Neuromuscular Blocking Agents (Systemic)

This monograph includes information on the following:

1) Atracurium Besylate
2) Cisatracurium
3) Doxacurium
4) Gallamine
5) Mivacurium
6) Pancuronium
7) Rapacuronium#
8) Rocuronium
9) Succinylcholine
10) Tubocurarine
11) Vecuronium

Note: See also the individual Cisatracurium (Systemic), Doxacurium (Systemic) , Mivacurium (Systemic), ,Rapacuronium and Rocuronium (Systemic) monographs.



INN:
Atracurium Besylate—Atracurium besilate
Succinylcholine—Suxamethonium

VA CLASSIFICATION
Atracurium
Primary: MS300

Cisatracurium
Primary: MS300

Doxacurium
Primary: MS300

Gallamine
Primary: MS300

Mivacurium
Primary: MS300

Pancuronium
Primary: MS300

Rapacuronium
#Primary: MS300

Rocuronium
Primary: MS300

Succinylcholine
Primary: MS300

Tubocurarine
Primary: MS300
Secondary: DX900

Vecuronium
Primary: MS300


Commonly used brand name(s): Anectine9; Flaxedil4; Mivacron5; Nimbex2; Norcuron11; Nuromax3; Pavulon6; Quelicin9; Sucostrin9; Tracrium1; Zemuron8.

# Rapacuronium was voluntarily withdrawn from the market on 03/2001 {67}
Other commonly used names are:
Atracurium besilate —Atracurium Besylate
; Curare —Tubocurarine
; and Suxamethonium —Succinylcholine

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Neuromuscular blocking paralyzing agent—
Note: Depolarizing neuromuscular blocking agent—Succinylcholine.
Nondepolarizing neuromuscular blocking agent—Atracurium, cisatracurium, doxacurium, gallamine, mivacurium, pancuronium, rapacuronium, rocuronium, tubocurarine, vecuronium.


Note: Rapacuronium was voluntarily withdrawn from the market on 03/2001{67}



Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Skeletal muscle paralysis—The neuromuscular blocking agents are indicated as adjuncts to anesthesia to induce skeletal muscle relaxation and to facilitate the management of patients undergoing mechanical ventilation {01} {02} {03} {04} {05} {06} {07} {08} {09} {10}.
—Generally, a relatively short-acting nondepolarizing neuromuscular blocking agent or a single dose of the depolarizing neuromuscular blocking agent succinylcholine is used to facilitate endotracheal intubation. Continuous infusion of succinylcholine may be used for short surgical procedures requiring muscle relaxation. Nondepolarizing neuromuscular blocking agents, or, less commonly, succinylcholine administered by continuous infusion, are used for surgical procedures requiring an intermediate or prolonged duration of muscle relaxant action and to facilitate controlled ventilation.

Convulsions (treatment)—[ Atracurium]1, {14} [ gallamine] , {02} {04} [pancuronium]1 , {14} [succinylcholine] , {07} tubocurarine, {08} {13} and [vecuronium]1 {14} are indicated to reduce the intensity of muscle contractions of pharmacologically or electrically induced convulsions. Succinylcholine is generally preferred because of its short duration of action.
—[Neuromuscular blocking agents are also used to decrease the muscular manifestations of persistent convulsions associated with toxic reactions to other medications {11} .]1

Myasthenia gravis (diagnosis)—Tubocurarine is indicated as a diagnostic aid for myasthenia gravis when the results of tests with neostigmine or edrophonium are inconclusive {08} {09}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Table 1. Pharmacology/Pharmacokinetics



Drug
Protein
Binding
Biotransformation
Half-life
Distribution/
Elimination
(min)
Elimination
Primary (% excreted
unchanged)/Secondary
(% excreted unchanged)
Depolarizing
 
       
Succinylcholine

In plasma, by
pseudocholinesterase *

Renal (about 10)
Nondepolarizing
 
       
Atracurium
High
In plasma
2–3.4/20
Renal and biliary (<10)
Gallamine

Essentially none
16/150
Renal (almost 100)
Pancuronium
Very low
Hepatic (in small
quantities)
10–13/89–161 {05}
Renal (about 80)/10% biliary
(up to 10)
Tubocurarine
Moderate §
Hepatic
4.8–6.4/84–120
Renal (about 40)/biliary (12)
Vecuronium
Moderate to high #
Hepatic **
4/65–75 ††
25–50% Biliary within 42 hr/3–
35% renal within 24 hr ‡‡
* Hydrolyzed rapidly to succinylmonocholine (a weak nondepolarizing neuromuscular blocking agent that is one-twentieth as potent as succinylcholine), then more slowly to succinic acid and choline.
 Metabolized by ester hydrolysis catalyzed by nonspecific esterases and by Hofmann elimination, a nonenzymatic chemical process that occurs at plasma pH; is independent of hepatic or renal function or plasma pseudocholinesterase activity.
§ With plasma concentrations of 5 to 50 mcg/mL.
# With doses of 40 to 100 mcg per kg of body weight.
** Only 5 to 10% of a dose is metabolized. However, one metabolite, 3-deacetyl vecuronium, has been shown in animal studies to have neuromuscular blocking activity that is 50% as potent as that of vecuronium.
†† May be decreased to 35 to 40 minutes in late pregnancy and prolonged in patients with cirrhosis or cholestasis.
‡‡ Up to 25% of a dose may be excreted in bile, and up to 10% of a dose may be excreted in urine, as 3-deacetyl vecuronium.

Table 2. Pharmacology/Pharmacokinetics *



Drug
Initial
Dose
(mg/kg)
Onset of Initial
Action (Time to
Intubation
Conditions)
(min)
Time to
Peak Effect
(min)
Duration of
Peak Effect
(min)/Effect
of Repeated Dosing
Time to Recovery in min
(% of twitch
response attained)
Depolarizing
Succinylcholine
         
Intramuscular
3–4
Up to 3

10–30

Intravenous
0.3–1
0.5–1
1–2
4–10

Nondepolarizing
Atracurium
        From time of injection—
Intravenous
0.4–0.5
Within 2
(2–2.5)
3–5 (range
1.7–10)
20–35 under balanced
anesthesia/no change
balanced anesthesia :
35–45 (25); 60–70 (95)
From beginning of recovery §
balanced anesthesia:
30 (95)
inhalation anesthesia:
40 (95)
Gallamine
         
Intravenous
1
1–2
3–5
15–30/increased #

Pancuronium
        From time of injection #:
Intravenous
0.04
0.06
0.08
Within 0.75
(2–3)
0.5
4.5

Within 3
—/increased #
35–45/increased #
—/increased #
<60 (90)


Tubocurarine
         
Intramuscular
0.1–0.3
15–25



Intravenous
0.1–0.3
Within 1
2–5
20–40/
increased #
From time of injection:
50 (50); 74–90 (95)
Vecuronium
        From time of injection—
Intravenous
0.08–0.1
1 (2.5–3)
3–5
25–30 under
balanced anesthesia/
no change
balanced anesthesia :
25–40 (25); 45–65 (95)
* Onset of initial action and of effective skeletal muscle relaxation (peak effect) are dose-dependent and decrease with increasing doses. Duration of effective skeletal muscle relaxation and time to recovery are also dose-dependent and increase with increasing doses. Other factors, especially administration of hydrocarbon inhalation anesthetics or other potentiating medications, also influence the duration of effective skeletal muscle relaxation and time to recovery.
 Duration of action and time to recovery with succinylcholine may be increased when plasma pseudocholinesterase activity is decreased.
 The duration of peak effect and time to recovery with atracurium or vecuronium are not affected by repeated administration of recommended maintenance doses, provided that recovery from the effects of the previous dose begins prior to administration of a subsequent dose.
§ Once recovery begins, the rate of recovery is independent of atracurium dosage; however, it is affected by the type of anesthesia administered.
# Following a single dose, the action of the medication is terminated by redistribution into inactive sites. However, following multiple doses, the inactive sites of uptake become saturated, and factors of degradation and/or elimination then directly influence the duration of action and time to recovery.

Physicochemical characteristics:
Molecular weight—
    Atracurium besylate: 1243.51 {17}
    Cisatracurium besylate: 1243.50 {51}
    Doxacurium chloride: 1106.14 {52}
    Gallamine triethiodide: 891.54 {18}
    Mivacurium chloride: 1100.18 {53}
    Pancuronium bromide: 732.68 {20}
    Rapacuronium bromide: 677.78 {54}

Note: Rapacuronium was voluntarily withdrawn from the market on 03/2001{67}

    Rocuronium bromide: 609.70 {55}
    Succinylcholine chloride: 361.31 {21}
    Tubocurarine chloride: 771.74 {22}
    Vecuronium bromide: 637.75 {17}

Mechanism of action/Effect:

Neuromuscular blocking agents produce skeletal muscle paralysis by blocking neural transmission at the myoneural junction. The paralysis is selective initially and usually appears in the following muscles consecutively: levator muscles of eyelids, muscles of mastication, limb muscles, abdominal muscles, muscles of the glottis, and finally, the intercostal muscles and the diaphragm. Neuromuscular blocking agents have no known effect on consciousness or the pain threshold.

Depolarizing neuromuscular blocking agents compete with acetylcholine for the cholinergic receptors of the motor end plate and, like acetylcholine, combine with these receptors to produce depolarization; however, because of their high affinity for the cholinergic receptors and their resistance to acetylcholinesterase, they produce a more prolonged depolarization than does acetylcholine. This results initially in transient muscle contractions, usually visible as fasciculations, followed by inhibition of neuromuscular transmission. This type of neuromuscular block is not antagonized, and may even be enhanced, by anticholinesterase agents. {12}

With prolonged or repeated use of depolarizing neuromuscular blocking agents, neuromuscular blockade resembling a nondepolarization block may be produced, resulting in prolonged respiratory depression or apnea.

Nondepolarizing neuromuscular blocking agents inhibit neuromuscular transmission by competing with acetylcholine for the cholinergic receptors of the motor end plate, thereby reducing the response of the end plate to acetylcholine. This type of neuromuscular block is usually antagonized by anticholinesterase agents.


Other actions/effects:

Tubocurarine and, to a lesser extent, atracurium, mivacurium, and succinylcholine may cause histamine release. Cisatracurium, doxacurium, and aminosteroid neuromuscular blockers such as gallamine, , pancuronium, rapacuronium, rocuronium, and vecuronium are least likely to cause histamine release {15}{56}.

Note: Rapacuronium was voluntarily withdrawn from the market on 03/2001{67}


Gallamine and pancuronium also have vagolytic activity {05} {16} {35} {36}.

Gallamine, and to a lesser extent, pancuronium, cause sympathetic stimulation{56}.

Tubocurarine can also cause ganglionic blockade{56}.

Succinylcholine may cause vagal stimulation {56}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to bromides may be sensitive to the bromide salts of pancuronium rapacuronium, rocuronium, or vecuronium also.

