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A muscle relaxant is a drug which affects skeletal muscle function and decreases

the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain,
and hyperreflexia. The term "muscle relaxant" is used to refer to two major
therapeutic groups thats neuromuscular blockers and spasmolytics. Neuromuscular
blockers act by interfering with transmission at the neuromuscular end plate and have
no central nervous system (CNS) activity. They are often used during surgical
in intensive
care and
medicine to
temporary paralysis. These medicines are often used during anesthesia, but they do
not usually affect whether you are awake. They also don't relieve pain.
Some general anesthetics also cause some muscle relaxation. But in many cases a
second medicine will be used during anesthesia to relax muscle tone throughout your
body or to relax specific muscles. For example, a muscle relaxant may be used to
relax muscles in the belly or chest for surgery in those parts of the body or to
relax eye muscles in certain kinds of eye surgery. A muscle relaxant may permit easy
movement of joints during bone and joint surgery.
Skeletal muscle relaxation can be produced by deep inhalational anesthesia,
regional nerve block, or neuromuscular blocking agents (commonly called muscle
relaxants ). Modern use of neuromuscular-blocking drugs dates from 1932, when
purified fractions of d-tubocurarine (dTc) were administered to control skeletal
muscle spasms in patients with tetanus, In 1940, dTc was administered as an adjuvant
to drug-induced electroshock therapy. The first use of dTc to produce surgical skeletal
muscle relaxation during general anesthesia was reported in 1942 (Griffith and
Johnson, 1942) , The use of curarized animals in experiments to determine the
parasympathomimetic effects of succinylcholine properties of this drug. It was not
until 1949 that the neuromuscular- blocking effects of SCh were recognized. Between
1949 and 1960, dTc and SCh remained the most commonly utilized neuromuscularblocking drugs. Pancuronium was introduced in 1960 as a long-acting aminosteroid
nondepolarizing neuromuscular-blocking drug. In 1980, two new nondepolarizing
neuromuscular-blocking drugs, atracurium (benzylisoquinoline) and vecuronium
(aminosteroid) were introduced. Cisatracurium followed in 1995, mivacurium in 1997
and most recently, rocuronium was introduced. (Hillier Textbook)
The principal pharmacologic effect of neuromuscular blocking drugs is to interrupt
transmission of nerve impulses at the neuromuscular junction (NMJ). On the basis of
distinct electrophysiologic differences in their mechanisms of action and duration of
action, these drugs can be classified as depolarizing neuromuscular-blocking drugs
(mimic the actions of acetylcholine) and nondepolarizing neuromuscular-blocking
drugs (interfere with the actions of acetylcholine), Neuromuscular-blocking drugs are
either benzylisoquinolinium compounds or aminosteroid compounds. Neuromuscular
blocking drugs produce phase I depolarizing neuromuscular blockade, phase II
depolarizing neuromuscular blockade, or non depolarizing neuromuscular blockade.
Currently, the principal uses of neuromuscular-blocking drugs are to provide skeletal
muscle relaxation to facilitate tracheal intubation and to improve surgical working
conditions during general anesthesia ( Hillier text book)

Neuromuscular Transmission
The cell membranes of the neuron and muscle fiber are separated by a narrow (20nm) gap,
the synaptic cleft . As a nerves action potential depolarizes its terminal, an influx of
calcium ions through voltage-gated calcium channels into the nerve cytoplasm allows
storage vesicles to fuse with the terminal plasma membrane and release their
contents(acetylcholine [ACh]). The ACh molecules diffuse across the synaptic cleft to
bind with nicotinic cholinergic receptors on a specialized portion of the muscle
membrane, the motor end-plate. Each neuromuscular junction contains approximately
5 million of these receptors, but activation of only about 500,000 receptors is required
for normal muscle contraction. The structure of ACh receptors varies in different
tissues and at different times in development. Each ACh receptor in the
neuromuscular junction normally consists of five protein subunits; two subunits;
and single , , and subunits. Only the two identical subunits are capable of
binding Ach molecules. If both binding sites are occupied by ACh, a conformational
change in the subunits briefly (1 ms) opens an ion channel in the core of the receptor.
The channel will not open if Ach binds on only one site. In contrast to the normal (or
mature) junctional ACh receptor, another isoform contains a subunit instead of the
subunit. This isoform is referred to as the fetal or immature receptor
because it is in the form 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.
Cations flow through the open ACh receptor channel (sodium and calcium in;
potassium out), generating an end-plate potential . The contents of a single vesicle, a
quantum of ACh (10 4 molecules per quantum), produce a miniature end-plate
potential. The number of quanta released by each nerve impulse, normally at least
200, is very sensitive to extracellular ionized calcium concentration; increasing
calcium concentration increases the number of quanta released. When
enough receptors are occupied by ACh, the end-plate potential will
be suffi ciently strong to depolarize the perijunctional membrane.
Voltage-gated sodium channels within this portion of the muscle
membrane open when a threshold voltage is developed across
them, as opposed to end-plate receptors that open when ACh is
applied. Perijunctional areas of muscle membrane have a higher
density of these sodium channels than other parts of the

