Pancuronium

Article Author:
Gyan Das
Article Editor:
Christopher Maani
Updated:
2/12/2019 7:53:44 PM
PubMed Link:
Pancuronium

Indications

Pancuronium bromide is a long-acting, bis-quaternary aminosteroid, non-depolarizing, neuromuscular blocking drug (NMBD) which was first synthesized in 1964 and was found to possess fewer adverse effects with regards to hemodynamic stability and histamine release as compared to the prototypical NMBD, d-tubocurarine.[1][2] After the arrival of intermediate-acting NMBDs such as vecuronium, rocuronium, cisatracurium, and atracurium, the use of pancuronium has fallen out of favor with many clinicians due to its long elimination and context sensitive half time and predominantly renal clearance.

The FDA approved indications for pancuronium are similar to those of other NMBDs and include laryngeal muscle relaxation that facilitates endotracheal intubation, skeletal muscle relaxation to support optimal surgical conditions and exposure, and chest wall and diaphragmatic muscle relaxation to improve thoracic compliance in mechanically ventilated patients.

NMBDs are as an adjunctive therapy which may decrease the inflammatory response associated with acute respiratory distress syndrome and lead to reduced mortality and barotrauma associated with mechanical ventilation; however, the studies which investigated utilized a 48-hour infusion of cisatracurium rather than pancuronium or other NMBDs.[3][4] Pancuronium has also been utilized to prevent shivering during therapeutic hypothermia protocols following cardiac arrest.[5]

Mechanism of Action

Pancuronium, as with other non-depolarizing NMBDs, is a competitive inhibitor at the postjunctional nicotinic acetylcholine (ACh) receptor; normally, the postjunctional ACh receptor in skeletal muscle functions as a ligand-gated ion channel which binds ACh to allow passage of sodium ions to cause depolarization of the cell membrane leading to skeletal muscle contraction. The nicotinic ACh receptor has five subunits; alpha subunits are two of the five subunits and serve as the binding site for ACh and NMBDs. Pancuronium is a steroidal molecule which contains ACh-like moieties, facilitating binding to the alpha subunit. Binding of pancuronium to at least one of the alpha subunits causes a conformational change in the ACh receptor and causes the ion channel to remain closed, preventing ion passage and depolarization. Additionally, pancuronium, owing to its large molecular size when compared to ACh, may physically occlude the ion channel and prevents ion passage; this mechanism of ACh receptor blockade becomes more significant with an increased number of molecules present.

Pharmacokinetically, pancuronium is a highly ionized and water-soluble compound at physiologic pH. Because of the poor lipid solubility of pancuronium, it does not cross the blood-brain barrier to exert central nervous system effects, renal tubular reabsorption is minimal, and does not traverse the placenta with minimal fetal effects. Owing to the pancuronium's poor lipid solubility, the volume of distribution is nearly equivalent to circulating plasma volume. Redistribution and diffusion away from the neuromuscular junction (NMJ) contribute significantly to the clinical characteristics of the drug. Pancuronium gets cleared from the plasma primarily through renal excretion (80%). Hepatic degradation (10%) and biliary excretion (10%) play minor roles in the clearance of this drug. Hepatic deacetylation leads to several inactive metabolites and 3-desacetylpancuronium which exhibits half to two-thirds of the potency of pancuronium at the NMJ; the effect of this metabolite can be clinically significant in renal impairment.

Pharmacodynamically, there are several drugs and clinical situations which may either potentiate or diminish the clinical effect of pancuronium.

Drugs and clinical syndromes which potentiate neuromuscular blockade:

  • Volatile anesthetics
  • Aminoglycoside antibiotics
  • Local anesthetics
  • Cardiac antiarrhythmic drugs
  • Dantrolene
  • Magnesium
  • Lithium
  • Tamoxifen
  • Myasthenia gravis
  • Duchenne muscular dystrophy

Drugs and clinical syndromes which diminish neuromuscular blockade:

  • Calcium
  • Corticosteroids
  • Anticonvulsant drugs
  • Burn Injury
  • Denervation injury
  • Immobility

Administration

Pancuronium administration is by intravenous bolus. A continuous IV infusion may be a consideration in the management of the critically ill patient.

The typical intubating dose is 0.1 mg/kg with a 3 to 5-minute onset to maximal muscle relaxation. The 95% Effective Dose is 0.07 mg/kg. There is a 60 to 90-minute duration of action (return to 25% of control twitches) with a typical intubating dose. Maintenance of neuromuscular blockade can be accomplished with a dose of 0.02 mg/kg, titrated to the level of blockade.

Typical infusion dosing may range from 0.7 to 2 mcg/kg/min.

Adverse Effects

Patients with renal failure may experience a 30 to 50% decrease in plasma clearance of pancuronium and associated prolonged neuromuscular blockade.

