on positions 3 and 17 of

aminosteroids are susceptible to hepatic
esterases for deacylation to 3-OH, 17-OH
and/or 3,17-dihydroxy- metabolites
• Exception: rapacuronium is rapidly hydrolyzed to

3-OH rapacuronium spontaneously or catalyzed
by esterases and liver is not the main site of
metabolism
• Vecuronium is the 2-desmethyl derivative of

pancuronium  more lipid soluble due to absence
of quaternizing methyl group on 2-position 
greater amount of metabolism and biliary
excretion, shorter duration
• Activity of A- and D-rings of

Aminosteroids: Beers & Reich’s Rule
– Aminosteroid molecules have moiety of ACh
incorporated into their structure
– Beers & Reich’s Rule: Distance from centre
of cationic N to O atom is important in
determining the activity of the neuromuscular
relaxant- 4.4 Å for muscarinic action and 5.9
Å for nicotinic action
– Pancuronium
• A-ring ACh moiety: distance between charged N
to ester O= 4.4 Å  muscarinic action
• D-ring ACh moiety obeys rules of Beers and Reich
to have nicotinic action
– Vecuronium: D-ring ACh moiety obeys rules of

Beers and Reich to act on nicotinic receptor as
the distance between the charged N to the
carbonyl O is 5.9 Å
– Generally D-ring ACh is associated with actions

on nAChR while A ring ACh is associated with
actions on mAChR
– This is applicable to metabolites of aminosteroids
• Metabolites with intact D-ring ACh have actions on
nAChR and possess neuromuscular relaxant activity
• 3-OH metabolites retain significant potency as the D
ring ACh is remained while 17-OH metabolites lack
nicotinic activity as the D-ring ACh is degraded
Classification of Neuromuscular
Relaxants
• Activity on NMJ: depolarizing and non-
depolarizing
• Chemical classes: benzylisoquinoliniums,
aminosteroids, phenolic ether, strychnos
alkaloid
• Onset of action
• Duration of action
Non-neuromuscular Actions of
• Autonomic effects
– Cardiovascular effects
– Effects on carotid bodies
• Respiratory effects
• Non-cholinergic actions (histamine
release)
• Cardiovascular Effects
– Action on nicotinic receptors in autonomic ganglia
and muscarinic receptors in heart
– Generally cardiovascular (CV) effects are related to
• Stimulation or inhibition of peripheral autonomic sites
• Release of histamine and possibly other vasoactive
substances from tissue mast cells and circulating basophils
• Increase in serum K+ following motor endplate depolarization
– Separation of neuromuscular blocking action from

autonomic effects can be described as autonomic
margin of safety which indicates number of multiples
of a dose of neuromuscular relaxant producing 95%
neuromuscular blockade which should be given to
produce cardiovascular side effects
– Side effect is considered to be absent clinically if
safety ratio is >5, weak or slight if ratio is 3-4,
moderate 2-3 and strong or prominent if ratio is less
than 1
– Neuromuscular relaxants with significant

autonomic ganglion effects: suxamethonium and
tubocurarine
– Suxamethonium
• Stimulation of sympathetic ganglia is a probable cause
of tachycardia and increase in blood pressure, which
sometimes occur transiently after administration
• Stimulation of parasympathetic ganglia, or direct
stimulation of cardiac muscarinic receptors, may be
responsible for the more commonly occurring
bradycardia
• Net effects dependent on pre-existing dynamic
equilibrium
– Children with elevated vagal tone  prone to have
bradycardia
– Pretreatment of atropine  tachycardia and hypertension
– Tubocurarine
• Prominent ganglion-blocking effects
• Blockade of sympathetic ganglia leads to
hypotension without any significant reflex
tachycardia
• Drop in blood pressure 20-30 mmHg or more
• Ganglion blocking effects occur closer to dose
required to achieve neuromuscular blockade in
comparison to other neuromuscular relaxants
(narrow safety index)
– Vagal block
• Resulting in tachycardia and hypertension via blockade
of M2 receptor at sinus node
• All steroidal neuromuscular blocking compounds
contain ACh-like fragment in the D-ring  potent
neuromuscular action
• Only pancuronium bromide, with ACh-like fragment in
the A-ring  potent blocker of muscarinic receptors
• Lack ACh moiety in the A-ring of the steroid nucleus of
pipecuronium bromide, vecuronium bromide and
rocuronium bromide  reduced potency in blocking
cardiac M2 muscarinic receptors
• Effects on Carotid Body

– Neuronal-type nAChR is important in signaling of
hypoxia from peripheral chemoreceptors of
carotid body to central nervous system
– Inhibition of neuronal acetylcholine receptors at
carotid body by neuromuscular relaxants reduces
acute hypoxic ventilatory response which
normally compensates for a reduction in O2
saturation by increasing minute volume
– In clinical dosing range, atracurium and
vecuronium are able to inhibit neuronal
acetylcholine signaling in carotid body
attenuating chemoreceptor responses to hypoxia
• Respiratory Effects
– At clinical doses, some relaxants are thought to
block the postjunctional M3 and prejunctional M2
receptors at parasympathetic (vagal)
neuroeffector junctions in lungs
• Actions on postjunctional M3 receptors  inhibit ACh-
induced bronchoconstriction
• Actions on prejunctional M2 receptors  blocking
negative-feedback effect of ACh on vagal nerve
terminals  increase bronchoconstriction
– Non-depolarizing neuromuscular relaxants

have different antagonistic effects on these
muscarinic receptors  net result depends
on relative actions on these receptors
• Affinity of rapacuronium to block M2 receptor is 15
times higher than that to block M3 receptor 
bronchospasm
• Vecuronium may have similar receptor action as
rapacuronium but the recommended intubation
dose is 15-20 times lower  no significant effects
• Pancuronium is a potent M2 and M3 antagonist 
no significant effects within clinical dosing range
• Rocuronium, mivacurium and cisatracurium do not
potentiate vagally induced bronchoconstriction
• Histamine release
– Most serious non-cholinergic side effect
– Usually caused by benzylisoquinolinium-
based compounds
– Short-lived (1-5 mins) and dose-related
– Possible mechanisms
• Direct action of neuromuscular relaxant molecules
on surface of mast cells (much common than
other mechanisms)
• Antigen-antibody reaction mediated by IgE
• Activation of complement system (IgG or IgM)
– Anaphylaxis
• Rare
• Cross-reactivity between neuromuscular relaxants and
food, cosmetics, disinfectants and industrial materials
• Female 2.5 times more common than male  causal
relationship with cosmetics and cleaning chemicals
which often have quaternary ammonium structures
– Histamine release is affected by several factors:
• Type of neuromuscular relaxant
• Rate of adminstration
• Drug dose
– Histamine release in various neuromuscular

relaxants
• Suxamethonium and benzylisoquinoliniums
directly liberates histamine from serosal mast cells
(vascular endothelium, skin and connective tissue)
• Large doses (>3 ED95) of atracurium administered
rapidly may elicit histamine release and
hypotension
• Rocuronium produces no significant histamine
release up to doses of 4 ED95
• Rapacuronium possesses histaminergic side
effects acting more on mucosal mast cells
(bronchial system and gastrointestinal tract)
Pharmacologic Variables of
• Potency
– ED95 = median dose corresponding to 95% of blockade of
single twitch of adductor muscle following a stimulation given to
ulnar nerve
• Onset
– Interval between injection of neuromuscular relaxant and
development of maximal neuromuscular block (95% block)
• Clinical duration of action
– Interval between injection of neuromuscular relaxant and
recovery of twitch to 25% or 95% of baseline twitch height
(75% and 5% twitch suppression) (dur25 and dur95)
• Recovery Index
– Time taken for recovery from 25% to 75% of
twitch height
– Measures rate of recovery rather than time of
beginning or end of recovery
– Preferred to duration of action as this parameter
does not depend heavily on dose administered
Pharmacokinetics
• Parameters of neuromuscular relaxants are
usually calculated from two-compartment model
– Central compartment: plasma, highly perfused
organs (liver, kidney)
– Peripheral compartment: tissue
– Effect compartment: neuromuscular junction
Initial drop in plasma level:

• Movement of drug from central
compartment to peripheral
compartment and effect
compartment
• Uptake by liver and kidney
Following initial process of

distribution to peripheral tissues,
plasma level falls more slowly:
• Plasma level is affected by rate at
which drug can move from
tissues to plasma and clearance
of drug from plasma
• removal of drugs via hepatic or
renal metabolism + elimination
• As neuromuscular relaxants are ionized

compounds:
– Not absorbed through gastrointestinal tract (prey
killed with curare could be eaten without risking
muscle paralysis)
– Not crossing placental barrier and blood-brain
barrier in appreciable amounts (foetal apnoea
very rarely found)
– Almost impossible to bind to lipids (Vd close to
extracellular volume 0.2-0.5 L/kg)
• Plasma protein binding
– Published values are inconsistent
– Albumin and globulins
– Increased 1-globulin in inflammation: reduced
free fraction in plasma
• Paediatrics
– Larger Vd  greater dose  prolonged duration
of action and elimination
– Subsequent doses at less frequent intervals than
in older children
– Onset faster due to higher heart rate and cardiac
index
– Neonatal NMJ is immature and continues to
develop after birth until  12 weeks
• Resistant to depolarizing neuromuscular relaxants
• Sensitive to non-depolarizing neuromuscular relaxants
• Geriatrics
– Impaired organ function  reduced
elimination and clearance
– Reduced Vd: reduction in total body water
and increase in body fat
– Sensitivity toward neuromuscular relaxants
unchanged
– Reduced activity of plasma ChE
– Reduced initial and subsequent doses
– Dosing interval increased
Factors Affecting Onset of Action