The resulting action potential propagates along the muscle

membrane and T-tubule system, opening sodium channels and
releasing calcium from the sarcoplasmic reticulum. This intracellular
calcium allows the contractile proteins actin and myosin to interact,
bringing about muscle contraction. The amount of ACh released and
the number of receptors subsequently activated will normally far
exceed the minimum required for the initiation of an action
potential. The nearly 10-fold margin of safety is lost in Eaton
Lambert myasthenic syndrome (decreased
release of ACh) and myasthenia gravis (decreased number of
receptors). ACh is rapidly hydrolyzed into acetate and choline by the
substrate-specific enzyme acetylcholinesterase. This enzyme
(also called specific cholinesterase or true cholinesterase) is
embedded into the
motor end-plate membrane immediately adjacent to the ACh
receptors. After unbinding ACh, the receptors ion channels close,
permitting the end-plate to repolarize. Calcium is re sequestered in
the sarcoplasmic reticulum, and the muscle cell relaxes.

Pharmacokinetics and Pharmacodynamics

Similar to ACh, all neuromuscular blocking agents are quaternary ammonium
compounds whose
positively charged nitrogen imparts an affinity to nicotinic ACh receptors. Muscle
relaxants very closely resemble ACh and readily bind to ACh receptors, generating a
muscle action potential.
Neuromuscular blocking drugs cannot easily cross lipid membrane barriers such as
the blood-brain barrier, renal tubular epithelium, gastrointestinal epithelium, or
placenta. Therefore, neuromuscular blocking drugs do not produce central nervous
system (CNS) effects, renal tubular reabsorption is minimal, oral absorption is
ineffective, and maternal administration does not affect the fetus. Redistribution of
nondepolarizing neuromuscular-blocking drugs also plays a role in the
pharmacokinetics of these drugs.
Continuous end-plate depolarization causes muscle relaxation because opening of
perijunctional sodium channels is time limited (sodium channels rapidly inactivate
with continuing depolarization). After the initial excitation and opening, these sodium
channels inactivate and cannot reopen until the end-plate repolarizes. The end-plate
cannot repolarize as long as the depolarizing muscle relaxant continues to bind to
ACh receptors; this is called a phase I block. After a period of time, prolonged endplate depolarization can cause poorly understood changes in the ACh receptor that
result in a phase II block, which clinically resembles that of nondepolarizing muscle
relaxants. 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 subunit is blocked.
Thus, depolarizing muscle relaxants act as Ach receptor agonists, whereas
nondepolarizing muscle relaxants function as competitive antagonists. This basic
difference in mechanism of action explains their varying effects in certain disease
states. For example, conditions associated with a chronic decrease in ACh release (eg,
muscle denervation injuries) stimulate a compensatory increase in the number of ACh
receptors within muscle membranes. These states also promote the expression of the

immature (extrajunctional) isoform of the ACh receptor, which displays low channel
conductance properties and prolonged open-channel time. This upregulation causes an
exaggerated response to depolarizing muscle relaxants (with more receptors being
depolarized), but a resistance to nondepolarizing relaxants (more receptors that must
be blocked). In contrast, conditions associated with fewer ACh receptors (eg,
downregulation in myasthenia gravis) demonstrate are resistance to depolarizing
relaxants and an increased sensitivity to nondepolarizing relaxants.
The muscles that involved in closure of the glottis have fast contraction times, The
density of acetylcholine receptors is greater in the fast contraction fibers. With
intermediate and short-acting nondepolarizing neuromuscular blocking drugs, the
period of laryngeal paralysis is briefly enough (Stoelting Textbook).
Depolarizing muscle relaxants very closely resemble ACh and readily bind to ACh
generating a muscle action potential. 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. is
not metabolized by acetylcholinesterase, it unbinds the receptor and diffuses away
from the neuromuscular junction to be hydrolyzed in the plasma and liver by another
enzyme, pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or
butyrylcholinesterase). Nondepolarizing agents are not
metabolized by either acetylcholinesterase or pseudocholinesterase. Clearance of their
depends on unbinding the receptor, redistribution, metabolism, and excretion of the
relaxant by the body, or administration of specific reversal agents (eg, cholinesterase
inhibitors) that inhibit acetylcholinesterase enzyme activity (Morgan Textbook). The
plasma clearance, volume of distribution, and elimination half-times of
neuromuscular-blocking drugs may be influenced by patient age, volatile
anesthetics( Stoelting Textbook).

