Neuromuscular blocking agents & reversal in anesthesia

Neuromuscular
Blocking Agents
& Reversal
Dr.Mushtaq Ahmad
Consultant Anesthetist
BVH,BWP

CONTENTS
 Introduction/history
 Neuromuscular transmission
 Distinctions Between
Depolarizing &
Nondepolarizing
Blockade...mechanism of
actions
 Classification depolarizing &
Nondepolarizing Muscle
Relaxants
 Reversal ...Cholinesterase
Inhibitors & Other
Pharmacologic Antagonists to
Neuromuscular Blocking
Agents

in 1942, when Griffith and Johnson in
Montreal used Intocostrin, a biologically
standardized mixture of the alkaloids of the
• Indian rubber plant Chondrodendron tomentosum,to
facilitate relaxation during cyclopropane anaesthesia.
However, as noted by Beecher and Todd in
1954:
• “muscle relaxants given inappropriately may provide the
surgeon with optimal operating conditions in . . .
• a patient [who] is paralyzed but not anesthetized—a
state that is wholly unacceptable for the patient.”
• In other words, muscle relaxation does not ensure
unconsciousness, amnesia, or analgesia

Definition
NMBA are the drugs that act
peripherally at NM-Junction and
muscle fiber itself to block
neuromuscular transmission.
• In order to facilitate muscle relaxation for
surgery and
• mechanical ventilation during surgery & in
ICU.

Neuromuscular
junction
Association between a motor
neuron and a muscle cell
• Synaptic cleft...The cell membranes of the
neuron and muscle fiber are separated by
a narrow (20-nm) gap
• Within the most distal aspect of the motor
neuron, vesicles containing the
neurotransmitter acetylcholine (ACh) can
be found.

The postjunctional motor membrane
... motor end-plate is
• highly specialized and invaginated, and the
shoulders of these folds are rich in ACh
receptors
acetylcholinesterase ......
• Th is enzyme (also called specific
cholinesterase or true cholinesterase) is
• embedded into the motor end-plate
membrane immediately adjacent to the ACh
receptors.

Structure of ACh receptors
structure of ACh receptors varies in diff erent tissues
and at different times in development……
• Nicotinic & muscurinic
Location of ACh receptors
• Post junctional nicotinic ACh recepters...... located on the
postjunctional motor membrane-.motor end-plate...
• approximately 5 million of these receptors, but activation of only
about 500,000 receptors is required for normal muscle contraction
• Prejunctional ACh receptors .......are present and influence the
release of ACh.
• The prejunctional and postjunctional receptors have different
affinities for ACh.
• Extrajunctional ACh receptors .......are located throughout the
skeletal muscle in relatively low numbers owing to suppression of
their synthesis by normal neural activity.

Postjunctional ACh receptors,
embedded in the lipid layer of the
postsynaptic muscle membrane.

Prejunctional Ach receptors
Pre- junctional
acetylcholine receptors are
present on the shoulders of
the axon terminal,
Stimulation of the
prejunctional receptors
mobilizes (MOB) the
vesicles of acetylcholine to
move into the active zone,
• Ready for release on arrival of
another nerve im-pulse. The
mechanism requires ca2+ ions.

Maturation of the postsynaptic apparatus
. At approximately 14 days after birth, the immature γ-subunit–
containing acetylcholine receptors (AChRs) are completely
replaced by mature AChRs containing α-subunit.
The neuromuscular junction is completely
developed at 30 days after birth

Each ACh receptor in the neuromuscular
junction normally consists of five protein
subunits;
• two α subunits; and
• single β, δ, and ε subunits.
Only the two identical α subunits are
capable of binding ACh molecules.
• If both binding sites are occupied by ACh, a
conformational change in the subunits briefl y (1 ms)
opens an ion channel in the core of the receptor

Ion channel in the core of the
ach receptor
Only the two identical α
subunits are capable of binding
ACh molecules.
The channel will not open if ACh
binds on only one site.
If both binding sites are occupied
by ACh, a conformational change
in the subunits briefl y (1 ms)
opens an ion channel in the core
of the receptor

Voltage-gated sodium
channels
resulting action potential propagates along the muscle membrane and T-tubule system,
opening sodium channels and releasing calcium from the sarcoplasmic reticulum
Voltage-gated sodium channels within this portion of the muscle membrane open when a
threshold voltage is developed across them
When enough receptors are occupied by ACh, the end-plate potential will be
sufficiently strong to depolarize the perijunctional membrane.
Perijunctional areas of muscle membrane have a higher density of these sodium
channels than other parts of the membrane.

 sodium channel is a
transmembrane protein
that can be conceptualized
as having two gates.
 Sodium ions pass only
when both gates are open.
 Opening of the gates is
time dependent and
voltage dependent.
 The channel therefore
possesses three
functional states.
 A...At rest, the lower gate
is open but the upper gate
is closed
 B...reaches threshold
voltage depolarization,
the upper gate opens and
sodium can pass
 C...Shortly after the upper
gate opens the
timedependent lower
gate closes

Fetal or immature extrajunctional
ach recepters
• another isoform contains a γ subunit
instead of the ε subunit.
• Th is isoform initially expressed in fetal
muscle.
• It is also often referred to as
extrajunctional because, unlike the
mature isoform, it may be located
anywhere in the muscle membrane,
inside or outside the neuromuscular
junction when expressed in adults.

Steps in normal NM
transmission.
Sodium and calcium flow through the open receptor channel generating an end-
plate potential.
Opening receptor channels. Receptors do not open unless both α receptors are
occupied by ach
Ach molecules bind to the α subunits of the ach receptor on the post junctional
membrane, generating A conformational change and
Ach is released from storage vesicles at the nerve terminal. Enough ach is
released to bind 500,000 receptors.
Nerve action potential is transmitted, and the nerve terminal is depolarized.

Aft er unbinding ACh, the receptors’ ion channels close, permitting the end-
plate to repolarize. Calcium is resequestered in the sarcoplasmic reticulum,
and the muscle cell relaxes.
ACh is rapidly hydrolyzed into acetate and choline by the substrate-
specific enzyme acetylcholinesterase .
when a threshold voltage is developed across them, a muscle action
potential (MAP) is generated
When between 5% and 20% of the receptor channels are open and
a threshold potential is reached, ....Voltage-gated sodium channels
within perijunctional portion of the muscle membrane open

CLASSIFICATION
DISTINCTIONS BETWEEN
DEPOLARIZING & NON
DEPOLARIZING BLOCKADE
(Mechanism of Actions)

Basis of
Classification
Mechanism of
action
Response
to peripheral
nerve
stimulation
Reversal of
block.
Duration of
action
Chemistry

Classification-mechanism &
duration of action
Depolarizing
Short-acting
• Succinylcholine
Nondepolarizing
Short-acting
• Gantacurium
• Mivacurium
• Rocuronium
Intermediate-acting
• Atracurium
• Cisatracurium
• Vecuronium
• Rocuronium
Long-acting
• Pancuronium
• Pipecuronium
• Doxacurium

Classification- Chemistry
Benzylisoquinolinium
Atracurium
Cisatracurium
Mivacurium
Doxacurium
AV002 (CW002)
Historical interest
• tubocurarine
• metocurine
• gallamine,
• alcuronium, ,
• decamethonium
Steroidal
Pancuronium
Vecuronium
Rocuronium
Pipecuronium
rapacuronium...historical interest
Others-
chlorofumarates
Gantacurium

MECHANISM OF ACTION of
depolarizing NMBA
1
• Depolarizing muscle relaxants closely resemble ACh and readily bind to ACh
receptors, generating a muscle action potential.
2
• Unlike ACh, however, these drugs are not metabolized by acetylcholinesterase,
and their concentration in the synaptic cleft does not fall as rapidly, resulting in a
prolonged depolarization of the muscle end-plate.
3
• Continuous end-plate depolarization causes muscle relaxation
4
• because opening of perijunctional sodium channels is time limited (sodium
channels rapidly “inactivate” with continuing depolarization)

Phases of block in
Depolarizing NMBA
Phase-1 block
• Perijunctional VGSC cannot reopen until the end-
plate repolarizes.
• Th e end-plate cannot repolarize as long as the
depolarizing muscle relaxant continues to bind to
ACh receptors; this is called a phase I block.
Phase ii Block
• Aft er a period of time, prolonged end-plate
depolarization can cause poorly understood changes
in the ACh receptor that result in a phase II block,

