rELAJANTES NEUROMUSCULARES.doc

8/10/2019 rELAJANTES NEUROMUSCULARES.doc

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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.


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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(


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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). &ethylene !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


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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


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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


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+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


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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


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(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


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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


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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


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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


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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


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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


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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


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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


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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


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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.


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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


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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


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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.


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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.

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