Pentobarbital

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Pentobarbital
Pentobarbital 2d.svg
Pentobarbital ball-and-stick.png
Clinical data
Trade names Nembutal
AHFS/Drugs.com Monograph
MedlinePlus a682416
License data
Pregnancy
category
  • AU:C
Routes of
administration 		By mouth, intravenous, intramuscular, rectal
Drug class Barbiturate
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 70–90% (oral); 90% (rectal)
Protein binding 20–45%
Metabolism Liver
Elimination half-life 15–48 hours
Excretion Kidney
Identifiers
  • 5-Ethyl-5-(1-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.895 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C11H18N2O3
Molar mass 226.276 g·mol−1
3D model (JSmol)
  • O=C1NC(=O)NC(=O)C1(C(C)CCC)CC
  • InChI=1S/C11H18N2O3/c1-4-6-7(3)11(5-2)8(14)12-10(16)13-9(11)15/h7H,4-6H2,1-3H3,(H2,12,13,14,15,16) Yes check.svgY
  • Key:WEXRUCMBJFQVBZ-UHFFFAOYSA-N Yes check.svgY
   (verify)

Pentobarbital (US) or pentobarbitone (British and Australian) is a short-acting barbiturate typically used as a sedative, a preanesthetic, and to control convulsions in emergencies. [3] It can also be used for short-term treatment of insomnia but has been largely replaced by the benzodiazepine family of drugs.

Contents

In high doses, pentobarbital causes death by respiratory arrest. It is used for veterinary euthanasia and is used by some US states and the United States federal government for executions of convicted criminals by lethal injection. [4] In some countries and states, it is also used for physician-assisted suicide. [5] [6]

Pentobarbital was widely abused beginning in the late 1930s and sometimes known as "yellow jackets" due to the yellow color of Nembutal-branded capsules. [7] Pentobarbital in oral (pill) form is not commercially available. [4] [ failed verification ]

Pentobarbital was developed by Ernest H. Volwiler and Donalee L. Tabern  [ de ] at Abbott Laboratories in 1930.

Uses

Medical

Typical applications for pentobarbital are sedative, short term hypnotic, preanesthetic, insomnia treatment, and control of convulsions in emergencies. [3] Abbott Pharmaceutical discontinued manufacture of their Nembutal brand of Pentobarbital capsules in 1999, largely replaced by the benzodiazepine family of drugs.

Pentobarbital can reduce intracranial pressure in Reye's syndrome, treat traumatic brain injury and induce coma in cerebral ischemia patients. [8] Pentobarbital-induced coma has been advocated in patients with acute liver failure refractory to mannitol. [9]

Pentobarbital is also used as a veterinary anesthetic agent. [10]

Euthanasia and assisted suicide

Pentobarbital can cause death when used in high doses. It is used for euthanasia for humans as well as animals. It is taken alone, or in combination with complementary agents such as phenytoin, in commercial animal euthanasia injectable solutions. [5] [6]

Pentobarbital sodium (CAS No. 57-33-0) Pentobarbital sodium.svg
Pentobarbital sodium (CAS No. 57-33-0)

In the Netherlands, pentobarbital is part of the standard protocol for physician-assisted suicide for self-administration by the patient. [11] It is given in liquid form, in a solution of sugar syrup and alcohol, containing 9 grams of pentobarbital. This is preceded by an antiemetic to prevent vomiting. [11]

It is taken by mouth for physician-assisted death in the United States states of Oregon, Washington, Vermont, and California (as of January 2016). [12] [13] The oral dosage of pentobarbital indicated for physician-assisted suicide in Oregon is typically 10 g of liquid. [12] [13]

In Switzerland, sodium pentobarbital is administered to the patient intravenously. Once administered, sleep is induced within 30 seconds, and the heart stops beating within 3 minutes. [14] Oral administration is also used. A Swiss pharmacist reported in 2022 that the dose for assisted suicide had been raised to 15 grams because with lower doses death was preceded by a coma of up to 10 hours in some cases. [15]