Note: Rapacuronium was voluntarily removed from the market on 03/2001{67}


Patients sensitive to iodine or iodides may be sensitive to the iodide salt of gallamine also.

Mutagenicity

Atracurium—Mutagenic activity was observed in the mouse lymphoma assay under conditions in which more than 80% of the treated cells were killed, i.e., a relatively strong effect with concentrations of 80 and 100 mcg per mL in the absence of metabolic activation and a much weaker effect with concentrations of 1.2 mg per mL or higher in the presence of metabolic activation. However, mutagenic activity has not been demonstrated in the Ames test or in a rat bone marrow cytogenicity assay {01}.

Cisatracurium—Positive results occurred in the mouse lymphoma assay, both in the presence and absence of exogenous metabolic activation (rat liver S-9) . In the absence of metabolic activation, cisatracurium was positive at in vitro concentrations of 40 micrograms per mL (mcg/mL) or higher . In the presence of S-9, cisatracurium was mutagenic at a concentration of 300 mcg/mL, but not at lower or higher concentrations . No mutagenicity was found in the Ames Salmonella mutation test, a rat bone marrow cytogenic assay, or an in vitro human lymphocyte cytogenic assay {51}.

Doxacurium—No mutagenicity was detected in the Ames Salmonella assay, mouse lymphoma assay, and human lymphocyte assay . However, statistically significant increases in the incidence of structural abnormalities, relative to vehicle controls, occurred in the in vivo rat bone marrow cytogenic assay in male rats receiving 0.1 mg per kg of body weight (mg/kg) (0.625 mg per square meter of body surface area [mg/m 2]) when the animals were sacrificed 6 hours, but not 24 or 48 hours, after administration. Structural abnormalities also occurred in female rats administered 0.2 mg/kg (1.25 mg/m 2) when the animals were sacrificed 24 hours, but not 6 or 48 hours, after administration. Abnormalities did not occur in male or female rats receiving 0.3 mg/kg (1.875 mg/m 2) at any time after administration. Because of the lack of a dose-dependent effect, the likelihood that the abnormalities found in this study were treatment-related or are clinically significant is low {52}.

Mivacurium—Mivacurium displayed no mutagenicity in the Ames Salmonella test, the mouse lymphoma assay, the human lymphocyte assay, or the in vivo rat bone marrow cytogenetic assay {53}.

Rapacuronium—No mutagenic effects were observed in either the Ames test or the Mouse Lymphoma cell assay. No chromosomal abnormalities were induced in mammalian cell cultures{54}.

Note: Rapacuronium was voluntarily removed from the market on 03/2001{67}


Pregnancy/Reproduction

Pregnancy—
Atracurium: Adequate and well-controlled studies have not been done in humans. However, studies in rabbits (doses of 0.15 mg per kg of body weight [mg/kg] once a day or 0.1 mg/kg twice a day on Day 6 through Day 18 of gestation) have shown that atracurium causes visceral and skeletal anomalies. Also, postimplantation losses were greater in the group given 0.15 mg/kg once daily than in controls.

FDA Pregnancy Category C {01}.

Cisatracurium:Adequate and well-controlled studies have not been done in humans. No maternal or fetal toxicity or teratogenicity was found in studies in nonventilated rats receiving maximum subparalyzing doses of 4 mg/kg subcutaneously (equivalent to eight times the intravenous human ED 95 [dose required to produce 95% suppression of the twitch response to peripheral nerve stimulation]) or in ventilated rats receiving paralyzing doses of 0.5 or 1 mg/kg intravenously (equivalent to 10 or 20 times the intravenous human ED 95, respectively) {51}

FDA Pregnancy Category B {51}.

Doxacurium:Adequate and well-controlled studies have not been done in pregnant women. No maternal or fetal toxicity or teratogenicity was found in animal studies performed in nonventilated mice and rats receiving subcutaneous injections of subparalyzing doses.

FDA Pregnancy Category C {52}.

Gallamine: Problems in humans have not been documented. However, it has been determined that gallamine crosses the placenta {02}.

Mivacurium:Adequate and well-controlled studies have not been done in pregnant women. However, the possibility of a prolonged response should be considered, because plasma cholinesterase activity may be reduced during pregnancy. In animal studies, no maternal or fetal toxicity or teratogenicity occurred with subcutaneous administration of maximal subparalyzing doses to nonventilated pregnant rats or mice.{53}

FDA Pregnancy Category C {53}.

Pancuronium: Studies have not been done in either animals or humans. However, problems in humans have not been documented. {38}

FDA Pregnancy Category C {38}.

Rapacuronium:Rapacuronium crosses the placenta. There are no adequate, well-controlled studies in humans. In animal studies, no teratogenic effects were observed in rabbits or rats at doses up to 3 mg/kg per day and 2.25 mg/kg per day (0.3 and 0.1 times the maximum recommended human intravenous dose for adults on a mg/m2 basis), respectively. Post-implantation loss in rabbits and fetotoxicity in rats were observed at 0.1 times the maximum recommended human intravenous dose for adults on a mg/m2 basis.{54}

FDA Pregnancy Category C{54}

Note: Rapacuronium was voluntarily withdrawn from the market on 03/2001.{67}


Rocuronium:Rocuronium crosses the placenta . Adequate and well-controlled studies in humans have not been done . No teratogenic effects were seen in a teratogenicity study in rats at dosages of 0.3 mg per kg of body weight (mg/kg) {55}.

FDA Pregnancy Category B {55}.

Succinylcholine: Studies have not been done in humans. However, succinylcholine has been shown to cause intrauterine growth retardation and limb deformities resembling clubfoot when administered to the rat fetus between the 16th and 19th days of gestation or when injected in chick embryos from the 5th to 15th days of incubation {12}.

FDA Pregnancy Category C {12}.

Tubocurarine: Although adequate and well-controlled studies have not been done in humans, it has been determined that tubocurarine crosses the placenta. In animal studies, intramuscular injection of tubocurarine into the intercapsular region of the rat fetus on the 16th and 19th days of gestation caused growth retardation (incidence 21 to 23%) and limb deformity (incidence 7 to 8%), respectively. Tubocurarine has also caused growth retardation and limb deformities when injected into chick embryos from the 5th to the 15th day of incubation.

Tubocurarine may cause congenital fetal contractures if large and repeated doses are administered during the early months of pregnancy, possibly by immobilizing the fetus at the time of joint formation {08}.

FDA Pregnancy Category C {08}.

Vecuronium: Vecuronium crosses the placenta. Studies have not been done in either animals or humans.

FDA Pregnancy Category C {39}.


Labor and delivery—

Atracurium has been shown to cross the placenta in small quantities following administration to pregnant women for delivery by cesarean section. Although no adverse effects in the neonates were reported with atracurium, tubocurarine has been reported to cause diminished skeletal muscle activity leading to respiratory difficulty in the newborn when large and repeated doses are given near delivery. The possibility of neonatal respiratory depression or reduced skeletal muscle activity should be considered when any of these agents is used near delivery.

Cisatracurium: Use of cisatracurium during labor, vaginal delivery, or cesarean section has not been studied in humans. Whether administration to the mother may affect the fetus has not been determined {51}. However, potentiation of neuromuscular blockade may occur if magnesium salts are used for management of toxemia of pregnancy .

Doxacurium:Doxacurium has not been studied in obstetrics (labor, vaginal delivery, or cesarean section). Doxacurium is not recommended for cesarean section because its duration of action exceeds the expected duration of the surgical procedure {52}.

Rapacuronium:Rapacuronium was administered in doses of 2.5 mg/kg to 15 patients for rapid sequence induction of anesthesia for Cesarean section. Patients also received thiopental at doses of 4 to 6 mg/kg. No neonates had APGAR scores below 6 at five minutes after birth. Measurable venous umbilical concentrations of rapacuronium and the 3–hydroxymetabolite indicate that maternal/fetal transfer of the drug occurs during delivery{54}

Note: Rapacuronium was voluntarily withdrawn from the market on 03/2001.{67}


Rocuronium:Rocuronium was administered in doses of 0.6 mg/kg to 55 patients for rapid-sequence induction of anesthesia for cesarean section. Patients were also given thiopental at doses of 4 to 6 mg/kg {57}. Anesthesia was maintained with isoflurane and nitrous oxide in oxygen. No neonate had an Apgar score below seven at 5 minutes after birth {55} {57}. Neonatal blood (umbilical venous) concentrations of rocuronium were 18% of maternal levels {57}. Intubating conditions were poor or inadequate at 1 minute in four patients receiving 4 mg/kg of thiopental {55} {57}. Increasing the thiopental dose to 6 mg/kg improved intubating conditions; however, increasing the thiopental dose to improve intubating conditions is controversial and is not recommended due to an increased chance of central nervous system (CNS) depression in the neonate {55} {57} {58}. Rocuronium is not recommended for rapid-sequence induction in cesarean section patients {55}

Breast-feeding

It is not known whether neuromuscular blocking agents are distributed into breast milk. However, problems in humans have not been documented.

Pediatrics

Note: Many multi-dose vials of neuromuscular blocking agents contain benzyl alcohol. Administration of excessive doses of benzyl alcohol to neonates has been associated with neurologic and other complications.


Atracurium, gallamine, and tubocurarine: Neonates up to 1 month of age may be more sensitive to the effects of nondepolarizing neuromuscular blocking agents {05} {08}. Older infants are more sensitive than children to the effects of nondepolarizing neuromuscular blocking agents {28}.

Cisatracurium:Appropriate studies on the relationship of age to the effects of cisatracurium in children 2 to 12 years of age have shown that the ED 95 of cisatracurium is lower, the onset of action is faster, the duration of action is shorter, and recovery time after administration of a reversal agent is more rapid than in adults {51} . However, pediatrics-specific adverse effects or other problems that would limit the use of cisatracurium in children have not been documented {51}.

Doxacurium: Doxacurium has been studied in a limited number of infants and children up to 2 years of age. A study that included fifteen infants up to 11 months of age found that the ED 50 and ED 75 of doxacurium in infants are about one half those observed in children 3 to 10 years of age {62}. Children ages 2 to 12 years are less sensitive to the effects of doxacurium than are adults or infants. Higher doses (on a mcg/kg basis) are required to achieve comparable levels of neuromuscular blockade {52} . Even with higher doses, the onset of action , the duration of clinical effect (time for the twitch response to peripheral stimulation to return to 25% of the control value) , and the recovery index (time for the spontaneous recovery from 25% to 75% of the twitch response to peripheral stimulation) are all significantly shorter in children than in adults {52} .

There may be a high incidence of myopathy in pediatric patients who receive doxacurium to facilitate mechanical ventilation in intensive care units. In a trial in fourteen pediatric patients 6 months to 10 years of age who received doxacurium in intensive care units for 4.7 to 12.3 days, prolonged recovery was observed in over 40% of the patients {63}.

