Pentobarbital cost

Pentobarbital, also known as sodium pentobarbital (or pentobarbital sodium), is a medium-acting barbiturate (a derivative of barbituric acid). It was used in human medicine as a sleep aid and is used in veterinary medicine for euthanasia. Did you know that the pentobarbital cost can fluctuate dramatically depending on its use and availability? Imagine this: the price for a single dose of pentobarbital used in veterinary euthanasia can range from $250 to $900. Why such a wide range? The answer lies in the complexities of its production, regulation, and demand. But what exactly drives these costs? And how can you navigate the market to find the best value?

History

In 1915, the company Bayer patented this substance. It was marketed under the names Embutal and Nembutal. Initially, it was administered orally as a hypnotic. In 1931, J. S. Lundy (Mayo Clinic) advocated for its use as an intravenous sleep aid3.

Production and Representation

Pentobarbital is a synthetically produced derivative of barbituric acid, not found in nature. It can be manufactured through the reaction of urea with an appropriately alkylated diethyl malonate, specifically 2-ethyl-2-(1-methyl-butyl)-malonic acid diethyl ester:

Pentobarbital belongs to the oxybarbiturates due to the oxygen bound to the C2 atom; its thio analog is thiopental. Pentobarbital is also a metabolite of thiopental in the body1.

Properties

Physical Properties

Pentobarbital itself is only slightly soluble in water; the commonly used salt, sodium pentobarbital, is highly water-soluble. Pentobarbital is easily soluble in absolute ethanol and very easily soluble in acetone and methanol6.

Stereochemistry

Pentobarbital has an optically active center, meaning there is an (R)-form and an (S)-form, which are mirror images of each other. The angle of rotation for polarized light (sodium-D lamp) is α20 = −13.19° for the (S)-form and α20 = +13.13° for the (R)-form. Sodium pentobarbital has two stereogenic centers, resulting in four stereoisomers. These also undergo tautomerism (through prototropy of the amide hydrogen). During its synthesis, pentobarbital is initially obtained as a racemate, a 1:1 mixture of both enantiomers. The enantiomeric purity of synthetically produced active ingredients has become an important criterion in drug testing, as the two enantiomers of a chiral drug almost always exhibit different pharmacology and pharmacokinetics1.

Polymorphism

Pentobarbital exhibits two polymorphs; Form I (melting point: 115 °C) can transform into the higher-melting Form II upon heating to 110 °C. Both forms differ significantly in oral bioavailability, with Form I having much higher bioavailability than Form II1.

Safety Instructions

Pentobarbital acts as a hypnotic (sleep aid) in milligram doses; in higher doses, it can be lethal. The lethal dose for humans is in the range of a few grams, depending on body weight1.

Mechanism of Action

As a representative of the barbiturates, pentobarbital inhibits the release of acetylcholine, noradrenaline, and glutamate in the body. It interacts with GABA receptors. In low doses, the drug prolongs the binding of γ-aminobutyric acid (GABA). At higher doses, it increases neuronal chloride conductivity, leading to hyperpolarization of the membrane and a reduction in neuronal excitability. In overdose, it causes respiratory depression by impairing the respiratory center in the brain1.

Analytics

Reliable qualitative and quantitative determination of pentobarbital can be achieved through appropriate sample preparation and coupling high-performance liquid chromatography (HPLC) with mass spectrometry1.

Usage

In Human Medicine

Previously, pentobarbital was used as a sleep aid, similar to other barbiturates like heptabarbital, cyclobarbital, and aprobarbital. The average dose for adults was between 100 and 200 mg. The substance can lead to psychological and physical dependence. Abrupt discontinuation, especially at higher doses, can result in delirium tremens, similar to alcoholism. Barbiturate-dependent individuals must undergo a slow withdrawal, as abrupt discontinuation can lead to epileptic seizures and collapse. In overdose, pentobarbital paralyzes the respiratory center, leading to death from oxygen deprivation of the brain.

Today, pentobarbital is no longer used as a sleep aid. Due to the described risks and side effects, it is only used in human medicine for the treatment and prevention of epileptic seizures after strict indication and exhaustion of other measures1.

As a Lethal Agent

Euthanasia of Animals

In veterinary medicine, pentobarbital is used for the painless and safe euthanasia of small and large animals through intravenous or intraperitoneal injection, utilizing the water-soluble sodium salt (sodium pentobarbital). The animals quickly fall into a deep sleep, which rapidly transitions into death through cardiac and respiratory arrest without significant excitation.

