VA Class:MS300

AHFS Class:

• Neuromuscular Blocking Agents 12:20.20

Generic Name(s):

• Pancuronium Bromide

Pancuronium bromide is an aminosteroid nondepolarizing neuromuscular blocking agent.100

Skeletal Muscle Relaxation

Pancuronium bromide is used to produce skeletal muscle relaxation during surgery after general anesthesia has been induced.100,420 The drug also is used to facilitate endotracheal intubation;100 however, a neuromuscular blocking agent with a rapid onset of action (e.g., succinylcholine, rocuronium) generally is preferred in emergency situations when rapid intubation is required.421,424

Pancuronium also is used to facilitate mechanical ventilation in the intensive care unit (ICU);341,420,421 however, the manufacturer states that insufficient data are available to support dosage recommendations for such use.100 Whenever neuromuscular blocking agents are used in the ICU, the benefits versus risks of such therapy must be considered and patients should be assessed frequently to determine the need for continued paralysis.100,421 (See Cautions: Precautions and Contraindications.)

Compared with other neuromuscular blocking agents, pancuronium has a slow onset and long duration of action.100,420 Because of these pharmacokinetic properties, pancuronium is not appropriate for emergency intubation but may be used for other indications (e.g., mechanical ventilation in the ICU) in which a rapid onset and short duration of action are not as important.421,424 The relatively long duration of action of pancuronium may be desirable for prolonged surgical procedures; however, residual paralysis is more common with the longer-acting neuromuscular blocking agents.420 The possibility of cumulative effects and prolonged recovery of neuromuscular function should be considered if the drug is used in patients with hepatic or renal impairment.100,420 Pancuronium has prominent vagolytic effects and generally should not be used in patients with preexisting tachycardia or in patients who cannot tolerate an increase in heart rate (e.g., those with cardiovascular disease).341,420,421,424

For additional information on uses and treatment principles of neuromuscular blocking agents, see Uses in the Neuromuscular Blocking Agents General Statement 12:20.20.

Administration

Pancuronium bromide is administered IV only.100 The drug usually is administered by direct IV injection, but also has been given as a continuous IV infusion.100,341

For continuous IV infusion, pancuronium bromide injection may be diluted with 5% dextrose, 5% dextrose and 0.9% sodium chloride, 0.9% sodium chloride, or lactated Ringer's injection.100 Infusion solutions are stable for 48 hours when mixed with these diluents.100 Use of a controlled-infusion device is recommended to ensure precise control of flow rate during continuous IV infusion of the drug.359

Dispensing and Administration Precautions

Neuromuscular blocking agents should be administered only by individuals who are adequately trained in their use and complications.100,359 For specific procedures and techniques of administration, specialized references should be consulted. Facilities and personnel necessary for intubation, administration of oxygen, and respiratory support should be immediately available whenever these drugs are used.100,359,424 In addition, a reversal agent should be readily available in the event of a failed intubation or to accelerate neuromuscular recovery after surgery.100,359,421 (See Dosage and Administration: Reversal of Neuromuscular Blockade.)

Because neuromuscular blocking agents can cause respiratory arrest, precautions (e.g., storage segregation, warning labels, access limitations) should be taken to ensure that these drugs are not administered without adequate respiratory support.425 Affixing warning labels to storage containers and final administration containers is recommended to clearly communicate that respiratory paralysis can occur and ventilator support is required.425 The Institute for Safe Medication Practices (ISMP) recommends the following wording for these containers: “Warning: Paralyzing agent—causes respiratory arrest—patient must be ventilated.”425

Neuromuscular blocking agents have no known effect on consciousness, pain, or cerebration, and should therefore be used in conjunction with adequate levels of anesthesia, and only after appropriate analgesics and sedatives are administered.100,359,421,423 To avoid distress to the patient, pancuronium should be administered only after unconsciousness has been induced.421,424

Dosage

Dosage of pancuronium must be carefully adjusted according to individual requirements and response.100 The use of a peripheral nerve stimulator is recommended to assess the degree of neuromuscular blockade and recovery, determine the need for additional doses, and minimize the risk of overdosage.100,421