Characteristics of Depolarizing
Neuromuscular Block
In the presence of a small dose of succinylcholine:
1.a decreased response to a single
• low-voltage (1 Hz) twitch stimulus applied to a peripheral nerve is detected.
2.Tetanic stimulation (e.g. at 50 Hz) produces a small, but sustained,
response
3.if four twitch stimuli are applied at 2 Hz over 2 s (train-of-four stimulus),
followed by a 10-s inter-val before the next train-of-four
• no decrease in the height of successive stimuli is noted
4.the application of a 5-s burst of tetanic stimula-tion after the application of
single twitch stim-uli,…. followed 3 s later by a further run of twitch stimuli
• produces no potentiation of the twitch height; there is no post-tetanic potentiation (sometimes
termed facilitation)

neuromuscular block is potentiated by the ad-
ministration of an anticholinesterase such as
neostigmine or edrophonium. OR if repeated doses
of succinylcholine are given, the characteristics of
this depolarizing block alter;
• signs typical of a non-depolarizing block develop
• Initially, such changes are demonstrable only at fast rates of
stimulation,
• but with further increments of succinylcholine they may occur at
slower rates. This phenomenon is termed ‘dual block’.
muscle fasciculation is typical of a depolarizing
block.

Mechanism of action of non-
depolarizing NMBA
depolarizing muscle
relaxants act as ACh
receptor agonists, whereas
nondepolarizing muscle
relaxants function as
competitive antagonists.
Nondepolarizing muscle
relaxants bind ACh receptors
but are incapable of
inducing the conformational
change necessary for ion
channel opening.
Because ACh is prevented
from binding to its
receptors, no end-plate
potential develops.
Neuromuscular blockade
occurs even if only one α
subunit is blocked.

Characteristics of Non-Depolarizing
Neuromuscular Block
If a small, subparalysing dose of a non-depolarizing
neuromuscular blocking drug is administered, the following
characteristics are recognized:
1. decreased response to a low-voltage twitch stimulus (e.g. 1
Hz) which,
• if repeated, decreases further in amplitude. This effect, which is in con-trast to
that produced by a depolarizing drug,
2.also occurs to a greater degree when the train-of-four (TOF)
twitch response is applied, and even more so with higher, tetanic
rates of stimulation. It is referred to as ‘fade’ or decrement.

3. post-tetanic potentiation (PTP) or
facilitation (PTF) of twitch response
may be demonstrated
4.neuromuscular block is reversed by
administration of ananticholinesterase.
5 no muscle fasciculation is visible.

OTHER MECHANISMS OF
NEUROMUSCULAR
BLOCKADE
Interference with the function of the Ach
receptor without acting as an agonist or
antagonist.
• Example....
• Inhaled anesthetic agents
• local anesthetics
• ketamine.
Interfere with normal functioning of the Ach
receptor binding site or with the opening
and closing of the receptor channel.

• During closed channel blockade
• the drug physically plugs up the channel, preventing
passage of cations
• whether or not ACh has activated the receptor.
• Open channel blockade
• use dependent,
• because the drug enters and obstructs the ACh receptor
channel only aft er it is opened by ACh binding
• Example...channel block in the laboratory include
• neostigmine,
• some antibiotics,
• cocaine, and
• quinidine.
closed or open channel blockade
Other drugs may impair the presynaptic
release of ACh

MONITORING NEUROMUSCULAR
BLOCKADE
Indications for Neuromuscular
Monitoring….. preferable always to
monitor neuromuscular function when
a muscle relaxant is used during an-
aesthesia
• 1.during prolonged anaesthesia, when repeated
increments of neuromuscular blocking agents
are required
• 2.when infusions of muscle relaxants are given (
including in the ICU)

3.in the presence of renal or hepatic
dysfunction
4. in patients with neuromuscular
disorders
5.in patients with a history of sensitivity to
a muscle relaxant or poor recovery
from block
6.when poor reversal of neuromuscular
block is encountered unexpectedly

Nerve Stimulator Characteristics
Response of the nerve to electrical stimulation depends on three factors:
• The current applied
• The duration of the current
• The position of the electrodes
Black electrode of the stimulator is negatively charged, and the red electrode is
positively charged
Usually, a nerve which is readily accessible to the anaesthetist
• The ulnar
• Facial
• Common peroneal nerve
The muscle response assessed by either
• Visual or tactile means, or it may be
• more sophisticated methods.
• Mechanomyography
• Electromyography
• Accelerography

Modes of Stimulation
Single stimulus
TOF stimulation
Tetanic stimulation
Posttetanic facilitation and posttetanic count
Double-burst (DB) stimulation

Single twitch
stimulus of short duration (0.1–0.2 ms)
delivery of single impulses separated by at
least 10 seconds.
It is of limited clinical use
• if applied re-peatedly, before and after a dose of a
muscle relaxant, it may be possible to assess the
effects of the drug.

Train-of-Four (TOF) Twitch
Response
Four stimuli (at 2 Hz) are applied over 2 s, with
at least a 10-s gap between each TOF
small dose of a non-depolarizing muscle
relaxant
• fade of the am -plitude of the TOF may be visible.
The ratio of the amplitude of the fourth to the
first twitch is called the train-of-four ratio (TOFR).

larger dose of such a drug,
• the fourth twitch disappears first, then the third, followed by the
second and, finally, the first twitch
• On recovery from neuro -muscular block, the first twitch
appears first, then the second then the third, and finally the
fourth
at least three of the four twitches must be absent
……for upper abdominal surgery.
Full reversal can only be relied upon if at least the
……second twitch is visible when an
anticholinesterase is given.

After reversal
• good muscle tone – as assessed
clinically ….being able to cough,
raise his or her head from the pillow
for at least 5 s, protrude the tongue
and have good grip strength – may
be anticipated when the TOFR has
reached at least 0.7
• TOFR of 0.9 has now been shown to
be necessary prior to extubation if the
airway is to be protected completely.

Why Fade ?
Fade may be due to a prejunctional efect of nondepolar-
izing relaxants
• that reduces the amount of ACh in the nerve terminal available for
release during stim-ulation (blockade of ACh mobilization).
Adequate clinical recovery correlates well with the
absence of fade.
Because fade is more obvious during
• sustained tetanic stimulation or double-burst stimulation than
following a train-of-four pattern or repeated twitches,
• the first two patterns are the preferred methods for determining
adequacy of recovery from a nondepolarizing block.

Tetanic Stimulation
Most sensitive form of neuromuscular stimulation.
• Loss of contraction during tetanic stimulation, known as tetanic fade , is a
sensitive indicator of residual neuromuscular blockade.
Repetitive high-frequency stimulation frequencies of 50–100
Hz are applied to a peripheral nerve to detect even minor
degrees of residual neuromuscular block
• Tetanic fade may be present when the twitch response is normal.
Tetanic rates of stimulation may be applied under
Anaesthesia,….. But in the awake patient painful

Post-Tetanic Potentiation or
Facilitation
Assess more profound degrees of neuro-muscular block produced by
non-depolarizing neuromuscular blocking agents.
If a single twitch stimulus is applied to the nerve with little or no
neuro-muscular response,…. >But after a 5 s delay a burst of 50-hz
tetanus is given for 5 s….,> The effect of a further twitch stimulus 3 s
later is enhanced
Profound block, ….The effect of repeated single twitches applied after
the tetanus until the response disappears can be counted; this is
termed the …..Post-tetanic count
• The number of twitches observed is inversely related to the degree
of blockade.

Why postte-tanic potentiation ?
ability of tetanic stimulation during a par-
tial nondepolarizing block to increase the
evoked response to a subsequent twitch
is termed postte-tanic potentiation.
Due to a transient increase in ACh
mobilization following tetanic stimulation

Double-Burst Stimulation
(DBS)
 More accurate assessment
of residual block by visual
or tactile means than fade
of the TOF response
 Application of two or three
short bursts of 50-hz
tetanus,…. Each
comprising two or three
impulses ….Separated by
a 750-ms interval.
……Each impulse lasts for
0.2 ms

Three short (0.2 ms) high-
frequency stimulations
separated by a 20-ms interval
(50 Hz) and followed ……750
ms later by
• two (DBS 3,2 ) or
• three (DBS 3,3 ) additional
impulses.