Depolarizing and Non Depolarizing Muscle Relaxants

Depolarizing Muscle Relaxant
Succinylcholinealso called diacetylcholine or suxamethoniumconsists of two
ACh molecules. This structure underlies succinylcholines mechanism of action, side
effects, and metabolism. The popularity of succinylcholine is due to its rapid onset of
action (3060 s) and short duration of action (typically less than 10 min).
Succinylcholine, like all neuromuscular blockers, has a small volume of distribution
due to its very low lipid solubility, and this also underlies a rapid onset of action.

Succinylcholine is the only available NMBD with a rapid onset of effect and an
ultrashort duration of action. Using cumulative dose-response techniques, Kopman
and co-workers estimated that its potency is far greater. Administration of 1 mg/kg of
succinylcholine results in
complete suppression of response to neuromuscular stimulation in approximately 60
seconds In patients with genotypically normal butyrylcholinesterase (also known as
plasma cholinesterase or pseudocholinesterase), recovery to 90% muscle strength
following administration of 1 mg/kg succinylcholine requires 9 to 13 minutes. The
short duration of action of succinylcholine results from its rapid hydrolysis by
butyrylcholinesterase to succinylmonocholine and choline. Butyrylcholinesterase has
a large enzymatic capacity to hydrolyze succinylcholine, and only 10% of the
administered drug reaches the neuromuscular junction. The initial metabolite,
succinylmonocholine, is a much weaker NMBD than succinylcholine and is
metabolized much more slowly to succinic acid and choline (Miller 2 nd). SCh
mimics the action of ACh and produces a sustained depolarization of the
postjunctional membrane. Skeletal muscle paralysis occurs because a depolarized
postjunctional membrane and inactivated sodium channels
cannot respond to subsequent release of ACh (hence, the designation depolarizing
neuromuscular blockade). Depolarizing neuromuscular blockade is also referred as
phase I block (Miller basic).
The elimination half-life of succinylcholine is estimated to be 47 seconds. Because
little or no butyrylcholinesterase is present at the neuromuscular junction, the
neuromuscular blockade of succinylcholine is terminated by its diffusion away from
the neuromuscular junction into the circulation. Butyrylcholinesterase therefore
influences the onset and duration of action of succinylcholine by controlling the rate
at which the drug is hydrolyzed before it reaches and after it leaves the neuromuscular
junction. (Miller Textbook 2nd)

Because of the rapid onset, short duration, and low cost of succinylcholine, many
clinicians believe that it is still a good choice for routine intubation in adults. Th e
usual adult dose of succinylcholine for intubation is 11.5 mg/kg intravenously. Doses
as small as 0.5 mg/kg will often 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 effect) can be
used during surgical procedures that require brief but intense paralysis (eg,
otolaryngological endoscopies). Neuromuscular function should be frequently
monitored with a nerve stimulator to prevent overdosing and to watch for phase II
The availability of intermediate-acting nondepolarizing muscle relaxants has reduced
the popularity of succinylcholine infusions. In the past, these infusions were a
mainstay of ambulatory practice in the United States. Because succinylcholine is not
lipid soluble, it has a small volume of distribution. Per kilogram, infants and neonates
have a larger extracellular space
than adults. Therefore, dosage requirements for pediatric patients are often greater
than for adults. If succinylcholine is administered intramuscularly to children, a dose
as high as 45 mg/kg does not always produce complete paralysis. Succinylcholine
should be stored under refrigeration (28C), and should generally be used within 14
days after removal from refrigeration and exposure to room temperature.

Side Effect
Succinylcholine is a relatively safe drugassuming that its many potential
complications are understood and avoided. Because of the risk of hyperkalemia,
rhabdomyolysis, and cardiac arrest in children with undiagnosed myopathies,
succinylcholine is considered relatively contraindicated in the routine management of
children and adolescent patients. Most clinicians have also abandoned the routine use
of succinylcholine for adults. Succinylcholine is still useful for rapid sequence
induction and for short periods of intense paralysis because none of the presently
available nondepolarizing muscle relaxants can match its very rapid onset and short
Sinus bradycardia, junctional rhythm, and even sinus arrest may follow the
administration of SCh. These responses reflect the action of SCh at cardiac
postganglionic muscarinic receptors, where this drug mimics the normal
effects of Ach
Administration of SCh can rapidly result in massive hyperkalemia, serious cardiac
arrythmias, and even cardiac
Postoperative skeletal muscle myalgia, manifested particularly in the muscles of the
neck, back, and abdomen, may follow the administration of SCh
SCh causes a maximum increase in intraocular pressure 2 to 4 minutes after its
administration. This increase in intraocular pressure is transient and lasts only 5 to 10
minutes (Miller basic).