• Pharmacokinetic factors
– Routes of administration
– Rate of administration
– Site of intravenous administration
– Absolute dose
– Priming
– Volume status
– Perfusion to various muscle groups
– Routes of administration
• Slower onset with intramuscular route as
compared to intravenous administration  time is
needed for drug to diffuse from intramuscular site
to circulation before it is transported to
neuromuscular junction
– Rate of administration
• With faster rate of injection, neuromuscular
relaxant is brought to the site of junction within a
shorter time as compared to slower rate of
injection  faster onset
– Site of administration
• Determines the time which is taken for the drug to
be carried to the heart before it is carried in arterial
blood to the neuromuscular junction
• Longer distance between site of injection and
heart  onset slower
• Central venous administration gives rise to faster
onset as compared to intravenous administration
at saphenous vein
– Absolute dose
• Larger dose  higher plasma
concentration of
neuromuscular relaxants +
greater concentration gradient
favouring the diffusion of drug
from plasma into
neuromuscular junction 
faster onset
• Increasing dose shortens
delay between drug
administration and onset of
clinical effects, especially with
doses within 1-3 ED95 range
– Priming
• Small subparalyzing dose which is about 20% of
ED95 or about 10% of intubating dose given 2-4
minutes before second large dose for tracheal
intubation  accelerate onset by 30-60 secs 
intubation within 90 secs following second dose
– Cardiac output and Volume status

• Cardiac output affects transition time from
peripheral vein (site of administration) to arterial
circulation (delivery of neuromuscular relaxant to
site of action)
– Higher cardiac index in infants  faster onset
– 1% per year reduction in cardiac output after 30 years of
age  delayed onset in elderly as distribution of drug to
neuromuscular junction is slowed
• Volume status determines the plasma
concentration of a dose of neuromuscular relaxant
– Similar dose creates a higher plasma concentration of
neuromuscular blocking agent in patients with
hypovolaemia  concentration gradient favouring drug
diffusion and hastens onset
– Perfusion to various muscle groups

• Affects the rate at which the neuromuscular blocking agent
is transported to the neuromuscular junction
• Depends on distance of muscle groups from heart and the
regional muscle blood flow
• Muscles closer to central circulation and have a better
perfusion tend to have faster onset than more peripheral,
less perfused muscles
– At intubating dose of a neuromuscular blocking agent, onset at
diaphragm is faster than that at adductor pollicis  diaphragm
receives better perfusion than adductor pollicis
diaphragm <laryngeal muscles <orbicularis oculi

<adductor pollicis
• Pharmacodynamic factors
– Potency
– Number of nicotinic acetylcholine receptors
to be blocked
– Drugs interactions
– Potency
• Neuromuscular blocking agents with higher
potency will be administered in lower dose
compared to those with lower potency
• Higher number of molecules will be administered
with less potent agents  creation of larger
concentration gradient favouring diffusion into
neuromuscular junction compared to drugs with
higher potency  shortens onset
• Administration of intubating dose (2x ED95) of
rocuronium tends to give faster onset compared to
an equipotent dose of a more potent drug like
pancuronium
• Molar potency
– Quantified in number of molecules per body weight
– Better in prediction of clinical effects as clinical effects
are related to number of molecule rather than amount of
neuromuscular relaxants interacting with nAChR
• Discrepancy in prediction of onset: ED95 mg/kg vs
ED95 M/kg
Molecular Molecular ED95- ED95- Molar potency- Onset time
weight of weight of salt cation cation (M/kg) to 90% of
cation salt (mg/kg) (mg/kg) peak effect
(secs)
Suxamethonium 290 360 0.260 0.209 0.7222 75
chloride
Rocuronium bromide 530 609 0.310 0.270 0.5090 105
Vecuronium bromide 558 637 0.041 0.036 0.0639 201
Mivacurium chloride 1029 1099 0.076 0.071 0.0691 201
Cisatracurium 929 1244 0.046* 0.046* 0.0495 268

besylate
Atracurium besylate 929 1244 0.210 0.157 0.1688 192
(a) Vecuronium vs mivacurium

(b) Cisatracurium vs vecuronium
– Number of nicotinic acetylcholine receptors

to be blocked
• Typically 75% of the nicotinic acetylcholine
receptors has to be blocked to cause an inhibition
in neuromuscular transmission
• In patients with myasthenia gravis, lesser number
of receptors is blocked to inhibit the
neuromuscular transmission  faster onset of non
depolarizing neuromuscular relaxants
– Drugs Interactions
• Drugs which hastens the onset of neuromuscular
relaxants include
– Inhalational anaesthetics (increased muscle blood flow)
– Opioids
– Magnesium sulphate
– Aminoglycosides
– Frusemide
Factors Affecting Clinical Pharmacology of

• Renal Insufficiency
– Drugs affected are those depends mainly on
kidneys for elimination: gallamine, metocurine,
tubocurarine, pipecuronium and pancuronium
– Disposition of vecuronium is marginally affected
• Prolonged action in Intensive Care Unit patients maybe
related to accumulation of 3-desacetylvecuronium
– Altered clinical response is due to

• Reduced clearance
– As effect of single dose of neuromuscular relaxant is
mainly terminated by redistribution  usually no
significant effect
– After repetitive or continuous administration
prolongation of effects
• Altered enzyme activity
– Elimination pathways of mivacurium and cisatracurium
make the terminal elimination mainly independent of
renal function, but these primarily kidney-independent
pathways are often impaired by concomitant diseases
– Activity of plasma enzymes (plasma cholinesterase) is
reduced probably related to loss through dialysis filter
membranes and reduced synthesis
• Altered fluid balance: effects on Vd make the

prediction of effects difficult
• Changes in acid-base balance
• Changes in electrolyte status
• Hepatic Insufficiency
– Affected drugs: pancuronium, vecuronium,
rocuronium, mivacurium, doxacurium and d-
tubocurarine
– Altered clinical response is due to
• Altered Vd
• Altered elimination
• Altered enzyme activity
– Altered Vd
• Liver failure is often associated with
hyperaldosteronism causing fluid retention and
increased Vd  greater dose
• Initial dose may need to be greater
• Subsequent recovery may be prolonged
– Altered elimination
• Increased plasma concentrations of bile salts
reduce hepatic uptake of pancuronium and
vecuronium  reduced hepatic clearance
• Higher dose may stay in central compartment for
longer time due to poor hepatic elimination
• After repetitive or continuous administration of
vecuronium, rocuronium and pancuronium,
accumulation occurs as the elimination is partly
dependent on liver function
– Altered enzyme activity

• Plasma cholinesterase activity is also reduced in
hepatic dysfunction due to reduced synthesis 
reduced ester hydrolysis of mivacurium by
approximately 50%
• Elimination of atracurium and cis-atracurium are
independent of hepatic function
• Electrolyte Imbalance
– Transmembrane potential can be predicted
with Goldman Constant-Field Equation:
– Hypokalaemia
• Increase endplate transmembrane potential (more
negative)
• Hyperpolarization  increased resistance to
depolarization
• Greater sensitivity to non-depolarizing
• Resistant to depolarizing neuromuscular relaxants
– Hyperkalaemia
• Lowers endplate transmembrane potential (less
negative)
• Partially depolarizes membrane
• Increases effects of depolarizing neuromuscular
relaxants but oppose the action of non-
– Calcium
• Action of non-depolarizing neuromuscular relaxants is
accentuated by hypocalcaemia while hypercalcaemia
reduces sensitivity to neuromuscular relaxants with
shortened time of blockade
– Magnesium
• Augments block produced by non-depolarizing
neuromuscular (reduced requirement, accelerates onset and
prolongs recovery)
• Neostigmine-induced recovery is also attenuated in patients
treated with magnesium
• Mechanism by which magnesium enhance neuromuscular
blockade produced by suxamethonium is not known
• Interaction of magnesium with suxamethonium is
controversial: potentiation, antagonism or no significant
effect
• It is possible that phase II blockade occurs more readily
when suxamethonium is administered in presence of
increased plasma concentrations of magnesium
• Acid-Base Imbalance
– Respiratory acidosis enhances blockade
produced by tubocurarine, vecuronium and
pancuronium
– Respiratory acidosis also opposes reversal by
neostigmine  Probability of achieving
adequate reversal in presence of significant
respiratory acidosis (PaCO2 >50 mmHg) is low
– Changes observed in metabolic acidosis and

respiratory and metabolic alkalosis have
produced conflicting results
– Exact mechanism unknown but may be
explained by changes in intracellular ion
concentrations in response to raised
extracellular H+ concentrations
– It is unclear whether metabolic acidosis also
prolongs neuromuscular blockade
• Hypothermia
– Prolongation of actions may be related to
changes in pharmacokinetic,
pharmacodynamic or both
– Clearance
• Actions of pancuronium, rocuronium and
vecuronium are prolonged due to reduced hepatic
enzyme activity and biliary and renal clearance of
drugs
• With hypothermia, Hoffman elimination and ester
hydrolysis are also slowed for atracurium and
cisatracurium
• Mivacurium is degraded by temperature
independent plasma cholinesterase  prolonged
action during hypothermia likely due to
pharmacodynamic interactions
– Changes in volume of distribution of

– Neuromuscular transmission
• Hypothermia reduces the speed of neural
conduction in humans
• Hypothermia appears to increase sensitivity of
neuromuscular junction to certain neuromuscular
relaxants  reduced requirement
• At low temperature, channel open time at
postjunctional AChR is altered: 20oC channel
open time is prolonged to 1.0 ms compared with
0.3 ms at 37oC
• Neuromuscular diseases
– Integrity and function of prejunctional structures
is important for development, function and
maintenance of neuromuscular endplate
– Any neuromuscular disease affecting nerve
conduction or electrical activity of muscle
membrane will influence neuromuscular
architecture and receptor function
• Upregulation of nAChR
• Downregulation of nAChR
– Upregulation of nAChR
• Denervation, immobilization, burns, chronic
neuromuscular blockade and possibly sepsis
• When innervation and electrical conductivity are
established between muscle and nerve, mature
receptors are localized to neuromuscular junction
• Deprivation of neural influences to muscles  up-
regulation of AChR and spread of receptors away
from neuromuscular junction into perijunctional
and extrajunctional sites (extrajunctional receptor)
• Ligand sensitivity and affinity of extrajunctional

receptors are altered
• Agonists like suxamethonium depolarize immature
extrajunctional receptors more easily 
exaggerated cation fluxes  hyperkalaemia
• Increased number of AChR  increased margin of
safety for neuromuscular blocks  resistance to
non-depolarizing neuromuscular relaxants
– Downregulation of nAChR
• Myasthenia gravis
– Postsynaptic lesion  number of quanta of ACh is
normal and their content is either normal or increased
– Increased sensitivity to non-depolarizing neuromuscular
relaxants  requirement reduced by 75% and
neuromuscular monitoring is required
– Suxamethonium can not depolarize endplate effectively
 resistance
– On the other hand, plasma cholinesterase activity may
be reduced by preoperative plasmapharesis or treatment
with pyridostigmine (or in combination)  potentiation
• Lambert-Eaton Myasthenic Syndrome

