rELAJANTES NEUROMUSCULARES.doc
-
Upload
wilmergallego -
Category
Documents
-
view
234 -
download
0
Transcript of rELAJANTES NEUROMUSCULARES.doc
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
1/39
RELAJANTES NEUROMUSCULARES
KEY CONCEPTS
It is important to realize that muscle relaxation does not ensure
unconsciousness, amnesia, or analgesia.
Depolarizing muscle relaxants act as acetylcholine (ACh) receptor
agonists, whereas nondepolarizing muscle relaxants function as competitive
antagonists.
ecause depolarizing muscle relaxants are not meta!olized !yacetylcholinesterase, they diffuse away from the neuromuscular "unction and
are hydrolyzed in the plasma and liver !y another enzyme,
pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or
!utyrylcholinesterase).
#ith the exception of mivacurium, nondepolarizing agents are not
significantly meta!olized !y either acetylcholinesterase or
pseudocholinesterase. $eversal of their !loc%ade depends on redistri!ution,
gradual meta!olism, and excretion of the relaxant !y the !ody, or
administration of specific reversal agents (eg, cholinesterase inhi!itors) thatinhi!it acetylcholinesterase enzyme activity.
&uscle relaxants owe their paralytic properties to mimicry of ACh. 'or
example, succinylcholine consists of two "oined ACh molecules.
Compared with patients with low enzyme levels or heterozygous atypical
enzyme in whom !loc%ade duration is dou!led or tripled, patients with
homozygous atypical enzyme will have a very long !loc%ade (eg, * h)
following succinylcholine administration.
+uccinylcholine is considered contraindicated in the routine management
of children and adolescents !ecause of the ris% of hyper%alemia,
rha!domyolysis, and cardiac arrest in children with undiagnosed myopathies.
ormal muscle releases enough potassium during succinylcholine-
induced depolarization to raise serum potassium !y ./ m0123. Although this
is usually insignificant in patients with normal !aseline potassium levels, a
life-threatening potassium elevation is possi!le in patients with !urn in"ury,
massive trauma, neurological disorders, and several other conditions.
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
2/39
As a general rule, the more potent the nondepolarizing muscle relaxant
the longer its speed of onset.
Doxacurium, pancuronium, vecuronium, and pipecuronium are partially
excreted !y the %idneys, and their action is prolonged in patients with renalfailure.
Cirrhotic liver disease and chronic renal failure often result in an
increased volume of distri!ution and a lower plasma concentration for a
given dose of water-solu!le drugs, such as muscle relaxants. 4n the other
hand, drugs dependent on hepatic or renal excretion may demonstrate
prolonged clearance. 5hus, depending on the drug, a greater initial dose6
!ut smaller maintenance doses6might !e re1uired in these diseases.
Atracurium and cisatracurium undergo degradation in plasma atphysiological p7 and temperature !y organ-independent 7ofmann
elimination. 5he resulting meta!olites (a mono1uaternary acrylate and
laudanosine) have no intrinsic neuromuscular !loc%ing effects.
&ivacurium, li%e succinylcholine, is meta!olized !y
pseudocholinesterase. It is only minimally meta!olized !y true
cholinesterase.
7ypertension and tachycardia may occur in patients given pancuronium.
5hese cardiovascular effects are caused !y the com!ination of vagal
!loc%ade and catecholamine release from adrenergic nerve endings.
3ong-term administration of vecuronium to patients in intensive care
units has resulted in prolonged neuromuscular !loc%ade (up to several
days), possi!ly from accumulation of its active 8-hydroxy meta!olite,
changing drug clearance, or the development of a polyneuropathy.
$ocuronium (.9:.; mg2%g) has an onset of action that approaches
succinylcholine (*9 s), ma%ing it a suita!le alternative for rapid-
se1uence inductions, !ut at the cost of a much longer duration of action.
3ange Anesthesiology< +ection II. Clinical =harmacology < Chapter 9.euromuscular loc%ing Agentsriffith pu!lished the results of a study using a refined
extract of curare (a +outh American arrow poison) during anesthesia. &uscle
relaxants rapidly !ecame a routine part of the anesthesiologist?s drug arsenal. As
>riffith noted, it is important to realize that neuromuscular "unction !loc%ing agents
produce paralysis, not anesthesia. In other words, muscle relaxation does not
ensure unconsciousness, amnesia, or analgesia. 5his chapter reviews the principles
of neuromuscular transmission and presents the mechanisms of action, physical
structures, routes of elimination, recommended dosages, and side effects of several
muscle relaxants.
3ange Anesthesiology< +ection II. Clinical =harmacology < Chapter 9.euromuscular loc%ing Agents>e*' (!N(!"e$(%&ri2i!gB%(*7&"e
C(
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
17/39
depolarizing phase I !loc%. ecause the drugs occupy some ACh receptors,
depolarization !y succinylcholine is partially prevented. An exception to
this interaction is pancuronium, which augments succinylcholine !loc%ade !y
inhi!iting pseudocholinesterase.
Intu!ating doses of succinylcholine consistently reduce some nondepolarizer
(atracurium and rocuronium) re1uirements for a!out 8 min no effect is reported
with mivacurium, pancuronium, or pipecuronium. +imilarly, if enough depolarizing
agent is administered to develop a phase II !loc%, a nondepolarizer will potentiate
paralysis.