(Miller Basic)
Non Depolarizing Muscle Relaxant
Physical Structure
Like all muscle relaxants, atracurium has a quaternary group; however, a
benzylisoquinoline structure is responsible for its unique method of degradation. The

drug is a mixture of 10 stereoisomers. Atracurium is so extensively metabolized that

its pharmacokinetics are independent of renal and hepatic function, and less than 10%
is excreted unchanged by renal and biliary routes. Two separate processes are
responsible for metabolism.
A. Ester Hydrolysis
This action is catalyzed by nonspecific esterases, not by acetylcholinesterase or
B. Hofmann Elimination
A spontaneous nonenzymatic chemical breakdown occurs at physiological pH and
Atracurium is an intermediate-duration drug, with a terminal half-life and duration of
approximately 20 minutes. Termination of effect occurs during the elimination phase
of the drug. Duration of action does not depend on age, renal function, or hepatic
function (Barash) .
The site of action of atracurium, like that of other nondepolarizing neuromuscular
blocking drugs, is on both presynaptic and postsynaptic cholinergic receptors. The
onset of action is 3 to
5 minutes. Onset of atracurium can be shortened if the dose is increased, but it is not
recommended to exceed 0.5 mg/kg because of hypotension and histamine release
( Barash) .
. Atracurium may also produce neuromuscular blockade by directly interfering with
passage of ions Atracurium undergoes spontaneous nonenzymatic degradation at
normal body temperature and pH by a base-catalyzed reaction termed Hofmann
elimination. A second and simultaneously occurring route of metabolism is hydrolysis
by nonspecific plasma esterases. through channels of nicotinic cholinergic rece
ptors.An estimated 82% of atracurium is bound to plasma proteins,
presumably albumin. Hofmann elimination represents a chemical mechanism of
elimination, whereas ester hydrolysis is a biologic mechanism. These two routes of
metabolism are independent of hepatic and renal function as well as plasma
cholinesterase activity. Absence of prolonged neuromuscular blockade after
administration of atracurium to patients with atypical cholinesterase emphas izes the
dependence of ester hydrolysis of atracurium on nonspecific plasma esterases that are
unrelated to plasma cholinesterase. Hofmann elimination and ester hydrolysis also
account for the lack of cumulative drug effects with repeated doses or continuous in
fusions of atracurium.
A dose of 0.5 mg/kg is administered intravenously for intubation. After
succinylcholine, intraoperative relaxation is achieved with 0.25 mg/kg initially, then
in incremental doses of 0.1 mg/kg every 1020 min. An infusion of 510 mcg/kg/min
can effectively replace intermittent boluses. Although dosage requirements do not
significantly vary with age, atracurium may be shorter acting in children and infants
than in adults. Atracurium is available as a solution of 10 mg/ mL. It must be stored at
28C, as it 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 to preserve

Side Effects & Clinical Considerations

Atracurium triggers dose-dependent histamine release that becomes signifi cant at

doses above
0.5 mg/kg.
A. Hypotension and Tachycardia
Cardiovascular side effects are unusual unless doses in excess of 0.5 mg/kg are
administered. Atracurium may also cause a transient drop in systemic vascular
resistance and an increase in cardiac index independent of any histamine release. A
slow rate of injection minimizes these effects.
B. Bronchospasm
Atracurium should be avoided in asthmatic patients. Severe bronchospasm is
occasionally seen in patients without a history of asthma.
C. Laudanosine Toxicity
Laudanosine, a tertiary amine, is a breakdown product of atracuriums Hofmann
elimination and has been associated with central nervous system excitation, resulting
in elevation of the minimum alveolar concentration and even precipitation of seizures.
Concerns about laudanosine are probably irrelevant unless a patient has received an
extremely large total dose or has hepatic failure. Laudanosine is metabolized by the
liver and excreted in urine and bile.
D. Temperature and pH Sensitivity
Because of its unique metabolism, atracuriums duration of action can be markedly
prolonged by hypothermia and to a lesser extent by acidosis.
E. Chemical Incompatibility
Atracurium will precipitate as a free acid if it is introduced into an intravenous line
containing an
alkaline solution such as thiopental.
F. Allergic Reactions
Rare anaphylactoid reactions to atracurium have been described. Proposed
mechanisms include direct immunogenicity and acrylate-mediated immune activation.
IgE-mediated antibody reactions directed against substituted ammonium compounds,
including muscle relaxants, have been described. Reactions to acrylate, a metabolite
of atracurium and a structural component of some dialysis membranes, have also been
reported in patients undergoing hemodialysis.


Physical Structure
Cisatracurium is a stereoisomer of atracurium that is four times more potent.
Atracurium contains approximately 15% cisatracurium. This Drugs has an onset of
action of 3 to 5 minutes and a duration of action of 20 to 35 minutes Structurally,
cisatracurium is an isolated form of 1 of the 10 stereoisomers of atracurium. This drug
principally undergoes degradation by Hofmann elimination (Basic Miller).
cisatracurium has a similar neuromuscular blocking profile to atracurium except that
the onset of cisatracurium is somewhat slower and its propensity to release histamine
is dramatically less.
Neuromuscular blockade is easily maintained at a stable level by infusion at a
constant rate and does not diminish over time. In contrast to vecuronium, the rate of
spontaneous recovel
from cisatracurium induced neuromuscular blockade is not influenced by the
prolonged (average 80 hours). Cisatracurium undergoes degradation principally by