Recording the Response
1. Visual and tactile evaluation
• is the easiest and least expensive way
to assess the response to electrical
stimulation applied to a peripheral
nerve
• The disadvantage of this technique is
the
• subjective nature of its interpretation
(present or absent, weak or strong)

2. Measurement of force-Mechanomyography
• using a force transducer provides accurate assessment
(quantitative or objective) of the response elicited by
electrical stimulation of a peripheral nerve.
3. Electromyography
• measures the electrical rather than mechanical response
of the skeletal muscle.
4. Accelerometry devices
• are usually attached to the thumb
• a digital readout is obtained
• The use of accelerometry is helpful in the diagnosis of
residual paralysis

Choice of Muscle
Muscles do not respond in a uniform fashion to
NMBAs…..differences in
• time to onset
• maximum blockade
• duration of action
muscles of physiologic importance
• abdominal muscles during surgery
• upper airway muscles postoperatively
• A common strategy is to monitor one site adductor
pollicis…Usually

1. Adductor pollicis muscle
• Supplied by the ulnar nerve
• This muscle is relatively sensitive to nondepolarizing muscle
relaxants(blocked SOONER than respiratory)
• During recovery, it is blocked more than some respiratory
muscles such as the diaphragm and laryngeal
adductors(recover LATE than respiratory)
2. Muscles surrounding the eye
• Innervated by the facial nerve
• A. The response of the orbicularis oculi over the eyelid is
similar to that of the adductor pollicis.
• B. The response the eyebrow (corrugator supercilii)
parallels the response of the laryngeal adductors.
• (Onset is more rapid and recovery is sooner than at the
adductor pollicis.) This response is useful for predicting
intubating conditions.

Clinical Applications
1. Monitoring Onset.
• After induction ,determine the time for tracheal intubation
• (maximum relaxation of laryngeal and respiratory
muscles).
• Single-twitch stimulation is often used to monitor the
onset of neuromuscular blockade.
2. Monitoring Surgical Relaxation
• Adequate surgical relaxation is usually present when
fewer than 2 or 3 visible twitches of the TOF are
observed in response to stimulation of the adductor
pollicis muscle

3. Monitoring Recovery.
• Complete return of neuromuscular function should be
achieved before extubation
• Respiratory and upper airway function does not
return to normal unless the TOF ratio at the
adductor pollicis muscle is ≥0.9.
• Anticholinesterase agents should be given only
when four twitches are visible
• The presence of spontaneous breathing is not a sign
of adequate neuromuscular recovery.
• (The diaphragm recovers earlier than upper airway
muscles that recover in parallel with the adductor
pollicis muscle.)
• the visual or tactile evaluation of TOF response is not
reliable for ruling out residual blockade

Depolarizing
NMBA
(Suxamethonium)

SUCCINYLCHOLINE
Succinylcholine quaternary ammonium
compound—also called diacetylcholine or
suxamethonium—
• consists of two joined ACh molecules
only depolarizing relaxant now available in
clinical practice is succinylcholine.
• Decamethonium was used clinically in the UK for
many years

Mechanism of action
Depolarizing muscle relaxants very
closely resemble ACh and readily bind to
ACh receptors, generating a muscle
action potential
Phase i block
Phase ii block

Metabolism & Excretion
Rapid onset of action (30–60 s) and
• Small volume of distribution due to its very low lipid solubility
• Relative overdose that is usually administered.
Short duration of action (usually less than 10
min).
In circulation.....Rapidly metabolized by
pseudocholinesterase into succinylmonocholine.
• 10% of the drug is excreted in the urine; there is very little
metabolism in the liver although some breakdown by non-
specific esterases occurs in the plasma.

Causes of prolonged effect of
Suxamethonium
Limited duration of action....Recovery from neuromuscular block
may start to occur within 3 min and is complete within 12–15 min.
• Drug levels fall in blood, succinylcholine molecules diffuse away from the
neuromuscular junction
Can be prolonged by
• High doses
• Infusion of succinylcholine
• Abnormal metabolism
• Hypothermia,
• Reduced pseudocholinesterase levels,
• Genetically aberrant enzyme

Decreased level of
pseudocholinesterase
Reduced pseudocholinesterase levels...Generally produce only modest
prolongation of succinylcholine’s actions (2–20 min).
• Pregnancy,
• Liver disease,
• Renal failure, and
• Carcinomatosis and starvation,
• Also because of reduced enzyme synthesis
• Hypothyroidism.,
• Cardiopulmonary bypass
• Plasmapheresis
Certain drug therapies
• Echothiophate......Organophosphate use for glaucoma
• Neostigmine ,pyridostigmine....Cholinesterase inhibitors
• Phenelzine.....Monoamine oxidase inhibitor
• Cyclophosphamide....Anti neoplastic
• Metoclopramide...Antiemetic & prokinetic
• Esmolol...Beta blocker
• Pancuronium....Non depolarizing nmba
• Oral contraceptives

Inherited factors
atypical/abnormal
pseudocholinesterse
Structure of plasma cholinesterase is determined genetically, by autosomal genes,
1.Heterozygote for the atypical gene
• One in 25-30 patients of european extraction is a heterozygote with one normal
and one abnormal (atypical) pseudocholinesterase gene, resulting in a slightly
prolonged block (20–30 min)
2.Homozygous atypical pseudocholinesterse gene.....1 in 3000 patients have
two copies of the abnormal gene (homozygous atypical) that produce an enzyme
with little or no affinity for succinylcholine.
• Will have a very long blockade eg, 4–8 h

Types of Homozygous
Pseudocholinesterse
1.The dibucaine-resistant (variant) allele
• Which produces an enzyme with 1/100 of
normal affinity for succinylcholine, is the most
common.
2.Fluoride-resistant
3.Silent (no activity) alleles.

Measurement of Atypical
Pseudocholinesterse
1.Qunatitative....determined in the
laboratory quantitatively in units
per liter (a minor factor)
2.Qualitative.......qualitatively by
dibucaine number (the major
factor)

Dibucaine Number
Dibucaine, a local anesthetic, inhibits normal
pseudocholinesterase activity by 80%, but inhibits
atypical enzyme activity by only 20%.
Serum from an individual who is heterozygous for
the atypical enzyme is characterized by an
intermediate 40% to 60% inhibition
percentage of inhibition of
pseudocholinesterase activity is termed the
dibucaine number

Method for detecting structurally
abnormal cholinesterase.
Dibucaine is also added to the water bath, this reaction is inhibited; no light is
produced. The percentage inhibition is referred to as the dibucaine number
1.Normal plasma cholinesterase has a
high dibucaine number of 77–83.
2.A heterozygote for the atypical gene
has a dibucaine number of 45–68
3.In a homozygote, the dibucaine
number is less than 30.
A chemical reaction occurs with plasma cholinesterase,
emitting light of a given wavelength, which may be
detected spectrophotometrically.
Plasma from a patient of normal is added to a water bath
containing a substrate such as benzoylcholine

When plasma sample
should be taken?
Plasma cholinesterase activity is
reduced by the presence of
succinylcholine, a plasma sample to
measure the patient’s cholinesterase
activity should not be taken for several
days after prolonged block has been
experienced, by which time new
enzyme has been synthesized.

Detection of geno type of
Atypical Pseudocholinesterse ?
If there is no reaction in the presence of the substrate
only,....... the silent gene is present.
If fluoride is added to the solution instead of
dibucaine, the ....fluoride gene may be detected
plasma from a patient is added to a water bath
containing a substrate such as benzoylcholine

Management of
succinylcholine Apnoea
This condition is not life-threatening, but the risk of
awareness is considerable
• especially after the end of surgery, when the anaesthetist, who
may not yet have made the diagnosis, is attempting to waken the
patient.
Anaesthesia must be continued until full recovery
from neuromuscular block is demonstrable.
• In such patients, non-specific esterases(10% metabolism)
gradually clear the drug from plasma.
source of cholinesterase, such as fresh frozen
plasma, should be administered

patient who is found to have reduced enzyme activity and structurally
abnormal enzyme should be given a warning card or alarm bracelet
monitor neuromuscular transmission accurately, until full recovery
from residual neuromuscular block.
Prolonged paralysis from succinylcholine caused by abnormal
pseudocholinesterase (atypical cholinesterase) should be treated with
continued mechanical ventilation and sedation until muscle function
returns to normal by clinical signs.
plasma sample should be taken..... Quantitative & Qualitave
measurements of Atypical cholinesterase

Drug interaction sepcial
considerations
1.Cholinesterase Inhibitors……markedly prolong a
depolarizing phase I block by two mechanisms.
• 1. inhibiting acetylcholinesterase....higher ACh concentration at
the nerve terminal, which intensifies depolarization
• 2.inhibiting pseudocholinesterase....reduce the hydrolysis of
succinylcholine
Example
• Organophosphate pesticides, for ......irreversible inhibition of
acetylcholinesterase and can prolong the action of
succinylcholine by 20–30 min.
• Echothiophate eye drops......can markedly prolong
succinylcholine

2. Nondepolarizing Relaxants
small doses of nondepolarizing relaxants
• antagonize a depolarizing phase I block. ....drugs
occupy some ACh receptors,.....so
• partial prevention of depolarization by succinylcholine
If enough depolarizing agent is
administered...... to develop a phase II
block,
• then a nondepolarizer will potentiate paralysis.