Mivacurium:Appropriate studies on the relationship of age to the effects of mivacurium in patients up to 2 years of age have not shown that mivacurium causes different, or more severe, adverse effects in infants than in children or adults {59}. No significant difference in the potency of a single dose of mivacurium was found between infants less than 6 months of age, infants 6 to 12 months of age, and older children during halothane anesthesia {59}. The effective infusion rate of mivacurium is similar in infants and children {59} {60} {61}

Pancuronium: The prolonged use of pancuronium to facilitate mechanical ventilation in neonates has been associated with myopathy {05}. Some premature neonates administered pancuronium for emergency anesthesia and surgery subsequently developed methemoglobinemia {05}. The cause of the methemoglobinemia has not been established {05}.

Rapacuronium:Rapacuronium was studied in 384 pediatric patients under halothane anesthesia, aged 1 month to 12 years, in clinical trials{54} Compared with adults, children exhibit increased clearance of rapacuronium 3 mg/kg {54}.

Note: Rapacuronium was voluntarily withdrawn from the market on 03/2001.{67}


Rocuronium: Appropriate studies on the relationship of age to the effects of rocuronium have not been performed in infants up to 3 months of age. Rocuronium was studied in 228 pediatric patients 3 months to 12 years of age in preapproval clinical trials {55}. When halothane anesthesia was used without atropine pretreatment, a high incidence of tachycardia (exceeding 30% over baseline) was observed in patients given 0.6 to 0.8 mg/kg of rocuronium {55}. A smaller, transient increase in heart rate was observed in another study of pediatric patients {64}. Compared with adults, children have increased clearance of rocuronium {55} . Compared with older children, infants have a longer duration of paralysis after an intubating dose of rocuronium {65}. Some pediatric patients have experienced tachycardia, increased blood pressure, and resistance to neuromuscular blockade when phenylephrine nose drops were administered after rocuronium {64}.

Succinylcholine: Hyperkalemic rhabdomyolysis resulting in cardiac arrest and death has occurred in apparently healthy pediatric patients after administration of succinylcholine {12} {27}. The adverse events occurred in pediatric patients with previously undiagnosed skeletal muscle myopathy (e.g., Duchenne's muscular dystrophy) {12} {27}. Because it is not possible to predict when a pediatric patient may experience a serious adverse reaction, it is recommended that the use of succinylcholine be restricted to emergency situations or other situations where the immediate securing of the airway is needed (e.g., laryngospasm) {12} {27}.

Vecuronium: Pediatric patients 7 weeks to 1 year of age are more sensitive to the effects of vecuronium (on a mg-per-kg basis) than are adults. Recovery time may be 11/2 times that of adults. {39}


Geriatrics


Although appropriate studies with neuromuscular blocking agents have not been performed in the geriatric population, geriatrics-specific problems that would limit the usefulness of these medications in the elderly are not expected. However, elderly patients are more likely to have age-related renal function impairment, which may decrease the rate of clearance ofgallamine, pancuronium, succinylcholine, tubocurarine, or vecuronium {66}from the body and thereby prolong their effects

Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of cisatracurium, doxacurium, mivacurium, rapacuronium or rocuronium in the elderly{51}{52}{53}{54}{55}

Note: Rapacuronium was voluntarily withdrawn from the market on 03/2001.{67}


Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Table 3. Drug Interactions and/or Related Problems



Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Depolarizing
Nondepolarizing

I=Succinylcholine

II=Atracurium
III=Gallamine


IV=Pancuronium
V=Tubocurarine
VI=Vecuronium
I
 
II
 
III
 
IV
 
V
 
VI
 
» Aminoglycosides, possibly including oral neomycin (if significant quantities are absorbed in patients with renal function impairment), or
           
» Anesthetics, parenteral-local (large doses leading to significant plasma concentrations) or
           
» Capreomycin or
           
» Citrate-anticoagulated blood (massive transfusions) or
           
» Clindamycin or
           
Lidocaine (intravenous doses > 5 mg per kg) or
           
» Lincomycin or
           
» Polymyxins or
           
Procaine (intravenous) or
           
Trimethaphan (large doses)
(neuromuscular blocking activity of these medications may be additive to that of neuromuscular blocking agents) *






Analgesics, opioid (narcotic), especially those commonly used as adjuncts to anesthesia
(central respiratory depressant effects of opioid analgesics may be additive to the respiratory depressant effects of neuromuscular blocking agents) *







(high doses of sufentanil may reduce the initial dosage requirements for a nondepolarizing neuromuscular blocking agent; it is recommended that a peripheral nerve stimulator be used to determine dosage)
 




(concurrent use of a neuromuscular blocking agent prevents or reverses muscle rigidity induced by sufficiently high doses of most opioid analgesics, especially alfentanil, fentanyl, or sufentanil)






(gallamine and pancuronium, because of their vagolytic activity, may decrease the risk of opioid analgesic–induced bradycardia or hypotension [especially in patients receiving chronic therapy with beta-adrenergic blocking agents and/or vasodilators for treatment of coronary artery disease], but may also increase the risk of tachycardia or hypertension in some patients)
   

   
(a nonvagolytic neuromuscular blocking agent will not decrease the risk of opioid analgesic-induced bradycardia or hypotension; in some patients [especially patients with compromised cardiac function and/or those receiving a beta-adrenergic blocking agent preoperatively], the incidence and/or severity of these effects may be increased)


   

(histamine release induced by tubocurarine or, to a lesser extent, atracurium or succinylcholine, may be additive to that induced by many opioid analgesics [except alfentanil, fentanyl, and sufentanil, which do not cause histamine release], leading to increased risk of hypotension; administration of histamine [both H 1 and H 2] receptor–blocking agents may prevent or reduce this effect)


   
 
Anesthetics, hydrocarbon inhalation, such as:
Chloroform
Cyclopropane
Enflurane {09}
Ether
Halothane {08} {09}
Isoflurane {08} {09}
Methoxyflurane
Trichloroethylene
(concurrent use with succinylcholine may increase the potential for malignant hyperthermia; also, repeated concurrent use may enhance the initial transient bradycardia produced by succinylcholine)

         
(neuromuscular blocking activity of inhalation anesthetics, especially enflurane or isoflurane {04} {08} {09}, may be additive to that of the nondepolarizing neuromuscular blocking agents {45}; dosage of vecuronium should be reduced by 15%, and dosage of other neuromuscular blocking agents should be reduced by 1/3 to 1/2 of the usual dose or as determined with a peripheral nerve stimulator {08}) *

 





(halogenated hydrocarbon anesthetics may also potentiate succinylcholine-induced neuromuscular blockade, but to a lesser extent than they potentiate the effects of nondepolarizing neuromuscular blocking agents) *

         
Antimyasthenics or
Edrophonium
(these agents may antagonize the effects of nondepolarizing neuromuscular blocking agents; parenteral neostigmine or pyridostigmine are indicated to reverse neuromuscular blockade following surgery {33}; although the usefulness of edrophonium for this purpose has been considered to be limited because of its brief duration of action, recent studies indicate that edrophonium is equivalent to neostigmine in reversing the effects of tubocurarine)

 





(these agents may prolong phase I block when used concurrently with succinylcholine *; however, if succinylcholine has been used for a prolonged period of time and the depolarization block has changed to a nondepolarization block, edrophonium, neostigmine, or pyridostigmine may reverse the nondepolarization block)

         
(neuromuscular blocking agents may antagonize the effects of antimyasthenics on skeletal muscle; temporary dosage adjustment may be required to control symptoms of myasthenia gravis following surgery)






Beta-adrenergic blocking agents
(concurrent use may enhance or prolong the blockade of the nondepolarizing neuromuscular blocking agents) *
   


 
Calcium salts
(calcium salts usually reverse the effects of nondepolarizing neuromuscular blocking agents)
 




(concurrent use has been reported to enhance or prolong the neuromuscular blocking action of tubocurarine) *
       
 
» Cholinesterase inhibitors, especially echothiophate, demecarium, and isoflurophate, or
           
Cyclophosphamide or
           
» Insecticides, neurotoxic, exposure to, possibly including large quantities of topical malathion, or
           
Phenelzine or
           
Thiotepa
(may decrease plasma concentrations or activity of pseudocholinesterase, the enzyme that metabolizes succinylcholine, thereby enhancing the neuromuscular blockade of succinylcholine; effects of echothiophate, demecarium, or isoflurophate may persist for weeks or months after the cholinesterase inhibitor has been discontinued) *

         
» Digitalis glycosides
(cardiac effects may be increased when digitalis glycosides are used concurrently with succinylcholine and, to a lesser extent, with pancuronium, possibly resulting in cardiac arrhythmias)

   
   
Doxapram
(the residual effects of neuromuscular blocking agents may be masked temporarily by doxapram when it is used post-anesthesia)






Hexafluorenium
(concurrent use may prolong the action of succinylcholine and may minimize or prevent the muscle fasciculations and pain that may occur when succinylcholine is used alone; however, concurrent use may increase the potential for development of a dual block) *

         
Lithium (chronic therapy)
(concurrent use may enhance or prolong the neuromuscular blockade of atracurium, succinylcholine, or pancuronium) *


 
   
Magnesium salts, parenteral, or
           
» Procainamide or
           
» Quinidine
(concurrent use may enhance the blockade of the neuromuscular blocking agents {05}) *






Methotrimeprazine
(concurrent use with succinylcholine may cause tachycardia, a fall in blood pressure, CNS stimulation and delirium, and an aggravation of extrapyramidal effects)

         
Neuromuscular blocking agents, depolarizing
(prior administration may enhance the blockade of nondepolarizing neuromuscular blocking agents; if a depolarizing agent is used before a nondepolarizing agent, administration of the nondepolarizing agent should be delayed until the effects of the depolarizing agent have decreased)
 




Neuromuscular blocking agents, nondepolarizing
(concurrent use may enhance the blockade of depolarizing neuromuscular blocking agents if they have been administered over a prolonged period of time and the depolarized block has gradually changed to a nondepolarized block)

         
(concurrent use of pancuronium and another nondepolarizing neuromuscular blocking agent may substantially reduce the required dose of both medications {05})
 
 


» Physostigmine
(concurrent use with succinylcholine is not recommended since high doses of physostigmine may cause muscle fasciculation and ultimately, a depolarization block, which may be additive to that produced by succinylcholine)

         
Potassium-depleting medications, such as:
Amphotericin B
Bumetanide
Carbonic anhydrase inhibitors
Corticosteroids, glucocorticoid, especially with signifi-
cant mineralocorticoid activity
Corticosteroids, mineralocorticoid
Corticotropin, chronic therapeutic use
Ethacrynic acid
Furosemide
Indapamide
Thiazide diuretics
(hypokalemia induced by these medications may enhance the blockade of nondepolarizing neuromuscular blocking agents; serum potassium determinations and correction of serum potassium concentration may be necessary prior to administration of nondepolarizing neuromuscular blocking agents) *
 




(hydrocortisone and prednisone have also been reported to decrease the efficacy of pancuronium by an unknown mechanism; increased dosage of pancuronium or use of an alternate neuromuscular blocking agent may be necessary {10} {11})
     
   
* Increased or prolonged respiratory depression or paralysis (apnea) may occur but is of minor clinical significance while the patient is being mechanically ventilated. However, caution and careful monitoring of the patient are recommended during and following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade postoperatively.


Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Succinylcholine
Serum potassium concentrations    (may be increased; increase may cause cardiac arrest or arrhythmias in patients with severe trauma, burns, or neurologic disorders; this effect may persist for several weeks or months after the initial trauma)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Table 4. Medical considerations/Contraindications


Note: A blank space usually signifies lack of information; it is not necessarily an indication that a given medical problem is of no concern. However, the pharmacologic similarity of the nondepolarizing neuromuscular blocking agents may suggest that if caution is required in particular medical problems for one agent, then it may be required for the others as well.



The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance).
Depolarizing
Nondepolarizing
I=Succinylcholine

II=Atracurium
III=Gallamine


IV=Pancuronium
V=Tubocurarine
VI=Vecuronium
I
 
II
 
III
 
IV
 
V
 
VI
 
Allergic reaction to the neuromuscular blocker considered for use, history of






» Burns, severe, or
Digitalis toxicity or in patients recently digitalized or
» Neuromuscular disease, degenerative or dystrophic {46}, or
Paraplegia or
Purpura fulminans {26} or
» Spinal cord injury or
» Trauma, severe
(succinylcholine is contraindicated in patients with skeletal muscle myopathies, major burn injury, severe trauma, extensive denervation of skeletal muscle, or upper neuron injury; use of succinylcholine in these patients may result in dangerous hyperkalemia {06} {07} {12}; serious cardiac arrhythmias including cardiac arrest have occurred when succinylcholine was used in patients with these conditions as a result of increased serum potassium concentrations)

         
Carcinoma, bronchogenic
(action of neuromuscular blocking agent may be enhanced)






Cardiac conditions in which tachycardia would be undesirable
(gallamine and pancuronium may cause tachycardia)
   

   
Cardiovascular function impairment

     

Conditions in which histamine release would be hazardous
(these neuromuscular blocking agents may cause histamine release)


 


Conditions in which low levels of plasma pseudocholinesterase activity may exist, such as:
Anemia, severe
Dehydration
Exposure to neurotoxic insecticides or other cholinesterase inhibitors
Hepatic disease, severe, or cirrhosis
Malnutrition
Pregnancy
Recessive hereditary trait
(prolonged respiratory depression or apnea may occur)

         
Dehydration or
           
Electrolyte or acid-base imbalance
(action of neuromuscular blocking agent may be altered)






Eye injury, open, or
Glaucoma or
Ocular surgery
(succinylcholine may increase intraocular pressure)

         
Fractures or muscle spasm
(initial muscle fasciculations may cause additional trauma)

         
Hepatic function impairment
(patients may have decreased levels of pseudocholinesterase activity, possibly resulting in prolonged respiratory depression or apnea)

         
(effect of panuronium or tubocurarine may be reduced)
     

 
(effect of vecuronium may be prolonged)
         
Hyperkalemia, preexisting
(may be exacerbated by succinylcholine-induced increases in serum potassium concentration)

         
Hypertension
(gallamine may increase blood pressure)
   
     
Hyperthermia
(intensity and duration of action of depolarizing agents may be decreased and that of nondepolarizing agents may be increased)

 


 
Hypotension
(rapid IV administration and/or large doses of atracurium or tubocurarine may cause hypotension)
 
   
 
Hypothermia
(intensity and/or duration of action of succinylcholine and atracurium may be increased and that of gallamine, pancuronium, and tubocurarine may be decreased {37})





 
» Malignant hyperthermia, history of in patient or close relative, or suspected predisposition to
(may be induced by succinylcholine)

         
Myasthenia gravis, except when tubocurarine is used as a diagnostic agent






Pulmonary function impairment or
           
Respiratory depression
(risk of additive respiratory depression)






Renal function impairment
(eliminated by kidneys; prolonged neuromuscular blockade may occur)

   

 
» Renal function impairment
(eliminated by kidneys primarily as unchanged drug; prolonged neuromuscular blockade may occur)
   
     
» Shock
(action of gallamine may be prolonged)
   
     
Shock
(action of tubocurarine may be prolonged)
       
 



Side/Adverse Effects

Table 5. Side/Adverse Effects *



The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Depolarizing
Nondepolarizing


I=Succinylcholine


II=Atracurium
III=Gallamine

IV=Pancuronium
V=Tubocurarine
VI=Vecuronium
I
 
II
 
III
 
IV
 
V
 
VI
 
Medical attention needed
 
           
Anaphylactic, anaphylactoid, or other hypersensitivity reaction
 
R
R
R
R
R
R
Bradycardia
 
L
R
U
U
R
R
Bronchospasm
 
R §
R §
U
R §
R §
R §
Cardiac arrhythmias
 
L
U
U
U
R
U
Circulatory depression or collapse—may occur in overdose
R §
R §
U
R §
R §
R §
Decreased blood pressure —may reach hypotensive levels; with usual doses of tubocurarine, or larger-than-recommended doses of atracurium, may be caused by ganglionic blockade; may also occur as a complication of high-dose positive pressure respiration
R §
L §
U
R §
M §
R §
Edema
 
R §
R §
U
R §
R §
R §
Erythema
 
R §
R §
U
R §
R §
R §
Flushing of skin
 
R §
M §
U
R §
R §
R §
Hives
 
U
R
U
U
U
U
Increased blood pressure—may reach hypertensive levels; with gallamine or pancuronium, may be caused by vagolytic activity
R
L
M
L
U
U
Increased intraocular pressure—possibly caused by contraction of extraocular muscle; occurs immediately after injection and during the fasciculation phase
M
U
U
U
U
U
Laryngospasm
 
U
R
U
U
U
U
Malignant hyperthermic crisis
 
R
U
U
U
U
U
Myoglobinemia and myoglobinuria caused by rhabdomyolysis—especially in children; may lead to myoglobinuric acute renal failure
R
U
U
U
U
U
Tachycardia—with gallamine, occurs after doses of 500 mcg (0.5 mg) per kg of body weight and reaches a maximum within 3 minutes, then declines gradually to the control level; with gallamine and pancuronium, may be due to vagolytic activity {35}
L §
L §
M
L §
R §
R §
Medical attention needed only if continuing or bothersome
 
           
Itching of skin
 
R §
R §
U
L §
R §
R §
Muscle pain and stiffness, postoperative—possibly caused by muscle fasciculations that occur immediately following injection; incidence may vary from 10% in patients maintained on bed rest for 1 day to 70% in ambulatory patients; symptoms usually appear 12 to 24 hours following administration and last for several hours to a few days
M





Salivation, excessive
 
L
U
U
L
U
U
Skin rash
 
R §
R §
U
L §
R §
R §
* Differences in frequency of occurrence may reflect either lack of clinical-use data or actual pharmacologic distinctions among agents (although their pharmacologic similarity suggests that side effects occurring with one may occur with the others). M=more frequent; L=less frequent; R=rare; U=unknown.
 Succinylcholine may cause transient bradycardia accompanied by hypotension, cardiac arrhythmias, and possibly a short period of sinus arrest due to increased vagal stimulation, especially with repeated administration and in children. Following these effects, tachycardia and hypertension may occur due to asphyxial pressor response and mild sympathetic ganglion stimulation.
 Atracurium and vecuronium have little or no direct effect on heart rate; bradycardia may occur because these medications do not counteract the bradycardia caused by other medications (e.g., anesthetics, opioid analgesics) or vagal stimulation.
§ May be caused by histamine release, especially following rapid intravenous injection and/or large doses, or an overdose. The risk of clinically significant histamine release is highest with tubocurarine; moderate with atracurium, or succinylcholine; relatively low with pancuronium or vecuronium; and least with gallamine.

Note: Overdose of the neuromuscular blocking agents may result in prolonged respiratory depression or apnea and cardiovascular collapse.




Overdose
For specific information on the agents used in the management of a neuromuscular blocking agent overdose, see:    • Atropine in Anticholinergics/Antispasmodics (Systemic) monograph;
   • Edrophonium (Systemic) monograph;
   • Neostigmine in Antimyasthenics (Systemic) monograph; and/or
   • Pyridostigmine in Antimyasthenics (Systemic) monograph.


For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Apnea
    
hypotension, severe
    
paralysis, prolonged
    
shock


Treatment of overdose


Specific treatment:
Administering anticholinesterase agents, such as edrophonium, neostigmine, or pyridostigmine, to antagonize the action of the nondepolarizing neuromuscular blocking agents. It is recommended that atropine or another suitable anticholinergic agent be administered prior to or concurrently with the antagonist to counteract its cholinergic side effects.

The depolarization block produced by succinylcholine is not antagonized by anticholinesterase agents such as edrophonium, neostigmine, and pyridostigmine. However, if succinylcholine has been administered over a prolonged period of time and the characteristic depolarization block has gradually changed to a nondepolarization block, as determined with a peripheral nerve stimulator, small doses of the anticholinesterase agent may be tried as an antagonist. If an anticholinesterase agent is used as an antagonist, it is recommended that atropine be administered prior to or concurrently with the antagonist to counteract its cholinergic side effects. Patients should be closely observed for at least 1 hour after reversal of nondepolarization block for possible return of muscle relaxation.

The antagonists are merely adjuncts to, and are not to be substituted for, the institution of measures to ensure adequate ventilation. Ventilatory assistance must be continued until the patient can maintain an adequate ventilatory exchange unassisted.



Monitoring:
Determining the nature and degree of the neuromuscular blockade, using a peripheral nerve stimulator.



Supportive care:
For apnea or prolonged paralysis—maintaining an adequate airway and administering manual or mechanical ventilation. Artificial respiration should be continued until complete recovery of normal respiration is assured.

For severe hypotension or shock—administering fluids and vasopressors as needed to treat



General Dosing Information
Neuromuscular blocking agents have no known effect on consciousness or the pain threshold; therefore, when used as an adjunct to surgery, the neuromuscular blocking agent should always be used with adequate anesthesia.

Since neuromuscular blocking agents may cause respiratory depression, they should be used only by those individuals experienced in the techniques of tracheal intubation, artificial respiration, and the administration of oxygen under positive pressure; facilities for these procedures should be immediately available.

The stated doses are intended as a guideline. Actual dosage must be individualized. To minimize the risk of overdosage, it is recommended that a peripheral nerve stimulator be used to monitor response to the neuromuscular blocking agents.