Hofmann elimination at physiologic pH and temperature to for laudanosine and a

monoquaternary acrylate (Stoelting).
Like atracurium, cisatracurium undergoes degradation in plasma at physiological pH
and temperature by organ-independent Hofmann elimination. The resulting
metabolites (a monoquaternary acrylate and laudanosine) have no neuromuscular
blocking effects. Because of cisatracuriums greater potency, the amount of
laudanosine produced for the same extent and duration of neuromuscular blockade is
much less than with atracurium. Nonspecific esterases are not involved in the
metabolism of cisatracurium. Metabolism and elimination are independent of renal or
liver failure. Minor variations in pharmacokinetic patterns due to age result in no
clinically important changes in duration of action ( Morgan). The elimination half-life
(22 to 25 minutes) is similar to that of atracurium ( Barash).
Cisatracurium produces good intubating conditions following a dose of 0.10.15
mg/kg within 2 min and results in muscle blockade of intermediate duration. The
typical maintenance infusion rate ranges from 1.02.0 mcg/kg/min. Th us, it is more
potent than atracurium. Cisatracurium should be stored under refrigeration (28C)
and should be used within 21 days
after removal from refrigeration and exposure to room temperature.
Side Effects & Clinical Considerations
Unlike atracurium, cisatracurium does not produce a consistent, dose-dependent
increase in plasma histamine levels following administration. Cisatracurium does not
alter heart rate or blood pressure, nor does it produce autonomic effects, even at doses
as high as eight times ED 95 . Cisatracurium shares with atracurium the production of
laudanosine, pH and temperature sensitivity, and chemical incompatibility.


Physical Structure
Pancuronium consists of a steroid ring on which two modified ACh molecules are
positioned (a bisquaternary relaxant). The steroid ring serves as a spacer between
the two quaternary amines. Pancuronium resembles ACh enough to bind (but not
activate) the nicotinic ACh receptor This bisquaternary amine, the first steroid muscle
relaxant used clinically, was developed by Savege and Hewitt and marketed in 1964.
The intubating dose is 0.1 mg kg1, which takes 34 min to reach its maximum effect
This drugs has an onset of action in 3 to 5 minutes and a duration of neuromuscular
blockade lasting 60 to 90 minutes. Pancuronium is metabolized (deacetylated) by the
liver to a limited degree. Its metabolic products have some neuromuscular blocking
activity. An estimated 10% to 40% of a dose o f pancuronium undergoes hepatic
deacetylation to 3-desacetylpan curonium, 17-desacetylpancuronium, and 3,1 7desacetylpancuronium. The 3-desacetylpancuronium metabolite is approximately
50% as potent as pancuronium at the NMJ, whereas the other metabolites have only
minimal activity (Stoelting). Excretion is primarily renal (40%), although some of the
drug is cleared by the bile (10%). Not surprisingly, elimination of pancuronium is
slowed and neuromuscular blockade is prolonged by renal failure. Patients with

cirrhosis may require a larger initial dose due to an increased volume of distribution
but have reduced (Morgan)
A dose of 0.080.12 mg/kg of pancuronium provides adequate relaxation for
intubation in 23 min. Intraoperative relaxation is achieved by administering 0.04
mg/kg initially followed every 2040 min by 0.01 mg/kg. Children may require
moderately larger doses of pancuronium. Pancuronium is available as a solution of 1
or 2 mg/mL and is stored at 28C but may be stable for up to 6 months at normal
room temperature.
Side Effects & Clinical Considerations
A. Hypertension and Tachycardia
These cardiovascular effects are caused by the combination of vagal blockade and
sympathetic stimulation. The latter is due to a combination of ganglionic stimulation,
catecholamine release from adrenergic nerve endings, and decreased catecholamine
reuptake. Large bolus doses of pancuronium should be given with caution to patients
in whom an increased heart rate would be particularly detrimental (eg, coronary artery
disease, hypertrophic cardiomyopathy, aortic

B. Arrhythmias
Increased atrioventricular conduction and catecholamine release increase the
likelihood of ventricular arrhythmias in predisposed individuals. The combination of
pancuronium, tricyclic antidepressants, and halothane has been reported to be
particularly arrhythmogenic.
C. Allergic Reactions
Patients who are hypersensitive to bromides may exhibit allergic reactions to
pancuronium (pancuronium bromide).
Physical Structure
Vecuronium is pancuronium minus a quaternary methyl group (a monoquaternary
relaxant). This minor structural change beneficially alters side effects without
affecting potency. This steroidal agent was developed in an attempt to reduce the
cardiovascular effects of pancuronium. It is similar in structure to the older drug,
differing only in the loss of a methyl group from one quaternary ammonium radical.
Thus it is a monoquaternary amine
Metabolism & Excretion
The monoquaternal Y structure of vecuronium increases its lipid solubility compared
with pancuronium. Vecuronium is unstable in solution and, for this reason, is supplied
as a lyophilized powder that must be dissolved in sterile water before its use.
Although it is a satisfactory drug for patients with renal failure, its duration of action
is somewhat prolonged. Vecuronium undergoes spontaneous deacetylation to produce
3-OH, 17-OH, and 3,17-(OH)2 metabolites. The most potent of these
metabolites is 3-OH vecuronium (Barash). Vecuronium is metabolized to a
small extent by the liver It depends primarily on biliary excretion and secondarily
(25%) on renal excretion. Vecuroniums brief duration of action is explained by its