Execution

Pentobarbital has been used or considered as a substitute for the barbiturate sodium thiopental used for capital punishment by lethal injection in the United States when that drug became unavailable. [16] In 2011 the U.S. manufacturer of sodium thiopental stopped production, and importation of the drug proved impossible. Pentobarbital was used in a U.S. execution for the first time in December 2010 in Oklahoma, as part of a three-drug protocol. [16] In March 2011 pentobarbital was used for the first time as the sole drug in a U.S. execution, in Ohio. Since then several states as well as the federal government have used pentobarbital for lethal injections; some use three-drug protocols and others use pentobarbital alone.

Pentobarbital is produced by the Danish company Lundbeck. Use of the drug for executions is illegal under Danish law, and when this was discovered, after public outcry in Danish media, Lundbeck stopped selling it to US states that impose the death penalty and prohibited US distributors from selling it to any customers, such as state authorities, that practice or participate in executions of humans. [17]

Texas began using the single-drug pentobarbital protocol for executing death-row inmates on 18 July 2012, [18] because of a shortage of pancuronium bromide, a muscle paralytic previously used as one component of a three-drug cocktail. [18] In October 2013, Missouri changed its protocol to allow for pentobarbital from a compounding pharmacy to be used in a lethal dose for executions. [19] It was first used in November 2013. [20] [21]

According to a December 2020 ProPublica article, by 2017 the federal Bureau of Prisons (BOP), in discussion with then Attorney General Jeff Sessions, had begun to search for suppliers of pentobarbital to be used in lethal injections. The BOP was aware that the use of pentobarbital as their "new drug choice" would be challenged in the courts because some lawyers had said that "pentobarbital would flood prisoners' lungs with froth and foam, inflicting pain and terror akin to a death by drowning." BOP claimed that these concerns were unjustified and that their two expert witnesses asserted that the use of pentobarbital was "humane". [22] On 25 July 2019, US Attorney General William Barr directed the federal government to resume capital punishment after 16 years. [23] The federal protocol provides for intravenous administration of two syringes each containing 2.5 grams of pentobarbital sodium followed by a saline flush. [24]

Pharmacology

Pharmacodynamics

Like other barbiturates, pentobarbital binds to the barbiturate-binding site on the GABA-A receptor. This action increases the duration of ion-channel opening. At high doses, pentobarbital is capable of opening the ion channel in the absence of GABA. [25]

Pharmacokinetics

Pentobarbital undergoes first-pass metabolism in the liver and possibly the intestines. [26]

Drug interactions

Administration of ethanol, benzodiazepines, opioids, antihistamines, other sedative-hypnotics, and other central nervous system depressants will cause possible additive effects. [8]

Chemistry

Pentobarbital is synthesized by methods analogous to that of amobarbital, the only difference being that the alkylation of α-ethylmalonic ester is carried out with 2-bromopentane in place of 1-bromo-3-methylbutane to give pentobarbital. [27] [28] [29]

Pentobarbital can occur as a free acid but is usually formulated as the sodium salt, pentobarbital sodium. The free acid is only slightly soluble in water and in ethanol [30] [31] while the sodium salt shows better solubility.

Society and culture

Pentobarbital is the INN, AAN, BAN, and USAN while pentobarbitone is a former AAN and BAN.

One brand name for this drug is Nembutal, coined by John S. Lundy, who started using it in 1930, from the structural formula of the sodium salt —Na (sodium) + ethyl + methyl + butyl + al (common suffix for barbiturates). [32] Nembutal is trademarked and manufactured by the Danish pharmaceutical company Lundbeck (now produced by Akorn Pharmaceuticals) is the only injectable form of pentobarbital approved for sale in the United States.