When nondepolarizing neuromuscular blocking agents are administered concurrently with potent general anesthetics such as enflurane, ether, isoflurane, methoxyflurane, or cyclopropane, the dosage of vecuronium should be decreased by 15%, and that of the other neuromuscular blocking agents should be reduced by 33 to 50%, or as determined with a peripheral nerve stimulator. Halothane causes less potentiation of neuromuscular blockade than either enflurane or isoflurane; therefore, a smaller reduction in the dosage of the neuromuscular blocking agent may be considered {01}.

ATRACURIUM

Summary of Differences


Pharmacology/pharmacokinetics:



Mechanism of action/effect:
A nondepolarizing neuromuscular blocking agent {01}.

Action is usually antagonized by anticholinesterase agents {01}.



Other actions/effects:
May cause histamine release {01}.



Protein-binding:
High.



Biotransformation:
In plasma, by ester hydrolysis and by Hofmann elimination; independent of hepatic or renal function or plasma pseudocholinesterase activity {01}.



Half-life:
Distribution: 2–3.4 minutes.

Elimination: 20 minutes.



Onset of action:
Initial effect within 2 minutes; intubation conditions in 2–2.5 minutes {01}.



Time to peak effect:
1.7–10 (average 3–5) minutes {01}.



Duration of peak effect:
20–35 minutes (balanced anesthesia); not changed by repeated dosing, provided that recovery from the prior dose begins before subsequent doses are given {01}.



Time to recovery:



From time of injection (balanced anesthesia):
25% of twitch response achieved in 35–45 minutes and 95% of twitch response achieved in 60–70 minutes {01}.



From beginning of recovery:
Balanced anesthesia—95% of twitch response achieved in 30 minutes {01}.

Inhalation anesthesia—95% of twitch response achieved in 40 minutes {01}.



Elimination:
Renal and biliary; less than 10% of the quantity excreted via the biliary route as unchanged atracurium {01}.



Precautions:



Pregnancy:
Teratogenic and embryotoxic effects have been demonstrated in rabbits {01}.

Has been shown to cross the human placenta {01}.



Drug interactions and/or related problems:
May increase incidence and severity of bradycardia and hypotension when used together with opioid analgesics; also, histamine release may be additive to that induced by many opioids {01}.

Use with digitalis glycosides not reported to cause cardiac arrhythmias or other undesirable cardiac effects.

Effects may be enhanced or prolonged in patients receiving chronic lithium therapy.

Effects not prolonged by cholinesterase inhibitors or hexafluorenium.

Alkaline solutions such as barbiturate injections should not be mixed in the same syringe, or administered simultaneously through the same intravenous needle, with atracurium {01}. Alkaline solutions may change the pH of the acidic atracurium solution, resulting in inactivation of atracurium or precipitation of a free acid {01}.

Serious side effects with concurrent use of methotrimeprazine have not been reported.

Additive effects with physostigmine have not been reported.



Medical considerations/contraindications:
Lower risk of problems than with gallamine or pancuronium if used in patients with cardiac conditions in which tachycardia would be undesirable.

Efficacy not reduced by hepatic function impairment.

Caution required in patients with pre-existing hypotension.

Effects not prolonged in patients with renal function impairment or shock.



Side/adverse effects:
Moderate risk of side effects associated with histamine release.

More likely than neuromuscular blocking agents with steroidal structure or doxacurium, but less likely than mivacurium or tubocurarine, to cause flushing of skin.

Hives and laryngospasm have been reported.



Additional Dosing Information
See also General Dosing Information .

Atracurium must be administered intravenously because intramuscular injection may cause tissue irritation and because there are no clinical data to support intramuscular administration.

A reduction in dosage and rate of administration is recommended for patients in whom histamine release may be hazardous. Also, patients with neuromuscular disease, severe electrolyte disorders, or carcinomatosis should receive lower doses because of potential enhancement of neuromuscular blockade or difficulties with reversal.

Bradycardia occurring during atracurium administration may be treated by intravenous administration of atropine.

The duration of effect is prolonged in obese patients when atracurium is dosed based on total body weight. One researcher recommends reducing the dose of atracurium by 2.3 mg for each 10 kg total body weight over 70 kg to avoid a prolonged effect {32}.


Parenteral Dosage Forms

ATRACURIUM BESYLATE INJECTION

Usual adult and adolescent dose {01}
Skeletal muscle paralysis
Initial
Intravenous, 400 to 500 mcg (0.4 to 0.5 mg) per kg of body weight {01}; or


For patients in whom histamine release might be hazardous:
Intravenous, 300 to 400 mcg (0.3 to 0.4 mg) per kg of body weight, administered slowly or in divided doses over a period of one minute {01}.



For administration after steady-state enflurane or isoflurane anesthesia has been established:
Intravenous, 250 to 350 mcg (0.25 to 0.35 mg) per kg of body weight, or approximately one-third less than the usual initial dose {01}. Halothane causes less potentiation of neuromuscular blockade; therefore, a smaller reduction in atracurium dosage may be considered.



After succinylcholine-assisted endotracheal intubation under balanced anesthesia:
Intravenous, 300 to 400 mcg (0.3 to 0.4 mg) per kg of body weight {01}. If a potent inhalation anesthetic is being administered, even lower doses may be required. The effects of succinylcholine, as determined using a peripheral nerve stimulator, should be permitted to subside prior to administration of atracurium.


Supplemental
Intravenous, 80 to 100 mcg (0.08 to 0.1 mg) per kg of body weight twenty to forty-five minutes following the initial dose, then every fifteen to twenty-five minutes or as required by clinical conditions {01}; or


Intravenous infusion (initiated after recovery from the effects of an initial intravenous dose of 300 to 500 mcg [0.3 to 0.5 mg]:



Balanced anesthesia:
9 to 10 mcg (0.009 to 0.01 mg) per kg of body weight per minute until the desired degree of neuromuscular blockade is re-established, after which the rate of infusion may be adjusted according to clinical requirements and patient response. Most patients require 5 to 9 mcg (0.005 to 0.009 mg) per kg of body weight per minute, although some may require as little as 2 mcg (0.002 mg) per kg of body weight per minute and others may require as much as 15 mcg (0.015 mg) per kg of body weight per minute {01}.



After steady-state enflurane or isoflurane anesthesia has been established :
The required rate of infusion may be reduced by approximately 33%. A smaller reduction in the rate of infusion may be considered for patients anesthetized with halothane.



For cardiopulmonary bypass procedures in which hypothermia is induced :
The required rate of infusion may be reduced by approximately 50%.



Usual pediatric dose
Neonates up to 1 month of age
Dosage has not been established {01}.

Children 1 month to 2 years of age (under halothane anesthesia)
Intravenous, 300 to 400 mcg (0.3 to 0.4 mg) per kg of body weight, initially {01}.

Children 2 years of age and over
See Usual adult and adolescent dose {01}.


Note: Maintenance doses may be required somewhat more frequently than in adults.


Strength(s) usually available
U.S.—


10 mg per mL (Rx) [Tracrium{01} ( benzyl alcohol [multiple-dose vials only])][Generic]

Canada—


10 mg per mL (Rx) [Tracrium][Generic]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), unless otherwise specified by manufacturer. Protect from freezing.

Preparation of dosage form:
For intravenous infusion—Atracurium besylate injection may be diluted with 0.9% sodium chloride injection, 5% dextrose injection, or 5% dextrose in 0.9% sodium chloride injection {01}. Lactated Ringer's injection should not be used (see Incompatibilities, below) {01}. A solution prepared by adding 2 mL of atracurium besylate injection (10 mg per mL) to 98 mL of diluent contains 200 mcg (0.2 mg) of atracurium besylate per mL; a solution prepared by adding 5 mL of atracurium besylate injection (10 mg per mL) to 95 mL of diluent contains 500 mcg (0.5 mg) per mL. {01}

Stability:
Intravenous infusion solutions prepared with 5% dextrose injection, 0.9% sodium chloride injection, or 5% dextrose in 0.9% sodium chloride injection may be stored in a refrigerator or at room temperature for up to 24 hours without significant loss of potency. Unused portions of such solutions should be discarded after 24 hours. {01}

Atracurium besylate injection should be used within 14 days if stored at room temperature (25 °C [77 °F]), even if later refrigerated {01}.

Incompatibilities:
Alkaline solutions such as barbiturate injections should not be mixed in the same syringe, or administered simultaneously through the same intravenous needle, with atracurium. Alkaline solutions may change the pH of the acidic atracurium solution, resulting in inactivation of atracurium or precipitation of a free acid.

Spontaneous degradation of atracurium has been shown to occur more rapidly when the medication is diluted with lactated Ringer's injection than when the medication is diluted with 0.9% sodium chloride injection. Therefore, it is recommended that lactated Ringer's injection not be used to prepare intravenous infusion solutions containing atracurium. {01}


CISATRACURIUM

Summary of Differences



Note: See Cisatracurium (Systemic) single drug monograph for specific information



CISATRACURIUM INJECTION

Strength(s) usually available
U.S.—


2 mg (base) per mL (Rx) [Nimbex{01} ( benzenesulfonic acid) (benzyl alcohol 0.9% [10-mL multiple-dose vial only])]


10 mg (base) per mL (Rx) [Nimbex{01} (benzenesulfonic acid)]

Canada—


2 mg (base) per mL (Rx) [Nimbex{02} ( benzenesulfonic acid) (benzyl alcohol 0.9% [10-mL multiple-dose vial only])]


10 mg (base) per mL (Rx) [Nimbex{02} (benzenesulfonic acid)]

Note: The 10-mg-per-mL strength is intended only for preparing intravenous infusions for adults to be used in the intensive care unit {01}. The 10-mg-per-mL vials contain benzyl alcohol and should not be used to prepare infusions for neonates.



DOXACURIUM

Summary of Differences



Note: See Doxacurium (Systemic) single drug monograph for specific information



DOXACURIUM CHLORIDE INJECTION

Strength(s) usually available
U.S.—


1 mg per mL (Rx) [Nuromax (0.9% benzyl alcohol)]

Canada—


1 mg per mL (Rx) [Nuromax (0.9% benzyl alcohol)]


GALLAMINE

Summary of Differences


Pharmacology/pharmacokinetics:



Mechanism of action/effect:
A nondepolarizing neuromuscular blocking agent {02}.

Action is usually antagonized by anticholinesterase agents {02}.



Other actions/effects:
Has vagolytic activity {02}.

Less likely than most other neuromuscular blocking agents to cause histamine release.



Biotransformation:
Essentially none.



Half-life:
Distribution: 16 minutes.

Elimination: 150 minutes.



Onset of action:
Initial effect within 1–2 minutes.



Time to peak effect:
3–5 minutes.



Duration of peak effect:
15–30 minutes; increased by repeated dosing.



Elimination:
Renal, almost completely as unchanged gallamine.



Precautions:



Cross-sensitivity and/or related problems:
Cross-sensitivity may occur in patients sensitive to iodine or iodides.