shorter elimination half-life and more rapid clearance compared with pancuronium.
Long-term administration of vecuronium to patients in intensive care units has
resulted in prolonged neuromuscular blockade (up to several days), possibly from
accumulation of its active 3-hydroxy metabolite, changing drug clearance, and in
some patients, leading to the development of a polyneuropathy (Stoelting).
Vecuronium is equipotent with pancuronium, and the intubating dose is 0.080.12
mg/kg. of 0.04 mg/kg initially followed by increments of 0.01 mg/kg every 1520
min provides intraoperative relaxation. Alternatively, an infusion of 12 mcg/kg/min
produces good maintenance of relaxation. Age does not aff ect initial dose
requirements, although subsequent doses are required less frequently in neonates and
infants. Women seem to be approximately 30% more sensitive than men to
vecuronium, as evidenced by a greater degree of blockade and longer duration of
action (this has also been seen with pancuronium and rocuronium). The cause for this
sensitivity may be related to gender-related differences in fat and muscle mass,
protein binding, volume of distribution, or metabolic activity. The duration of action
of vecuronium may be further prolonged in postpartum patients due to alterations in
hepatic blood flow or liver uptake.
Side Effects & Clinical Considerations
A. Cardiovascular
Even at doses of 0.28 mg/kg, vecuronium is devoid of significant cardiovascular
effects. Potentiation of opioid-induced bradycardia may be observed in some patients.
B. Liver Failure
Although it is dependent on biliary excretion, the duration of action of vecuronium is
usually not
significantly prolonged in patients with cirrhosis unless doses greater than 0.15 mg/kg
are given.
Vecuronium requirements are reduced during the anhepatic phase of liver

Physical Structure
Rocuronium is a monoquaternary aminosteroid nondepolarizing
NMBD with an ED95 of 0.3 mg/kg that has an onset of action of 1 to
2 minutes and a duration of action of 20 to 35 minutes. This
monoquaternary steroid analogue of vecuronium was designed to
provide a rapid onset of action ( Basic Miller).

Farmakokinetik dan Farmakodinamik

This drug has an onset of action in 1 to 2 minutes and a duration of neuromuscular
blockade lasting 20 to 35 minutes. Rocuronium undergoes no metabolism and is
eliminated primarily by the liver and slightly by the kidneys. Its duration of action is
not significantly affected by renal disease, but it is modestly. Plasma concentrations of
rocuronium decrease rapidly after

bolus injection because of hepatic uptake Thus, the duration of action of the drug is
determined chiefly by redistribution, rather than by its rather long terminal
elimination half-life (1 to
2 hours). Metabolism to 17-deacetylrocuronium is a very minor elimination pathway.
Most of the drug is excreted unchanged in the urine, bile, or feces. Rocuronium has
one-sixth the potency of vecuronium, a more rapid onset, but a similar duration of
action and similar pharmacokinetic behavior. With equipotent doses, rocuronium
onset at the adductor pollicis muscle is much faster than that of cisatracurium,
atracurium, and vecuronium (Morgan). Rocuronium is largely excreted unchanged
(up to 50% in 2 hours) in the bile. Deacetylation of rocuronium does no t occur, and,
unlike vecuronium, 3-hydroxy metabolites with neuromuscular blocking activity do
not occur. Renal excretion of rocuronium may be > 30% in 24 hours, and
administration of this drug to patients in renal failure may produce a modestly
prolonged duration of action. Liver disease increases the volume of distribution of
rocuronium and could result in a longer duration of action of the dmg, especially with
repeated doses or prolonged IV administration (Stoelting).
Rocuronium requires 0.450.9 mg/kg intravenously for intubation and 0.15 mg/kg
for maintenance. A lower dose of 0.4 mg/kg may allow reversal as soon as 25 min aft
er intubation. Intramuscular rocuronium (1 mg/kg for infants; 2 mg/kg for children)
provides adequate vocal cord and diaphragmatic paralysis for intubation, but not until
aft er 36 min (deltoid injection has a faster onset than quadriceps), and can be
reversed after about 1 hr. The infusion requirements for rocuronium range from 512
Side Effects & Clinical Considerations
Rocuronium (at a dose of 0.91.2 mg/kg) has an onset of action that approaches
(6090 s), making it a suitable alternative for rapid-sequence inductions, but at the
cost of a
much longer duration of action. This intermediate duration of action is comparable to
vecuronium or atracurium. The drug stimulates little histamine release or
cardiovascular disturbance, although in high doses it has a mild vagolytic property
which sometimes results
in an increase in heart rate Anaphylactic reactions are more common after rocuronium
than after any other aminosteroid neuromuscular blocking drug. They occur at a
similar rate to anaphylactic reactions to atracurium and mivacurium (Smith).
Gantacurium belongs to a new class of nondepolarizing neuromuscular blockers
called chlorofumarates. It is provided as a lyophilized powder, because it is not stable
as an aqueous solution; therefore, it requires reconstitution prior to administration.
In preclinical trials, gantacurium demonstrated an ultrashort duration of action, the
of action has been estimated to be 1-2 min, with a duration of blockade similar to that
of succinylcholine. Its pharmacokinetic profile is explained by the fact that it
undergoes nonenzymatic degradation by two chemical mechanisms: rapid formation