Dosage & Storage
usual adult dose of succinylcholine for intubation is 1–1.5
mg/kg intravenously.
• Doses as small as 0.5 mg/kg will oft en provide acceptable intubating
conditions if a defasciculating dose of a nondepolarizing agent is not used.
Repeated small boluses (10 mg) or a succinylcholine drip (1
g in 500 or 1000 mL, titrated to eff ect) can be used during
surgical procedures that require brief but intense paralysis
• ENT procedures...endoscopy
• Neuromuscular function should be frequently monitored with a nerve
stimulator to prevent overdosing and to watch for phase II block.

Pediatric patients are often need greater
than for adults.....
• Suxamethonium not lipid soluble & infants and neonates
have a larger extracellular space than adults
Intramuscularly to children
• A dose as high as 4–5 mg/kg does not always produce
complete paralysis.
Storage...
• Stored under refrigeration (2–8°C), and should be used
within 14 days after removal from refrigeration and
exposure to room temperature.

Side Effects & Clinical
Considerations
Succinylcholine is still useful for rapid sequence
induction and for short periods of intense
paralysis
succinylcholine is considered relatively
contraindicated in the routine management of
children and adolescent patients...undiagnosed
myopathies
Most clinicians have also abandoned the
routine use of succinylcholine for adults

1.Cardiovascular
Suxamethonium acts cholinergic
ach receptors in addition to those
at the neuromuscular junction
• Entire parasympathetic nervous system and
• Parts of the sympathetic nervous system
• Sympathetic ganglions
• Adrenal medulla
• Sweat glands

Stimulation of nicotinic receptors in
parasympathetic and sympathetic ganglia, and
muscarinic receptors in the sinoatrial node of
the heart......complex effects
increase or
decrease
blood pressure
and heart rate.
Low doses of
succinylcholine
can produce
negative
chronotropic
and inotropic
effects
higher doses
usually
increase heart
rate and
contractility
and elevate
circulating
catecholamine
levels

Children are particularly susceptible to profound
bradycardia following administration of
succinylcholine.
in adults Bradycardia will sometimes occur when
a second bolus of succinylcholine is administered
approximately 3–8 min after the first dose
• succinylmonocholine, sensitizes muscarinic cholinergic
receptors in the sinoatrial node
• Intravenous atropine (0.02 mg/kg in children, 0.4 mg in
adults) is normally given prophylactically to children prior to
the first and subsequent doses in adults.
arrhythmias.....nodal bradycardia and ventricular
ectopy

B. Fasciculations
• Visible motor unit contractions
called fasciculation
Onset of paralysis
by
succinylcholine.....
• Pretreatment with a small dose of
nondepolarizing relaxant...Then
Prevented by
• (1.5 mg/kg)
Larger dose of
succinylcholine is
required
• Young children and
• Elderly patients.
Not observed in

C. Hyperkalemia
• to increase serum potassium by 0.5 mEq/L.
• insignificant in patients with normal
baseline potassium levels
• can be life- threatening in patients with
preexisting hyperkalemia.
succinylcholine-
induced
depolarization
• can prove to be quite refractory to routine
cardiopulmonary resuscitation
• requiring calcium, insulin, glucose,
bicarbonate, and even cardiopulmonary
bypass
Hyperkalemic
cardiac arrest

Conditions causing susceptibility to
succinylcholine-induced hyperkalemia
Burn injury
Massive trauma
Severe intraabdominal infection
Spinal cord injury
Encephalitis
Stroke
Guillain-Barré syndrome
Severe Parkinson’s disease
Tetanus
Prolonged total body
immobilization
Ruptured cerebral aneurysm
Polyneuropathy
Closed head injury
Hemorrhagic shock with metabolic
acidosis
Myopathies (eg, Duchenne’s
dystrophy)

Mechanism of hyperkalemia
succinylcholine to effect widespread depolarization and extensive
potassium release.
Life-threatening potassium
release is not reliably
prevented by pretreatment
with a nondepolarizer
risk of hyperkalemia usually
seems to peak in 7–10 days
following the injury
risk of hyperkalemia from
succinylcholine is minimal in
the fi rst 2 days after spinal
cord or burn injury.
Immature isoform of the Ach receptor may be expressed inside and outside
the neuromuscular junction (up-regulation).
Denervation injuries (spinal cord injuries, larger burns)

D. Muscle Pains
• Rocuronium (0.06–0.1 mg/kg) prior to
succinylcholine has been reported to be
effective
Increased incidence of
postoperative
myalgia…..Prevention
by
• Myoglobinemia and increases in serum
creatine kinase can be detected following
administration of succinylcholine
Myalgias are theorized
to be due to the initial
unsynchronized
contraction of muscle
groups
• Use of nonsteroidal antiinfl ammatory
drugs may reduce the incidence and
severity of myalgias.
Treatment

E. Intragastric Pressure
Elevation
Abdominal wall muscle fasciculations
offset by an increase in lower esophageal
sphincter tone.
no evidence that the risk of gastric reflux or
pulmonary aspiration is increased by
succinylcholine

F. Intraocular Pressure
Elevation
Extraocular muscle.....multiple motor end-plates on each cell.
Prolonged membrane depolarization and contraction of
extraocular muscles
transiently raise intraocular pressure and theoretically could
compromise an injured eye
• no evidence that succinylcholine leads to worsened outcome in patients with
“open” eye injuries
Prevention
• not always prevented by pretreatment with a nondepolarizing agent.

G. Masseter Muscle
Rigidity
• Some difficulty .... In
opening the mouth
Transiently
increases
muscle tone in
the masseter
muscles.
• Premonitory sign of
malignant hyperthermia
Marked increase
in tone
preventing
laryngoscopy is
abnormal .......

H. Malignant
Hyperthermia
Acute hypermetabolic disorder of skeletal
muscle.....
• Pharmacogenetic pathology
• Potent volatile anaesthetics with suxamethonium
Succinylcholine is a potent triggering agent in
patients susceptible
no need to avoid use of succinylcholine in
patients with NMS.

I. Generalized Contractions
Patients afflicted with myotonia may develop
myoclonus after administration of succinylcholine.
Patients with reduced levels of normal
pseudocholinesterase may have a longer than
normal duration of action,
Whereas patients with atypical
pseudocholinesterase will experience markedly
prolonged paralysis.

J. Prolonged
Paralysis
Patients with reduced levels of normal
pseudocholinesterase may have a longer
than normal duration of action,
Whereas patients with atypical
pseudocholinesterase will experience
markedly prolonged paralysis.....Sux. apnea

K. Intracranial Pressure
Succinylcholine may lead to an activation of the
electroencephalogram
Slight increases in cerebral blood flow and
intracranial pressure
Fasciculations stimulate muscle stretch
receptors, which subsequently increase cerebral
activity.

Prevention
• Increase in intracranial pressure can be attenuated by
maintaining good airway control and instituting
hyperventilation.
• Pretreating with a nondepolarizing muscle relaxant
• Administering intravenous lidocaine (1.5–2.0 mg/kg) 2–3 min
prior to intubation.
Succinylcholine is NOT contraindicated for rapid
sequence induction of patients with intracranial
mass lesions or other causes of increased
intracranial pressure....If benefits overweights

L. Histamine
Release
Slight increase in histamine
after suxamethonium
administration

Nondepolarizing
Muscle Relaxants

1.Unique Pharmacological
Characteristics
classified as
• benzylisoquinolinium,
• steroidal, or other compounds.
In general, steroidal compounds can be vagolytic, but this property is
most notable with pancuronium
Benzylisoquinolines tend to release histamine
Because of structural similarities, an allergic history to one muscle
relaxant strongly suggests the possibility of allergic reactions to
other muscle relaxants, particularly those in the same chemical class.