Drug interactions and/or related problems:
Vagolytic activity may decrease risk of opioid analgesic–induced bradycardia and/or hypotension, but may increase risk of tachycardia and/or hypertension in some patients.

Use with digitalis glycosides not reported to cause cardiac arrhythmias or other undesirable cardiac effects.

Effects may be enhanced or prolonged by beta-adrenergic blocking agents.



Medical considerations/contraindications:
More likely than most other neuromuscular blocking agents to cause problems in patients with cardiac conditions in which tachycardia would be undesirable.

Less likely than other neuromuscular blocking agents to cause problems in patients for whom histamine release would be hazardous.

Caution required in patients with pre-existing hypertension.

Prolongation of effects in patients with renal function impairment or shock more likely and/or more severe than with other neuromuscular blocking agents.



Side/adverse effects:
Side effects caused by histamine release have not been reported.

More likely than other neuromuscular blocking agents to cause hypertension and/or tachycardia.



Additional Dosing Information
See also General Dosing Information.

In usual doses, gallamine has a slightly shorter duration of action than tubocurarine; however, in very large doses, its duration of action may be longer.


Parenteral Dosage Forms

GALLAMINE TRIETHIODIDE INJECTION USP

Usual adult and adolescent dose
Skeletal muscle paralysis
Surgery
Initially 1 mg per kg of body weight, not to exceed 80 mg per dose; then 500 mcg (0.5 mg) to 1 mg per kg of body weight after an interval of fifty to sixty minutes, if necessary, for prolonged procedures {02}.

Convulsions (treatment), electrically induced
Intravenous, 40 to 60 mg


Note: A dose of 1 mg per kg of body weight produces a 50% reduction in respiratory minute volume; a dose of 1.5 mg per kg of body weight produces a 75% reduction in respiratory minute volume.


Usual pediatric dose
Intravenous, 2 mg per kg of body weight {02}. A dose of 4 mg per kg of body weight is sometimes used in pediatric patients to provide good intubating conditions in one to two minutes {30} {31}. An increase in heart rate to over one hundred and fifty beats per minute should be anticipated when a dose of 4 mg per kg of body weight is administered {30}.

Note: Caution in use is recommended, especially for patients weighing less than 5 kg.


Strength(s) usually available
U.S.—


20 mg per mL (Rx) [Flaxedil (edetate disodium ) (sodium bisulfite)]

Canada—


20 mg per mL (Rx) [Flaxedil (potassium metabisulfite 1 mg per mL) (sodium sulfite 2 mg per mL)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.


MIVACURIUM

Summary of Differences



Note: See Mivacurium (Systemic) single drug monograph for specific information



MIVACURIUM INJECTION

Strength(s) usually available
U.S.—


2 mg per mL (Rx) [Mivacron]{01}

Canada—


2 mg per mL (Rx) [Mivacron]{50}


PANCURONIUM

Summary of Differences


Pharmacology/pharmacokinetics:



Mechanism of action/effect:
A nondepolarizing neuromuscular blocking agent {05} {35}.

Action is usually antagonized by anticholinesterase agents {05} {33} {35}.



Other actions/effects:
Has vagolytic activity {05} {35}.

Less likely than most other neuromuscular blocking agents to cause histamine release.



Protein-binding:
Very low.



Biotransformation:
Hepatic, in small quantities.



Half-life:
Distribution: 10–13 minutes.

Elimination: 114–116 minutes.



Onset of action:
Initial effect within 1 minute; intubation conditions in 2–3 minutes.



Time to peak effect:
3–4.5 minutes, depending on dose.



Duration of peak effect:
35–45 minutes; increased by repeated dosing.



Time to recovery:
From time of injection: 90% of twitch response achieved in <60 minutes.



Elimination:
Renal (about 80% as unchanged pancuronium); about 10% biliary (up to 10% as unchanged pancuronium).



Precautions:



Cross-sensitivity and/or related problems:
Cross-sensitivity may occur in patients sensitive to bromides.



Pediatrics:
The prolonged use of pancuronium to facilitate mechanical ventilation in neonates has been associated with myopathy {05}. Some premature neonates administered pancuronium for emergency anesthesia and surgery subsequently developed methemoglobinemia {05}. The cause of the methemoglobinemia has not been established {05}.



Drug interactions and/or related problems:
Vagolytic activity may decrease risk of opioid analgesic–induced bradycardia and/or hypotension, but may increase risk of tachycardia and/or hypertension in some patients {05}.

Use with digitalis glycosides may cause cardiac arrhythmias or other undesirable cardiac effects.

Effects may be enhanced or prolonged by beta-adrenergic blocking agents.

Effects may be enhanced or prolonged in patients receiving chronic lithium therapy.

Effects not prolonged by cholinesterase inhibitors or hexafluorenium.

Serious side effects with concurrent use of methotrimeprazine have not been reported.

Additive effects with physostigmine have not been reported.

Effects may be decreased by hydrocortisone or prednisone.



Medical considerations/contraindications:
More likely than most other neuromuscular blocking agents to cause problems in patients with cardiac conditions in which tachycardia would be undesirable.

Caution required in patients for whom histamine release would be hazardous.

Effects may be prolonged by hepatic function impairment {05}.

Effects may be prolonged by renal function impairment {05}, but to a lesser extent than for gallamine.



Side/adverse effects:
Relatively low risk of side effects associated with histamine release {05}.

May cause itching of skin more frequently than other neuromuscular blocking agents {05}.

Excessive salivation has been reported {05}.



Additional Dosing Information
See also General Dosing Information.

Pancuronium is approximately 5 times as potent as tubocurarine {05}.


Parenteral Dosage Forms

PANCURONIUM BROMIDE INJECTION

Usual adult and adolescent dose
Initial
Intravenous, 40 to 100 mcg (0.04 to 0.1 mg) per kg of body weight {05}. Incremental doses starting at 10 mcg (0.01 mg) per kg of body weight may then be administered, generally every twenty to sixty minutes, the dosage being adjusted as needed {05}.

For administration after steady-state enflurane or isoflurane anesthesia has been established and/or after succinylcholine-assisted endotracheal intubation
Intravenous, 40 mcg (0.04 mg) per kg of body weight, initially, then adjusted according to patient response {05}.

For endotracheal intubation
Intravenous, 60 to 100 mcg (0.06 to 0.1 mg) per kg of body weight {05}.


Usual pediatric dose
Neonates up to 1 month of age
Dosage must be individualized by the physician. Dosage may be based on the patient's response to a test dose of 20 mcg (0.02 mg) per kg of body weight {05}.

Children 1 month of age and over
See Usual adult and adolescent dose. {01}


Strength(s) usually available
U.S.—


1 mg per mL (Rx) [Pavulon{38} ( benzyl alcohol)]


2 mg per mL (Rx) [Pavulon{38} ( benzyl alcohol)]

Canada—


1 mg per mL (Rx) [Pavulon]


2 mg per mL (Rx) [Pavulon]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F), unless otherwise specified by manufacturer. Protect from freezing.


RAPACURONIUM

Summary of Differences



Note: See Rapacuronium (Systemic) single drug monograph for specific information


Note: Rapacuronium was voluntarily withdrawn from the market on 03/2001{67}



RAPACURONIUM BROMIDE FOR INJECTION

Strength(s) usually available
U.S.—

Note: Rapacuronium bromide was voluntarily withdrawn from the United States market by the manufacturer (Organon, Inc.) on March 27, 2001. {02}

Not commercially available


ROCURONIUM

Summary of Differences



Note: See Rocuronium (Systemic) single drug monograph for specific information



ROCURONIUM BROMIDE FOR INJECTION

Strength(s) usually available
U.S.—


10 mg/mL (Rx) [Zemuron{01}]

Canada—


10 mg/mL (Rx) [Zemuron]


SUCCINYLCHOLINE

Summary of Differences


Pharmacology/pharmacokinetics:



Mechanism of action/effect:
A depolarizing neuromuscular blocking agent {06} {07} {12}.

Action not antagonized by anticholinesterase agents.



Other actions/effects:
May cause histamine release {06} {07}.



Biotransformation:
In plasma; rapidly hydrolyzed by pseudocholinesterase.



Onset of action:

Intravenous: Initial effect within 0.5–1 minute {12}.

Intramuscular: Initial effect within 3 minutes {06} {07} {12}.



Time to peak effect:
Intravenous: 1–2 minutes {06} {07} {12}.



Duration of peak effect:
Intravenous: 4 to 6 minutes {06} {07} {12}.

Intramuscular: 10–30 minutes.



Elimination:
Renal; about 10% as unchanged succinylcholine.



Precautions:



Pediatrics:
Pediatric patients are especially susceptible to succinylcholine-induced myoglobinemia, myoglobinuria, and cardiac effects. Hyperkalemic rhabdomyolysis resulting in cardiac arrest and death has occurred in apparently healthy pediatric patients after administration of succinylcholine {12} {27}. The adverse events occurred in pediatric patients with previously undiagnosed skeletal muscle myopathy (e.g., Duchenne's muscular dystrophy) {12} {27}. Because it is not possible to predict when a pediatric patient may experience a serious adverse reaction, it is recommended that the use of succinylcholine be restricted to emergency situations or other situations where the immediate securing of the airway is needed (e.g., laryngospasm) {12} {27}.



Drug interactions and/or related problems:
May increase incidence and severity of bradycardia and hypotension when used together with opioid analgesics; also, histamine release may be additive to that induced by many opioids.

Potentiation of effect by hydrocarbon inhalation anesthetics less than for nondepolarizing neuromuscular blocking agents.

Effects not enhanced or prolonged by beta-adrenergic blocking agents.

Effects not reversed by calcium salts.

Effects prolonged by cholinesterase inhibitors or hexafluorenium.

Use with digitalis glycosides may cause cardiac arrhythmias or other undesirable cardiac effects.

Effects may be enhanced or prolonged in patients receiving chronic lithium therapy.

Serious side effects with concurrent use of methotrimeprazine have been reported.

Additive effects with physostigmine have been reported.

Effects may be enhanced by potassium-depleting medications.



Laboratory value alterations:
Serum potassium concentration may be increased. Carbon dioxide production and oxygen consumption may be increased transiently {48}.



Medical considerations/contraindications:
Succinylcholine is contraindicated in patients with skeletal muscle myopathies. Additionally, succinylcholine should not be used in patients with major burn injury, severe trauma, extensive denervation of skeletal muscle, or upper neuron injury. Use of succinylcholine in these patients may result in dangerous hyperkalemia {06} {07} {12}. Cardiac arrest has occurred when succinylcholine was used in patients with these conditions.

Caution required in patients with cardiovascular function impairment.

Effects may be prolonged in patients with renal function impairment, but to a lesser extent than for gallamine.



Caution also required in:
Conditions that may lead to low plasma pseudocholinesterase activity (severe anemia, dehydration, exposure to neurotoxic insecticides or other cholinesterase inhibitors, severe hepatic disease or cirrhosis, malnutrition, pregnancy, recessive hereditary trait) {06} {07} {12}.