D(-&ge
ecause of the rapid onset, short duration, and low cost of succinylcholine,
many clinicians !elieve that it is still a good choice for routine intu!ation in adults.5he usual adult dose of succinylcholine needed for intu!ation is ::./ mg2%g
intravenously. Doses as small as ./ mg2%g may provide accepta!le intu!ating
conditions if a defasciculating dose of a nondepolarizer is not used. $epeated small
!oluses (: mg) or a succinylcholine drip (: g in / or : m3, titrated to effect)
can !e used during surgical procedures that re1uire !rief !ut intense paralysis (eg,
otolaryngological endoscopies). ðylene !lue indicator dye is often added to
succinylcholine drips to prevent confusion with other intravenous fluids. In addition,
neuromuscular function should !e constantly monitored with a nerve stimulator to
prevent overdosing and the development of phase II !loc%. 5he availa!ility of short-
acting nondepolarizing muscle relaxants (eg, mivacurium) has reduced the
popularity of this techni1ue.
ecause succinylcholine is not lipid solu!le, its distri!ution is limited to the
extracellular space. =er %ilogram, infants and neonates have a larger extracellular
space than adults. 5herefore, dosage re1uirements for pediatric patients are often
greater than for adults. If succinylcholine is administered intramuscularly to
children, a dose as high as / mg2%g does not always produce complete paralysis.
+uccinylcholine should !e stored under refrigeration (;ELC), and should
generally !e used within : days after removal from refrigeration and exposure to
room temperature.
Si"e E>>e*'- 0 C%i!i*&% C(!-i"er&'i(!-
+uccinylcholine is a relatively safe drug6assuming that its many potential
complications are understood and avoided. ecause of the ris% of hyper%alemia,
rha!domyolysis, and cardiac arrest in children with undiagnosed myopathies,
however, succinylcholine is considered contraindicated in the routine management
of children and adolescent patients. In the a!sence of a difficult airway or full
stomach, many clinicians have also a!andoned the routine use of succinylcholine
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
18/39
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
19/39
threatening in patients with preexisting hyper%alemia or those with !urn in"ury,
massive trauma, neurological disorders, and several other conditions (5a!le 9/).
+u!se1uent cardiac arrest can prove to !e 1uite refractory to routine
cardiopulmonary resuscitation, re1uiring calcium, insulin, glucose, !icar!onate,
epinephrine, cation-exchange resin, dantrolene, and even cardiopulmonary !ypassto reduce meta!olic acidosis and serum potassium levels.
T&%e 9@. C(!"i'i(!- C&u-i!g Su-*e$'ii%i'+ '( Su**i!+%*,(%i!e#
I!"u*e" 4+$er7&%euillain-arrM syndrome
+evere =ar%inson?s disease
5etanus
=rolonged total !ody immo!ilization
$uptured cere!ral aneurysm
=olyneuropathy
Closed head in"ury
7emorrhagic shoc% with meta!olic acidosis
&yopathies (eg, Duchenne?s dystrophy)
'ollowing denervation in"uries, the immature isoform of the ACh receptor
may !e expressed inside and outside the neuromuscular "unction (up-regulation).
5hese extra"unctional receptors allow succinylcholine to effect widespread
depolarization and extensive potassium release. 3ife-threatening potassium release
is not relia!ly prevented !y pretreatment with a nondepolarizer. 5he ris% of
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
20/39
hyper%alemia usually appears to pea% in : days following the in"ury, !ut the
exact time of onset and the duration of the ris% period vary.
MUSCLE PAINS
=atients who have received succinylcholine have an increased incidence of
postoperative myalgia. 5his complaint is most common in females and outpatients.
=regnancy and extremes of age seem to !e protective. 5he efficacy of
nondepolarizing pretreatment is controversial !ut most clinicians feel it is effective.
Administration of rocuronium .*.: mg2%g prior to succinylcholine has !een
reported to !e effective in preventing fasciculations and reducing postoperative
myalgias. 5he relationship !etween fasciculations and postoperative myalgias is
also inconsistent. 5he myalgias are theorized to !e due to the initial unsynchronized
contraction of muscle groups myoglo!inemia and increases in serum creatine
%inase can !e detected following administration of succinylcholine. =erioperative
use of nonsteroidal antiinflammatory drugs may reduce the incidence and severity
of myalgias.
INTRAGASTRIC PRESSURE ELE5ATION
A!dominal wall muscle fasciculations increase intragastric pressure, which is
offset !y an increase in lower esophageal sphincter tone. 5herefore, the ris% of
gastric reflux or pulmonary aspiration is pro!a!ly not increased !y succinylcholine.
Although pretreatment with nondepolarizers a!olishes the rise in gastric pressure, italso prevents the increase in lower esophageal sphincter tone.
INTRAOCULAR PRESSURE ELE5ATION
0xtraocular muscle differs from other striated muscle in that it has multiple
motor end-plates on each cell. =rolonged mem!rane depolarization and contraction
of extraocular muscles following administration of succinylcholine transiently raise
intraocular pressure and could compromise an in"ured eye (see Case Discussion,
Chapter 8E). 5he elevation in intraocular pressure is not always prevented !y
pretreatment with a nondepolarizer.