– Acquired (immune mediated) channelophathy
– Autoimmune disorder caused by presence of antibodies
directed against P/Q type, voltage-gated Ca2+ channels
possibly because of cross-reaction with Ca2+ channels on
carcinomatous cells and possibly another presynaptic
component (synaptotagmin)  prejunctional mechanism
resulting in reduced quantal release of ACh in the presence
of normal postjunctional nicotinic AChR
– Approximately 60% of patients show a paraneoplastic
response, often in association with small cell carcinoma of
lung
– Increased sensitivity to both depolarizing and non-
– Critical Illness Myopathy

• Also known as acute quadriplegic myopathy,
acute (necrotizing) myopathy of intensive care,
thick filament myopathy, acute corticosteroid
myopathy and critical care myopathy
• Residual weakness for unexpectedly long periods
after discontinuation of neuromuscular relaxant in
critically ill patients
• Reported in:
– Asthmatics receiving high doses of methylprednisolone
– Acutely injured patients with multiple organ system
failure
– Patients requiring muscle relaxation for prolonged
periods (> 6 days)
• Time course of weakness unpredictable and may

progress and persist for weeks or months despite
discontinuation of non-depolarizing
• Pancuronium and vecuronium has been the
relaxant used most frequently but descriptions of
similar syndromes after atracurium suggest that
this reflects their popularity rather than a particular
association with steroid-based relaxants
• Some cases are the result of impaired organ
excretion of drug or active metabolite such as high
concentration of 3-OH vecuronium in patients with
renal failure
• Other predisposing factors: electrolyte
abnormalities, acid-base disturbances,
aminoglycoside antibiotics and cyclosporine
• Proposed mechanisms:
– Failure of synthesis and release of ACh
– Interference with Ca2+ currents
– Disorganization of postjunctional membrane
– Channel block
– Down-regulation of receptor
– Local immune activation by cytokine expression in
skeletal muscles causing destruction of the nAChR
• Gender
– Sensitivity of patients to pancuronium,
rocuronium and vecuronium is different
between men and women  women more
sensitive  dose adjustment
– Reason unclear but may be related to
differences in body composition, distribution
volume and plasma protein concentrations
– Greater percentage of skeletal muscle mass
in men  increased requirement
Drugs Interaction
• Many drugs apart from neuromuscular relaxants will
interfere with neuromuscular transmission and they
may interact with neuromuscular relaxants
• Mechanisms responsible for such drug interactions
include
– Prejunctional inhibition of propagation of nerve action
potential
– Impaired release of ACh due to deficient storage,
synthesis or release of neurotransmitter from motor nerve
terminal
– Postjunctional receptor block
– Combined prejunctional and postjunctional block
• Antibiotics
– Neomycin, streptomycin, dihydrostreptomycin,
kanamycin, gentamycin, polymyxin A, polymyxin
B, colistin, lincomycin and tetracycline have all
been found to augment action of non-
– Mechanisms not the same for all antibiotics and
it is possible for an antibiotic to have
prejunctional, postjunctional or combined effects
– Inhibition of prejunctional release of ACh may
reflect competition by antibiotics with Ca2+
– Streptomycin and aminoglycosides gentamicin,

kanamycin and neomycin potentiate effect of non-
depolarizing neuromuscular relaxants via
• Reduction in quantal release of ACh from presynaptic
membrane
• Depression of postjunctional nAChR sensitivity to
acetylcholine (Stabilization of postjunctional
membrane)
– Aminoglycoside-induced neuromuscular block is
reversible with 4-aminopyridine
– Polymyxins block the ACh recognition site on 

subunits of ACh receptor  induce neuromuscular
block of their own as well as potentiating effects of
non-depolarizing neuromuscular relaxants
– Clindamycin reduces open channel life-time and
prolongs neuromuscular blockade
• Anticholinesterases
– Echothiopate, tetrahydroaminoacrine,
hexafluronium, procaine, trimetaphan, phenelzine,
chlorpromazine and some insecticides inhibit
plasma cholinesterase  possible prolonged
action of suxamethonium
– Besides inhibiting plasma cholinesterase,
trimetaphan also influence clinical responses by:
• Reduces skeletal muscle blood flow (ganglionic blockade)
 delay onset and prolong duration of action
• Reduced sensitivity of postjunctional membranes
• Cardiovascular Drugs
–Antiarrhythmic drugs
• Quinidine, procainamide and
propranolol
• Augment effects of neuromuscular
relaxants
• Quinidine acts by interfering with
prejunctional release of ACh
– Diuretics
• Intensify effects of non-depolarizing
neuromuscular relaxants by reduction in Vd
and associated hypokalaemia
• Frusemide and thiazides have bimodal effect
at neuromuscular junction: low doses
augment and high doses antagonize
neuromuscular block
• Low doses of intravenous frusemide (1
mg/kg) probably inhibit protein kinases and
cAMP production  breakdown of
adenosine triphosphate is inhibited and
causes reduced prejunctional release of ACh
• High doses of intravenous frusemide inhibit
phosphodiesterase  more cAMP available
 antagonism of non-depolarizing
• Local Anaesthetics
– Enhances neuromuscular block produced by
depolarizing and non-depolarizing
neuromuscular relaxants via several
mechanisms
• Interfere with prejunctional release of ACh
• Direct depression of skeletal muscle fibres
(stabilizing effect on postjunctional membrane)
– Ester local anaesthetics compete with other
drugs for plasma cholinesterase  prolongs
effects of suxamethonium and mivacurium
• Benzodiazepines
– Diazepam may slightly prolong non-
depolarizing block by a combination of
central and prejunctional effects
– Central effect involves depression of somatic
reflexes in central nervous system which
consequently reduces transmitter release at
motor nerve terminal
• Inhalational Anaesthetics
– All inhalation agents augment both degree and
duration of neuromuscular block induced by non-
– Possible mechanisms:
• Depression of α-motor neurons and interneuron synapses in the
central nervous system  reduction of skeletal muscle tone
• Prejunctional inhibition of ACh mobilization and release 
greater effect on tetanic and train of four responses than on
single twitch responses suggests that prejunctional
mechanisms are involved
• Decrease sensitivity of postjunctional membranes to
depolarization (postjunctional receptor desensitization)
• Action upon muscle at some point distal to cholinergic receptor
• Increased skeletal muscle blood flow to deliver more drug to
neuromuscular junction (particularly isoflurane)
– Inhalational agents augment the

neuromuscular block in dose-dependent
manner in the following decreasing order:
desflurane> sevoflurane> isoflurane>
halothane> nitrous oxide-barbiturate-opioid
or propofol anaesthesia
• Miscellaneous
– Lithium
• Resembles Na+, K+, Mg2+ and Ca2+ and may therefore
affect the distribution and kinetics of all these electrolytes
• Enters cells through sodium channels and tends to
accumulate within cells
• Augments effects of both depolarizing and non-
• Mechanisms unknown, but probably:
– Depression of electrophysiological phenomena as Li+ is
being substituted for Na+ at prejunctional level
– Activation of K+ channels inhibits neuromuscular
transmission presynaptically and muscular contraction
postsynaptically
– Interferes with ACh synthesis and/or release
– Postjunctional effect
– Ketamine
• Potentiates neuromuscular blockade produced by tubocurarine
and atracurium but not that produced by pancuronium or
suxamethonium
• Mechanism unclear and may be related to reduction in
prejunctional release of ACh and reduction of sensitivity of
motor endplate to ACh
– Aminophylline
• Phosphodiesterase inhibitor
• Antagonize neuromuscular block
– Azathioprine
• Antagonizes non-depolarizing neuromuscular block probably by
inhibiting phosphodiesterase
• Augments neuromuscular block produced by suxamethonium
– Cyclosporine may prolong duration of neuromuscular
block produced by non-depolarizing neuromuscular
relaxants
• Antiepileptics
– Depressant action on ACh at neuromuscular junction
– Acute treatment causes augmentation of
neuromuscular blockade
– Chronic anticonvulsant therapy
• Resistant to neuromuscular blocking effects of non-
depolarizing neuromuscular relaxants  accelerated
recovery and increased requirement
• Mechanisms may be related to pharmacokinetic or
pharmacodynamics factors
• Phenytoin and carbamazepine cause resistance via
increased hepatic clearance and reduced elimination half
time, perhaps reflecting hepatic enzyme induction and/or
increased binding (reduced free fraction) of
neuromuscular relaxants to α1-acid glycoproteins
• Upregulation of neuromuscular acetylcholine
• Corticosteroids
– Improve neuromuscular function in patients with
myasthenia gravis
– It does not alter the characteristics of neuromuscular
blockade produced by non-depolarizing
– Enhanced neuromuscular blockade produced when
corticosteroids are combined with vecuronium may
reflect pharmacologic denervation of nAChRs and
contribute to prolonged weakness observed in some
critically ill patients
• Calcium channel blockers

– Ca2+ channels located at terminal of the mammalian
neuromuscular junction are P/Q type or P channels
– P channels are not affected by therapeutic doses of
verapamil, diltiazem and nifedipine which have
profound effects on the slower L channels present in
cardiovascular system  L calcium channel blockers
at therapeutic doses have no significant effect on
normal release of ACh
– There have been reports that calcium entry blocking
drugs may increase the block of neuromuscular
transmission induced by non-depolarizing relaxants
 effects are small and not all investigators have
been able to observe it  probably due to presence
of some L-type calcium channels in nerve endings
Depolarizing Neuromuscular
Relaxants
Suxamethonium: History
• Synthesized in 1906 by Hunt & Taveau who were
investigating the actions of drugs with a similarity
of ACh in an attempt to elucidate muscarinic
actions of ACh
• They did not comment on its neuromuscular
blocking activity
• Muscle relaxant properties were not described
until 1949
• Introduced into clinical practice by Thesleff in
Sweden, Scurr in Great Britain and von Dardel
and Meyerhofer in Austria in 1951
• Other agents such as suxethonium and
decamethonium have been used clinically
Suxamethonium: Chemistry
• Chemistry
– Condensation of two molecules of ACh which are joined
together at their non-quaternary ends through the acetyl
groups (dicholine ester of ACh)  also known as
succinyldicholine
– Supplied as chloride or bromide salt
– Preparations available:
• White crystalline solid with melting point of 160oC
• Clear aqueous solution
– pH of 3-5
– Containing 50 mg/ml as suxamethonium chloride with
stabilizers and buffers (benzylalcohol, benzoate and
sodium chloride)  which may account for side effects
– Shelf life 2 years
– Some amount of spontaneous hydrolysis
does occur especially in warm surroundings
 stored at 4oC
– When added to solution of thiopentone, white
precipitate forms which redissolves though
probably both drugs retain their potency
Suxamethonium: Dose, Onset &

