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Pancuronium

Clinical data
AHFS/Drugs.com	Monograph
Pregnancy category	AU: B2
Routes of administration	Intravenous
ATC code	M03AC01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	NA
Protein binding	77 to 91%
Metabolism	Hepatic
Elimination half-life	1.5 to 2.7 hours
Excretion	Renal and biliary
Identifiers
IUPAC name [(2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-17-Acetyloxy-10,13-dimethyl-2,16-bis(1-methyl-3,4,5,6-tetrahydro-2H-pyridin-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 Number	16974-53-1 Y 15500-66-0 (bromide)
PubChem CID	441289
IUPHAR/BPS	4001
DrugBank	DB01337 Y
ChemSpider	25453 N
UNII	U9LY9Y75X2
KEGG	D00492 Y
ChEBI	CHEBI:7908 N
ChEMBL	ChEMBL185073 N
Chemical and physical data
Formula	C35H60N2O4
Molar mass	572.861 g/mol g·mol−1
InChI InChI=1S/C35H60N2O4.2BrH/c1-24(38)40-32-21-26-13-14-27-28(35(26,4)23-31(32)37(6)19-11-8-12-20-37)15-16-34(3)29(27)22-30(33(34)41-25(2)39)36(5)17-9-7-10-18-36;;/h26-33H,7-23H2,1-6H3;2*1H/q+2;;/p-2/t26-,27+,28-,29-,30-,31-,32-,33-,34-,35-;;/m0../s1 N Key:NPIJXCQZLFKBMV-YTGGZNJNSA-L N
NY (what is this?)  (verify)

Pancuronium (trademarked as Pavulon) is an aminosteroid muscle relaxant with various medical uses. It is used in euthanasia and is the second of three drugs administered during most lethal injections in the United States.

The lethal injection kills.

Mechanism of Action

Pancuronium is a typical non-depolarizing curare-mimetic muscle relaxant. It competitively inhibits the nicotinic acetylcholine receptor at the neuromuscular junction by blocking the binding of acetylcholine, hence its identification as a nicotinic antagonist. Pancuronium is a bis-quaternary ammonium muscle relaxant and the bis-quaternary ammoniums in the molecule provide pancuronium with the ability to serve as a nicotinic antagonist and inhibit the receptor by blocking acetylcholine. The similarities between the structures of acetylcholine and pancuronium contribute to the ability of pancuronium to act as a nicotinic antagonist and compete for cholinergic receptors, therefore reducing the response of the end plate to acetylcholine. The structural similarities, quaternary ammoniums and carboxylic acid esters, between the two compounds can be seen in the following figure and chemically enable pancuronium to undergo breakdown at the acetylcholine receptor.

It has slight vagolytic activity, causing an increase in heart rate, but no ganglioplegic (i.e., blocking ganglions) activity. It is a very potent muscle relaxant drug, with an ED95 (i.e., the dose that causes 95% depression of muscle twitch response) of only 60 µg/kg body weight. Onset of action is relatively slow compared to other similar drugs, in part due to its low dose - an intubating dose takes 3–6 minutes for full effect. Clinical effects (muscle activity lower than 25% of physiological) last for about 100 minutes. The time needed for full (over 90% muscle activity) recovery after single administration is about 120–180 minutes in healthy adults. The effects of pancuronium can be at least partially reversed by anticholinesterasics, such as neostigmine, pyridostigmine, and edrophonium.

Development

Pancuronium is designed to mimic the action of two molecules of acetylcholine with the quaternary nitrogen atoms spaced rigidly apart by the steroid rings at a distance of ten atoms (interonium distance). Decamethonium and suxamethonium also have this same interonium distance.

Uses in Medicine

General Anesthesia Adjunct

Pancuronium is used with general anesthesia in surgery for muscle relaxation and as an aid to intubation or ventilation. It does not have sedative or analgesic effects. When used for adults under balanced anesthesia, the initial dosage range for IV administration is 0.04 to 0.1 mg/kg, with incremental doses starting at 0.01 mg/kg. If used for endotracheal intubation, a bolus dose of 0.06 to 0.1 mg/kg are recommended, with the conditions needed for intubation occurring in between two and three minutes.

Cesarean Section

Pancuronium bromide is also utilized as a muscle relaxant in operational obstetrics, like Cesarean sections. Pancuronium is used to provide relaxation for intubation and operation and uses the same dosage as general surgical procedures.

Side Effects

Side-effects include moderately raised heart rate and thereby arterial pressure and cardiac output, excessive salivation, apnea and respiratory depression, rashes, flushing, and sweating. The muscular relaxation can be dangerous in the seriously ill and it can accumulate leading to extended weakness. Pancuronium is not preferable in long-term use in ICU-ventilated patients.