A. Suitability for
Intubation
None of the currently available nondepolarizing muscle
relaxants equals succinylcholine
onset of nondepolarizing relaxants can be quickened by
using
• either a larger dose or
• a priming dose.
ED 95 of any drug ....is the eff ective dose of a drug in
95% of individuals
But for neuromuscular blockers ED95 is.... the dose that
produces 95% twitch depression in 50% of individuals.

larger intubating dose speeds onset,
it exacerbates side eff ects and
prolongs the duration of blockade.
• For example, a dose of 0.15 mg/kg of
pancuronium may produce intubating
conditions in 90 sec, but at the cost of more
pronounced tachycardia—and a block that
may be irreversible (by neostigmine) for
more than 60 min

Why potent NMBA has slow onset
of action? What is priming dose ?
General rule,..... The more potent the nondepolarizing muscle
relaxant, the slower its speed of onset
• More the no. Of molecules available at receptors for effect …..More rapid onset
• Less number of molecules required will be available at receptors to get the
response…..In case of potent drug
Priming doses...Giving 10% to 15% of the usual intubating
dose 5 min before induction will occupy enough receptors so that
paralysis will quickly follow when the balance of relaxant is
administered.
• Can produce conditions suitable for intubation as soon as 60 sec following
administration of rocuronium or 90 sec following administration of other
intermediate-acting nondepolarizers

Priming dose.....Not usually lead to clinically significant
paralysis, which requires that 75% to 80% of the receptors
be blocked (a neuromuscular margin of safety).
Side effects of priming dose...
• Distressing dyspnea, diplopia, or dysphagia;
• In such instances, the patient should be reassured
• Induction of anesthesia should proceed without delay.
• Oxygen desaturation in patients with marginal pulmonary reserve
Muscle groups vary in their sensitivity to muscle
relaxants..Laryngeal muscle recover first

B. Suitability for Preventing
Fasciculations
To prevent fasciculations and myalgias, 10% to
15% of a nondepolarizer intubating dose.........5 min
before succinylcholine.
Shortly before succinylcholine, myalgias, but not
fasciculations, will be inhibited.
Tubocurarine and rocuronium have been most
popular for precurarization

C. Maintenance Relaxation
Following intubation, muscle paralysis may need to be maintained
• To facilitate surgery, (eg, abdominal operations),
• To permit a reduced depth of anesthesia,
• To control ventilation
Prevention of over- and under dosing ...... to reduce the likelihood
of serious residual muscle paralysis in the recovery room...
Use nerve stimulator for monitoring neuromuscular function
Techniques of maintenance doses...Should be guided by the nerve
stimulator and clinical signs
• Intermittent boluses or
• Continuous infusion

D. Potentiation by
Inhalational Anesthetics
Volatile agents decrease nondepolarizer
dosage requirements by at least 15%
Postsynaptic augmentation depends on
• Inhalational anesthetic (desflurane > sevofl
urane > isofl urane and enfl urane > halothane >
N 2 O/O 2 / narcotic)
• Muscle relaxant employed (pancuronium >
vecuronium and atracurium)

E. Potentiation by Other
Nondepolarizers
Synergistic
• combinations of nondepolarizers produce a
greater than additive (synergistic)
neuromuscular blockade.
Additive
• Th e lack of synergism (ie, the drugs are only
additive) by closely related compounds (eg,
vecuronium and pancuronium)

F. Autonomic Side Effects
Nondepolarizers differ in their relative effects on nicotinic and
muscarinic cholinergic receptors.
Autonomic ganglion blockade
• Reducing the ability of the sympathetic nervous system to increase heart contractility
and rate in response to hypotension and other intraoperative stresses....Eg,tubocurarine
and, to a lesser extent, metocurine
Block vagal muscarinic receptors in the sinoatrial node....
• Tachycardia.Eg,pancuronium
Newer nondepolarizing relaxants, including atracurium, cisatracurium,
vecuronium, and rocuronium, are devoid of significant autonomic
effects

G. Histamine Release
Histamine release from mast cells
• bronchospasm
• skin flushing
• hypotension
atracurium and mivacurium are capable of triggering
histamine release, particularly at higher doses
Prevention
• Slow injection rates
• H 1 and H 2 antihistamine pretreatment

H. Hepatic Clearance
Only pancuronium and vecuronium are metabolized to any significant
degree by the liver.
• Active metabolites likely contribute... clinical effect.
Vecuronium and rocuronium depend heavily on biliary excretion.
liver failure
• prolongs pancuronium and rocuronium blockade
• less eff ect on vecuronium,
• no eff ect on pipecuronium.
Extra hepatic metabolism
• Atracurium,cisatracurium &mivacurium, although extensively metabolized, depend on
extrahepatic mechanisms
Severe liver disease....decrease in pseudocholinesterase levels may slow
the metabolism of mivacurium.

I. Renal Excretion
Action is prolonged in patients with renal
failure......
• Doxacurium, pancuronium, vecuronium, and
pipecuronium are partially excreted by the
kidneys,
Independent of kidney function.
• Elimination of atracurium, cisatracurium,
mivacurium, and rocuronium

2.General Pharmacological
Characteristics of Non
depolarizing MNBA

A. Temperature
 Hypothermia prolongs blockade by
 1.decreasing metabolism
 (eg, mivacurium, atracurium, and
cisatracurium) and
 2.delaying excretion
 (eg, pancuronium and vecuronium).

B. Acid–Base
Balance
 Respiratory acidosis potentiates the
blockade of most nondepolarizing relaxants
and antagonizes its reversal.
 due to coexisting alterations in
 extracellular pH,
 intracellular pH,
 electrolyte concentrations, or
 structural diff erences between drugs

C. Electrolyte
Abnormalities
 Hypokalemia and hypocalcemia ....augment a
nondepolarizing block.
 Th e responses with hypercalcemia are
......unpredictable.
 Hypermagnesemia..... potentiates a
nondepolarizing blockade by competing with
calcium at the motor end-plate.

D. Age
 Neonates have an increased sensitivity to
nondepolarizing relaxants because of their
immature neuromuscular junctions
 does not necessarily decrease dosage
requirements, as the neonate’s greater
extracellular space provides a larger volume
of distribution.

Additional considerations in special populations.

E. Drug Interactions
 many drugs augment nondepolarizing
blockade multiple sites of interaction:
 prejunctional structures
 postjunctional cholinergic receptors
 muscle membranes

F. Concurrent
Disease
 neurological or muscular disease can have
profound eff ects on an individual’s response to
muscle relaxants
 Cirrhotic liver disease and chronic renal failure
 increased volume of distribution and a lower
plasma concentration for a given dose of water-
soluble drugs, such as muscle relaxants
 drugs dependent on hepatic or renal excretion
may demonstrate prolonged clearance
 greater initial (loading) dose—but smaller
maintenance doses

G. Muscle Groups
 The onset and intensity of blockade vary among muscle groups.
 differences in blood flow,
 distance from the central circulation, or
 different fiber types.
 choice of muscle relaxant.
 diaphragm, jaw, larynx, and facial muscles (orbicularis oculi)
respond to and recover from muscle relaxation sooner than the
thumb.
 Glottic musculature is also quite resistant to blockade, as is
often confirmed during laryngoscopy.
 intubating conditions are usually associated with visual loss of
the orbicularis oculi twitch response.
 However...Wide variability in sensitivity to nondepolarizing
muscle relaxants is oft en encountered in clinical practice

INDIVIDUAL
NON-DEPOLARIZING
NMBAs

ATRACURIUM
Physical structure
• Atracurium has a quaternary group
Benzylisoquinoline structure
• Is responsible for its unique method of degradation.
Hofmann degradation may be considered as a ‘safety
net’ in the sick patient with impaired liver or renal
function
• A mixture of 10 stereoisomers.

Extensively metabolized …automatic
degradation….Ph & temperature dependent
Pharmacokinetics are independent of renal and
hepatic function
Less than 10% is excreted unchanged by renal
and biliary routes.

Two separate processes are responsible for
metabolism
A. Ester Hydrolysis
• nonspecifi c esterases, not by acetylcholinesterase or
pseudocholinesterase
B. Hofmann Elimination
• spontaneous nonenzymatic chemical breakdown occurs
at
• physiological pH and
• temperature.