Conditions that may be adversely affected by increase in intraocular pressure (open eye injury, glaucoma, ocular surgery) {06} {07} {12}.

Fractures or muscle spasm {06} {07} {12}.

Malignant hyperthermia, history of in patient or close relative {06} {07} {12}.



Side/adverse effects:
Moderate risk of side effects associated with histamine release.

More likely than other neuromuscular blocking agents to cause bradycardia or cardiac arrhythmias.

Increased intraocular pressure, malignant hyperthermia, rhabdomyolysis leading to myoglobinemia and myoglobinuria, postoperative muscle pains and stiffness, and excessive salivation have been reported.



Additional Dosing Information
See also General Dosing Information.

Succinylcholine is usually administered intravenously but may be administered intramuscularly if necessary {06} {07} {12}.

When administered intramuscularly, the injection should be deep and high into the deltoid muscle.

An initial test dose of 10 mg may be administered to determine the sensitivity of the patient and recovery time.

Patients with low levels of pseudocholinesterase activity will require reduced doses, because they are unusually sensitive to the effects of succinylcholine {06} {07} {12}.

If low pseudocholinesterase activity is suspected, a test dose of 5 to 10 mg may be administered {06} {07} {12}.

Premedication with atropine or scopolamine is recommended to prevent excessive salivation.

To reduce the severity of muscle fasciculations, a small dose of a nondepolarizing agent may be administered prior to administration of succinylcholine.

Following administration, succinylcholine may cause transient bradycardia accompanied by hypotension, cardiac arrhythmias, and possibly a short period of sinus arrest due to vagal stimulation, especially with repeated administration and in children. These effects may be inhibited by prior administration of atropine or thiopental sodium.

Succinylcholine may cause myoglobinemia and myoglobinuria, especially in children {06} {07} {12}. Administration of small doses of tubocurarine prior to succinylcholine has been shown to decrease the incidence of myoglobinuria.

Repeated doses of succinylcholine may result in tachyphylaxis {06} {07} {12}.

Succinylcholine produces transient increase in the resting tension of muscles at the time neuromuscular transmission is blocked in normal people. This may be detected as an increase in jaw tension in some children anesthetized with potent inhalation agents {50}.


Parenteral Dosage Forms

SUCCINYLCHOLINE CHLORIDE INJECTION USP

Usual adult and adolescent dose
For short surgical procedures
Intravenous, usually 600 mcg (0.6 mg) (range 300 mcg [0.3 mg] to 1.1 mg) per kg of body weight, initially. Repeated doses may be administered, if necessary, calculated on the basis of response to the first dose. {12}
Intramuscular, 3 to 4 mg per kg of body weight, not to exceed a total dose of 150 mg. {12}

For prolonged surgical procedures
Intravenous, initially 600 mcg (0.6 mg) to 1.1 mg per kg of body weight; subsequent doses to be individualized for maintaining degree of relaxation required.

Note: Administration of repeated fractional doses is generally not recommended because of possible tachyphylaxis and prolonged apnea; continuous infusion is preferred for prolonged surgical procedures.

Intravenous infusion, as a 0.1 to 0.2% solution in 5% dextrose injection, sodium chloride injection, or other appropriate diluent, administered at a rate of 500 mcg (0.5 mg) to 10 mg per minute, depending on patient response and degree of relaxation required, {12} for up to one hour.

Note: When succinylcholine is administered by infusion, careful monitoring of neuromuscular function with a peripheral nerve stimulator is recommended to avoid overdose and to detect development of a nondepolarizing block. {12}


Electroshock therapy
Intravenous, 10 to 30 mg administered approximately one minute before the shock, although dosage must be individualized according to the size and physical condition of the patient.
Intramuscular, up to 2.5 mg per kg of body weight, not to exceed a total dose of 150 mg.


Usual pediatric dose
Endotracheal intubation
Intramuscular, up to 2.5 mg per kg of body weight, not to exceed a total dose of 150 mg.
Intravenous, 1 to 2 mg per kg of body weight. Repeated doses may be administered, if necessary, calculated on the basis of response to the first dose {06} {07} {12}.


Note: Administration of succinylcholine by continuous intravenous infusion is considered to be unsafe in neonates and children because of the risk of malignant hyperpyrexia.


Strength(s) usually available
U.S.—


20 mg per mL (Rx) [Anectine (methylparaben )] [Quelicin (methylparaben ) (propylparaben)] [Sucostrin (methylparaben) ( propylparaben)]


50 mg per mL (Rx) [Quelicin]

Canada—


20 mg per mL (Rx) [Quelicin (methylparaben ) (propylparaben)]


100 mg per mL (Rx) [Quelicin]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F). Protect from freezing.

Stability:
Do not use if the solution is not absolutely clear.

Only freshly prepared solutions of succinylcholine should be used.

The stability of diluted solutions may vary, depending on the specific product. See the manufacturer's prescribing information for product-specific information.

Succinylcholine is rapidly hydrolyzed, quickly loses potency, and may cause formation of a precipitate when mixed with alkaline solutions of other medications. Therefore, succinylcholine should not be mixed in the same syringe or administered simultaneously through the same needle with solutions of short-acting barbiturates such as thiopental sodium or other medications that have an alkaline pH. It should be injected separately.


SUCCINYLCHOLINE CHLORIDE STERILE USP

Note: Because succinylcholine chloride sterile is not commercially available in the U.S. or Canada, the bracketed uses and the use of the superscript 1 in this section reflect the lack of labeled (approved) indications for this medication in these countries.


Usual adult and adolescent dose
[Intravenous infusion, as a 0.1 to 0.2% solution in 5% dextrose injection]1, sodium chloride injection, or other appropriate diluent, administered at a rate of 500 mcg (0.5 mg) to 10 mg per minute, depending on patient response and degree of relaxation required, {12} for up to one hour.

Note: When succinylcholine is administered by infusion, careful monitoring of neuromuscular function with a peripheral nerve stimulator is recommended to avoid overdose and to detect development of a nondepolarizing block. {12}


Usual pediatric dose
Use of succinylcholine by continuous intravenous infusion is not recommended, because of the risk of malignant hyperpyrexia.

Size(s) usually available:
U.S.—
Not commercially available.

Canada—
Not commercially available.

Packaging and storage:
Prior to reconstitution, store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
For intravenous infusion, sterile succinylcholine chloride may be dissolved in 0.9% sodium chloride injection, 5% dextrose injection, or other appropriate infusion solution. {12}

Stability:
Only freshly prepared solutions of succinylcholine should be used.

The reconstituted solution should be used within 24 hours.

Succinylcholine is rapidly hydrolyzed, quickly loses potency, and may cause formation of a precipitate when mixed with alkaline solutions of other medications. Therefore, succinylcholine should not be mixed in the same syringe or administered simultaneously through the same needle with solutions of short-acting barbiturates such as thiopental sodium or other medications that have an alkaline pH. It should be injected separately.


TUBOCURARINE

Summary of Differences


Indications:
Also indicated as a diagnostic aid for myasthenia gravis {13}.



Pharmacology/pharmacokinetics:



Mechanism of action/effect:
A nondepolarizing neuromuscular blocking agent {13}.

Action is usually antagonized by anticholinesterase agents.



Other actions/effects:
Most likely of the neuromuscular blocking agents to cause histamine release.



Protein-binding:
Moderate.



Biotransformation:
Hepatic.



Half-life:
Distribution: 4.8–6.4 minutes.

Elimination: 84–120 minutes.



Onset of action:
Intravenous: Initial effect within 1 minute.

Intramuscular: Initial effect within 15–25 minutes.



Time to peak effect:
Intravenous: 2–5 minutes.



Duration of peak effect:
20–40 minutes; increased with repeated dosing.



Time to recovery:
From time of injection: 50% of twitch response achieved in 50 minutes and 95% of twitch response achieved in 74–90 minutes.



Elimination:
Renal (about 40% as unchanged tubocurarine) and biliary (about 12% as unchanged tubocurarine).



Precautions:



Pregnancy:
May cause congenital fetal contractures if large and repeated doses are administered during the early months of pregnancy.

Also, diminished skeletal muscle activity of the newborn may occur if large and repeated doses are administered near delivery.



Drug interactions and/or related problems:
May increase incidence and severity of bradycardia and hypotension when used together with opioid analgesics; also, histamine release may be additive to that induced by many opioids.

Use with digitalis glycosides not reported to cause cardiac arrhythmias or other undesirable cardiac effects.

Effects not prolonged by cholinesterase inhibitors or hexafluorenium.

Effects may be prolonged or enhanced by calcium salts.

Serious side effects with concurrent use of methotrimeprazine have not been reported.

Additive effects with physostigmine have not been reported.



Medical considerations/contraindications:
Caution required in patients with cardiovascular function impairment.

Effects may be reduced by hepatic function impairment.

Caution required in patients with pre-existing hypotension.

Effects may be prolonged in patients with renal function impairment or shock, but to a lesser extent than for gallamine.



Side/adverse effects:
Relatively high risk of side effects associated with histamine release.

Decrease in blood pressure occurs more frequently than with other neuromuscular blocking agents.



Additional Dosing Information
See also General Dosing Information.

Tubocurarine is usually administered intravenously as a sustained injection over a period of 1 to 1.5 minutes {13}. It may also be administered intramuscularly, if necessary, but is slowly and irregularly absorbed.

Rapid intravenous injection and/or large doses of tubocurarine may cause an increased release of histamine, resulting in hypotension and in decreased respiratory capacity due to bronchospasm combined with drug-induced paralysis of the respiratory muscles. Hypotension may also occur because of ganglionic blockade or as a complication of positive pressure respiration {13}.


Parenteral Dosage Forms

TUBOCURARINE CHLORIDE INJECTION USP

Usual adult and adolescent dose
Skeletal muscle paralysis


Adjunct to surgical anesthesia:
Intramuscular or intravenous, 6 to 9 mg initially, then 3 to 4.5 mg in three to five minutes if necessary {13}. For prolonged procedures, supplemental doses of 3 mg may be administered {13}.

Note: Dosage may generally be calculated on the basis of 157 mcg (0.157 mg) per kg of body weight.




Aid to controlled respiration:
Intravenous, initially 16.5 mcg (0.0165 mg) per kg of body weight, the subsequent doses being adjusted as needed.



Electroshock therapy:
Intravenous, 157 mcg (0.157 mg) per kg of body weight, administered over a period of thirty to ninety seconds {13}.

Note: Initially, a dose of 3 mg less than the calculated total dose should be used {13}.



Diagnostic aid (myasthenia gravis)
Intravenous, 4 to 33 mcg (0.004 to 0.033 mg) per kg of body weight {13}.

Note: It is recommended that the test be terminated within two to three minutes by intravenous injection of 1.5 mg of neostigmine, since the marked exaggeration of myasthenia gravis symptoms may result in prolonged respiratory paralysis.