MASSETER MUSCLE RIGIDITY
+uccinylcholine transiently increases muscle tone in the masseter muscles.
+ome difficulty may initially !e encountered in opening the mouth !ecause of
incomplete relaxation of the "aw. A mar%ed increase in tone preventing
laryngoscopy is a!normal and may !e a premonitory sign of malignant
hyperthermia.
MALIGNANT 4YPERT4ERMIA
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
21/39
+uccinylcholine is a potent triggering agent in patients suscepti!le to
malignant hyperthermia, a hypermeta!olic disorder of s%eletal muscle (see Case
Discussion, Chapter ). Although the signs and symptoms of neuroleptic
malignant syndrome (&+) resem!le those of malignant hyperthermia, the
pathogenesis is completely different and there is no need to avoid use ofsuccinylcholine in patients with &+.
GENERALI/ED CONTRACTIONS
=atients afflicted with myotonia may develop myoclonus after administration
of succinylcholine.
PROLONGED PARALYSIS
As discussed a!ove, patients with low levels of normal pseudocholinesterasemay have a longer than normal duration of action, whereas patients with atypical
pseudocholinesterase will experience mar%edly prolonged paralysis.
INTRACRANIAL PRESSURE
+uccinylcholine may lead to an activation of the electroencephalogram and
slight increases in cere!ral !lood flow and intracranial pressure in some patients.
&uscle fasciculations stimulate muscle stretch receptors, which su!se1uently
increase cere!ral activity. 5he increase in intracranial pressure can !e attenuated
!y maintaining good airway control and instituting hyperventilation. It can !eprevented !y pretreating with a nondepolarizing muscle relaxant and administering
intravenous lidocaine (:./;. mg2%g) ;8 min prior to intu!ation. 5he effects of
intu!ation on intracranial pressure far outweigh any increase caused !y
succinylcholine.
4ISTAMINE RELEASE
+light histamine release may !e o!served following succinylcholine in some
patients.
3ange Anesthesiology< +ection II. Clinical =harmacology < Chapter 9.euromuscular loc%ing Agents N(!"e$(%&ri2i!g Mu-*%e
Re%&3&!'-.
Drug ED9@>(rA""u*'(rP(%%i*i-Duri!gNOA!e-',e-i&8(rI!'u&'i!gD(-e8
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
24/39
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
25/39
should proceed without delay. =riming can additionally cause significant
deterioration in respiratory function (eg, decreased forced vital capacity) and may
lead to oxygen desaturation in patients with marginal pulmonary reserve. 5hese
negative side effects are more common in elderly patients.
It is important to %eep in mind that muscle groups vary in their sensitivity to
muscle relaxants (see Chapter * and the section on &uscle >roups !elow). 'or
example, the laryngeal muscles6whose relaxation is important during intu!ation6
recover from !loc%ade more 1uic%ly than the adductor pollicis, which is commonly
monitored !y the peripheral nerve stimulator.
SUITABILITY FOR PRE5ENTING FASCICULATIONS
5o prevent fasciculations, ::/G of a nondepolarizer intu!ating dose can
!e administered / min !efore succinylcholine. Although most nondepolarizers have
!een successfully used for this purpose, tu!ocurarine and rocuronium appear to !e
particularly efficacious (precurarization) tu!ocurarine is no longer availa!le in the
Fnited +tates. ecause of the antagonism !etween most nondepolarizers and a
phase I !loc%, the su!se1uent dose of succinylcholine should !e raised to :./
mg2%g.
MAINTENANCE RELAATION
'ollowing intu!ation, muscle paralysis may need to !e continued to facilitate
surgery, eg, a!dominal operations, or anesthetic management, eg, hemodynamiccompromise precluding deepening anesthesia or the need to control ventilation.
5he varia!ility !etween patients in dose responses to muscle relaxants cannot !e
overemphasized. &onitoring neuromuscular function with a nerve stimulator
(Chapter *) helps prevent over- and underdosing, as well as serious residual
muscle paralysis in the recovery room. &aintenance doses whether !y intermittent
!oluses or continuous infusion (5a!le 9) should !e guided !y the nerve
stimulator andclinical signs (eg, spontaneous respiratory efforts or movement). In
some instances clinical signs may precede twitch recovery !ecause of differing
sensitivities to muscle relaxants !etween muscle groups or technical pro!lems withthe nerve stimulator. +ome return of neuromuscular transmission should !e evident
prior to administering each maintenance dose. #hen an infusion is used for
maintenance, the rate should !e ad"usted at or "ust a!ove the rate that allows
some return of neuromuscular transmission.
POTENTIATION BY IN4ALATIONAL ANEST4ETICS
@olatile agents decrease nondepolarizer dosage re1uirements !y at least
:/G. 5he actual degree of this postsynaptic augmentation depends on !oth the
inhalational anesthetic (desflurane < sevoflurane < isoflurane and
enflurane < halothane < ;424;2narcotic) and the muscle relaxant employed
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
26/39
(pancuronium < vecuronium and atracurium). @olatile anesthetic-induced enhanced
affinity for nondepolarizing relaxants has !een proposed.
