Description of Pancuronium (PAVULON)

Pancuronium is a parenteral, long-acting, nondepolarizing, neuromuscular blocking agent indicated as an adjunct to general anesthesia to facilitate tracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. Pancuronium is approximately one-third less potent than vecuronium, with a longer duration of action at initially equipotent doses.

Pancuronium has little effect on histamine release at usual doses and is not likely to cause clinically significant bronchospasm compared to agents with histamine-releasing properties such as atracurium and succinylcholine; however, pancuronium may cause significant tachycardia and hypertension due to vagolytic properties.

Mechanism of Action of Pancuronium (Pavulon)

Muscle contraction is initiated by an action potential traveling from the central nervous system to the nerve terminal. At the nerve terminal, the action potential causes an influx of calcium, initiating release of acetylcholine (ACh) into the synaptic cleft. ACh binds to ACh receptors on the muscle fiber’s motor end-plate causing a conformational change that briefly opens sodium ion channels.

When an adequate number of ACh receptors are activated, membrane potential decreases and voltage-dependent sodium ion channels of adjacent muscle membranes activate, transmitting the action potential throughout the muscle fiber and resulting in muscle contraction. Nondepolarizing neuromuscular blocking agents (NMBAs) such as pancuronium produce skeletal muscle paralysis by competing with ACh for cholinergic receptor sites at the motor end-plate.

Neuromuscular blockade progresses in a predictable order, beginning with muscles associated with fine movements (e.g., eyes, face, and neck), followed by muscles of the limbs, chest, and abdomen and, finally, the diaphragm. Larger doses increase the chance of respiratory depression associated with relaxation of the intercostal muscles and the diaphragm. Muscle tone returns in the reverse order.
 
Pancuronium (Pavulon) is a bisquaternary aminosteroid. In addition to its therapeutic actions, pancuronium can cause an increase in heart rate and blood pressure due to vagolytic and weak sympathomimetic properties. Pancuronium produces little histamine release and no ganglion blockade, so hypotension and bronchospasm are not associated with its use.

Pharmacokinetics

Pancuronium is administered intravenously. Protein binding is approximately 87%, primarily to gamma globulin and albumin. After administration, pancuronium distributes to the extracellular space. Vd ranges from 0.24 to 0.28 L/kg in adult patients, which is similar to that of children (0.2 L/kg). Plasma clearance is approximately 1.1 to 1.9 mL/kg/minute in both pediatric and adult patients.

Metabolism occurs via hepatic pathways to at least 3 metabolites. Up to 25% of an administered pancuronium dose is recovered as the 3-hydroxy metabolite, which is approximately half as potent as the parent drug. Less than 5% of the administered dose is recovered as the 17-hydroxy and 3, 17-hydroxy metabolites, both of which are 50 times less potent than pancuronium. Of a pancuronium dose, 40% is excreted in the urine and 11% in the bile. Elimination half-life ranges from 89 to 161 minutes.
 
Affected cytochrome P450 isoenzymes and drug transporters: none

Route-Specific Pharmacokinetics

Intravenous Route
In general, neuromuscular blockade begins within 2 to 3 minutes, peaks in approximately 4 minutes, and persists 22 to 100 minutes in adults. Intensity and duration of action are affected by the dose, age of the patient, and the use of concurrent anesthetics and other neuromuscular blocking agents.

•Special Populations
Hepatic Impairment
Vd is increased by approximately 50%, plasma clearance is reduced by 22%, and elimination half-life is doubled in patients with hepatic cirrhosis. In patients with biliary obstruction, similar changes are seen in Vd and elimination half-life; plasma clearance is reduced by at least 50%.

Renal Impairment
Vd of pancuronium is often variable and may be increased in patients with renal failure. Plasma clearance is reduced by approximately 60% and elimination half-life is doubled. Rate of recovery is variable and may be prolonged.

Pediatrics
Children
In general, the pharmacokinetic parameters of pancuronium in children are comparable to those in adults. Vd of pancuronium in children is 0.2 L/kg, compared to 0.24 to 0.28 L/kg in adults. Although a smaller Vd suggests a smaller dosage requirement, acetylcholine receptor availability must also be considered. Children have a larger number of acetylcholine receptors compared to infants and adults due to their larger muscle mass to fat ratio. The plasma concentration of a drug needed to maintain paralysis increases as receptor numbers increase.

Therefore, dosage requirements on mg/kg basis are higher in children than in infants and adults. The dose required to produce 95% suppression of the muscle twitch response (ED95) of pancuronium is significantly greater in children (93 mcg/kg) than in infants (50 to 66 mcg/kg) and adults (50 to 67 mcg/kg). In a pharmacokinetic study of children ages 3 to 6 years (n = 12), those receiving pancuronium 0.1 mg/kg demonstrated a clearance of 1.7 ± 0.2 mL/kg/minute and an elimination half-life of 103 ± 23 minutes. These values are consistent with adult parameters. Onset of action is 2 to 4 minutes, and duration of clinical effect is approximately 24 minutes in children.
 
Neonates and Infants
Neonates and infants have less muscle mass, and therefore fewer acetylcholine receptors, compared to older pediatric populations; this results in the need for lower plasma concentrations of pancuronium to maintain paralysis. Additionally, hepatic enzyme immaturity may play a role in the lower dosage requirement. The dose required to produce 95% suppression of the muscle twitch response (ED95) of pancuronium in infants is 50 to 66 mcg/kg, which is less than children (93 mcg/kg) but comparable to adults (50 to 67 mcg/kg). Onset of action after a dose of 0.15 mg/kg in neonates is 1.5 to 2 minutes. Onset of action in infants is 2 to 5 minutes.

Generic Name

• Pancuronium Bromide

• Pavulon

• Musculoskeletal Agent
• Neuromuscular Blocker, Non-Depolarizing

• General anesthesia; Adjunct: Adult
• General anesthesia; Adjunct: Pediatric

• Musculoskeletal: Prolonged neuromuscular block

• Cardiovascular: Cardiovascular system problem, Hypertension
• Immunologic: Anaphylaxis
• Respiratory: Apnea, Respiratory depression

• Intravenous: for IV administration only
• Intravenous: injection is compatible in solution with NS, D5W, D5NS, and LR; when mixed, solutions will remain stable for 48 hrs

• Intravenous Solution: 1 MG/1 ML, 2 MG/1 ML

• General Dosage Information: dosage must be individualized
• General anesthesia; Adjunct: initial, 0.04 to 0.1 mg/kg IV (endotracheal intubation, 0.06 to 0.1 mg/kg IV); later incremental doses starting at 0.01 mg/kg may be used

• General Dosage Information: dosage must be individualized
• General anesthesia; Adjunct: (all ages except neonates) initial, 0.04 to 0.1 mg/kg IV (endotracheal intubation, 0.06 to 0.1 mg/kg IV); later incremental doses starting at 0.01 mg/kg may be used
• General anesthesia; Adjunct: (neonates) administer a test dose of 0.02 mg/kg IV to measure responsivenessa