Usual pediatric dose
Skeletal muscle paralysis
Adjunct to surgical anesthesia
Neonates up to 4 weeks of age—Intravenous, 250 to 500 mcg (0.25 to 0.5 mg) per kg of body weight initially {15}; then subsequent doses in increments of one-fifth or one-sixth of the initial doses, if necessary.

Infants and children—Intravenous, 500 mcg (0.5 mg) per kg of body weight {16}.


Strength(s) usually available
U.S.—


3 mg (20 Units) per mL (Rx)

Canada—


3 mg (20 Units) per mL (Rx)

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Stability:
When tubocurarine is mixed with a barbiturate solution such as methohexital sodium or thiopental sodium, a precipitate may form because of the high pH of the barbiturate solution. Each medication should be given in a separate syringe. {13}


VECURONIUM

Summary of Differences


Pharmacology/pharmacokinetics:



Mechanism of action/effect:
A nondepolarizing neuromuscular blocking agent {39} {44}.

Action is usually antagonized by anticholinesterase agents {39} {44}.



Other actions/effects:
Less likely than most other neuromuscular blocking agents to cause histamine release {47}.



Protein-binding:
Moderate to high.



Biotransformation:
Hepatic; only 5–10% of a dose is metabolized. One metabolite has some neuromuscular blocking activity.



Half-life:
Distribution: 4 minutes {39} {44}.

Elimination: 65 to 75 minutes {39} {44}.



Onset of action:
Initial effect within 1 minute; intubation conditions in 2.5–3 minutes.



Time to peak effect:
3–5 minutes.



Duration of peak effect:
25–30 minutes (balanced anesthesia); not changed by repeated dosing, provided that recovery from the prior dose begins before subsequent doses are given.



Time to recovery:
From time of injection (balanced anesthesia): 25% of twitch response achieved in 25–40 minutes and 95% of twitch response achieved in 45–65 minutes {39} {44}.



Elimination:
Biliary (25–50% of a dose) and renal (3–35% of a dose) {39} {44}.



Precautions:



Cross-sensitivity and/or related problems:
Cross-sensitivity may occur in patients sensitive to bromides.



Pregnancy/reproduction:
Has been shown to cross the human placenta.



Pediatrics:
Patients 7 weeks to 1 year of age are more sensitive to the effects of vecuronium than are adults; recovery time may be 11/2 times that of adults {39} {40}. The dose of vecuronium preventing skeletal muscle movement in response to a surgical skin incision in 95% of patients (ED 95) is about 45 to 50 mcg per kg of body weight in neonates and infants, 82 mcg per kg of body weight for children 5 to 7 years of age, and 55 mcg per kg of body weight for adolescents 13 to 16 years of age {30} {40} {41} {42} {43}. Similar age-related differences in continuous infusion requirements have been observed such that it could be expected that the infusion rate required for a child 5 years of age may be twice that of an adult {30} {43}.



Drug interactions and/or related problems:
May increase incidence and severity of bradycardia and hypotension when used together with opioid analgesics.

Use with digitalis glycosides not reported to cause cardiac arrhythmias or other undesirable cardiac effects.

Effects not prolonged by cholinesterase inhibitors or hexafluorenium.

Serious side effects with concurrent use of methotrimeprazine have not been reported.

Additive effects with physostigmine have not been reported.



Medical considerations/contraindications:
Caution required in patients with cardiovascular function impairment {39} {44}.

Effects may be prolonged by hepatic function impairment {39} {44}.



Side/adverse effects:
Relatively low risk of side effects caused by histamine release {39} {44} {47}.

Long-term use in the intensive care unit to facilitate mechanical ventilation has been associated with prolonged paralysis and skeletal muscle weakness {39}.



Additional Dosing Information
See also General Dosing Information .

Vecuronium is to be administered by intravenous injection only {39} {44}.


Parenteral Dosage Forms

VECURONIUM BROMIDE FOR INJECTION

Usual adult and adolescent dose
Initial


For intubation:
Intravenous, 80 to 100 mcg (0.08 to 0.1 mg) per kg of body weight {39}.



For administration after the patient has been anesthetized with enflurane or isoflurane (i.e., more than 5 minutes after anesthesia has been instituted or after steady state has been achieved):
Intravenous, 60 to 85 mcg (0.06 to 0.085 mg) per kg of body weight, or approximately 15% less than the usual initial dose {39}.



For administration after succinylcholine-assisted endotracheal intubation :
Intravenous, 40 to 60 mcg (0.04 to 0.06 mg) per kg of body weight under inhalation anesthesia, or 50 to 60 mcg (0.05 to 0.06 mg) per kg of body weight under balanced anesthesia {39}. The effects of succinylcholine, as determined with a peripheral nerve stimulator, should be permitted to subside prior to administration of vecuronium {39}.


Note: If larger initial doses are required by the individual patient, initial doses ranging from 150 to 280 mcg (0.15 to 0.28 mg) per kg of body weight have been administered during surgery with halothane anesthesia without adverse effects on the cardiovascular system occurring, provided that adequate ventilation was maintained {39}.


Supplemental
Intravenous, 10 to 15 mcg (0.01 to 0.015 mg) per kg of body weight, administered twenty-five to forty minutes following the initial dose, then every twelve to fifteen minutes or as required by clinical conditions {39}; or

Intravenous infusion (initiated after recovery from the effects of an initial intravenous dose of 80 to 100 mcg per kg of body weight has begun): 1 mcg (0.001 mg) per kg of body weight per minute, initially, then adjusted according to clinical requirements and patient response {39}. Average infusion rates may range from 0.8 to 1.2 mcg (0.0008 to 0.0012 mg) per kg of body weight per minute {39}.



After steady-state enflurane or isoflurane anesthesia has been established :
The required rate of infusion may be reduced by 25 to 60%. This reduction may not be required for patients anesthetized with halothane {39}.



Usual pediatric dose {10}
Neonates
Dosage has not been established.

Patients 7 weeks to 1 year of age
Dosage must be individualized. Pediatric patients 7 weeks to 1 year of age are more sensitive to the effects of vecuronium than adults and recovery time may be 11/2 times that of adults {39}.

Patients 1 to 10 years of age
Dosage must be individualized. Pediatric patients 1 to 10 years of age may require a slightly higher initial dose and slightly more frequent supplemental doses than adults {39}.

Patients 10 years of age and older


Initial:
See Usual adult and adolescent dose {39}.



Supplemental:
Intravenous—See Usual adult and adolescent dose.

Intravenous infusion—Dosage has not been established {39}.



Size(s) usually available:
U.S.—


10 mg (Rx) [Norcuron (lyophylized) ( citric acid anhydrous 20.75 mg) (mannitol 97 mg ) (sodium phosphate dibasic anhydrous 16.25 mg)]


20 mg (Rx) [Norcuron (citric acid anhydrous 41.5 mg) (mannitol 194 mg) (sodium phosphate dibasic anhydrous 32.5 mg)]

Canada—


10 mg (Rx) [Norcuron]


20 mg (Rx)

Packaging and storage:
Prior to reconstitution, store between 15 and 30 °C (59 and 86 °F), protected from light, unless otherwise specified by manufacturer.

Preparation of dosage form:
Reconstitute using bacteriostatic water for injection (provided by the manufacturer in some packages of vecuronium bromide for injection) or another compatible intravenous solution, such as 5% dextrose injection, 0.9% sodium chloride injection, 5% dextrose in sodium chloride injection, or lactated Ringer's injection. For direct intravenous injection, the medication is generally reconstituted using 5 or 10 mL of diluent. For intravenous infusion, the medication is diluted to a convenient concentration, such as 10 or 20 mg per 100 mL of infusion solution.

Stability:
After reconstitution with bacteriostatic water for injection, the solution may be stored at room temperature or in a refrigerator; it should be used within 5 days. After reconstitution with other compatible intravenous solutions, the solution should be stored in a refrigerator and used within 24 hours. Reconstituted solutions are intended to be used only once; unused portions should be discarded.

Incompatibilities:
Alkaline solutions such as barbiturate injections should not be mixed in the same syringe, or administered simultaneously through the same intravenous needle, with vecuronium.



Revised: 11/08/2001



References
  1. Atracurium package insert (Tracrium, Glaxo Wellcome—US), Rev 11/97, Rec 11/98.
  1. Gallamine triethiodide product monograph (Flaxedil, Rhône-Poulenc Rorer—Canada), Rev 5/91, Rec 11/98.
  1. Katende RS, Dimich I. Resistance to nondepolarizing muscle relaxants in a patient treated with ranitidine. Mt Sinai J Med 1987; 54: 330-1.
  1. Withington DE, Donati F, Bevan DR, et al. Potentiation of atracurium neuromuscular blockade by enflurane: time- course of effect. Anesth Analg 1991; 72: 469-73.
  1. Pancuronium bromide package insert (Astra—US), Rev 7/96, Rec 10/98.
  1. Succinylcholine package insert (Quelicin, Abbott—US), Rev 1/95, Rec 10/98.
  1. Succinylcholine package insert (Anectine, Glaxo Wellcome—Canada), Rev 11/98, Rec 12/98.
  1. Bennett MJ, Hahn JF. Potentiation of the combination of pancuronium and metocurine by halothane and isoflurane in humans with and without renal failure. Anesthesiology 1985; 62: 759-64
  1. Rupp SM, Miller RD, Gencarelli PJ. Vecuronium-induced neuromuscular blockade during enflurane, isoflurane, and halothane anesthesia in humans. Anesthesiology 1984; 60: 102-5.
  1. Laflin MJ. Interaction of pancuronium and corticosteroids. Anesthesiology 1977; 47: 471-2.
  1. Meyers EF. Partial recovery from pancuronium neuromuscular blockade following hydrocortisone administration. Anesthesiology 1977; 46: 148-50.
  1. Succinylcholine package insert (Anectine, Glaxo Wellcome—US), Rev 11/94, Rec 10/98.
  1. Tubocurarine chloride package insert (Eli Lilly—US), Rev 3/97, Rec 9/97.
  1. Panel comment
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  1. Product Information: Nimbex, cisatracurium besylate. Abbott Laboratories, North Chicago, IL, (PI revised 08/1999) reviewed 06/2000.
  1. Product Information: Nuromax, doxacurium chloride. Abbot Laboratories, North Chicago, IL, (PI revised 12/1997) reviewed 06/2000.
  1. Product Information: Mivacron, mivacurium chloride. Abbot Laboratories, North Chicago, IL, (PI revised 08/1998) reviewed 06/2000.
  1. Product Information: Raplon, rapacuronium bromide. Organon, West Orange, NJ, (PI revised 08/1999) reviewed 06/2000.
  1. Product Information: Zemuron, rocuronium bromide. Organon, West Orange, NJ, PI reviewed 06/2000.
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