Nembutal capsule Pentobarbital DOJ.jpg
Nembutal capsule

Abbott discontinued its Nembutal brand of pentobarbital capsules in 1999, largely replaced by the benzodiazepine family of drugs. Abbott's Nembutal, known on the streets as "yellow jackets", was widely abused. [33] [34] They were available as 30, 50, and 100 mg capsules of yellow, white-orange, and yellow colors, respectively. [35]

Related Research Articles

<span class="mw-page-title-main">Sodium thiopental</span> Barbiturate general anesthetic

Sodium thiopental, also known as Sodium Pentothal, thiopental, thiopentone, or Trapanal, is a rapid-onset short-acting barbiturate general anesthetic. It is the thiobarbiturate analog of pentobarbital, and an analog of thiobarbital. Sodium thiopental was a core medicine in the World Health Organization's List of Essential Medicines, but was supplanted by propofol. Despite this, thiopental is listed as an acceptable alternative to propofol, depending on local availability and cost of these agents. It was the first of three drugs administered during most lethal injections in the United States until the US division of Hospira objected and stopped manufacturing the drug in 2011, and the European Union banned the export of the drug for this purpose. Although thiopental abuse carries a dependency risk, its recreational use is rare.

<span class="mw-page-title-main">Lethal injection</span> Form of execution involving injection of chemicals into the bloodstream

Lethal injection is the practice of injecting one or more drugs into a person for the express purpose of causing rapid death. The main application for this procedure is capital punishment, but the term may also be applied in a broader sense to include euthanasia and other forms of suicide. The drugs cause the person to become unconscious, stops their breathing, and causes a heart arrhythmia, in that order.

<span class="mw-page-title-main">Pancuronium bromide</span> Aminosteroid muscle relaxant

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

<span class="mw-page-title-main">Sedative</span> Drug that reduces excitement without inducing sleep

A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but the majority of them affect the neurotransmitter gamma-aminobutyric acid (GABA). In spite of the fact that each sedative acts in its own way, most produce relaxing effects by increasing GABA activity.

<span class="mw-page-title-main">Ethchlorvynol</span> Group of stereoisomers

Ethchlorvynol is a GABA-ergic sedative and hypnotic/soporific medication first developed by Pfizer in the 1950s. In the United States it was sold by Abbott Laboratories under the trade name Placidyl. Placidyl was available in 200 mg, 500 mg, and 750 mg strength gel filled capsules. While the 500 mg and 750 mg strength capsules were for use in reducing sleep latency, the 200 mg strength capsules were intended to be used to re-induce sleep in case of early awakening. Abbott discontinued production in 1999, due to it being replaced by the benzodiazepine family and its widespread abuse, after which Placidyl was available for about a year in the United States. Although, theoretically, ethchlorvynol could be manufactured for sale in the United States by another pharmaceutical company, no pharmaceutical company has chosen to do so. Individuals with a valid prescription for the substance may legally transport a reasonable amount of ethclorvynol with them into the United States.

<span class="mw-page-title-main">Lundbeck</span> Danish pharmaceutical company

H. Lundbeck A/S, commonly referred to as Lundbeck, is a Danish international pharmaceutical company engaged in the research, development, manufacturing, marketing and sale of pharmaceuticals across the world. The company’s products are targeted at brain diseases, including depression, schizophrenia, Alzheimer's disease, Parkinson's disease and migraine.

<span class="mw-page-title-main">Amobarbital</span> Barbiturate

Amobarbital is a drug that is a barbiturate derivative. It has sedative-hypnotic properties. It is a white crystalline powder with no odor and a slightly bitter taste. It was first synthesized in Germany in 1923. It is considered a short to intermediate acting barbiturate.

<span class="mw-page-title-main">Phenobarbital</span> Medication of the barbiturate type

Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of epilepsy in developing countries. In the developed world, it is commonly used to treat seizures in young children, while other medications are generally used in older children and adults. It is also used for veterinary purposes.