POTENTIATION BY OT4ER NONDEPOLARI/ERS
+ome com!inations of nondepolarizers (eg, mivacurium and pancuronium)
produce a greater than additive neuromuscular !loc%ade. 5he lac% of augmentation
!y closely related compounds (eg, vecuronium and pancuronium) lends credence to
the theory that potentiation results from slightly differing mechanisms of action.
AUTONOMIC SIDE EFFECTS
In clinical doses, the nondepolarizers can significantly differ in their effects
on nicotinic and muscarinic cholinergic receptors. +ome older agents (tu!ocurarine
and, to a lesser extent, metocurine) !loc%ed autonomic ganglia, compromising thea!ility of the sympathetic nervous system to increase heart contractility and rate in
response to hypotension and other intraoperative stresses. In contrast,
pancuronium (and gallamine) !loc% vagal muscarinic receptors in the sinoatrial
node, resulting in tachycardia. All newer nondepolarizing relaxants, including
atracurium, cisatracurium, mivacurium, doxacurium, vecuronium, and
pipecuronium, are devoid of significant autonomic effects in their recommended
dosage ranges.
4ISTAMINE RELEASE
7istamine release from mast cells can result in !ronchospasm, s%in flushing,
and hypotension from peripheral vasodilation. oth atracurium and mivacurium are
capa!le of triggering histamine release, particularly at higher doses. +low in"ection
rates and 7:and 7;antihistamine pretreatment ameliorate these side effects.
4EPATIC CLEARANCE
4nly pancuronium and vecuronium are meta!olized to any significant degree
!y the liver. Active meta!olites li%ely contri!ute to their clinical effect. @ecuroniumand rocuronium depend heavily on !iliary excretion. Clinically, liver failure prolongs
pancuronium and rocuronium !loc%ade, with less effect on vecuronium, and no
effect on pipecuronium. Atracurium, cisatracurium, and mivacurium, although
extensively meta!olized, depend on extrahepatic mechanisms. +evere liver disease
does not significantly affect clearance of atracurium or cisatracurium, !ut the
associated decrease in pseudocholinesterase levels may slow the meta!olism of
mivacurium.
RENAL ECRETION
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
27/39
Doxacurium, pancuronium, vecuronium, and pipecuronium are partially
excreted !y the %idneys, and their action is prolonged in patients with renal failure.
5he elimination of atracurium, cisatracurium, mivacurium, and rocuronium is
independent of %idney function.
Ge!er&% P,&r
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
28/39
CONCURRENT DISEASE
5he presence of neurological or muscular disease can have profound effects on
an individual?s response to muscle relaxants (5a!le 9E). Cirrhotic liver disease and
chronic renal failure often result in an increased volume of distri!ution and a lower
plasma concentration for a given dose of water-solu!le drugs, such as muscle
relaxants. 4n the other hand, drugs dependent on hepatic or renal excretion may
demonstrate prolonged clearance. 5hus, depending on the drug chosen, a greater
initial (loading) dose6!ut smaller maintenance doses6might !e re1uired in these
diseases.
T&%e 9. Di-e&-e- =i', A%'ere" Re-$(!-e- '( Mu-*%e Re%&3&!'-.
Di-e&-e Re-$(!-e '(De$(%&ri2er-
Re-$(!-e '(N(!"e$(%&ri2er-
Amyotrophic lateral sclerosis Contracture 7ypersensitivity
Autoimmune disorders (systemic
lupus erythematosus,
polymyositis, dermatomyositis)
7ypersensitivity 7ypersensitivity
urn in"ury 7yper%alemia $esistance
Cere!ral palsy +light hypersensitivity $esistance
'amilial periodic paralysis
(hyper%alemic)
&yotonia and
hyper%alemia
7ypersensitivity
>uillainarrM syndrome 7yper%alemia 7ypersensitivity
7emiplegia 7yper%alemia $esistance on affected
side
&uscular denervation
(peripheral nerve in"ury)
7yper%alemia and
contracture
ormal response or
resistance
&uscular dystrophy (Duchenne
type)
7yper%alemia and
malignant
hyperthemia
7ypersensitivity
&yasthenia gravis $esistance and
proneness to phase II
!loc%
7ypersensitivity
&yasthenic syndrome 7ypersensitivity 7ypersensitivity
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
29/39
Di-e&-e Re-$(!-e '(De$(%&ri2er-
Re-$(!-e '(N(!"e$(%&ri2er-
&yotonia (dystrophica,
congenita, paramyotonia)
>eneralized muscular
contractions
ormal or
hypersensitivity
+evere chronic infection
(tetanus, !otulism)
7yper%alemia $esistance
MUSCLE GROUPS
5he onset and intensity of !loc%ade vary among muscle groups. 5his may !e
due to differences in !lood flow, distance from the central circulation, or different
fi!er types. 'urthermore, the relative sensitivity of a muscle group may depend on
the choice of muscle relaxant. In general, the diaphragm, "aw, larynx, and facial
muscles (or!icularis oculi) respond to and recover from muscle relaxation sooner
than the thum!. Although they are a fortuitous safety feature, persistent
diaphragmatic contractions can !e disconcerting in the face of complete adductor
pollicis paralysis. >lottic musculature is also 1uite resistant to !loc%ade, as is often
confirmed during laryngoscopy. 5he 0D9/for laryngeal muscles is nearly two times
that for the adductor pollicis muscle. >ood intu!ating conditions are usually
associated with visual loss of the or!icularis oculi twitch response.