Duration of Action
• Dose, Onset and Duration of Action
– Administered intravenous and intramuscularly
– Generally ultra rapid onset (30-60s) consistent with one
circulation time and ultra short duration of action (3-5 min)
– ED95= 0.25-0.6 mg/kg (variable sources)
– Intravenous suxamethonium:
• High dose at 3 xED95, 1 mg/kg is used clinically to
ensure fast and complete paralysis and with this dose,
complete neuromuscular block in about 60 secs
• With 1.0 mg/kg, recovery to 90% muscle strength
occurs within 9-13 mins
– Intramuscular 2.5-4.0 mg/kg (onset 2-3min )
– Intravenous infusion as 0.1% solution
Suxamethonium: Pharmacokinetics
• Pharmacokinetics
– Rapid hydrolysis makes it difficult to obtain
pharmacokinetic data
– Distribution
• Poor lipid solubility due to presence of quaternary
ammonium group
• Protein binding occurs but extent is not known
due to transient nature of drug
– Metabolism
• Not a substrate for acetylcholinesterase at
neuromuscular junction
• Rapidly hydrolyzed by plasma ChE  when
injected intravenously, about 90% of
suxamethonium is metabolized within the first
minute  Only a small fraction (10%) of original
dose actually reaches neuromuscular junction
• Plasma ChEs influence the duration of action of
suxamethonium by controlling the amount of
suxamethonium hydrolyzed before it reaches NMJ
• It is estimated that even a reduction to 30% of

original ChE activity will only cause a moderate
prolongation of suxamethonium-induced apnoea
• Removed from NMJ 1,000 times slower than ACh
by plasma ChE as there is litttle or no plasma ChE
at NMJ  neuromuscular block of
suxamethonium is terminated by its diffusion into
circulation
– Hydrolysis by plasma ChE

is a two stages process:
• First rapidly degraded to
succinylmonocholine which
is the monocholine ester of
succinic acid and choline
• Succinylmonocholine has
1/20-1/70 activity of
suxamethonium as
• Succinylmonocholine is
then hydrolyzed at a slower
rate to choline and succinic
acid (succinate)
• First stage is about 6 times
faster than second stage
– Elimination
• Approximately 2-20% is excreted unchanged in
urine
• T½ <1-3.5 mins (variable sources)
Suxamethonium: Adverse Effects

• Adverse Effects
– Structural similarity with acetylcholine is
responsible for adverse effects caused by
stimulation of receptors other than
acetylcholine receptors of neuromuscular
junction such as muscarinic receptors and
receptors in ganglia. Because of these many
adverse effects, suxamethonium is usually
indicated only to gain control of airway in
emergency situation.
• Nervous and Muscular Systems
– Muscle fasciculation, muscle pain
– Profound & prolonged muscle relaxation
– Increased IOP &ICP
• Gastrointestinal System
– Excessive salivation
– Decreased tone & motility of GIT
• Cardiovascular System
– Bradycardia, Hypotension
– Tachycardia, Hypertension
– Arrhythmia, Junctional rhythm, Sinus arrest
• Respiratory System
– Respiratory depression
– Prolonged apnoea
– Bronchospasm
• Metabolic
– Hyperkalemia
– Histamine release
• Others
– Malignant hyperthermia
– Hypersensitivity
• Cardiac arrhythmias
– Bradycardia
• Suppression of sinus node (sinus bradycardia,
junctional rhythm, ventricular arrhythmias and
cardiac arrest if suppression is complete)
– Stimulation of musarinic AChR in heart (Structural
similarity between suxamethonium and ACh)
– Role of suxamethonium in sensitizing heart to
subsequent doses  supported by bradycardia after
repeated doses of suxamethonium
• Sinus bradycardia often occurs in

conditions
– Pre-existing high vagal tone (paediatric
patients)  develop bradycardia even after a
single dose of suxamethonium
– Post-intubation (vagal stimulation stimulated
by laryngoscope blade)
– Stimulation of other parasympathetically
innervated structures (dilation of cervix,
stimulation of carotid body or eye balls)
– Repeated doses of suxamethonium especially
if 2nd dose is given 5 mins after the first dose
 asystole has been described with repeat
doses
– Cardiac arrest is an extreme response and

reported particularly in patients recovering
from severe burns where hyperkalaemia may
be a contributory factor
– Prevention of sinus bradycardia
• Anti-cholinergic drugs: Atropine (10 g/kg)
or glycopyrrolate (3 g/kg) given before
suxamethonium will prevent such
bradycardia but ventricular arrhythmias are
not attenuated by atropine pretreatment
– Tachycardia
• Exact mechanism unknown
• Lack of effect of suxamethonium on ganglionic
receptors (α3β4) suggests that tachyarrhythmias
occasionally seen with suxamethonium are
unrelated to this interaction
• This finding puts to rest previous hypotheses that
such tachyarrhythmias are related to stimulatory
effects on the autonomic ganglia or release of
catecholamines from the adrenal medulla by
suxamethonium
– Ventricular arrhythmias
• Suxamethonium lowers threshold of ventricle to
catecholamine-induced arrhythmias
• Catecholamine levels are raised in
– Suxamethonium administration
– Endotracheal intubation
– Hypoxia
– Hypercapnia
– Surgery
• Development of ventricular arrhythmias may be
encouraged by release of K+ from skeletal muscle
following depolarization of muscles
• Prolonged Apnoea
– Related to atypical ChE or development of dual
block
– Cause can be determined with peripheral nerve
stimulator
– Inherited abnormal enzymes cause the more
prolonged apnoeas
• Atypical homozygote 1-2 hours
• Heterozygous causes prolongation for about 10 mins
– Patients with acquired low cholinesterase are
unlikely to show apnoeas beyond 20-30 mins
– Intermittent positive pressure ventilation should be

continued and sedation assured until there are sings
that block has worn off
– Blood is taken and assayed for cholinesterase activity
and inhibition tests
– Close family and relatives should be screened with
appropriate counseling whenever indicated
– Although it is possible to hasten recovery using stored
blood, fresh frozen plasma or a purified human form of
cholinesterase, use of these is controversial in these
days of heightened awareness of blood-product-borne
diseases
• Hyperkalaemia
– Initial depolarization releases substances
normally retained within muscle cells: K+,
myoglobin and creatine phosphokinase
– Normal elevation: Average of 0.5 -1.0 mmol/L
over the next 10 mins
– Serum K+ after administration in patients with

renal failure increase to a similar extent as in
normal patients  usage is appropriate in
renal failure with normal K+ level
– Common feature in such patients is extensive

damage to muscle and/or nerve tissue which
is associated with denervation and
appearance of extrajunctional receptors 
more sites for K+ efflux
– Hyperkalaemic response is potentiated in
hypovolaemia and acidosis  severe
hyperkalaemia resulting in cardiac arrest in
acidotic hypovolaemic patients
– Data on risk period varies among authors:
• For burn: occurs after 2 days may last up to 6
months (various sources)
• For neurologic injury: occurs after 4 days may last
up to ≥ 6 months (various sources)
• Fasciculations
– Most pronounced in young and muscular
patients
– Observed clinically as disorganized muscular
activity following injection of suxamethonium
– Probably due to depolarization of nerve
terminal produced by activation of
presynaptic receptors
– Seen in 15-30 secs after intravenous

administration which is followed immediately
by paralysis
– Moderate and severe fasciculations can
facilitate venous return and cause increase in
cardiac output, arterial blood pressure,
intracranial pressure and intragastric pressure
– Prevention of muscle fasciulations reduces
incidence of myalgias and avoids increase in
intraocular and intragastric pressures
– Prevention of muscle fasciculations

• Precurarization
• Self taming
– Precurarization
• May be reduced but not necessarily abolished by
administration of small dose of non-depolarizing
neuromuscular relaxant 3-5 mins before
suxamethonium
– Self taming
• Self taming or administration of small (10 mg)
doses of suxamethonium 1 min before intubating
dose is an effective method but has largely been
abandoned due to considerable blockade which
may be produced by this taming dose
• Myalgia
– Muscle pain resemble those which follow
unaccustomed exercise
– No consistent relationship between
fasciculations and myalgia
– Incidence varies widely among authors: 1.5-
90%
– Begins usually on morning following
anaesthetic and may last for up to one week
though it usually disappears within 2 days
– More common in young adults, women,

patients who ambulate quickly on the day of
surgery (day case surgery) and patients
undergo simple diagnostic procedure like
bronchoscopy
– Less frequently found at extremes of life
– Pain is characteristic in its distribution: back
of neck, back and shoulders and area of
lower ribs
– Myalgia localized to neck may be perceived as

pharyngitis (sore throat) by patient and
attributed to tracheal intubation
– May be worse than the discomfort from
surgical procedure
– Biochemical changes following suxamethonium
administration (increased in myoglobin and
creatine kinase) are not related to severity of
muscle pains and strength of muscle
fasciculation
• Masseter Muscle Rigidity (MMR)

– Contracture of masseter to a degree which
will interfere with tracheal intubation despite
adequate dose of suxamethonium
– Increase in tone of up to 500G lasting 1-2
mins is a normal finding
– Mechanism is unknown but is most likely
mediated by AChR as it is blocked by large
amounts of non-depolarizing drugs
– It was suggested that the frequent

occurrence of spasm in children may be due
to an inadequate dose of suxamethonium
– Traditionally MMR has been taken to herald
development of malignant hyperthermia (MH)
– Most cases of MMR may simply represent
extreme of a spectrum of tension changes in
response to suxamethonium
– Incidence of MMR is within 0.5-1% whereas

incidence of MH is about 1: 12,000 (children)
and 1: 30,000 (adults)
– Sustained skeletal muscle spasm may be
found in patient with myotonia congenital /
myotonia dystrophica
• Malignant Hyperthermia
– Genetic disorder affecting myoplasmic Ca2+
regulation
– Triggered by suxamethonium
– Initial dose may fail to produce muscle
relaxation but generalized muscle rigidity
associated with other signs and symptoms of
hypermetabolism
– Suxamethonium probably precipitates release
of Ca2+ from sarcoplasmic reticulum of
susceptible individuals leading to sustained
contraction and subsequent muscle damage
• Myoglobinuria
– Damage to skeletal muscles associated with
fasciculations
– Especially in paediatric patients
– Rare in adults ( ? reason )
• Raised Intraocular Pressure