<span class="mw-page-title-main">Secobarbital</span> Obsolete sedative-hypnotic

Secobarbital, sold under the brand name Seconal among others, is a short-acting barbiturate drug originally used for the treatment of insomnia. It was patented by Eli Lilly and Company in 1934 in the United States. It possesses anesthetic, anticonvulsant, anxiolytic, sedative, and hypnotic properties. In the United Kingdom, it was known as quinalbarbitone. Secobarbital is considered to be an obsolete sedative-hypnotic and has largely been replaced by the benzodiazepine family. It was widely abused, known on the street as "red devils" or "reds." Among barbiturates, secobarbital carries a particularly high risk of abuse and addiction, which is largely responsible for it falling out of use.

<span class="mw-page-title-main">Butabarbital</span> Chemical compound

Butabarbital is a prescription barbiturate sleep aid and anxiety medication. Butabarbital has a particularly fast onset of effects and short duration of action compared to other barbiturates, which makes it useful for certain applications such as treating severe insomnia, relieving general anxiety and relieving anxiety before surgical procedures; however it is also relatively dangerous particularly when combined with alcohol, and so is now rarely used, although it is still prescribed in some Eastern European and South American countries. Its intermediate duration of action gives butabarbital an abuse potential slightly lower than secobarbital. Butabarbital can be hydrolyzed to valnoctamide.

Central nervous system (CNS) depression is a physiological state that can result in a decreased rate of breathing, decreased heart rate, and loss of consciousness, possibly leading to coma or death.

Veterinary anesthesia is a specialization in the veterinary medicine field dedicated to the proper administration of anesthetic agents to non-human animals to control their consciousness during procedures. A veterinarian or a Registered Veterinary Technician administers these drugs to minimize stress, destructive behavior, and the threat of injury to both the patient and the doctor. The duration of the anesthesia process goes from the time before an animal leaves for the visit to the time after the animal reaches home after the visit, meaning it includes care from both the owner and the veterinary staff. Generally, anesthesia is used for a wider range of circumstances in animals than in people not only due to their inability to cooperate with certain diagnostic or therapeutic procedures, but also due to their species, breed, size, and corresponding anatomy. Veterinary anesthesia includes anesthesia of the major species: dogs, cats, horses, cattle, sheep, goats, and pigs, as well as all other animals requiring veterinary care such as birds, pocket pets, and wildlife.

<span class="mw-page-title-main">Alcohol detoxification</span> Abrupt cessation of alcohol intake

Alcohol detoxification is the abrupt cessation of alcohol intake in individuals that have alcohol use disorder. This process is often coupled with substitution of drugs that have effects similar to the effects of alcohol in order to lessen the symptoms of alcohol withdrawal. When withdrawal does occur, it results in symptoms of varying severity.

<span class="mw-page-title-main">Embutramide</span> Chemical compound

Embutramide is a potent sedative drug that is structurally related to GHB. It was developed by Hoechst A.G. in 1958 and was investigated as a general anesthetic agent, but was found to have a very narrow therapeutic window, with a 50 mg/kg dose producing effective sedation and a 75 mg/kg dose being fatal. Along with strong sedative effects, embutramide also produces respiratory depression and ventricular arrhythmia. Because of these properties, it was never adopted for medical use as an anesthetic as it was considered too dangerous for this purpose. Instead it is used for euthanasia in veterinary medicine, mainly for the euthanization of dogs.

Desbutal was a brand name drug by Abbott containing 5 mg methamphetamine hydrochloride (Desoxyn) and 30 mg pentobarbital sodium (Nembutal); a substituted amphetamine and a barbiturate combined within the same pill. Desbutal was marketed as an antidepressant as well as a medication for the treatment of obesity, narcolepsy, parkinsonism, and alcoholism, although it was commonly also prescribed off-label for miscellaneous ailments. It had a high abuse potential and is no longer manufactured.

A euthanasia device is a machine engineered to allow an individual to die quickly with minimal pain. The most common devices are those designed to help terminally ill people die by voluntary euthanasia or assisted suicide without prolonged pain. They may be operated by a second party, such as a physician, or by the person wishing to die. There is an ongoing debate on the ethics of euthanasia and the use of euthanasia devices.