Considering the multitude of factors influencing the duration and magnitude
of muscle relaxation, it !ecomes clear that an individual?s response to
neuromuscular !loc%ing agents should !e monitored. Dosage recommendations,
including those in this chapter, should !e considered guidelines that re1uire
modification for individual patients. #ide varia!ility in sensitivity to nondepolarizing
muscle relaxants is often encountered in clinical practice.
ATRACURIUM
P,+-i*&% S'ru*'ure
3i%e all muscle relaxants, atracurium has a 1uaternary group however, a
!enzyliso1uinoline structure is responsi!le for its uni1ue method of degradation.
5he drug is a mixture of : stereoisomers.
Me'&(%i-< 0 E3*re'i(!
Atracurium is so extensively meta!olized that its pharmaco%inetics areindependent of renal and hepatic function, and less than :G is excreted
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
30/39
unchanged !y renal and !iliary routes. 5wo separate processes are responsi!le for
meta!olism.
ESTER 4YDROLYSIS
5his action is catalyzed !y nonspecific esterases, not !y acetylcholinesteraseor pseudocholinesterase.
4OFMANN ELIMINATION
A spontaneous nonenzymatic chemical !rea%down occurs at physiological p7
and temperature.
D(-&ge
A dose of ./ mg2%g is administered intravenously over 8* s forintu!ation. Intraoperative relaxation is achieved with .;/ mg2%g initially, then in
incremental doses of .: mg2%g every :; min. An infusion of /: g2%g2min
can effectively replace intermittent !oluses.
Although dosage re1uirements do not significantly vary with age, atracurium
may !e shorter-acting in children and infants than in adults.
Atracurium is availa!le as a solution of : mg2m3. It must !e stored at ;
ELC, as it loses /:G of its potency for each month it is exposed to room
temperature. At room temperature it should !e used within : days to preserve
potency.
Si"e E>>e*'- 0 C%i!i*&% C(!-i"er&'i(!-
Atracurium triggers dose-dependent histamine release that !ecomes
significant at doses a!ove ./ mg2%g.
4YPOTENSION AND TAC4YCARDIA
Cardiovascular side effects are unusual unless doses in excess of ./ mg2%g
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 in"ection minimizes these effects.
BRONC4OSPASM
Atracurium should !e avoided in asthmatic patients. onetheless, severe
!ronchospasm is possi!le even in patients without a history of asthma.
LAUDANOSINE TOICITY
3audanosine, a tertiary amine, is a !rea%down product of atracurium?s
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
31/39
7ofmann elimination and has !een associated with central nervous system
excitation, resulting in elevation of the minimum alveolar concentration and even
precipitation of seizures. 5hese are pro!a!ly irrelevant considerations unless a
patient has received an extremely high total dose or has hepatic failure.
3audanosine is meta!olized !y the liver and excreted in urine and !ile.
TEMPERATURE AND P4 SENSITI5ITY
ecause of its uni1ue meta!olism, atracurium?s duration of action can !e
mar%edly prolonged !y hypothermia and to a lesser extent !y acidosis.
C4EMICAL INCOMPATIBILITY
Atracurium will precipitate as a free acid if it is introduced into an
intravenous line containing an al%aline solution such as thiopental.
ALLERGIC REACTIONS
$are anaphylactoid reactions to atracurium have !een descri!ed. =roposed
mechanisms include direct immunogenicity and acrylate-mediated immune
activation. Ig0-mediated anti!ody reactions directed against su!stituted ammonium
compounds, including muscle relaxants, have !een descri!ed. $eactions to
acrylate, a meta!olite of atracurium and a structural component of some dialysis
mem!ranes, have also !een reported in patients undergoing hemodialysis.
CISATRACURIUM
P,+-i*&% S'ru*'ure
Cisatracurium is a stereoisomer of atracurium that is four times more potent.
Atracurium contains approximately :/G cisatracurium.
Me'&(%i-< 0 E3*re'i(!
3i%e atracurium, cisatracurium undergoes degradation in plasma at
physiological p7 and temperature !y organ-independent 7ofmann elimination. 5he
resulting meta!olites (a mono1uaternary acrylate and laudanosine) have no
intrinsic neuromuscular !loc%ing effects. ecause of its higher potency the amount
of laudanosine produced is significantly less than atracurium. onspecific esterases
do not appear to !e involved in the meta!olism of cisatracurium. &eta!olism and
elimination appear to !e independent of renal or liver failure. &inor variations in
pharmaco%inetic patterns due to age do not tend to result in clinically significant
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
32/39
changes in duration of action.
D(-&ge
Cisatracurium produces good intu!ating conditions following a dose of .:.:/ mg2%g within ; min and results in muscle !loc%ade of intermediate duration.
5he average infusion rate ranges from :.;. g2%g2min. 5hus, it is e1uipotent
with vecuronium and more potent than atracurium.
Cisatracurium should !e stored under refrigeration (;ELC), and should !e
used within ;: days after removal from refrigeration and exposure to room
temperature.