of inactive cysteine adduction product and ester hydrolysis, which occurs much more
quickly through the adduction of cysteine, a nonessential amino acid, to create a new
compound that can no longer bind to the acetylcholine receptor of the neuromuscular
junction. This unique means of inactivation likely accounts for the drugs ultrashort
duration of effect. It also provides a novel means of shortening recovery from
gantacurium induced neuromuscular block (Miller 2 .


Because succinylcholine is not metabolized by acetylcholinesterase, it unbinds the
and diffuses away from the neuromuscular junction to be hydrolyzed in the plasma
and liver by another enzyme, pseudocholinesterase (nonspecific cholinesterase,
plasma cholinesterase, or butyrylcholinesterase). Fortunately, this is a fairly rapid
process, because no specific agent to reverse a depolarizing blockade is available.
nondepolarizing agents are not
metabolized by either acetylcholinesterase or pseudocholinesterase. Reversal of their
depends on unbinding the receptor, redistribution, metabolism, and excretion of the
relaxant by the body, or administration of specifi c reversal agents (eg, cholinesterase
inhibitors) that inhibit acetylcholinesterase enzyme activity. Because this inhibition
increases the amount of ACh that is available at the neuromuscular junction and can
compete with the nondepolarizing agent, clearly, the reversal agents are of no benefit
in reversing a depolarizing block. In fact, by increasing neuromuscular junction ACh
concentration and inhibiting pseudocholinesterase- induced metabolism of
succinylcholine, cholinesterase inhibitors can prolong neuromuscular
blockade produced by succinylcholine . The ONLY time neostigmine reverses
neuromuscular block after succinylcholine is when there is a phase II block (fade of
the train-of-four) AND sufficient time has passed for the circulating concentration of
succinylcholine to be negligible.
Sugammadex, a cyclodextrin, is the first selective relaxant-binding agent; it exerts its
effect by forming tight complexes in a 1:1 ratio with steroidal nondepolarizing agents
(vecuronium, rocuronium,). This drug has been in use in the European Union for the
past few years, but is not yet commercially available in the United States. The newer
neuromuscular blocking agents, such as gantacurium, which are still under
investigation, show promise as ultrashort-acting nondepolarizing agents; they undergo
chemical degradation by rapid adduction with L-cysteine.

Specific Cholinesterase Inhibitors

Neostigmine consists of a carbamate moiety and a quaternary ammonium group. The
former provides covalent bonding to acetylcholinesterase. The latter renders the
molecule lipid insoluble, so that it cannot pass through the bloodbrain barrier. It