<span class="mw-page-title-main">Barbiturate</span> Class of depressant drugs derived from barbituric acid

Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as well as overdose potential among other possible adverse effects. They have been used recreationally for their anti-anxiety and sedative effects, and are thus controlled in most countries due to the risks associated with such use.

Suicide tourism, or euthanasia tourism, is the practice of potential suicide candidates travelling to a jurisdiction to die by suicide or assisted suicide which is legal in some jurisdictions, or the practice of travelling to a jurisdiction in order to obtain drugs that can aid in the process of ending one's own life.

Capital punishment is a legal penalty in the U.S. state of Montana.

<span class="mw-page-title-main">Euthanasia solution</span> Drug-containing solution for intentionally ending life

A euthanasia solution is a drug-containing aqueous solution for intentionally ending life to either relieve pain and suffering or execute convicts. The drugs used in euthanasia solution do not only need to be safe to personnel, but they also need to have a rapid onset of action and minimize the possible pain felt by humans and animals. To satisfy these requirements, the active ingredients in the euthanasia solution are usually anaesthetics, respiratory depressants, cardiotoxic drugs and cytotoxic drugs.

References

  1. ↑ "Therapeutic Goods (Poisons Standard—June 2024) Instrument 2024". 30 May 2024.
  2. ↑ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  3. 1 2 "Nembutal sodium- pentobarbital sodium injection". DailyMed. 31 December 2016. Retrieved 29 January 2020.
  4. 1 2 Palmer K (28 October 2013). "Ohio says it will switch to new drugs for executions". Reuters.
  5. 1 2 Chaar B, Sami Isaac S (20 October 2017). "Euthanasia drugs: What is needed from medications for assisted deaths?". abc.net.au. Australian Broadcasting Corporation . Retrieved 22 September 2021. Both secobarbital capsules and pentobarbital (usually known as the brand name, Nembutal) liquid — (not to be mistaken for epilepsy medication phenobarbital) have been used either alone or in combination for physician-assisted suicide or euthanasia. They are also used in injectable forms for animal euthanasia.
  6. 1 2 Martin H (13 August 2020). "Euthanasia referendum: What drugs are used in assisted dying, and how do they work?". Stuff . Retrieved 22 September 2021. In Australia, most people will ingest the lethal dose of pentobarbital as a drink – a white powder mixed with about 30 millilitres of a liquid suspension. [...] However, in cases where the person is too ill to ingest the medication themselves, a doctor or nurse practitioner could administer the dose, under the proposed Act.
  7. ↑ Cozanitis, Dimitri A (December 2004). "One hundred years of barbiturates and their saint". Journal of the Royal Society of Medicine. 97 (12): 594–598. doi:10.1177/014107680409701214. ISSN   0141-0768. PMC   1079678 . PMID   15574863.
  8. 1 2 "Pentobarbital" (Monograph). Drugs.com. AHFS.
  9. ↑ Stravitz RT, Kramer AH, Davern T, Shaikh AO, Caldwell SH, Mehta RL, et al. (November 2007). "Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group". Critical Care Medicine. 35 (11): 2498–2508. doi:10.1097/01.CCM.0000287592.94554.5F. PMID   17901832. S2CID   11924124.
  10. ↑ "Pentobarbital". Drugs.com.
  11. 1 2 Köhler W (23 November 2000). "Euthanica". Euthanesia Dossier (in Dutch). NRC Webpagina's.