Si"e E>>e*'- 0 C%i!i*&% C(!-i"er&'i(!-
Fnli%e atracurium, cisatracurium does not produce a consistent, dose-
dependent increase in plasma histamine levels following administration.
Cisatracurium does not affect heart rate or !lood pressure, nor does it produce
autonomic effects, even at doses as high as eight times 0D9/.
Cisatracurium shares with atracurium the considerations discussed a!ove
with regard to laudanosine toxicity (although levels appear to !e lower due to its
greater potency), p7 and temperature sensitivity, and chemical incompati!ility.
MI5ACURIUM
P,+-i*&% S'ru*'ure
&ivacurium is a !enzyliso1uinoline derivative.
Me'&(%i-< 0 E3*re'i(!
&ivacurium, li%e succinylcholine, is meta!olized !y pseudocholinesterase. It is
only minimally meta!olized !y true cholinesterase. 5his introduces the possi!ility of
$r(%(!ge" &*'i(! i! $&'ie!'- =i', %(= $-eu"(*,(%i!e-'er&-e %e6e%- (see
5a!le 98) or variants of the pseudocholinesterase gene. In fact, patients who are
heterozygous for the atypical gene will experience a !loc% approximately twice the
normal duration, whereas atypical homozygous patients will remain paralyzed for
hours. ecause atypical homozygotes cannot meta!olize mivacurium, the
neuromuscular !loc%ade may last 8 h. In contrast to succinylcholine-induced
paralysis in these patients, pharmacological antagonism with cholinesteraseinhi!itors will 1uic%en reversal of mivacurium !loc%ade once some response to
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
33/39
nerve stimulation !ecomes apparent. 0drophonium more effectively reverses
mivacurium !loc%ade than neostigmine !ecause neostigmine inhi!its plasma
cholinesterase activity (see Chapter :). Although mivacurium meta!olism and
excretion do not directly depend on the %idneys or liver, duration of action can !e
prolonged in patients with renal or hepatic failure or in patients who are pregnantor postpartum as a result of decreased plasma cholinesterase levels.
D(-&ge
5he usual intu!ating dose of mivacurium is .:/.; mg2%g. +teady-state
infusion rates for intraoperative relaxation vary with pseudocholinesterase levels
!ut can !e initiated at : g2%g2min. Children re1uire higher dosages than adults
if dosage is calculated in terms of !ody weight, !ut not if !ased on surface area.
&ivacurium has a shelf-life of :E months when stored at room temperature.
Si"e E>>e*'- 0 C%i!i*&% C(!-i"er&'i(!-
&ivacurium releases histamine to a!out the same degree as atracurium. 5he
conse1uent cardiovascular side effects can !e minimized !y slow in"ection over :
min. onetheless, patients with cardiac disease may rarely experience a significant
drop in arterial !lood pressure after doses larger than .:/ mg2%g, despite a slow
in"ection rate. 5he onset time of mivacurium is similar to that of atracurium (;8
min). Its principal advantage is its !rief duration of action (;8 min), which is
still two to three times longer than a phase I !loc% from succinylcholine6!ut half
the duration of atracurium, vecuronium, or rocuronium. Children tend to exhi!it a
faster onset and shorter duration of action than adults. Despite relatively rapid
recovery after mivacurium, neuromuscular function must !e monitored in all
patients to determine whether pharmacological reversal is necessary. 5he short
duration of action of mivacurium can !e mar%edly prolonged !y prior administration
of pancuronium.
DOACURIUM
P,+-i*&% S'ru*'ure
Doxacurium is a !enzyliso1uinoline compound closely related to mivacurium
and atracurium.
Me'&(%i-< 0 E3*re'i(!
5his potent, long-acting relaxant undergoes a minor degree of slow
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
34/39
hydrolysis !y plasma cholinesterase. 3i%e other long-acting muscle relaxants,
however, its primary route of elimination is renal excretion. =redicta!ly, the
duration of action of doxacurium is prolonged and more varia!le in patients with
renal disease. 7epato!iliary excretion appears to play a minor role in doxacurium
clearance.
D(-&ge
Ade1uate conditions for tracheal intu!ation within / min re1uire ./ mg2%g.
Intraoperative relaxation is achieved with an initial dose of .; mg2%g followed !y
doses of ./ mg2%g. Doxacurium may !e given in similar weight-ad"usted
dosages to young and elderly patients, although the latter demonstrate a prolonged
duration of action.
Si"e E>>e*'- 0 C%i!i*&% C(!-i"er&'i(!-
Doxacurium is essentially devoid of cardiovascular and histamine-releasing
side effects. ecause of its greater potency, doxacurium has an onset of action
slightly slower than that of other long-acting nondepolarizing relaxants (* min).
Its duration of action is similar to that of pancuronium (*9 min).
PANCURONIUM
P,+-i*&% S'ru*'ure
=ancuronium consists of a steroid ring on which two modified ACh molecules
are positioned (a !is1uaternary relaxant). 5o an ACh receptor, pancuronium
resem!les ACh enough to !ind6!ut not enough to open6the loc%.
Me'&(%i-< 0 E3*re'i(!