– Magnitude & Duration: manifested within 1
min, peak at about 1 min, rise in order of 5-15
mmHg, for up to 10 mins
– Proposed mechanism
• Cycloplegic action of suxamethonium 
deepening of anterior chamber and increased
resistance to aqueous humor outflow
• Slight increase in choroidal blood volume and CVP
• Fasciculation of the multiply innervated extrinsic
ocular muscles
– Prevention
• Controversial views on prevention of rise in
intraocular pressure with preliminary
administration of non-depolarizing neuromuscular
relaxants
• Sublingual nifedipine may attenuate increase in
intraocular pressure suggesting a circulatory
mechanism
• Raised Intragastric Pressure

– Controversial findings on increases in
intragastric pressures: 0-40 cmH2O
– Mechanisms
• Mainly due to fasciculations of abdominal muscles
 extent related to intensity of fasciculations
• Acetylcholine-like effect of suxamethonium
– Lower oesophageal sphincter tone increased

 barrier pressure maintained lessen risk of
aspiration
– Minimal to absent skeletal muscle
fasciculations in children are consistent with
absence of appreciable increases in
intragastric pressure
– Blocked by precurarization due to reduction
or prevention of fasciculations
• Raised Intracranial Pressure

– Magnitude of increase 2-20 mmHg (Various
sources)
– Mechanisms:
• Mechanisms and clinical significance unknown
• Indirect effect related to increase in PaCO2
produced by fasciculations
• Indirectly contributed by increase in intrathoracic
and intraabdominal pressure
• Direct effect of suxamethonium on intracranial
pressure is minimal as there are no changes in
intracranial pressure, cerebral blood flow and
electroencephalogram observed when
suxamethonium is given to patients with
neurologic injury receiving mechanical ventilation
• Histamine Release
– May be dependent or independent of allergic
response
– Occurred in cases where there was no sensitivity
on subsequent skin testing but in other
instances, testing has revealed definite evidence
of allergy
– Incidence of anaphylactic reactions may be close
to 0.06%
– Patient with history of anaphylactic reaction to
suxamethonium may exhibit cross-reaction with
non-depolarizing neuromuscular relaxants due to
common structural features of these drugs as all
of them contain quaternary NH4+ ions
(rocuronium, pancuronium, atracurium and
mivacurium)
Suxamethonium: Contraindications
Variations in Plasma
Cholinesterase Activity
• Activity of enzyme refers to number of
substrate molecules (mol) hydrolyzed per
unit of time, often expressed in international
units (IU)
• Levels of <75% are necessary for
prolongation of suxamethonium effect
• Causes
– Congenital
– Acquired
• Physiological variation
• Pathological variation
• Pharmacological factors
• Non-pharmacological factors
• Acquired Physiological Variation in Activity

– Gender
• Controversial: no difference vs difference present
• No gender-related differences
• Study by Propert & Brackenbridge (1976): males
have higher activity and may be explained by
gender related differences in muscle mass and
extracellular fluid volume
– Age
• No influence of age upon enzyme activity in adult
population but difference was noted in infants and
children
• Study by Ryan et al (1957): tendency for lower
activity in newborns with low birth weights
• Mean value even for heavier babies was well
below the low end of adult normal range
• Subsequently the activity increased rapidly within
2 months to levels equal to or above the normal
adult levels
• This activity continues to climb although less
rapidly and reaches peak at average age of 6
years from which there is gradual decline to adult
levels at puberty
– Pregnancy
• Reduction in activity of about 20% in first
trimester  maintained until delivery: may be
related to high levels of oestrogen
• About 2-4 days after delivery, there is a further
33% reduction in activity
• Return to prepregnant levels by sixth
postpartum week
• No pregnant woman who is homozygous for
normal gene should have prolonged apnoea
• Duration of action of suxamethonium is not
prolonged probably reflecting an increased Vd
at term
• Acquired Pathological Variation in Activity

– Liver disease
• Plasma cholinesterase is synthesized in liver and
any hepatocellular impairment will be reflected in
reduction in enzyme activity
– Malignancy
• As malignancy develops and metastases appear,
there is reduction in plasma cholinesterase activity
and theoretical increased sensitivity to
suxamethonium and other ester drugs
– Collagen Diseases
• Activity is reduced in collagen disease like
progressive muscular dystrophy, congenital
myotonia and dermatomyositis
– Malnutrition
• Anorexia following carcinoma
• Anorexia nervosa
– Heart disease
• Lower levels found in patients with severe heart
failure and following acute myocardial infarction
• With subsequent recovery, enzyme activity in
patients with acute myocardial infarction increases
– Renal disease
• Reduction of 15-20% of activity in end stage renal
failure
• Cause uncertain but it has been shown not to be an
effect of haemodialysis or peritoneal dialysis
– Burns
• Reduced activity in days following burn and
maximum depression on 5-6 days following the
injury
• Extent of reduction and rate of recovery are
dependent on severity of burns
• Explanations
– Loss of enzyme through increased permeability of damaged
endothelial wall
– Catabolism of enzyme
– Dilution by vigorous intravenous fluid therapy
– Secondary disturbance in liver function  prolonged reduction
of activity to up to 4 months
– Diseases associated with increased activity

• Thyroid disease
– Approximately 20% increase and 30% decrease in
activity in patients with hyper- and hypo-thyroidism
respectively
– Plasma cholinesterase level returns to normal as
treatment makes patient euthyroid
• Nephrotic syndrome
– Only condition in which a high cholinesterase activity
and hypoalbuminaemia regularly coexist
• Obesity
– Plasma cholinesterase increases in obesity and in
patients with normal body weight and hyperlipidaemia
– There is good statistical correlation between plasma
cholinesterase and serum cholesterol level and the
logarithm of serum triglyceride concentration
• Mental retardation and illness
– Increased in activity: mental retardation > Down’s
syndrome > normal subjects
– Significant increase in activity of about 20% in
depression with anxiety, retarded depression, agitated
depression and depression with schizophrenia 
duration of action of suxamethonium seemed shorter in
patients undergoing electroconvulsive therapy
• Pharmacological Causes of Varied Activity

of Enzyme
– Oral Contraceptives
– Noncompetitive cholinesterase inhibitors:
Ecothiopate, Organophosphates,
Cytotoxics
– Competitive cholinesterase inhibitors:
• Pyridostigmine, physostigmine and neostigmine
• Tacrine
• Bambuterol
• Ketamine
• Metoclopramide
• Pancuronium
– Other drugs
• Ester local anaesthetics (procaine, amethocaine)
which are themselves substrates for ChE
• Monoamine oxidase inhibitors
• Esmolol (inhibits plasma ChE but causes only
insignificant prolongation of action)
• Propanidid
• Phenothiazines (chlorpromazine)
• Oxytocin
• Trimetaphan
• Nonpharmacological Causes of Varied

Activity of Enzyme
– Plasmapharesis
• Single plasmapharesis reduces plasma
cholinesterase by 64% and by multiple and
regular plasma exchanges, plasma
cholinesterase may reduce by 100%
– Cardiopulmonary bypass
• Plasma cholinesterase levels decrease by an
average of 56% due to haemodilutional
cardiopulmonary bypass  persists for 7 days
following surgery
• It is claimed to be due entirely to priming of
bypass machine as opposed to factors like
temperature variations or absorption in bypass
tubing or in-line filters
• Congenital Variation in Enzyme Activity

– Gene encoding for plasma cholinesterase has
been localized to a single autosomal location:
long arm of chromosome 3 (3q26.1-q26.2)
– Inheritance of abnormal ChE is linked to
several autosomal recessive genes
– Biosynthesis of plasma cholinesterase is

controlled by more than 40 different
genotypes and some of these lead to an
abnormal (usually reduced) enzyme activity in
plasma
– Classification proposed by Motulsky which is
commonly used  4 allels recognized as E1u
as normal gene, E1a as atypical or dibucaine-
resistant gene, E1s as silent gene and E1f as
fluoride resistant gene  10 recognized
genotype
1: 3,200
1: 480
– Dibucaine Test
• Introduced by Kalow and Genest in 1957
• Measurement of ChE activity
• Plasma (containing cholinesterase) added with
benzylcholine (benzoyl choline) which is a
substract of cholinesterase
• Chemical reaction emitting light of a given wave
length, detected spectrophotometrically
• 10-5 molar (10 M) of dibucaine (known as
cinchocaine in UK) is added as inhibitor
• Inhibition of reaction reflected by inhibition of light
production  dibucaine inhibits normal
pseudocholinesterase to greater extent than
abnormal enzyme
• Under normal circumstances, dibucaine inhibits

normal enzyme about 80% and atypical enzyme
about 20%
• Dibucaine number, DN
– Percentage of inhibition of plasma ChE activity
produced by a standard titer of dibucaine at 10-5 M
– Reflects quality of cholinesterase enzyme and it does
not measure concentration of enzyme in plasma
– Decrease in enzyme activity due to liver disease and
anticholinesterase drugs  normal DN
– If abnormality is found: whole family should be screened
– Atypical gene
• Atypical cholinesterase AA = commonest genetic
variant in patients with abnormal response to
suxamethonium
– Atypical cholinesterase has a single substitution
at nucleotide 209 which changes aspartic acid
70 to glycine
– Normal concentration of ChE but reduced affinity
to suxamethonium
– Asp 70 is likely part of the anionic site 
absence of this negatively charged amino acid
explains the reduced affinity of atypical
cholinesterase for positively charged
suxamethonium
– None of the suxamethonium is hydrolyzed in
blood and a large overdose reaches the
neuromuscular junction where it causes
prolonged muscle paralysis
– Silent Gene
• No cholinesterase activity and contributed nothing
to dibucaine or fluoride numbers  DN and FN
can not be identified
• Homozygote for one of the silent genes (S/S or
equivalent) would be very sensitive to
suxamethonium  apnoea for 3-4 hours
– The Fluoride-Resistant Gene