  12. 1 2 Fass J, Fass A (May 2011). "Physician-assisted suicide: ongoing challenges for pharmacists". American Journal of Health-System Pharmacy. 68 (9): 846–849. doi:10.2146/ajhp100333. PMID   21515870.
  13. 1 2 Philip N, Stewart F (2006). The Peaceful Pill Handbook. Exit International US Ltd. p. 137. ISBN   0978878809 – via Google Books.
  14. ↑ Assisted dying in Switzerland (Video), Dying with Dignity in Canada, 15 February 2022, 39:00 min - 41:19 min, retrieved 6 November 2022
  15. ↑ Keller M (22 May 2022). "Assistierter Suizid in der Schweiz - Sterben auf Wunsch" [Assisted suicide in Switzerland - dying on request]. Deutschlandfunk (in German). Deutschlandradio. Retrieved 6 November 2022.
  16. 1 2 Mears B (21 May 2012). "States urge feds to help import lethal injection drugs". CNN.
  17. ↑ Sanburn J (7 August 2013). "The Hidden Hand Squeezing Texas' Supply of Execution Drugs". Time .
  18. 1 2 "Texas executes Yokamon Hearn with pentobarbitol". bbc.co.uk. BBC News. 18 July 2012. Retrieved 9 December 2017.
  19. ↑ Lewis A (15 November 2013). "Lethal injection: Secretive US states resort to untested drugs". bbc.co.uk. BBC News. Retrieved 17 March 2016.
  20. ↑ Salter J (20 November 2013). "Missouri executes serial killer Franklin". Yahoo News. Archived from the original on 23 November 2013.
  21. ↑ Martin SK (20 November 2013). "Joseph Paul Franklin Executed; First MO Inmate Killed Using Pentobarbital". Christian Post .
  22. ↑ Arnsdorf I (23 December 2020). "Inside Trump and Barr's Last-Minute Killing Spree". ProPublica. Retrieved 11 January 2021.
  23. ↑ Williams P, Arkin D (25 July 2019). "AG Barr orders reinstatement of the federal death penalty". NBC News.
  24. ↑ Notice of Adoption of Revised Protocol, U.S. Department of Justice, 25 July 2019
  25. ↑ Baer AB, Holstege CP (January 2005). "Barbiturates, Long-Acting". In Wexler P (ed.). Encyclopedia of Toxicology (Second ed.). New York: Elsevier. pp. 209–210. doi:10.1016/b0-12-369400-0/00104-6. ISBN   978-0-12-369400-3.
  26. ↑ Knodell RG, Spector MH, Brooks DA, Keller FX, Kyner WT (December 1980). "Alterations in pentobarbital pharmacokinetics in response to parenteral and enteral alimentation in the rat". Gastroenterology. 79 (6): 1211–1216. doi: 10.1016/0016-5085(80)90915-4 . PMID   6777235.
  27. ↑ Volwiler EH, Tabern DL (1930). "5,5-Substituted Barbituric Acids1". Journal of the American Chemical Society. 52 (4): 1676–1679. doi:10.1021/ja01367a061.
  28. ↑ Kaiserliches Patentamt German imperial patent, D.R.P. 293163 (16 July 1916), Bayer& Co
  29. ↑ GBpatent 650354,Wilde BE, Balaban IE,"Improvements in the manufacture of substituted barbituric and thiobarbituric acids",issued 21 February 1951, assigned to Geigy
  30. ↑ "Pentobarbital Compound summary". PubChem. U.S National Library of Medicine. CID4737.
  31. ↑ "FR1972_08_25_17226" (PDF). Food and Drug Administration. Archived from the original (PDF) on 11 March 2016.
  32. ↑ Fosburgh LC (August 1997). "From this point in time: some memories of my part in the history of anesthesia--John S. Lundy, MD". AANA Journal. 65 (4): 323–328. PMID   9281913.
  33. ↑ Jolly D (1 July 2011). "Danish Company Blocks Sale of Drug for U.S. Executions". The New York Times . Retrieved 20 November 2013.
  34. ↑ Aldrich MR, Ashley R, Horowitz M (1978). High Times Encyclopedia of Recreational Drugs. New York: Stonehill. p. 243. ISBN   0-88373-082-0. OCLC   4557439.
  35. ↑ Physicians' Desk Reference (33rd ed.). Oradell, New Jersey: Medical Economics Co. 1979. p. 403. ISBN   0-87489-999-0. OCLC   4636066.
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