Dosage & Storage
Onset....2.0 - 2.5 mins
Intubation
• 0.5 mg/kg ...intravenously for intubation
After succinylcholine, intraoperative relaxation
• 0.25 mg/kg initially, then
• in incremental doses of 0.1 mg/kg every 10–20 min
infusion
• 5–10 mcg/kg/min can effectively replace intermittent boluses.
Storage & availability
• available as a solution of 10 mg/ mL
• It must be stored at 2–8°C
• loses 5% to 10% of its potency for each month it is exposed to room
temperature.
• At room temperature, it should be used within 14 days

Side Effects & Clinical
Considerations
Dose-dependent histamine release
...Significant at doses above 0.5 mg/kg.
1.Hypotension and tachycardia
• Unusual unless doses in excess of 0.5 mg/kg
• Transient drop in systemic vascular resistance and
• Increase in cardiac index independent of any histamine
release.
• Prevention
• A slow rate of injection minimizes these eff ects.

2.Bronchospasm
• Avoided in asthmatic patients.
• Severe bronchospasm is occasionally seen in
patients without a history of asthma
3.Laudanosine toxicity
• Tertiary amine, is a breakdown product of
atracurium’s hofmann elimination
• Associated with central nervous system excitation,
• Resulting in elevation of the minimum alveolar
concentration
• Precipitation of seizures.
• Laudanosine is metabolized by the liver and
excreted in urine and bile.

4.Temperature and pH Sensitivity
• Hoffman degredation... pH & temperature
dependant
• duration of action can be markedly
prolonged by hypothermia and to a lesser
extent by acidosis.
5.Chemical Incompatibility
• Atracurium will precipitate as a free acid
if it is introduced into an intravenous line
containing an alkaline solution such as
thiopental.

6.Allergic Reactions
• Histamine release....local wheal and flare
around the injection site
• Anaphylactoid reactions ... but rare
• Proposed mechanisms include
• direct immunogenicity
• acrylate-mediated immune activation.
• IgE-mediated antibody reactions directed
against substituted ammonium
compounds...muscle relaxants,
• Reactions to acrylate, a metabolite of atracurium
and a structural component of some dialysis
membranes

CISATRACURIUM
Physical Structure
• Cisatracurium is a stereoisomer of
atracurium
• four times more potent.
• Atracurium contains approximately
15% cisatracurium.

• Hofmann elimination ....
• degradation in plasma at physiological pH
and temperature …. organ-independent .
• metabolites (a monoquaternary acrylate
and laudanosine) have no neuromuscular
blocking eff ects
• Nonspecific esterases are not involved in
the metabolism of cisatracurium.
• Metabolism and elimination are independent
of renal or liver failure.

Dosage & Storage
• intubating dose .......0.1–0.15 mg/kg
within 2 min and results in muscle
blockade of intermediate duration.
• maintenance infusion rate ranges
from 1.0–2.0 mcg/kg/min.
• Refrigeration (2–8°C)
• used within 21 days after removal
from refrigeration and exposure
to room temperature.

Side Eff ects & Clinical
Considerations
• does not produce a consistent, dose-
dependent increase in plasma histamine
levels
• does not alter heart rate or blood
pressure, nor does it produce autonomic
effects
• Cisatracurium shares with atracurium the
• production of laudanosine,
• pH and temperature sensitivity &
chemical incompatibility.

ROCURONIUM
Physical Structure
• monoquaternary steroid
• analogue of vecuronium
rapid onset of action.
6-8 times less potent than vecuronium but has
approximately the same molecular weight.......
• greater number of drug molecules may reach the
postjunctional receptors within the first few
circulations.......faster development of neuromuscular block

Metabolism & Excretion…..
• no metabolism and is eliminated primarily by
the liver and slightly by the kidneys.
Duration of action....
• prolonged by severe hepatic failure and
pregnancy
• Elderly patients may experience a prolonged
duration of action due to decreased liver
mass.
• Not significantly affected by renal disease
• does not have active metabolites....better
choice than vecuronium in the patient requiring
prolonged infusions in the intensive care unit

Dosage
• Rocuronium is less potent than most other
steroidal muscle relaxants (potency seems to
be inversely related to speed of onset)
• for intubation........0.45–0.9 mg/kg intravenously
and 0.15 mg/kg boluses for maintenance.
• A lower dose of 0.4 mg/kg may allow reversal
as soon as 25 min after intubation.
• Intramuscular rocuronium (1 mg/kg for infants; 2
mg/kg for children) .....for intubation ...after 3–6
min..... can be reversed aft er about 1 hr.
• infusion requirements for rocuronium range
from 5–12 mcg/kg/min.

Side Effects & Clinical Considerations
• Rocuronium (at a dose of 0.9–1.2 mg/kg) has an onset of
action that approaches succinylcholine (60–90 s), making it a
suitable
• alternative for rapid-sequence inductions, but at the cost of
a much longer duration of action
• Rocuronium (0.1 mg/kg) has been shown to be a rapid (90 s) and
effective agent ) for precurarization prior to administration of
succinylcholine
• decreased fasciculations and postoperative myalgias
• drug stimulates little histamine release or cardiovascular
disturbance, although in high doses it has a mild vagolytic
property
• Anaphylactic reactions are more common after rocuronium than
after any other aminosteroid neuromuscular blocking drug. ...at a
similar rate to anaphylactic reactions to atracurium and
mivacurium.

PANCURONIUM
Physical Structure
• steroid ring on which two modifi ed ACh molecules
are positioned (a bisquaternary relaxant).
• metabolized (deacetylated) by the liver to a limited
degree.
• Its metabolic products have some neuromuscular
blocking activity.
• Excretion is primarily renal (40%), although some of
the drug is cleared by the bile (10%)

renal failure......
• elimination of pancuronium is slowed
and neuromuscular blockade is
prolonged
cirrhosis.......
• may require a larger initial dose due to
an increased volume of distribution but
have reduced maintenance
requirements because of a decreased
rate of plasma clearance.

Dosage
• intubation..... 0.08–0.12 mg/kg of pancuronium
provides adequate relaxation in 2–3 min.
• Intraoperative relaxation .... 0.04 mg/kg initially
followed every 20–40 min by 0.01 mg/kg.
Storage
• available as a solution of 1 or 2 mg/mL
• stored at 2–8°C but
• stable for up to 6 months at normal room
temperature.

A. Hypertension and Tachycardia
• vagal blockade
• sympathetic stimulation.
• ganglionic stimulation,
• catecholamine release from adrenergic nerve endings
• decreased catecholamine reuptake
Large bolus doses of pancuronium.....caution to
patients in whom an increased heart rate would be
particularly detrimental
• (eg, coronary artery disease, hypertrophic cardiomyopathy, aortic
stenosis)

B. Arrhythmias
• ventricular arrhythmias...due to
• Increased atrioventricular conduction and
• catecholamine release
• pancuronium, tricyclic antidepressants
and halothane...arrhythmogenic
C. Allergic Reactions
• hypersensitive to bromides may exhibit
allergic reactions to pancuronium
(pancuronium bromide).

VECURONIUM
Physical Structure
• pancuronium minus a quaternary methyl group (a monoquaternary relaxant).
• alters side effects without affecting potency.
• metabolized to a small extent by the liver.
excretion......
• primarily on biliary excretion and secondarily (25%) on renal
shorter elimination half-life and more rapid clearance compared
with pancuronium

Long-term administration in ICU.....prolonged
neuromuscular blockade (up to several days)
• from accumulation of its active 3-hydroxy metabolite, changing drug
clearance, and in some patients..... polyneuropathy.
• Risk factors ‫۔۔۔‬gender, renal failure, long-term or high-dose
corticosteroid therapy, and
Tolerance to non depolarizing muscle relaxants can also
develop after long term use.
Dosage
• equipotent with pancuronium, and the intubating dose is 0.08–0.12
mg/kg.
• maintenance of relaxation.‫40.0۔۔‬ mg/kg initially followed by increments
of 0.01 mg/kg every 15–20 min provides intraoperative relaxation.
• infusion of 1–2 mcg/kg/min produces good

Women seem to be approximately 30% more
sensitive than men to vecuronium, .....(this has also
been seen with pancuronium and rocuronium).
• cause .......gender-related diff erences in fat and muscle mass,
protein binding, volume of distribution, or metabolic activity.
• 1.Cardiovascular
• No significant cardiovascular effects.
• Potentiation of opioid-induced bradycardia .
• 2.Liver Failure
• dependent on biliary excretion,
• duration of action of vecuronium is usually not signifi cantly
prolonged in patients with cirrhosis unless doses greater than
0.15 mg/kg are given.