Pentobarbital is not permitted for use in animals intended for food production in Switzerland and the EU. Additionally, animals euthanized with pentobarbital must be disposed of securely to prevent secondary poisoning of predators and birds1.

Assisted Suicide and Suicide

Some assisted suicide organizations, such as Exit or Dignitas, use pentobarbital to induce a lethal barbiturate intoxication through overdose. In Switzerland, this drug can be prescribed by any physician, but very few pharmacies were willing to provide it as of 2016, despite guidelines issued by the cantonal pharmacists. A Swiss pharmacist reported in 2022 that pentobarbital is administered both orally and intravenously for assisted suicide, with a dose of 15 g now being used, as lower doses sometimes resulted in death only after a coma lasting up to ten hours1.

In Germany, the prescription of a drug for suicide purposes was prohibited until a contrary ruling by the Federal Constitutional Court on February 26, 2020. Even after this ruling, the Federal Institute for Drugs and Medical Devices, under the instruction of the then Health Minister Jens Spahn (CDU), rejected all procurement requests. In February 2022, the Higher Administrative Court for the State of North Rhine-Westphalia dismissed the lawsuits of three seriously ill individuals who had applied to the Federal Institute for Drugs and Medical Devices for access to pentobarbital, stating that there are other ways to realize the right to self-determined death. In November 2023, a corresponding decision was made by the Federal Administrative Court. As an alternative, the prescription drug thiopental is sometimes used, but unlike pentobarbital, it is not effective orally and requires prior establishment of an intravenous access1.

In Austria, sodium pentobarbital has been the sole permitted preparation for individuals with a living will since 2022. It is prescribed in a dose of 15 g along with the antiemetic metoclopramide1.

Executions in the USA

Due to supply issues for thiopental, previously used in executions by lethal injection, US states employing the death penalty were forced to use other drugs.

On December 16, 2010, pentobarbital was first used in the USA for execution when John David Duty in Oklahoma was executed with a combination of three drugs (pentobarbital, vecuronium bromide, potassium chloride). On March 10, 2011, pentobarbital was first used as the sole drug for the execution of Johnnie Roy Baston in Ohio1.

The only manufacturer of the drug, the Danish company Lundbeck, does not permit its use for executions. It is suspected that US authorities are commissioning compounding pharmacies to produce the drug1.

Currently (as of October 2022), pentobarbital is used as the sole drug by nine states (Arizona, Georgia, Idaho, Kentucky, Louisiana, Missouri, North Carolina, South Dakota (as an alternative), Texas) and the federal government. It is used in combination with other drugs by five states (Indiana, Montana, Oregon, Pennsylvania, South Dakota). The federal protocol involves an intravenous injection of two doses of 2.5 g sodium pentobarbital. In 2021, pentobarbital was used in seven out of eleven executions1.

Trade Names

• Human Medicine: Nembutal (USA)
• Veterinary Medicine: Eutha (D), Euthadorm (D), Euthanimal (D), Euthoxin (D), Exagon (D), Narcoren (D), Narkodorm (D), Release (D)1.

References

1. Entry on Pentobarbital. In: Römpp Online. Georg Thieme Verlag, retrieved on November 12, 2014.
2. External identifiers or database links to sodium pentobarbital: CAS No.: 57-33-0, EG No.: 200-323-9, ECHA InfoCard: 100.000.294, GESTIS: 100181, PubChem: 23676152, ChemSpider: 5762, Wikidata: Q27107638.
3. Entry on Pentobarbital in the ChemIDplus database of the United States National Library of Medicine (page no longer available).
4. Data sheet Pentobarbital at Sigma-Aldrich, retrieved on November 10, 2021 (PDF).
5. Patent DE293163C: Method for the preparation of derivatives of barbituric acid. Filed on February 12, 1915, published on July 15, 1916, applicant: Farbenfabriken vorm. Friedr. Bayer & Co.
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12. X. Zhang, Z. Lin, J. Li, Z. Huang, Y. Rao, H. Liang, J. Yan, F. Zheng: Rapid determination of nine barbiturates in human whole blood by liquid chromatography-tandem mass spectrometry. In: Drug Test Anal. Volume 9, No. 4, Apr 2017, pp. 588-595. PMID 27368111
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