• Instead of dibucaine, 50 mM of sodium fluoride
can be used to inhibit activity of ChE
• Normal enzyme showed high degree of inhibition
as in case of dibucaine (FN 50-70)
• Heterozygotes for this abnormality showed 25-
45% inhibition (FN 25-45)
• Other Variants
– J-variant
– K-variant
– C5-variant
Non-depolarizing
• Benzylisoquinoliniums
– Atracurium, cisatracurium, mivacurium
• Aminosteroids
– Vecuronium, pancuronium, rocuronium
Atracurium
• Bisquaternary diester benzylisoquinolinium,
intermediate-acting non-depolarizing
• First non-depolarizing neuromuscular relaxant to
be largely broken down in blood stream
• Orientation of two ester linkages is reverse and
this favours Hofmann elimination at physiological
pH
• Emerged from a series of studies by Stenlake and

colleagues in mid 1970s which were designed to
produce a non-depolarizing agent which might
undergo Hofmann elimination
• Introduced into clinical practice in Britain by
Payne and Hughes in 1981 and in US by Basta et
al in 1982
• Available as 25mg in 2.5ml or 50mg in 5ml sterile,
clear, faintly yellow solution in a clear glass
ampoule  each ml contains 10mg of atracurium
besylate
• Structure of atracurium and stereoisomerism

– Consists of two tetrahydropapaverine units
– Has 4 chiral centres at C1 and N2 in the two
tetrahydropapaverine units
– Due to molecular symmetry, atracurium has 16
isomers theoretically but only a mixture of 10
optical and geometric isomers exist in
commercial preparation (6 isomers are repetition)
– The isomers are denoted by defining the

absolute stereochemistry (R or S) at C1 of the
tetrahydropapaverine ring and the relative cis
or trans geometry of the bulky
dimethoxybenzyl and alkyester groups at C1
and N2 respectively
– cis configuration is termed arbitrarily as that
in which the two bulky substituents, 1-(3,4-
dimethoxylbenzyl) and 2-alkylene-ester
groups are cis
– These isomers have been separated into 3 geometric

isomer groups which are designated cis-cis, cis-trans
and trans-trans each comprising 3, 4 and 3 variants
respectively
– Among the stereoisomers of atracurium are:
• 1R cis-1’R cis (cis-atracurium)
• 1S cis-1’S cis
• 1R trans- 1’R trans
• 1R trans- 1’S trans
• 1S trans- 1’S trans
• 1S cis- 1’S trans
• 1R cis- 1’R trans
– Ratio of cis-cis, cis-trans and trans-trans isomers is
approximately 10: 6: 1 which corresponds to about
50-55% cis-cis, 35-38% cis-trans and 6-7% trans-
trans isomers
Atracurium: Physicochemical
Properties
• Besylate provides water solubility and
adjusting pH of commercial solution to 3.25-
3.65 to minimize the likelihood of
spontaneous degradation and Hofmann
degradation is inhibited totally at pH of 3.5
• In view of its acid pH in vitro, it should not be
mixed with alkaline drugs (barbiturates) or
exposed to solutions with more alkaline pHs
• Potency of atracurium stored at room
temperature decreases about 5% every 30
days
Atracurium: Dosing, Onset and

Duration of Action
• Given intravenously with onset 3-4 mins after a
dose of 2 x ED95
• Similar onset as equipotent dose of vecuronium
• Duration of action is similar to that of vecuronium
but shorter than pancuronium
Dosage (mg/kg) Clinical Duration
(min)
ED95 0.23
Intubation 0.5-0.6 30-45
Relaxation (N2O/O2) 0.3-0.4 30-45
Maintenance 0.1-0.15 15-20
Infusion 4-12 g/kg/min
Atracurium: Pharmacokinetics
• Distribution
– Protein binding 50-82% mainly albumin
– Vd= 180-280 ml/kg
– Does not cross placenta & Blood-brain-barrier
• Metabolism
– In tissues and plasma
– Two pathways: Hofmann elimination and ester
hydrolysis
– Relative roles of the enzymatic hydrolysis and
Hofmann elimination in man have yet to be
determined
– Hofmann Degradation
• Spontaneous non-enzymatic non-biologic degradation
• Cleavage of a C-N bond at normal body temperature &
pH
• Base-catalyzed reaction
• Metabolites: laudanosine (tertiary amine), quarternary
monoacrylate and diacrylic acid ester
• pH and temperature dependent

– Favoured in higher pH and temperature environment 
relatively stable at pH 3.0 and 4oC and become unstable
when injected into bloodstream
– Reduction in body temperature <34oC will slow the
reaction and prolong its action
– Alteration in pH within physiologic range do not cause a
significant change in its degradation
– Ester hydrolysis
• Biological elimination  hydrolysis by nonspecific
plasma esterases, carboxylesterase
• Presence of reverse ester linkage different from those
in acetylcholine, suxamethonium and mivacurium 
not a substrate for cholinesterase and hence safe in
patients with atypical plasma pseudocholinesterase
• pH changes influence the rate of hydrolysis

opposite to that of Hofmann degradation 
theoretically compensate each other in response
to change in pH
*May undergo Hoffman
• Metabolites degradation to produce
– Quaternary carboxylic acid laundanosine
– Quaternary alcohol
– Dialcohol
– Laundanosine*
• Elimination
– Clearance 5-10ml/kg/min
– Elimination half life 17-21 min, independent of
liver / kidney function
– Rapid clearance independent of renal or hepatic
function  absence of significant cumulative
effects  good for infusion
– Effects of Organ Failure and Age
• Pharmacokinetics and pharmacodynamics are not
significantly altered in renal failure
• In hepatic failure, clearance and Vd are increased 
elimination half life remains unchanged
• Pharmacodynamics are little affected in elderly
probably because atracurium elimination is organ
independent
• In children, onset is more rapid but duration of action is
shorter than in adults
• Metabolites of Atracurium
– No significant neuromuscular and
cardiovascular effects unless in high doses
• Quaternary monoacrylate, quaternary alcohol and
monoquaternary analogs produce neuromuscular
blockade in high doses
• Quarternary monoacrylate, laundanosine,
quaternary alcohol, metholaudanosine and
monoquaternary analog reduce blood pressure at
concentrations higher than those found in clinical
practice
Laundanosine
• Major metabolite of both pathways
• It may be present in commercial
preparations of atracurium and
cisatracurium because of its increase in
concentration during storage even if the
product is stored at low temperatures
• This supports the necessity of cold
storage and of limiting the storage time at
room temperature
• Depends on liver and kidney for clearance

 70% in bile, 30% via kidneys
• Longer elimination half life than atracurium
• Accumulate in patients with renal failure
but the concentration reached when
administered by continuous infusion is 10
times less than toxic level
• As it is a tertiary amine, it crosses blood-
brain-barrier freely
• Central Nervous Effects of Laundanosine

– Stimulant: increase MAC of volatile agents
and seizures
– Ability of laudanosine to cause CNS
stimulation depends on total dose of
atracurium given
– Very high doses (5-15 mg/kg) or high plasma
concentrations (17 g/ml) may cause CNS
stimulation (convulsions) in experimental
animals  adverse effects are unlikely to
occur with clinical use of atracurium
– Clinical significance of laudanosine is unclear

in humans even when renal and hepatic
failures are present
– Laundanosine probably will not cause seizure
in anaesthetized patients due to muscle
paralysis and CNS depressant effects of
intravenous and inhaled anaesthetics
• Cardiovascular Effects of Laundanosine

– Peripheral vasodilation
– Occurs at lower plasma levels (>6g/ml) than
that is required to induce epileptic spiking on
electroencephalogram (10g/ml) and to induce
seizures (>17g/ml) in anaesthetized animals
– Unlikely within clinical dosage of atracurium 
plasma level only 0.3 g/ml after an intubating
dose which is about 20 times less than that
required to produce cardiovascular effects in
animals
Atracurium: Cardiovascular Effects

• Systemic blood pressure and heart rate changes
do not accompany rapid injection in doses up to 2
x ED95
• Rarely causes significant reduction in blood
pressure or other histamine-related symptoms
• Rapid administration (<30 secs) of higher doses >
3 x ED95 induce histamine release  hypotension
• Circulatory changes are transient, occurs 60-90
secs after administration of atracurium and
disappears within 5 mins
• Non-vagolytic and does not block autonomic
ganglia
Cisatracurium: Physicochemical
Properties
• Purified form of one of the 10 stereoisomers of atracurium: 1R-cis,
1R’-cis configuration of atracurium (R indicates the absolute
stereochemistry of benzyltetrahydroisoquinoline rings and cis
represents relative geometry of bulky dimethoxy and 2-alkyester
groups at C1 and N1 respectively)
• Was initially known as 51W89
• Atracurium mixture of isomers consists of about 15% cis-
atracurium
• Available as cis-atracurium besylate in clear, slightly yellow
aqueous solution with concentration of 2 mg cisatracurium
cation/ml (2.5, 5 or 10 ml) without an antimicrobial preservative
• Comparison of potency of atracurium and

cisatracurium
– ED95 of cisatracurium was about 0.05 mg/kg
(cation, molecular weight 929), while the ED95 of
atracurium (besylate salt, molecular weight 1245)
was 0.25 mg/kg or 0.16 mg/kg (cation, molecular
weight 929)
– On a molar basis in adult patients, cisatracurium
is about 3.5 times as potent as the racemic
atracurium mixture (0.05 M/kg vs 0.17 M/kg;
cation)
– Due to higher potency, cisatracurium gives rise to
• Slower onset compared with equipotent doses of
atracurium
• Lesser production of laundanosine
– Cisatracurium is associated with minimal
cardiovascular side effects
Cisatracurium: Dosing, Onset and