Gantacurium
New class of nondepolarizing neuromuscular
blockers called chlorofumarates.
It is provided as a lyophilized powder, because it is
not stable as an aqueous solution
ultrashort duration of action, similar to that of
succinylcholine.
undergoes nonenzymatic degradation by two
chemical mechanisms:
• rapid formation of inactive cysteine adduction product and
• ester hydrolysis

Dosage
• dose of 0.2 mg/kg (ED 95 ), the onset of action has been
estimated to be 1-2 min, with a duration of blockade similar to
that of succinylcholine.
Its clinical duration of action ranged from 5-10 min;
recovery can be accelerated by
• edrophonium
• exogenous cysteine.
Cardiovascular effects
• histamine release were observed following the use of three
times the ED 95 dosage.

AV002 (CW002)
is another investigational nondepolarizing agent.
It is a benzylisoquinolinium fumarate ester-based
compound
intermediate duration of action
metabolism and elimination similar to that of
gantacurium.

OTHER RELAXANTS
(Historical interest)
no longer manufactured or not clinically used
Tubocurarine
• the first muscle relaxant used clinical
• Histamine release
• produce or exacerbate bronchospasm
• often produced hypotension and tachycardia through
histamine release
• ability to block autonomic ganglia .
• Tubocurarine is not metabolized significantly,
• elimination is primarily renal and secondarily biliary.

Metocurine
• shares many of the side effects of tubocurarin
• primarily dependent on renal function for elimination.
• Patients allergic to iodine (eg, shellfish allergies) could exhibit hypersensitivity to
metocurarine.... contain iodide.
Gallamine
• the most potent vagolytic properties of any relaxant,
• entirely dependent on renal function for elimination.
Alcuronium
• long-acting nondepolarizer
• mild vagolytic properties
• primarily dependent on renal function for elimination
Rapacuronium
• has a rapid onset of action,
• minimal cardiovascular side eff ects, and a
• short duration of action.
• withdrawn by the manufacturer following multiple reports of serious
bronchospasm, Histamine release may have been a factor.

Decamethonium
• An older depolarizing agent
Mivacurium
• Benzylisoquinolinium derivative,
• Metabolized by pseudocholinesterase
• Duration of action may be prolonged in pathophysiological states
that result in low pseudocholinesterase levels.
• Intubating dose is 0.2 mg/kg, ... infusion rate being 4-10 mcg/kg/ min.
• Releases histamine to about the same degree as atracurium; the
• Cardiovascular effects can be minimized by slow injection.
• Mivacurium is useful particularly for surgical procedures requiring
muscle relaxation in which even atracurium and vecuronium seem
too long-acting, and when it is desirable to avoid the side-effects of
succinylcholine, tonsillectomy
• E.G. For bronchoscopy, oesophagoscopy, laparoscopy or
tonsillectomy

Doxacurium
• Potent long-acting benzylisoquinolinium compound
• Primarily eliminated by renal excretion.
• Intubating conditions are achieved in 5 min with 0.05 mg/
kg.
• Devoid of cardiovascular and histamine-releasing side eff
ects.
Pipecuronium
• A bisquarternary steroidal compound similar to
pancuronium
• Without the vagolytic eff ects.
• Onset and duration of action are also similar to
pancuronium;
• Elimination is primarily through renal (70%) and biliary
(20%) excretion.
• Intubating dose ranges from 0.06-0.1 mg/kg

REVERSAL
AGENTS
Cholinesterase Inhibitors & Other
Pharmacologic Antagonists to Neuromuscular
Blocking Agents

Anticholinesterases
Inhibit the action of acetylcholinesterase at the neuromuscular
junction,
• Thus prolonging the half-life of acetylcholine and potentiating its effect, especially in the
presence of residual amounts of non-depolarizing muscle relaxant at the end of surgery.
The primary clinical use of cholinesterase inhibitors, also called
anticholinesterases, is to reverse nondepolarizing muscle blockade.
Some of these agents are also used to diagnose and treat myasthenia
gravis.
Newer agents, such as cyclodextrins and cysteine, with superior ability
to reverse neuromuscular blockade from specific agents, are being
investigated

Cholinergic
Pharmacology
cholinergic .....effects of the neurotransmitter acetylcholine
• as opposed to the adrenergic eff ects of nor adrenaline (norepinephrine).
Synthesis & metabolism of ACh
• Acetylcholine is synthesized in the nerve terminal by the enzyme
cholineacetyltransferase, which catalyzes the reaction between acetylcoenzyme A
and choline
• Aft er its release, acetylcholine is rapidly hydrolyzed by acetylcholinesterase (true
cholinesterase) into acetate and choline.
Acetylcholine is the neurotransmitter for
• the entire parasympathetic nervous system (parasympathetic ganglions and effector
cells),
• parts of the sympathetic nervous system (sympathetic ganglions, adrenal medulla,
and sweat glands),
• some neurons in the central nervous system, and
• somatic nerves innervating skeletal muscle

Cholinergic receptors
subdivided...... based on their reaction to the
alkaloids muscarine and nicotine
1.Nicotine stimulates the…nicotinic receptors
• autonomic ganglia and
• skeletal muscle receptors (nicotinic receptors)
2. muscarine activates end-organ eff ector
cells....muscarinic receptors
• bronchial smooth muscle,
• salivary glands, and the
• sinoatrial node (muscarinic receptors).

Blockade of ACh receptors
Nicotinic receptors are blocked by muscle relaxants
(also called neuromuscular blockers), and
muscarinic receptors are blocked by anticholinergic
drugs....atropine.
Although nicotinic and muscarinic receptors differ in
their response to some agonists (eg, nicotine,
muscarine) and some antagonists (eg, vecuronium vs
atropine), they both respond to acetylcholine

Methacholine...primarily muscarinic
agonists
• by inhalation used as a provocative test in
asthma
bethanechol...primarily muscarinic
agonists
• used for bladder atony,
carbachol has both muscarinic and
nicotinic agonist activities.
• used topically for wide-angle glaucoma.

Ach Receptors
Distribution
&
Agonists
&
Antagonists

Goals of Reversal of NM
Blockade
primary goal is to
maximize nicotinic
transmission with a minimum
of muscarinic side effects.

MECHANISM OF ACTION
Normal neuromuscular transmission critically depends on acetylcholine
binding to nicotinic cholinergic receptors on the motor endplate.
Nondepolarizing muscle relaxants act by competing with acetylcholine for
these binding sites, thereby blocking neuromuscular transmission.
Reversal of blockade
• spontaneous reversal
• redistribution,
• metabolism, and
• excretion from the body
• pharmacological reversal
Cholinesterase inhibitors indirectly increase the amount of
acetylcholine available to compete with the nondepolarizing agent,
thereby reestablishing normal neuromuscular transmission.

Cholinesterase inhibitors inactivate
acetylcholinesterase by reversibly binding to the
enzyme
covalent bonds....neostigmine & pyridostigmine...
Long duration
electrostatic attraction and hydrogen
bonding....edrophonium...short duration
clinical duration of the cholinesterase inhibitors
used in anesthesia......influenced by the rate of drug
disappearance from the plasma.

Mechanisms of action other than
acetylcholinesterase inactivation
Edrophonium seems to have prejunctional
effects that enhance the release of acetylcholine.
Neostigmine has a direct (but weak) agonist effect
on nicotinic receptors.
• Acetylcholine mobilization and release by the nerve may also
be enhanced (a presynaptic mechanism).
In excessive doses, acetylcholinesterase
inhibitors
• paradoxically potentiate a nondepolarizing neuromuscular
blockade....may cause receptor channel blockade

Cholinesterase inhibitors prolong the
depolarization blockade of succinylcholine.
Two mechanisms may explain this latter effect:
• increase in acetylcholine (which increases motor end-plate depolarization)
• inhibition of pseudocholinesterase activity.
Neostigmine and to some extent pyridostigmine display some limited
pseudocholinesterase-inhibiting activity, but their effect on
acetylcholinesterase is much greater.
Edrophonium has little or no effect on pseudocholinesterase.
In large doses, neostigmine can cause a weak depolarizing neuromuscular
blockade.