The usual initial dose of pancuronium bromide as an adjunct to balanced anesthesia in adults and children older than 1 month of age is 0.04-0.1 mg/kg.100 For endotracheal intubation in adults and children older than 1 month of age, a pancuronium bromide dose of 0.06-0.1 mg/kg is recommended; doses within this range generally provide satisfactory conditions for intubation within 2-3 minutes.100 An intubating dose of 0.1 mg/kg under balanced anesthesia generally produces maximum neuromuscular blockade in about 4 minutes and clinically sufficient neuromuscular blockade for about 100 minutes.100 Although doses of up to 0.16 mg/kg have been used, large doses may increase the frequency and severity of tachycardia. Additional incremental doses starting at 0.01 mg/kg may be administered to maintain skeletal muscle relaxation during prolonged surgery.100

Dosage of pancuronium bromide in neonates up to 1 month of age must be carefully individualized since neonates are particularly sensitive to the effects of nondepolarizing neuromuscular blocking agents; the manufacturer recommends that a test dose of 0.02 mg/kg be given first to determine responsiveness.100 (See Cautions: Pediatric Precautions.)

A reduction in the dosage of pancuronium bromide may be required when the drug is used concomitantly with inhalation anesthetics (e.g., enflurane, isoflurane).100 If administered following succinylcholine, pancuronium doses at the lower end of the recommended range may be sufficient; pancuronium should be administered after the effects of succinylcholine have subsided.100

Although patients with slower circulation times (e.g., those with cardiovascular disease, edema, or advanced age) may have delayed onset of action, dosage of pancuronium bromide should not be increased.100

When pancuronium is used in women undergoing cesarean section, the usual dosage of the drug as an adjunct to general anesthesia and for endotracheal intubation may be employed; however, dosage should usually be reduced in women receiving magnesium sulfate for toxemia of pregnancy, since magnesium salts can enhance neuromuscular blockade.100

The manufacturer states that continuous IV infusions or intermittent IV injections of pancuronium to support mechanical ventilation in the intensive care unit (ICU) have not been adequately studied to establish dosage recommendations.100

Reversal of Neuromuscular Blockade

Neuromuscular blockade induced by pancuronium can be reversed by administering a cholinesterase inhibitor (e.g., neostigmine, pyridostigmine, edrophonium) in conjunction with an anticholinergic agent such as atropine or glycopyrrolate to block the adverse muscarinic effects of the cholinesterase inhibitor.100 For specific information on the uses and dosage and administration of these other drugs, see the individual monographs .

To minimize the risk of residual neuromuscular blockade, reversal should only be attempted after some degree of spontaneous recovery has occurred; patients should be closely monitored until adequate recovery of normal neuromuscular function is assured (i.e., ability to maintain satisfactory ventilation and a patent airway).100,355,356,357,358,421

Adverse Effects

Adverse effects of pancuronium bromide generally are manifestations of the usual pharmacologic actions of the nondepolarizing neuromuscular blocking agents, including skeletal muscle weakness or paralysis and respiratory insufficiency or apnea.100 Pancuronium has a high potential for causing adverse cardiac effects because of its affinity for muscarinic receptors in the parasympathetic and peripheral sympathetic nervous systems; the predominant manifestation is tachycardia (resulting from vagolysis and increased release of norepinephrine).100,420,422,423 Slight elevations in heart rate, mean arterial pressure, and cardiac output have been reported in patients receiving pancuronium.100,420 Excessive salivation sometimes occurs during very light anesthesia, particularly in children or when no anticholinergic agent is administered prior to pancuronium. Excessive sweating has occurred in children; however, this may have resulted from the light levels of anesthesia used. Occasionally, transient rashes and wheezing have been reported and a burning sensation along the vein has occurred in conscious patients who received pancuronium.

Serious hypersensitivity reactions, including anaphylaxis, have been reported rarely with all neuromuscular blocking agents; such reactions have been life-threatening or fatal in some cases.100,422 Pancuronium is associated with minimal histamine release and rarely causes histamine-related hypersensitivity reactions (e.g., bronchospasm, flushing, erythema, hypotension, tachycardia).100

Precautions and Contraindications

Pancuronium shares the toxic potentials of the nondepolarizing neuromuscular blocking agents, and the usual precautions of neuromuscular blocking agent administration should be observed. (See Cautions in the Neuromuscular Blocking Agents General Statement 12:20.20.)