Duration of Action
• Resembles atracurium in duration of action and
rate of recovery
• At equipotent dose, slower onset than atracurium
• Clinical duration of action not affected by renal or
hepatic failure
(min)
ED95 0.05
Relaxation (N2O/O2) 0.05 30-45
Cisatracurium: Pharmacokinetics
• Metabolism
– Non specific plasma esterase hydrolysis + Hofmann
degradation
– Hofmann degradation probably
• Contributes more to degradation
• Greater than that of atracurium
– Lesser production of laundanosine as compared with
atracurium (higher potency = lesser dose)  peak
plasma concentrations of laundanosine following 2x
ED95 of cisatracurium is about 5-fold less that
produced following similar dose of atracurium
• Effects of Age
– Children: slightly more potent, quicker onset
and shorter recovery
– Pharmacokinetics marginally affected by
advanced age:
• No change in recovery profile
• Onset delayed by 1 min due to slower biophase
equilibration
Cisatracurium: Cardiovascular
Effects
• Higher autonomic safety ratios than
atracurium as it has lesser propensity to
cause histamine release
• No significant effect on plasma histamine
levels in doses as high as 80 times ED95 but
marked histamine release occurs at doses
25-50 times ED95 for atracurium in cats
• In humans, doses of 8x ED95 do not cause
cardiovascular changes suggestive of
histamine release
Mivacurium: Physicochemical
Properties
• Short-acting, benzylisoquinolinium diester non-
depolarizing neuromuscular relaxant
• Was initially known as BW B1090U (Burroughs
Wellcome)
• Structurally related to atracurium
• Longer interonium chain of 16C in comparison to
other isoquinolinium neuromuscular relaxants
• Isomers of Mivacurium
– Consists of 3 stereoisomers
– More potent cis-trans 36% and trans-trans 58% isomers make
up about 95% of preparation
– They are rapidly hydrolyzed by plasma cholinesterase with
elimination half lives of 2-3 mins
– Cis-cis isomer
• constitutes only 4-10% of preparation of mivacurium
and is about 10-15 times less potent than cis-trans
and trans-trans isomers  unlikely to contribute
significantly to blocking activity of mivacurium
• Cis-cis is more slowly hydrolyzed with elimination half
life of 55 mins
• Available as clear, colourless, aqueous
solution of mivacurium chloride with pH 4.5
(2 mg/ml, 5 and 10 ml ampoules) containing
3 isomers
Mivacurium: Dosing, Onset and

Duration of Action
• Slow onset due to potency  larger doses 0.2 mg/kg for
tracheal intubation after 2 mins after administration
• Duration of relaxation is 33-50% of intermediate acting non-
depolarizing neuromuscular relaxants but about 2-3 times
that of suxamethonium with a dose of 2x ED95
• Short duration of action enables maintenance by continuous
infusion for short- to intermediate-length surgical procedures
(min)
ED95 0.07-0.08
Mivacurium: Pharmacokinetics
• Metabolism
– Nearly completely metabolized in plasma by
hydrolysis by plasma cholinesterase
– cis-trans & trans-trans isomers are hydrolyzed by
plasma cholinesterase at a rate equivalent to
88% of suxamethonium  short duration of
mivacurium which is shorter than atracurium and
vecuronium and about twice that of
suxamethonium
– Duration of action is prolonged for up to several
hours in patients who are homozygotes with
genetically atypical plasma cholinesterase
• Metabolites
– Quaternary amino alcohols (cis & trans) and quarternary
monoesters (cis & trans)  excreted in urine and bile
– Positively charged metabolites making CNS entry unlikely
– Show <1% neuromuscular blocking activity of parent
compound
– No effects on autonomic system
• Elimination
– Plasma cholinesterase is not present in significant
amount in NMJ
– Termination of NMJ blockade is by diffusion away
from NMJ into extracellular fluid
– Plasma cholinesterase influence the duration of
action of mivacurium by controlling the amount of
mivacurium hydrolyzed before it reaches NMJ
Pinnock et al Bovill & Howie Calvey & Williams Miller

cis-trans 93-106 26-147 90 100
trans-trans 51-63 18-79 90 50-70
cis-cis 3.7-4.6 2-5 5.5 3
Plasma clearance of various isomers (mL/kg/min)

– Clerance of cis-trans and trans-trans isomers correlates with

plasma pseudocholinesterase activity
– Up to 7% may be excreted unchanged in urine
Pinnock et al Bovill & Howie Calvey & Williams Miller

cis-trans 1.8-2.9 1-5 2 2-3
trans-trans 1.9-3.6 2-8 2 2-3
cis-cis 34.7-52.9 41-200 55 55
Elimination half lives of various isomers (mins)

• Altered Pharmacokinetics in Special

Conditions
– Renal Failure
• Duration of action prolonged by 10-15 mins
• Alterations likely due to reduced plasma cholinesterase
activity
• Plasma cholinesterase is synthesized in normal liver
and reduced in presence of uraemia
• Activity of plasma cholinesterase may be reduced by
30-50%
– Hepatic Failure
• Onset similar in cirrhosis but duration of action
prolonged  associated with reduced plasma
cholinesterase activity
• Increased extracellular volume leads to increased Vd 
less intense neuromuscular blockade
– Atypical Plasma Cholinesterase

• Effect of atypical plasma cholinesterase is the
same as for suxamethonium
• Heterozygous: prolonged action by 30-100% (10-
30 mins)
• Homozygous: markedly prolonged 3-8 hours
• About 4-5 times more potent in homozygous
abnormal patients than in those with normal
phenotype
Mivacurium: Cardiovascular Effects

• Minimal cardiovascular response at doses of
2-3x ED95
• Less histamine release than atracurium
– Doses of 3x ED95 over 10-15 secs evokes
sufficient histamine release to drop the mean
arterial pressure transiently by about 15%
– Increased histamine release with higher doses
and increased rate of administration
• No blockade of autonomic ganglion
• No vagolysis
Vecuronium: Physicochemical
Properties
• Monoquaternary aminosteroid intermediate-acting
non-depolarizing neuromuscular relaxant
• Relation to pancuronium
– 2-desmethyl analogue of pancuronium
demethylation of pancuronium A ring
– 16-monoquaternary derivative of pancuronium
• Consequences of difference in molecular

structure between vecuronium and
pancuronium
– Increased lipid solubility with vecuronium 
taken up into liver by a carrier-mediated transport
system  undergoes 2-3 times more metabolism
than pancuronium
– Slight increase in potency in vecuronium
– Adjacent basic piperidine at 2-position facilitates
hydrolysis of 3-acetate  less stable in solution
• Available as free-dried, buffered and

lyophilized powder containing vecuronium
bromide, citric acid monohydrate, disodium
hydrogen phosphate dehydrate and mannitol
(4mg ampoules or 10mg vial)
• Reconstitution with water for injections
produces clear, colourless solution of pH 4.0
• The powder is stable for at least 3 years and
aqueous solution for at least 24 hrs at room
temperature but may extend to several days
if stored at 4oC
Vecuronium: Dosing, Onset &

Duration of Action
• Given intravenously with onset 3 min and
clinical duration of 25-40 mins, 23 min to
25% recovery which approximates half that
of equipotent dose of pancuronium after 2x
ED95 dose
(min)
ED95 0.05
Infusion 0.8-2 g/kg/min
• Larger doses (0.2-0.4 mg/kg) have been

used to provide rapid intubating
conditions in place of suxamethonium 
prolonged duration 90-120 mins
• Although elimination half life of
vecuronium > atracurium, duration of
action and rate of recovery are similar
after as a single dose but not after
repeated doses or infusion
Vecuronium: Pharmacokinetic
• Distribution
– 30-57% protein-bound [similar to
pancuronium]
– Vd approximately 180-250 ml/kg
– Large Vd  rapid decline in plasma
concentration after single dose due to rapid
redistribution
– Does not cross placenta & blood-brain-barrier
– With subsequent doses or prolonged

infusions, vecuronium presents in various
peripheral compartments and limits the
distribution phase as peripheral storage sites
have become saturated  decrease in
plasma level dependent upon metabolism
and excretion and not upon distribution 
the rate of decrease of plasma concentration
slower causing cumulative effect
– Cumulative effect is larger than atracurium
but lesser than pancuronium
• Metabolism
– Increased lipid solubility facilitates hepatic
metabolism
– Main metabolites: 30-40% 3- and 17-
desacetylvecuronium with 3-desacetylvecuronium
being the major product
– These metabolites are also formed via spontaneous
deacetylation in addition to formation in liver
– 3-desacetylvecuronium
• Approximately 50-80% as potent as parent compound
but is rapidly converted to 3, 17-desacetylvecuronium
• 3-desacetylvecuronium has a lower plasma clearance
and longer duration of action than vecuronium
• Clearance of 3.5 mL/kg/min and renal clearance
accounts for approximately 1/6 of its elimination
• No clinical significance unless vecuronium is used in
long-term administration in intensive care units
• Patients with renal failure in intensive care unit may
have accumulation of 3-desacetylvecuronium 
prolonged neuromuscular blockade
– 3, 17 & 17-desacetylvecuronium have < 1/10
potency of parent compound
• Elimination
– Increased lipid solubility also facilitates biliary
excretion  approximately 30-50% of the drug is
excreted unchanged in bile in first 24 hrs
– Approximately 10-25% is excreted unchanged in
urine  proportion of free drug excreted in urine
is much smaller than other conventional
– Plasma clearance 3-6 ml/kg/min which is 2-3
times that of long-acting neuromuscular
relaxants
– Elimination half life between 50-120 mins which
may be half that of pancuronium