Euthanasia

In Belgium and the Netherlands, pancuronium is recommended in the protocol for euthanasia. After administering sodium thiopental to induce coma, pancuronium is delivered in order to stop breathing.

Uses in Lethal Injection Execution (United States)

Background

Lethal injection in the United States of America is practiced using one, two, and three drug sequences, with the three-drug sequence for lethal injection proving the most utilized. This protocol includes an anesthetic or sedative, followed by a muscle relaxant to paralyze the inmate, which is usually pancuronium bromide, and lastly potassium chloride to stop the inmate’s heart.

Sodium thiopental is the most commonly used anesthetic as it spares the inmate from conscious suffocation due to the pancuronium bromide and the immense pain from the potassium chloride. When administered with the correct dosage ranging from 1200 - 5000 milligrams, the anesthesia should prove more than enough to induce unconsciousness and eventually would lead to death. This is often the drug in the protocol that leads to improper executions.

As a paralytic drug, pancuronium bromide paralyzes all voluntary muscles, as well as the lungs and diaphragm. If given enough time, pancuronium would eventually lead to asphyxiation, but have no effect on consciousness or pain. Because of its effect solely as a paralytic, if the anesthetic or sedative used for the first drug did not work, the inmate would consciously suffer asphyxiation with no outward indications to the viewers because of paralysis. Additionally, if the potassium chloride is administered after the pancuronium and the anesthesia had yet to work appropriately, the inmate would suffer immense pain, but with no indication to the executioners or witnesses.

Potassium chloride is the last drug in the sequence and causes the inmate’s death. The other drugs would eventually cause death, but potassium chloride causes cardiac arrest and death within one minute of its injection. Without proper anesthesia, potassium chloride administration is excruciatingly painful, as the drug inflames potassium ions in the sensory nerve fibers, which causes the veins to burn as the drug moves to the heart.

Controversy

Like all non-depolarising muscle relaxants, pancuronium has no effect on level of consciousness. Therefore, if the anaesthetic used is insufficient, the individual may be awake but unable to cry out or move due to the effect of the pancuronium. There have been several civil lawsuits alleging similar failures of adequate anaesthesia during general surgical procedures. These have been largely due to improper or insufficient dosages of anaesthetic in concert with normal dosages of muscle relaxants such as pancuronium.

Amnesty International has objected to its use in lethal injections on the grounds that it "may mask the condemned prisoner's suffering during the execution," thereby leading observers to conclude that lethal injection is painless, or less cruel than other forms of execution.

Relevant Cases

Baze v. Rees (2008)

In Baze v. Rees the court held the Kentucky’s three-drug protocol was not unconstitutional because “proper administration of the first drug”, which is characterized as a “fast-acting barbiturate” that creates “a deep coma-like unconsciousness,” ensures that the inmate will not suffer the known pain from the second and third drugs in the protocol, pancuronium bromide and potassium chloride. This case set the precedent that a stay would not be permitted unless a “demonstrated risk of severe pain” that was “substantial when compared to the known and available alternatives.”

Glossip v. Gross (2015)

In Glossip v. Gross the court held that the “petitioners have failed to establish a likelihood of success on the merits of their claim that the use of midazolam violates the Eighth Amendment.” The adopted protocol for lethal injection in Oklahoma entailed three drugs, sodium thiopental, pancuronium bromide, and potassium chloride. Due to a shortage, the correctional facility was unable to obtain sodium thiopental or its common substitute in lethal injection, pentobarbital. Oklahoma then decided on a 500 milligram dose of the sedative midazolam. Oklahoma death row inmates filed an action claiming that the use of midazolam violated the Eighth Amendment. The District Court denied the motion after a three-day evidentiary hearing and held that the prisoners were unable to identify a “known and available alternate method of execution that presented a substantially less severe risk of pain” and also held that the prisoners “failed to establish a likelihood of showing that the use of midazolam created a demonstrated risk of severe pain,” which was affirmed by the Tenth Circuit.

General Medical Council Hearing of Dr. Michael Munro (2007)

In 2007, Michael Munro, a Scottish neonatologist at Aberdeen Maternity Hospital, was cleared of malpractice by the GMC Fitness to Practice panel after giving 23 times the standard dose of pancuronium to two dying neonates. In the final minutes of life, each baby was suffering from agonal gasping and violent body spasms, which was highly distressing for the parents to witness. Munro administered pancuronium to the babies after advising the parents that this would ease their suffering and could also hasten death. It is on record that neither of the children's parents was unhappy with Dr Munro's treatment of their babies.

Export limitations

The United Kingdom bans the export of pancuronium bromide to the United States.

Uses in Crime

Pancuronium was used in Efren Saldivar's killing spree. It was also used by the Skin Hunters to kill patients in the Polish city of Łódź. Pavulon was also used by Richard Angelo in 1987 to kill at least 10 patients under his care at the Good Samaritan Hospital in New York.