When used inappropriately, neuromuscular blocking agents can severely compromise respiratory function and induce respiratory paralysis.100 Special precautions should be taken during and after administration of these drugs.100 (See Dispensing and Administration Precautions under Dosage and Administration: Administration.) The degree of neuromuscular blockade produced by pancuronium should be monitored with a peripheral nerve stimulator, particularly in patients with conditions that may potentiate (e.g., neuromuscular diseases) or cause resistance to (e.g., burns) the neuromuscular blocking effects of the drug.100

Pancuronium should be used with caution in patients with preexisting pulmonary, renal, or hepatic disease.100 Because pancuronium is mainly excreted in urine, the effects of the drug may be prolonged in patients with poor renal perfusion or severe renal disease.100 Pancuronium also may have a slower onset and prolonged duration of action in patients with hepatic or biliary disease; because volume of distribution may be increased in these patients, a higher total initial dose may be required to achieve adequate muscle relaxation, but the duration of action may be prolonged.100

Long-term use of neuromuscular blocking agents to support mechanical ventilation in the intensive care unit (ICU) has been associated with prolonged paralysis and/or skeletal muscle weakness.100 (See Cautions: Pediatric Precautions.) Appropriate neuromuscular monitoring with a peripheral nerve stimulator is recommended whenever pancuronium is used in the ICU.100

Particular care may be required to maintain an adequate airway and ventilation support prior to, during, and following administration of pancuronium in severely obese patients and those with neuromuscular diseases (e.g., myasthenia gravis, Eaton-Lambert syndrome).100

Since neuromuscular blocking agents have been reported to cause severe anaphylactic reactions, appropriate emergency treatment should be readily available whenever these drugs are administered.100 Pancuronium is contraindicated in patients with known hypersensitivity to the drug.100 Because of potential cross-sensitivity, pancuronium should be used with caution in patients who have experienced previous anaphylactic reactions to other neuromuscular blocking agents (depolarizing or nondepolarizing).100,422

Pediatric Precautions

Prolonged use of pancuronium in neonates undergoing mechanical ventilation in the ICU has been associated rarely with prolonged paralysis and severe muscle weakness.100 Although confounding factors were present and a causal relationship has not been definitively established, the risks versus benefits of neuromuscular blockade should be considered whenever there is a need for long-term mechanical ventilation.100 In addition, unexplained, clinically important methemoglobinemia has been reported rarely in premature neonates receiving pancuronium in combination with fentanyl and atropine for emergency anesthesia and surgery. However, the manufacturers state that a direct causal relationship between use of this combination and occurrence of methemoglobinemia has not been established.

Each mL of pancuronium bromide injection contain benzyl alcohol as a preservative.100 Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates.100,114,115,116,117,118 Toxicity appears to have resulted from administration of large amounts (i.e., 100-400 mg/kg daily) of benzyl alcohol in these neonates.114,115,116,117,118 Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible, the American Academy of Pediatrics (AAP) states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when indicated in neonates.114

Pregnancy, Fertility, and Lactation

Pregnancy

Animal reproduction studies have not been performed with pancuronium.100 It is not known whether the drug can cause fetal harm when administered to pregnant women or can affect reproductive capacity.100 Pancuronium should be administered in pregnant women only if the benefits outweigh the risks.100

When pancuronium is used in pregnant women receiving magnesium sulfate for toxemias of pregnancy, neuromuscular blockade may be potentiated and its reversal impeded.100

Lactation

It is not known whether pancuronium is distributed into milk.106

Anti-infectives

Certain anti-infective agents (e.g., aminoglycosides, bacitracin, polymyxins, tetracyclines) may prolong the duration of neuromuscular blockade produced by pancuronium.100

General Anesthetics

Inhalational anesthetics (principally enflurane and isoflurane) may potentiate the neuromuscular blockade produced by pancuronium.100

Some evidence suggests that ventricular arrhythmias may result from concomitant use of pancuronium, halothane, and tricyclic antidepressants; the severity of interaction appears to be related to the dose of pancuronium used.100

Magnesium Sulfate

Increased pancuronium-induced neuromuscular blockade and incomplete reversal are possible in women undergoing cesarean section who have received magnesium sulfate for toxemias of pregnancy.100 Dosage of pancuronium should be reduced if necessary.100

Nondepolarizing Neuromuscular Blocking Agents

There is insufficient information to support the use of pancuronium with other nondepolarizing neuromuscular blocking agents.100