Conditions
– Renal failure
• Prolonged elimination half life due to reduced drug
clearance
• Increased plasma concentrations of 3-
desacetylvecuronium may contribute to persistent
skeletal muscle paralysis after prolonged infusion
(6 hrs-7 days) in patients with renal failure
– Hepatic failure
• Prolonged elimination half life and duration of
action with 0.2 mg/kg in patients with liver
cirrhosis
• Vd unchanged
• Administration in patients with renal or hepatic
failure requires neuromuscular monitoring
– Paediatrics
• Onset is more rapid in infants than adults while
duration of action is longest in infants and shortest
in children
• High cardiac output in infants  speeds up onset
• Immature enzyme systems or increased Vd in
neonates  prolonged duration
• Increased Vd  more drug is sequestered in
peripheral compartments  inaccessible to
hepatic and renal clearance mechanisms
– Geriatrics
• Vd reduced due to age-related decrease in skeletal
muscle mass and total body water
• Reduced plasma clearance is due to age-related
decrease in hepatic and renal blood flow and possibly
reduced hepatic microsomal enzyme activity
• Prone to have prolonged duration of action and slow
recovery
– Sex
• Less potent and shorter duration of action in men than
women
• Probably due to smaller Vd with increased plasma
concentrations in women
– Obstetrics
• Insufficient amounts cross placenta limit foetal
effects
• Clearance may be accelerated during late
pregnancy possibly due to stimulation of hepatic
microsomal enzymes by progesterone,
cardiovascular changes and fluid shifts which
occur during pregnancy
• Duration of action is prolonged in immediate post-
partum period
Vecuronium: Cardiovascular
Effects
• Absence of 2-methyl
quaternizing group 
markedly reduces ACh-like
character of A-ring
substitutions causing less
attraction to cardiac
muscarinic receptors
A Ring= D Ring=
Muscarinic Nicotinic
Effects Effects
• About 20 times weaker as vagolytic

substance than pancuronium
• Absence of ganglionic blocking and
histamine-releasing effects
• Lack of cardiovascular responses from 1-
8x ED95
Pancuronium
• Synthetic bisquaternary aminosteroid long-
acting non-depolarizing neuromuscular
relaxant without hormonal activity
• Instant success due its high potency, lack of
hypotensive effect and mild to moderate
vagolytic effect contrasted markedly with
tubocurarine and gallamine (most commonly
used neuromuscular relaxants used in US at
that time)
• Inhibitor of butyrylcholinesterase
• Suitable in long operations (3-4 hours) and

prompt extubation is not necessary and in
which mild to moderate increase in heart rate
and blood pressure might be desirable
• 2-piperidine is quaternized and catalysis of
3-acetate hydrolysis is minimized  stable in
solution
• Available as clear solution, containing
2mg/ml of pancuronium bromide
Pancuronium: Dosing, Onset &

Duration of Action
• Given intravenously with onset 3-5 mins
after 2 x ED95 dose
• Recovery index after an intubating dose=
30-40 mins
(min)
ED95 0.06-0.07
Intubation 0.08-0.12 60-120
Relaxation (N2O/O2) 0.05-0.06 30-60
Maintenance 0.01-0.015 30-40
Pancuronium: Pharmacokinetics
• Distribution
– Variable estimates of protein binding: 10-87%
– Extent of protein binding does not appear to
be important for clinical activity
– Vd approximately 240-280 ml/kg
– Distribution half life 10-13 mins
– Does not cross placenta & blood-brain-barrier
• Metabolism & Elimination

– Incorporates renal, biliary and biotransformation
routes of clearance
– Total plasma clearance 1.9-2.1 ml/kg/min
(various sources)
– Cleared largely by kidney  38-80% (various
sources)
– About 5-10% appears in the bile over first 24
hours
– Metabolites
• Deacetylation: About 10-40% is metabolized by
deacetylation to 3-hydroxy, 17-hydroxy, and 3,17-
dihydroxy or 3-desacetyl, 17-desacetyl and 3,17-
desacetyl derivatives
• 3-OH metabolite
– Only metabolite detected in humans
– Possesses most muscle-relaxant activity of the
metabolites
– About half as potent as parent compound as
– Duration of action and kinetic pattern similar to that of
pancuronium
– Most likely excreted largely by kidney
– Cleared in small amount through a minor liver pathway
– As much as 25% of 3-OH but <5% of 17 and 3,17 di-
hydroxy derivatives are found in urine and bile
• 17-OH and 3,17-OH derivatives possess 2% and
1.8% of pancuronium potency respectively
• 3-OH and 3,17 dihydroxy pancuronium has similar
duration of action but 17-OH pancuronium has
shorter duration of action
• Elimination half live: 100-150 mins

• Varied pharmacokinetics in
– Total biliary obstruction, liver cirrhosis and renal
failure  increased Vd, decreased plasma
clearance  prolonged elimination half-time
• Large Vd  large initial dose to produce same plasma
concentration  prolonged blockade due to reduced
clearance, possibility of recurarization
– Ageing: decreased renal function  decreased
clearance
Pancuronium: Cardiovascular
Effects
• Binds to muscarinic receptors in sino-atrial
node and inhibits release and reuptake of
noradrenaline  moderate vagolysis,
increase in heart rate and blood pressure
• Direct heart stimulation may increase
myocardial oxygen consumption and cause
cardiac ischaemia in patients with ischaemic
heart disease
• No effects on autonomic ganglia
• No significant histamine release
Rocuronium: Physicochemical
Properties
• Was initially known as ORG 9426
• Monoquarternary aminosteroid, fast-
onset, intermediate-acting non-
depolarizing neuromuscular relaxant
• Modifications made on vecuronium to produce

rocuronium
– Acetoxy substitution at position 3 to hydroxyl group
– Position 2 substitution of piperidino by morpholino
(2-morphilino-)
– Position 16 substitution of piperidino with methyl
quaternization by pyrrolidino with allyl quaternization
(16N-allyl pyrrolidino-)
• Potency of rocuronium is reduced seven to eightfold (7-8
Results
times less potent) despite sharing the similar molecular

weight in comparison to vecuronium
• Rocuronium has different time-course from vecuronium
• Better stability in solution for rocuronium
• With rocuronium lag time between drug injection and first
depression of twitch height is shorter and initial rate of onset
is faster compared with vecuronium  onset comparable to
suxamethonium with duration of action similar to vecuronium
• Replacement of acetyl ester attached to A ring by hydroxyl
group has made rocuronium stable in solution  at room
temperature, rocuronium is stable for 60 days whereas
pancuroncium is stable for 6 months (180 days)
• Available as clear solution containing 10mg/ml rocuronium
bromide in 5mls or 10mls
• Stored in fridge at 2-8oC and protected from light
Rocuronium: Dosing, Onset &

Duration of Action
• With 2x ED95, onset time is about 1.5 mins
with total duration of action of 30-40 mins
whereas in equipotent dose of
vecuronium produces an onset of 3 mins
(min)
ED95 0.3-0.4
Intubation 0.6-1 35-75
Relaxation (N2O/O2) 0.3-0.4 30-40
• Higher doses at 0.9-1.2 mg/kg, tracheal

intubation can be done within 60-90 secs
 substitute for suxamethonium
• Following equipotent doses, duration of
action of rocuronium is similar to that of
atracurium and vecuronium
Rocuronium: Pharmacokinetics
• Pharmacokinetics of rocuronium and
vecuronium are very similar
• Distribution
– Protein binding approximately 25%
– Vd 170-270 mL/kg
– Does not cross placenta or blood-brain-
barrier
• Metabolism
– Hepatic uptake via carrier-mediated active
transport system
– No appreciable hepatic metabolism
– Controversial role of hepatic deacetylation
• Deacetylation does not occur and no metabolites
can be found
• Some deacetylated metabolites may be produced
• Elimination
– Plasma clearance 3-6 ml/kg/min
– Eliminated unchanged by kidneys and liver
– Mainly excreted unchanged in bile 50-55%
and urine 30-35% within 24 hours
– Normal t½ of 56-97 mins
– Minimal cumulative effects observed with up
to 3 repeated doses under halothane
anaesthesia

Conditions
– Hepatic Failure
• Vd increased + clearance reduced  prolonged
onset + duration
• Duration of action increased 2-3 fold
– Renal Failure
• Prolonged duration and elimination half life
– Geriatrics
• Reduced clearance + increased Vd  prolonged
duration of action
Rocuronium: Cardiovascular
Effects
• Autonomic safety ratio for vagal block (3.0-5.0) is
about 10 times less than that of vecuronium
• No detectable histamine release following doses
up to 1.2 mg/kg (4x ED95 dose)
• Slight to moderate tachycardia may be due to
either pain on injection or weak vagolysis
• Heart rate increases 10-25% at higher doses (0.9-
1.2 mg/kg)
• Heart rate increase may be controlled with prior
administration of fentanyl

Neuromuscular Relaxants Sungai Buluh 2017

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Neuromuscular Relaxants Sungai Buluh 2017

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Neuromuscular Relaxants

• Neuromuscular relaxants are drugs which

• Prejunctional Motor Ending

– These terminals form expansions known as

– Active zone (AZ)

– Acetylcholinesterase is anchored to the basal

– Nicotinic acetylcholine receptors (nAChR) are

Acetylcholine: Synthesis & Storage

• Choline is quarternary amine which is a

• Acetyl-Co-A (AcCoA) is also required in the

• Approximately 50-80% of synthesized ACh is

• Two pools of synaptic vesicles which release ACh:

Nicotinic Acetylcholine Receptors

– Muscle type nAChRs are composed of 2 1 subunits

– Facilitatory process enhances further mobilization of

– Each subunit consists of approximately 400-

– Two  subunits are noncontiguous

• Immature/ Extrajunctional Receptors

– With innervation,  subunit is replaced by ε

– Found in various situations

– As the ion channel of immature extrajunctional

• Generation of Action Potential and

• Vesicle mobilization, docking, fusion &

– Vesicles are then attached to active zone of

• Synaptobrevin (Integral protein of synaptic vesicle membrane)

– Further priming is required to convert a docked

– After the vesicle fusion, fusion pore is formed

– A nerve impulse causes the release of

– Structure of AChE Choline

– Anionic subsite of the active site is negatively charged

– Approximately 3 millions AChE molecules per

– Released Ca2+ are bound by troponin C

Margin of Safety of Neuromuscular

– Number of nAChR opened is in excess of those

• Approximately 13,000 of activated nAChR are required

– Amount of ACh released is in excess of those

– Structural features which may contribute to

Drugs Affecting Neuromuscular

• Generally drugs that modify

• Drugs affecting ACh Release

– Drugs affecting Ca2+ transport

• Therapeutic doses of verapamil, diltiazem and

– Local & General Anaesthetics

• Guanidine & Aminopyridine

– Drugs Affecting Acetylcholine Action

 Inactivation of Na+ channel

• Shortly after upper voltage-dependent gate opens,

– As suxamethonium is not hydrolyzed rapidly,

– Increase in desensitized receptors can be

• Features of Depolarizing Block

• Exact mechanism unclear and possible

– Changes caused by inhalational anaesthetics

Activation of nAChR becomes impossible as

Reduced number of effective ACh-nAChR

– Physical occlusion of ion channels on

• Features of Non-depolarizing Block

• Quaternary ammonium group and

• Number of quaternary ammonium group

• Interonium distance and Neuromuscular

– Molecular length of decamethonium best fits

• Substitution on Quaternary Nitrogen and

– By having a bulkier group, potency is

• Addition of Methoxy groups and

– Atracurium, mivacurium and doxacurium