Owing to its blockade of muscarinic receptors, mainly M2 receptors found in the atria, pancuronium results in increases in heart rate, mean arterial pressure, and cardiac output.[6]

Pancuronium and other NMBDs have been associated with persistent weakness syndromes in critically ill patients requiring prolonged infusions of these drugs. Critically ill patients have many comorbidities such as acid-base derangements, electrolyte imbalances, and organ system failure which may lead to myopathies and polyneuropathies.[7][8]

It is important to note that pancuronium has no anesthetic, amnestic, or analgesic properties and patients may have intraoperative recall leading to significant morbidity and psychological trauma without the use of sufficient anesthetic agents.

Contraindications

History of hypersensitivity or anaphylactic reaction is an absolute contraindication to the use of pancuronium.

Renal disease is a relative contraindication to the use of pancuronium, especially with other available NMBDs which have decreased or absent renal clearance such as rocuronium, vecuronium, and cisatracurium.

Use of pancuronium should merit careful consideration in cardiac dysfunction, and myocardial disease due to concerns for myocardial ischemia, ventricular ectopy, and cardiovascular collapse secondary to vagolytically mediated tachycardia.[9]

Monitoring

Monitoring of neuromuscular blockade with pancuronium should be through qualitative and/or quantitative peripheral nerve stimulation. Most often, this is accomplished by placement of electrodes overlying the facial nerve on the lateral face, the ulnar nerve at the wrist, or the tibial nerve at the ankle. Supramaximal electrical stimulation produces muscular contraction which may be observed to achieve qualitative evaluation or measured by acceleromyography to achieve quantitative assessment. There are patterns of neural stimulation to monitor neuromuscular blockade including train-of-four (TOF), tetanus, and double burst stimulation (DBS).

Typical TOF stimulation occurs with four electrical impulses at 2 Hz. With each repetitive stimulation in the presence of pancuronium or other nondepolarizing NMBD, ACh is released at the NMJ in diminishing amounts correlating to the decreased amplitude of muscular contraction. The ratio of the first and fourth muscular contraction is measured as the TOF ratio which allows for quantification and estimation of recovery from the neuromuscular blockade. Typical tetanic stimulation occurs with a continuous electrical stimulation at 50 Hz over 5 seconds. Pancuronium and other nondepolarizing NMBD result in a non-sustained or fading, the amplitude of muscular contraction. DBS is characterized by two bursts of three electrical stimuli separated by 750 ms which are recognized clinically as two separated twitches. DBS provides an improved ability to discern deep levels of neuromuscular blockade.[10] Monitoring of neuromuscular blockade is imperative for maintaining appropriate blockade and allowing for recovery from and reversal of blockade at the end of a surgical case.

Enhancing Healthcare Team Outcomes

Recovery from pancuronium can be prolonged compared to other NMBDs. The use of an anticholinesterase drug can help hasten this recovery; neostigmine is a typical drug for reversal of NBMD in the peri-operative setting although edrophonium or pyridostigmine are also options. Reversal of neuromuscular blockade occurs by increasing the ACh available at the NMJ by inhibition of cholinesterase, allowing for ACh to competitively inhibit pancuronium to bind and block the postjunctional receptors. It is critical to note that the administration of anticholinesterase medications may be ineffective with a significant depth of blockade. Anticholinesterase drugs should be administered with anticholinergic drugs to prevent bradycardia in the reversed patient.

Due to the long duration of action of pancuronium, it may be associated with more residual blockade after reversal when compared to intermediate- and short-acting NMBDs.[11]


References

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[7] Op de Coul AA,Lambregts PC,Koeman J,van Puyenbroek MJ,Ter Laak HJ,Gabreëls-Festen AA, Neuromuscular complications in patients given Pavulon (pancuronium bromide) during artificial ventilation. Clinical neurology and neurosurgery. 1985;     [PubMed PMID: 3987137]
[8] Segredo V,Caldwell JE,Matthay MA,Sharma ML,Gruenke LD,Miller RD, Persistent paralysis in critically ill patients after long-term administration of vecuronium. The New England journal of medicine. 1992 Aug 20;     [PubMed PMID: 1353252]
[9] Murray MJ,DeBlock H,Erstad B,Gray A,Jacobi J,Jordan C,McGee W,McManus C,Meade M,Nix S,Patterson A,Sands MK,Pino R,Tescher A,Arbour R,Rochwerg B,Murray CF,Mehta S, Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient. Critical care medicine. 2016 Nov;     [PubMed PMID: 27755068]
[10] Murphy GS, Neuromuscular Monitoring in the Perioperative Period. Anesthesia and analgesia. 2018 Feb;     [PubMed PMID: 28795964]
[11] Hunter JM, Reversal of residual neuromuscular block: complications associated with perioperative management of muscle relaxation. British journal of anaesthesia. 2017 Dec 1;     [PubMed PMID: 29161387]