Quinidine

Recurrence of paralysis is possible in patients who receive quinidine during recovery from neuromuscular blocking agents.100

Succinylcholine

Prior administration of succinylcholine has been reported to increase the intensity and duration of neuromuscular blockade produced by pancuronium, and the effects of succinylcholine should be allowed to subside before the administration of pancuronium.100

Pharmacology

Pancuronium bromide produces pharmacologic effects similar to those of other nondepolarizing neuromuscular blocking agents. (See Pharmacology in the Neuromuscular Blocking Agents General Statement 12:20.20.) The drug may produce an increase in heart rate which appears to result from a direct blocking effect on the acetylcholine receptors of the heart. (See Cautions: Adverse Effects.) The increase in heart rate appears to be dose related and is minimal with usual doses. Despite its steroidal structure, the drug exhibits no hormonal activity.

Pharmacokinetics

Absorption

Following IV administration of pancuronium bromide 0.06-0.1 mg/kg, muscle relaxation reaches a level suitable for endotracheal intubation within 2-3 minutes.100 The onset and duration of paralysis are dose related. After a dose of 0.06 mg/kg, the effects of the drug begin to subside in about 35-45 minutes. Supplemental doses may increase the magnitude and duration of the neuromuscular blockade.

Distribution

Because of evidence that alterations in plasma protein concentrations may not affect the dose-response of pancuronium substantially, it was thought that the drug was not substantially protein bound. However, more recent in vitro evidence indicates that pancuronium is approximately 87% (range: 77-91%) bound to plasma proteins, mainly to γ-globulin and to a lesser extent to albumin.100,101,102,104 Protein binding of the drug appears to be complex,100,101,102,103,104,105 and the extent to which pancuronium is bound to plasma proteins may vary,103,104 as lower values (e.g., 13-30%) have been reported in some studies.103,104,105 Some clinicians have postulated that pancuronium may exhibit concentration-dependent protein binding.101,103,104 At an in vitro plasma pancuronium concentration of 0.3 or 1-2 mcg/mL, 30 or 87% protein binding has been reported, respectively.103,104 Binding of pancuronium may also be method dependent.101,103 It appears that protein binding of pancuronium is not affected by hepatic103 or renal105 impairment. The activity of the drug is not greatly affected by plasma carbon dioxide concentrations or pH. Redistribution is responsible for termination of activity following single doses. Pancuronium does cross the placenta, apparently in small amounts.

Elimination

Plasma concentrations of pancuronium appear to decline in a triphasic manner. In adults with normal renal and hepatic function, the half-life in the terminal phase is about 2 hours. The elimination half-life may be prolonged in patients with impaired renal and/or hepatic function. The drug is eliminated mainly unchanged by the kidneys, although small amounts may be metabolized and some of the drug may be eliminated in the bile.

Chemistry and Stability

Chemistry

Pancuronium bromide is a synthetic, nondepolarizing neuromuscular blocking agent. The drug occurs as a fine, white, hygroscopic powder with a bitter taste and is freely soluble in water and very soluble in alcohol. Commercially available pancuronium bromide injections are adjusted to pH 4 with acetic acid.

Stability

Pancuronium bromide injection should be stored at 2-8°C.100 Alternatively, if stored at room temperature, the injection reportedly is stable for 6 months. When pancuronium bromide injection is mixed with a barbiturate, a precipitate may be formed. Because of its steroidal structure, pancuronium may be adsorbed to plastic containers during prolonged contact. However, the manufacturers state that at concentrations of 74-78 mcg/mL, pancuronium bromide is chemically and physically compatible for 48 hours at 15-30°C in glass or plastic containers of the following IV solutions: 5% dextrose, lactated Ringer's, 0.9% sodium chloride, or 5% dextrose and 0.45 or 0.9% sodium chloride and that no adsorption to either glass or plastic occurs in these solutions during this time period.

Additional Information

For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, drug interactions, and dosage and administration of pancuronium bromide, see the Neuromuscular Blocking Agents General Statement 12:20.20.

Only references cited for selected revisions after 1984 are available electronically.

100. Hospira. Pancuronium bromide injection prescribing information. Lake Forest, IL; 2016 Dec.

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106. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2002:1058-62.

114. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics. 1983; 72:356 8.

115. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull. 1982; 12(2):10 11.

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