=ancuronium is meta!olized (deacetylated) !y the liver to a limited degree.
Its meta!olic products have some neuromuscular !loc%ing activity. 0xcretion is
primarily renal (G), although some of the drug is cleared !y the !ile (:G). ot
surprisingly, elimination of pancuronium is slowed and neuromuscular !loc%ade is
prolonged !y renal failure. =atients with cirrhosis may re1uire a higher initial dose
due to an increased volume of distri!ution !ut have lower maintenance
re1uirements !ecause of a decreased rate of plasma clearance.
D(-&ge
A dose of .E.:; mg2%g of pancuronium provides ade1uate relaxation for
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
35/39
intu!ation in ;8 min. Intraoperative relaxation is achieved !y administering .
mg2%g initially followed every ; min !y .: mg2%g.
Children may re1uire moderately higher doses of pancuronium. =ancuronium
is availa!le as a solution of : or ; mg2m3 and is stored at ;ELC !ut may !e sta!le
for up to * months at normal room temperature.
Si"e E>>e*'- 0 C%i!i*&% C(!-i"er&'i(!-
4YPERTENSION AND TAC4YCARDIA
5hese cardiovascular effects are caused !y the com!ination of vagal !loc%ade
and sympathetic stimulation. 5he latter is due to a com!ination of ganglionic
stimulation, catecholamine release from adrenergic nerve endings, and decreased
catecholamine reupta%e. =ancuronium should !e given with caution to patients in
whom an increased heart rate would !e particularly detrimental (eg, coronary
artery disease, idiopathic hypertrophic su!aortic stenosis).
ARR4YT4MIAS
Increased atrioventricular conduction and catecholamine release increase the
li%elihood of ventricular dysrhythmias in predisposed individuals. 5he com!ination
of pancuronium, tricyclic antidepressants, and halothane has !een reported to !e
particularly arrhythmogenic.
ALLERGIC REACTIONS
=atients who are hypersensitive to !romides may exhi!it allergic reactions to
pancuronium (pancuronium !romide).
PIPECURONIUM
P,+-i*&% S'ru*'ure
=ipecuronium has a !is1uaternary steroidal structure very similar to that of
pancuronium.
Me'&(%i-< 0 E3*re'i(!
'or pipecuronium, meta!olism plays a very minor role. 0limination depends
on excretion, which is primarily renal (G) and secondarily !iliary (;G). 5he
duration of action is increased in patients with renal failure, !ut not in those with
hepatic insufficiency.
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
36/39
D(-&ge
=ipecuronium is slightly more potent than pancuronium, and the usual
intu!ating dose ranges from .*.: mg2%g. 3i%ewise, maintenance relaxation
doses can !e reduced !y approximately ;G compared with pancuronium. Infants
re1uire less pipecuronium on a per %ilogram !asis than children or adults.
=ipecuronium?s pharmacological profile is relatively unchanged in elderly patients.
Si"e E>>e*'- 0 C%i!i*&% C(!-i"er&'i(!-
5he principal advantage of pipecuronium over pancuronium is its lac% of
cardiovascular side effects due to a decreased !inding to cardiac muscarinic
receptors. 3i%e other steroidal relaxants, pipecuronium is not associated with
histamine release. 5he onset of action and duration of action are similar topancuronium.
5ECURONIUM
P,+-i*&% S'ru*'ure
@ecuronium is pancuronium minus a 1uaternary methyl group (amono1uaternary relaxant). 5his minor structural change !eneficially alters side
effects without affecting potency.
Me'&(%i-< 0 E3*re'i(!
@ecuronium is meta!olized to a small extent !y the liver. It depends primarily
on !iliary excretion and secondarily (;/G) on renal excretion. Although it is a
satisfactory drug for patients with renal failure, its duration of action is somewhat
prolonged. @ecuronium?s !rief duration of action is explained !y its shorterelimination half-life and more rapid clearance compared with pancuronium. 3ong-
term administration of vecuronium to patients in intensive care units has resulted in
prolonged neuromuscular !loc%ade (up to several days), possi!ly from
accumulation of its active 8-hydroxy meta!olite, changing drug clearance, or the
development of a polyneuropathy. $is% factors appear to include female gender,
renal failure, long-term or high-dose corticosteroid therapy, and sepsis. 5hus, these
patients must !e closely monitored and the dose of vecuronium carefully titrated.
3ong-term relaxant administration and the su!se1uent prolonged lac% of ACh
!inding at the postsynaptic nicotinic ACh receptors may mimic a chronic
denervation state and cause lasting receptor dysfunction and paralysis. 5he
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
37/39
neuromuscular effects of vecuronium may !e prolonged in patients with AID+.
5olerance to nondepolarizing muscle relaxants can also develop after long-term
use.
D(-&ge
@ecuronium is e1uipotent with pancuronium, and the intu!ating dose is
.E.:; mg2%g. A dose of . mg2%g initially followed !y increments of .:
mg2%g every :/; min provides intraoperative relaxation. Alternatively, an
infusion of :; g2%g2min produces good maintenance of relaxation.