accelerate the already established pattern of spontaneous recovery at the

neuromuscular junction by inhibiting
the activity of acetylcholinesterase (Basic Miller).
Farmakologi dan Farmakodinamik
Following bolus intravenous injection, the plasma concentration of neostigmine
decreases rapidly during the first 5 to 10 minutes and then more slowly. Its volume of
distribution is in the range of 0.7 to 1.4 L/kg and the elimination half-life is 60 to 120
minutes ( Barash ). The effect of inhibition is present at all cholinergic synapses in
the peripheral nervous system. Thus, neostigmine has potent parasympathomimetic
activity, which is attenuated or abolished by
the administration of an antimuscarinic agent, atropine or glycopyrrolate. Inhibition of
acetylcholinesterase results in an increased amount of acetylcholine reaching the
receptor and in a longer time for acetylcholine to remain in the synaptic cleft. This
causes an increase in the size and duration of the end plate potentials (Morgan).
Neostigmine is a water soluble, ionized compound and its principal route of excretion
is the kidney. Clearance is in the range of 8 to 16 mL/kg/min, much greater than the
glomerular filtration rate because they are actively secreted into the tubular lumen.
Clearance is reduced markedly in patients in renal failure (Barash).
Dosage & Packaging
The maximum recommended dose of neostigmine is 0.08 mg/kg (up to 5 mg in
adults), but smaller amounts often suffice and larger doses have also been given
safely. Neostigmine is most commonly packaged as 10 mL of a 1 mg/mL solution,
although 0.5 mg/mL and 0.25 mg/mL concentrations are also available.
Clinical Considerations
The effects of neostigmine (0.04 mg/kg) are usually apparent in 5min, peak at 10 min,
and last more than 1 hr. If reversal is not complete in 10 min after 0.08 mg/kg, the
time for full recovery of neuromuscular function will depend on the nondepolarizing
agent used and the intensity of blockade. The duration of action is prolonged in
geriatric patients. Muscarinic side effects are
minimized by prior or concomitant administration of an anticholinergic agent. It has
been reported that neostigmine crosses the placenta, resulting in fetal bradycardia.
Thus, theoretically , atropine may be a better choice of an anticholinergic agent than
glycopyrrolate in pregnant patients receiving neostigmine
Physical Structure
Pyridostigmine is structurally similar to neostigmine except that the quaternary
ammonium is incorporated into the phenol ring. Pyridostigmine shares neostigmines
covalent binding to acetylcholinesterase and its lipid insolubility.
Dosage & Packaging
Pyridostigmine is 20% as potent as neostigmine and may be administered in doses up
to 0.25 mg/kg (a total of 20 mg in adults). It is available as a solution of 5 mg/mL.
Clinical Considerations
The onset of action of pyridostigmine is slower (1015 min) than that of neostigmine,
and its
duration is slightly longer (>2 h). Glycopyrrolate (0.05 mg per 1 mg of
pyridostigmine) or atropine (0.1 mg per 1 mg of pyridostigmine) must also be
administered to prevent bradycardia. Glycopyrrolate is preferred because its slower

onset of action better matches that of pyridostigmine, again resulting in less

Sugammadex is a novel selective relaxant-binding agent that is currently available for
clinical use in Europe. It is a modified gamma-cyclodextrin.
Physical Structure
Its three-dimensional structure resembles a hollow truncated cone or doughnut with a
hydrophobic cavity and a hydrophilic exterior. Hydrophobic interactions trap the drug
(eg, rocuronium) in the cyclodextrin cavity (doughnut hole), resulting in tight
formation of a water-soluble guesthost complex in a 1:1 ratio. This terminates the
neuromuscular blocking action and restrains the drug in extracellular fluid where it
cannot interact with nicotinic acetylcholine receptors.
In patients receiving rocuronium, return of a TOF ratio to 0.9 is accelerated by
sugammadex in a dose-dependent manner. If sugammadex is given on return of the
second twitch in the TOF, doses of 2 mg/kg result in the return of train-of-four ratio to
0.9 within approximately 2 to 4 minute. Neuromuscular transmission can be restored
by injection of suggamadex, an agent that binds specifically in a 1:1 molar ratio to
rocuronium and vecuronium. Sugammadex has a molecular weight of 2,178
daltons153 and binds with rocuronium or vecuronium in a 1:1 molar ratio. The
rocuronium molecule is less bulky (610 daltons), so 3.6 mg (or mg/kg) of
sugammadex is required to bind 1.0 mg (or mg/kg) of rocuronium. Binding is tight,
but not irreversible (Barash).
After injection of sugammadex, evidence suggests that binding of rocuronium in
plasma leads to a marked decrease in free (unbound) rocuronium concentration,
leading to a large concentration gradient of free rocuronium between the
neuromuscular junction and plasma. This favors movement of rocuronium from
neuromuscular junction to plasma, down its concentration gradient, thus producing
less neuromuscular block. Its terminal half life is approximately 2 hours. Both
sugammadex and sugammadexrocuronium complexes are excreted unchanged via
the kidney (barash).
Clinical Considerations
Sugammadex has been administered in doses of 48 mg/kg. With an injection of 8
given 3 min after administration of 0.6 mg/kg of rocuronium, recovery of TOF ratio to
0.9 was
observed within 2 min. It produces rapid and effective reversal of both shallow and
profound rocuronium-induced neuromuscular blockade in a consistent manner.
Because of some concerns about hypersensitivity and allergic reactions, sugammadex
has not yet been approved by the US Food and Drug Administration.

L -cysteine is an endogenous amino acid that is often added to total parenteral
nutrition regimens
to enhance calcium and phosphate solubility. The ultrashort-acting neuromuscular

gantacurium, and other fumarates rapidly combine with L -cysteine in vitro to form
less active degradation products (adducts). Exogenous administration of L -cysteine
(1050 mg/kg intravenously) given to anesthetized monkeys 1 min after these
neuromuscular blocking agents abolished the block within 23 min; this antagonism
was found to be superior to that produced by anticholinesterases. This unique method
of antagonism by adduct formation and inactivation is still in the investigative stage,
especially in terms of its safety and efficacy in humans.