Organophosphates
special class of cholinesterase
inhibitors, form very stable,
irreversible bonds to the
enzyme Acetalcholinesterase....
• ophthalmology
• pesticides.

CLINICAL PHARMACOLOGY
General Pharmacological
Characteristics
Cholinesterase inhibitors can act at cholinergic
receptors of several other organ systems
Cardiovascular receptors —Th e predominant
muscarinic eff ect on the heart is
• bradycardia that
• sinus arrest.
Pulmonary receptors —Muscarinic stimulation can
result in
• bronchospasm (smooth muscle contraction) and
• increased respiratory tract secretions.

Cerebral receptors —
• Physostigmine is a cholinesterase inhibitor that
crosses the bloodbrain barrier and can cause
• diffuse activation of the electroencephalogram by
stimulating muscarinic and nicotinic receptors within
the central nervous system.
• Unlike physostigmine, cholinesterase inhibitors used to
reverse neuromuscular blockers do not cross the
blood–brain barrier.
Gastrointestinal receptors —
• Muscarinic stimulation increases peristaltic activity
(esophageal, gastric, and intestinal)
• glandular secretions (eg, salivary).
• Postoperative nausea, vomiting,
• fecal incontinence

Unwanted muscarinic side eff ects are
minimized by
• Prior or concomitant administration of anticholinergic
medications, such as
• Atropine sulfate or
• Glycopyrrolate.
Clearance
• Hepatic metabolism (25% to 50%)
• Renal excretion (50% to 75%).
• Any prolongation of action of a nondepolarizing muscle
relaxant from renal or hepatic insufficiency will probably
be accompanied by a corresponding increase in the
duration of action of a cholinesterase inhibitor.

When reversal agent should be given?
no amount of cholinesterase inhibitor can immediately reverse a
block that is so intense that..... cannot be reversed if
• there is no response to tetanic peripheral nerve stimulation.
• Moreover, absence of any palpable single twitches following 5 sec of tetanic stimulation
at 50 Hz .
Some evidence of spontaneous recovery ...(ie, the first twitch of the
train-of-four [TOF]) should be present before reversal is attempted.
The posttetanic count (the number of palpable twitches after tetanus)
generally correlates with the time of return of the first twitch of the
TOF and therefore the ability to reverse intense paralysis.....

Example
intermediate-acting agents, such as
atracurium and vecuronium.....
• a palpable posttetanic twitch appears about 10 min
before spontaneous recovery of the first twitch of
the TOF
for longer-acting agents, such as
pancuronium.....
• a palpable posttetanic twitch appears about 40 min
before spontaneous recovery of the first twitch of
the TOF

Factors effecting The time
required to fully reverse a
nondepolarizing block
1.Choice cholinesterase inhibitor administered
2.Dose of cholinesterase inhibitor administered
3.The muscle relaxant being antagonized,
4.Extent of the blockade before reversal.

example
• reversal with edrophonium is usually faster than with
neostigmine
• large doses of neostigmine lead to faster reversal than small
doses
• intermediate-acting relaxants reverse sooner than long-acting
relaxants
• a shallow block is easier to reverse than a deep block (ie, twitch
height >10%).
intermediate-acting relaxants require a lower dose of
reversal agent (for the same degree of blockade) than
long-acting agents, and
• concurrent excretion or metabolism provides a proportionally faster
reversal of the short- and intermediate-acting agents.

Factors associated with faster reversal are
also associated with
• a lower incidence of residual paralysis in the
recovery room and a
• lower risk of postoperative respiratory complications
A reversal agent should be routinely given
to all patients who have received
nondepolarizing muscle relaxants unless
• full reversal can be demon-strated or
• postoperative plan includes continued intubation and
ventilation.

Has patient reversed adequately?
A peripheral nerve stimulator should also be used to monitor
the progress and confirm the adequacy of reversal.
In general, the higher the frequency of stimulation, the greater
the sensitivity of the test
• (100-Hz tetany > 50-Hz tetany or TOF >single-twitch height).
Clinical signs of adequate reversal also vary in sensitivity
• (sustained head lift >inspiratory force > vital capacity > tidal volume).
Thus ....end points of recov-ery are
• sustained tetanus for 5 sec in response to a 100-Hz stimulus in anesthetized
patients or
• sus-tained head or leg lift for at least 5 sec in awake patients.

NEOSTIGMINE
Physical Structure
• consists of a carbamate moiety......provides covalent bonding to
acetylcholines-terase.
• quaternary ammonium group.....renders the molecule lipid insoluble,
so that it cannot pass through the blood–brain barrier.
Dosage & Packaging
• The usual dose of neostigmine ........0.04-0.08mg / kg in
combination with either
• atropine 0.02 mg /kg OR 0.4 mg of atropine per 1 mg of neostigmine
or
• glycopyrrolate 0.01 mg/kg OR 0.2 mg glycopyrrolate per 1 mg of
neostigmine
Neostigmine takes at least 2 min to have an initial effect, and recovery
from neuromuscular block is maximally enhanced by 10 min.

OR
0.01 mg/kg
a 0.02 mg /kg OR 0.4 mg of atropine per 1 mg of neostigmine

Clinical Considerations
Effects of neostigmine (0.04 mg/kg) are usually apparent in 5min, peak at
10 min, and last more than 1 hr.
Many clinicians use a dose of
• 0.04 mg/kg (or 2.5 mg) if the preexisting blockade is mild to moderate
• 0.08 mg/kg (or 5 mg) if intense paralysis is being reversed
Neostigmine crosses the placenta, resulting in fetal bradycardia.
.........Atropine may be a better choice of an anticholinergic agent than
glycopyrrolate in pregnant
Neostigmine is also used to treat myasthenia gravis, urinary bladder
atony, and paralytic ileus.

OTHER
CONSIDERATIONS
Recovery from neuromuscular blockade
is influenced by the
• Depth of block at the time of antagonism
• Clearance and half-life of the relaxant used
• Other factors that aff ect neuromuscular blockade
• Drugs
• Electrolyte
• Acid/base balance
• Temperature

NON-CLASSIC
REVERSAL AGENTS
Two unique drugs , under investigation these
agents act as selective antagonists of
nondepolarizing neuromuscular blockade.
Sugammadex....Able to reverse aminosteroid-
induced neuromuscular blockade
L-cysteine....Reverse the neuromuscular blocking
effects of gantacurium and other fumarates.

SUGAMMADEX
modified gamma-cyclodextrin ......
• SU- refers to sugar
• gammadex ...... refers to the structural molecule
gamma-cyclodextrin
Sugammadex is a novel selective relaxant-
binding agent that is currently available for
clinical use in Europe

Physical Structure
three-dimensional structure resembles a hollow
truncated cone or doughnut with a hydrophobic
cavity and a hydrophilic exterior.
MECHANISM
• Hydrophobic interactions trap the drug (eg, rocuronium) in the
cyclodextrin cavity (doughnut hole), resulting in tight formation
of a water-soluble guest–host complex in a 1:1 ratio.
• terminates the neuromuscular blocking action and restrains the
drug in extracellular fluid where it cannot interact with nicotinic
acetylcholine receptors.
• eliminated unchanged via the kidneys.

Clinical Considerations
doses of 4–8 mg/kg.
• injection of 8 mg/kg, given 3 min after administration of 0.6 mg/kg of
rocuronium, recovery of TOF ratio to 0.9 was observed within 2 min.
produces rapid and effective reversal of both shallow and
profound rocuronium-induced neuromuscular blockade
Due to hypersensitivity and allergic reactions, sugammadex
has not yet been approved by the US Food and Drug
Administration.

L -CYSTEINE
An endogenous amino acid that is oft en added to total parenteral nutrition
regimens to enhance calcium and phosphate solubility.
Reverse the neuromuscular blocking effects of gantacurium and other
fumarates.
Mechanism
• Ultrashort-acting neuromuscular blocker, gantacurium, and other fumarates
rapidly combine with L -cysteine in vitro to form less active degradation
products (adducts).
• L -cysteine (10–50 mg/kg intravenously) given to anesthetized monkeys 1 min
after these neuromuscular blocking agents....
• Abolished the block within 2–3 min
Antagonism was found to be superior to that produced by anticholinesterases
Unique method of antagonism by adduct formation and inactivation is still in the
investigative stage in humans.

Neuromuscular blocking agents & reversal in anesthesia

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