Age does not affect initial dose re1uirements, although su!se1uent doses
are re1uired less fre1uently in neonates and infants. #omen appear to !e
approximately 8G more sensitive than men to vecuronium as evidenced !y a
greater degree of !loc%ade and longer duration of action (this has also !een seenwith pancuronium and rocuronium). 5he cause for this sensitivity may !e related to
gender-related differences in fat and muscle mass, protein !inding, volume of
distri!ution, or meta!olic activity. 5he duration of action of vecuronium may !e
further prolonged in postpartum patients due to alterations in hepatic !lood flow or
liver upta%e.
@ecuronium is pac%aged as : mg of powder, which is reconstituted with /
or : m3 of preservative-free water immediately !efore use. Fnused portions are
discarded after ; h. @ecuronium and thiopental can form a precipitate that can
o!struct flow through an intravenous line and lead to particulate pulmonary em!oli.
Si"e E>>e*'- 0 C%i!i*&% C(!-i"er&'i(!-
CARDIO5ASCULAR
0ven at doses of .;E mg2%g, vecuronium is devoid of significant
cardiovascular effects. =otentiation of opioid-induced !radycardia may !e o!served
in some patients.
LI5ER FAILURE
Although it is dependent on !iliary excretion, the duration of action of
vecuronium is usually not significantly prolonged in patients with cirrhosis unless
doses greater than .:/ mg2%g are given. @ecuronium re1uirements are reduced
during the anhepatic phase of liver transplantation.
ROCURONIUM
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
38/39
P,+-i*&% S'ru*'ure
5his mono1uaternary steroid analogue of vecuronium was designed to
provide a rapid onset of action.
Me'&(%i-< 0 E3*re'i(!
$ocuronium undergoes no meta!olism and is eliminated primarily !y the
liver and slightly !y the %idneys. Its duration of action is not significantly affected
!y renal disease, !ut it is modestly prolonged !y severe hepatic failure and
pregnancy. ecause rocuronium does not have active meta!olites, it may !e a
!etter choice than vecuronium for prolonged infusions (eg, the intensive care unit
setting). 0lderly patients may experience a prolonged duration of action due to
decreased liver mass.
D(-&ge
$ocuronium is less potent than most other steroidal muscle relaxants
(potency appears to !e inversely related to speed of onset). It re1uires ./.9
mg2%g intravenously for intu!ation and .:/ mg2%g !oluses for maintenance. A
lower dose of . mg2%g may allow reversal as soon as ;/ min after intu!ation.
Intramuscular rocuronium (: mg2%g for infants ; mg2%g for children) provides
ade1uate vocal cord and diaphragmatic paralysis for intu!ation, !ut not until after
8* min (deltoid in"ection has a faster onset than 1uadriceps), and can !e reversed
after a!out : h. 5he infusion re1uirements for rocuronium range from /:;
g2%g2min. $ocuronium can produce a prolonged duration of action in elderly
patients. Initial dosage re1uirements are modestly increased in patients with
advanced liver disease, presuma!ly due to a larger volume of distri!ution.
Si"e E>>e*'- 0 C%i!i*&% C(!-i"er&'i(!-
$ocuronium (at a dose of .9:.; mg2%g) has an onset of action that
approaches succinylcholine (*9 s), ma%ing it a suita!le alternative for rapid-
se1uence inductions, !ut at the cost of a much longer duration of action. 5his
intermediate duration of action is compara!le to vecuronium or atracurium.
+ome clinicians compensate for rocuronium?s longer onset of action
(compared with that of succinylcholine) !y administering it ; s !efore propofol or
thiopental (the Ntiming principleN). Disadvantages to this techni1ue include the
possi!ility of delayed administration of induction agent (eg, due to intravenous line
precipitate) resulting in a conscious !ut paralyzed patient.
$ocuronium (.: mg2%g) has !een shown to !e a rapid (9 s) and effective
agent (decreased fasciculations and postoperative myalgias) for precurarizationprior to administration of succinylcholine. It has slight vagolytic tendencies.
-
8/10/2019 rELAJANTES NEUROMUSCULARES.doc
39/39
OT4ER RELAANTS
&uscle relaxants primarily of historical interest are either no longermanufactured or not clinically used. 5hey include tu!ocurarine, metocurine,
gallamine, alcuronium, rapacuronium, and decamethonium. 5u!ocurarine, the first
muscle relaxant used clinically, often produced hypotension and tachycardia
through histamine release its a!ility to !loc% autonomic ganglia was of secondary
importance. 7istamine release could also produce or exacer!ate !ronchospasm.
5u!ocurarine is not meta!olized significantly and its elimination is primarily renal
and secondarily !iliary. &etocurine, a closely related agent, shares many of the side
effects of tu!ocurarine. It is primarily dependent on renal function for elimination.
=atients allergic to iodine (eg, shellfish allergies) could exhi!it hypersensitivity to
metocurine preparations as they too contain iodide. >allamine has potent vagolytic
properties and is entirely dependent on renal function for elimination. Alcuronium, a
long-acting nondepolarizer with mild vagolytic properties, is also primarily
dependent on renal function for elimination. $apacuronium has a rapid onset of
action, minimal cardiovascular side effects, and a short duration of action. It was
withdrawn !y the manufacturer following several reports of serious !ronchospasm,
including a few unexplained fatalities. 7istamine release may have !een a factor.
Decamethonium was an older depolarizing agent.