Pancuronium

M03A - Muscle relaxants, peripherally acting agents ATC M03AC01 Small molecule approved 1972 Parenteral Natural product Black-box warning

JFDA label: Alpax Ampoules 2 ml

⚠ Black-Box Warning

Experienced personnel:

Mechanism of Action

Blocks neural transmission at the myoneural junction by binding with cholinergic receptor sites

Contraindications

Source: Lexicomp

Hypersensitivity to pancuronium, bromide, or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (5)

Not Known Flushing · increased blood pressure · increased cardiac work · increased pulse · severe myasthenia (long-term use)

Nervous system disorders (1)

Not Known Paralysis (long-term use)

Gastrointestinal disorders (1)

Not Known Sialorrhea

Skin and subcutaneous tissue disorders (1)

Not Known Skin rash (transient)

Dosing

Source: Lexicomp

Administer IV; dose to effect; doses will vary due to interpatient variability Surgery: Initial: 0.06-0.1 mg/kg or 0.05 mg/kg after initial dose of succinylcholine for intubation; maintenance dose: 0.01 mg/kg administered 60-100 minutes after initial dose and then 0.01 mg/kg every 25-60 minutes Pretreatment/priming: 10% of intubating dose given 3-5 minutes before intubating dose ICU paralysis (eg, facilitate mechanical ventilation) in select adequately sedated patients: 0.06-0.1 mg/kg bolus followed by either: Continuous infusion: 1-2 mcg/kg/minute (0.06-0.12 mg/kg/hour) (Murray, 2002) or 0.8-1.7 mcg/kg/minute (0.048-0.102 mg/kg/hour) (Greenberg, 2013) or Intermittent bolus: 0.1-0.2 mg/kg every 1-3 hours

(For additional information see "Pancuronium: Pediatric drug information") Infants >1 month and Children: Refer to adult dosing.

Refer to adult dosing.

Elimination half-life is doubled, plasma clearance is reduced and rate of recovery is sometimes much slower. No dosage adjustment provided in manufacturer’s labeling; however, the following adjustments have been recommended (Aronoff 2007): CrCl >50 mL/minute: No dosage adjustment necessary. CrCl 10-50 mL/minute: Administer 50% of normal dose CrCl Hemodialysis/peritoneal dialysis: Avoid use. CRRT: Administer 50% of normal dose.

Elimination half-life is doubled, plasma clearance is doubled, recovery time is prolonged, volume of distribution is increased (50%) and results in a slower onset, higher total dosage, and prolongation of neuromuscular blockade. Patients with liver disease may develop slow resistance to nondepolarizing muscle relaxant. Large doses may be required and problems may arise in antagonism.

Warnings & Precautions

Source: Lexicomp

Neuromuscular cross-sensitivity

Cross-sensitivity with other neuromuscular-blocking agents may occur; use extreme caution in patients with previous anaphylactic reactions. Disease-related concerns:

Burn injury

Resistance may occur in burn patients (≥20% of total body surface area), usually several days after the injury, and may persist for several months after wound healing (Han, 2009).

Conditions which may antagonize neuromuscular blockade

Respiratory alkalosis, hypercalcemia, demyelinating lesions, peripheral neuropathies, denervation, and muscle trauma may result in antagonism of neuromuscular blockade (Greenberg, 2013; Miller, 2010; Murray, 2002; Naguib, 2002).

Conditions which may potentiate neuromuscular blockade

Electrolyte abnormalities (eg, severe hypocalcemia, severe hypokalemia, hypermagnesemia), neuromuscular diseases, metabolic acidosis, metabolic alkalosis, respiratory acidosis, Eaton-Lambert syndrome and myasthenia gravis may result in potentiation of neuromuscular blockade (Greenberg, 2013; Miller, 2010; Naguib, 2002).

Hepatic impairment

Elimination half-life is doubled due to reduced clearance of pancuronium and recovery is prolonged; use with caution in patients with hepatic impairment and adjust dose appropriately.

Renal impairment

Elimination half-life is doubled due to reduced clearance of pancuronium and recovery is prolonged; use with caution in patients with renal impairment and adjust dose appropriately. Special populations:

Elderly

Use with caution in the elderly, effects and duration are more variable.

Immobilized patients

Resistance may occur in patients who are immobilized. Dosage form specific issues:

Benzyl alcohol and derivatives

Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling. Other warnings/precautions:

Appropriate use

Maintenance of an adequate airway and respiratory support is critical.

Experienced personnel

[U.S. Boxed Warning]: Should be administered by adequately trained individuals familiar with its use.

Pregnancy & Lactation

Pregnancy

FDA category C

Animal reproduction studies have not been conducted. Small amounts of pancuronium cross the placenta (Daily, 1984). May be used short-term in cesarean section; reduced doses recommended in patients also receiving magnesium sulfate due to enhanced effects.

Lactation

No Data Hale L3

No information is available on the use of pancuronium during breastfeeding.

Monitoring

Clinical pearl	Heart rate, blood pressure, assisted ventilation status; cardiac monitor, blood pressure monitor, and ventilator required

Chemistry & Properties

Formula	C35H60N2O4+2
Molecular weight	572.88 g/mol
IUPAC name	[(2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-17-acetyloxy-10,13-dimethyl-2,16-bis(1-methylpiperidin-1-ium-1-yl)-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl] acetate
CAS	16974-53-1
PubChem CID	441289
InChIKey	`GVEAYVLWDAFXET-XGHATYIMSA-N`
logP	6.11 (XLogP 6.6)
Polar surface area	52.6 Å²
H-bond acceptors / donors	4 / 0
Drug-likeness (QED)	0.30
Lipinski violations	2

SMILES

CC(=O)O[C@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@@]4(C)[C@H]3C[C@H]([N+]3(C)CCCCC3)[C@@H]4OC(C)=O)[C@@]2(C)C[C@@H]1[N+]1(C)CCCCC1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCT1 (Inhibitor)P-gp (Inhibitor)OCT1 (Substrate)P-gp (Substrate)

Drug–drug interactions (53, DDInter)

Interacting drug	Severity	Management
Amikacin	major
Amikacin (liposome)	major
Gentamicin	major
Kanamycin	major
Neomycin	major
Paromomycin	major
Polymyxin B	major
Streptomycin	major
Aminophylline	moderate
Amphotericin B	moderate
Amphotericin B (cholesteryl sulfate)	moderate
Amphotericin B (lipid complex)	moderate
Amphotericin B (liposomal)	moderate
Bacitracin	moderate
Betamethasone	moderate
Chloroquine	moderate
Clindamycin	moderate
Clindamycin (topical)	moderate
Cyclophosphamide	moderate
Cyclosporine	moderate
Demeclocycline	moderate
Dexamethasone	moderate
Doxycycline	moderate
Dyphylline	moderate
Fludrocortisone	moderate
Gentamicin (topical)	moderate
Hydrocortisone	moderate
Lidocaine	moderate
Magnesium chloride	moderate
Magnesium sulfate	moderate
Mannitol	moderate
Methylprednisolone	moderate
Metoclopramide	moderate
Minocycline	moderate
Neomycin (topical)	moderate
Oxtriphylline	moderate
Oxytetracycline	moderate
Oxytocin	moderate
Prednisolone	moderate
Prednisone	moderate

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Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Alpax Ampoules	Ampoule 2 mg/ml	2 ml	Hikma Pharmaceuticals Co.Ltd/Jordan	—