Chemistry:Sodium thiopental

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Short description: Barbiturate general anesthetic
Sodium thiopental
Sodium thiopental.svg
Clinical data
Trade namesPentothal, Trapanal
Other namesTruth serum, thiopentone, thiopental
AHFS/Drugs.comMonograph
Pregnancy
category
  • AU: D
Routes of
administration		Intravenous (most common), oral, or rectal
Drug classBarbiturate
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding80%
MetabolismLiver
MetabolitesPentobarbital, others
Onset of action30–45 seconds
Elimination half-life5.5[1]–26 hours[2]
Duration of action5–10 minutes
Identifiers
CAS Number
  • 71-73-8 ☑Y (sodium salt)
    76-75-5 (free acid)
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC11H17N2NaO2S
Molar mass264.32 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
 ☒N☑Y (what is this?)  (verify)

Sodium thiopental, also known as Sodium Pentothal (a trademark of Abbott Laboratories), thiopental, thiopentone, or Trapanal (also a trademark), 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,[3] but was supplanted by propofol.[4][5][6] Despite this, thiopental is listed as an acceptable alternative to propofol, depending on local availability and cost of these agents.[6] It was previously the first of three drugs administered during most lethal injections in the United States, but the US manufacturer Hospira stopped manufacturing the drug in 2011 and the European Union banned the export of the drug for this purpose.[7] Although thiopental abuse carries a dependency risk, its recreational use is rare.[8]

Uses

Anesthesia

Sodium thiopental is an ultra-short-acting barbiturate and has been used commonly in the induction phase of general anesthesia. Its use has been largely replaced with that of propofol, but may retain some popularity as an induction agent for rapid-sequence induction and intubation, such as in obstetrics.[9] Following intravenous injection, the drug rapidly reaches the brain and causes unconsciousness within 30–45 seconds. At one minute, the drug attains a peak concentration of about 60% of the total dose in the brain. Thereafter, the drug distributes to the rest of the body, and in about 5–10 minutes the concentration is low enough in the brain that consciousness returns.

A normal dose of sodium thiopental (usually 4–6 mg/kg) given to a pregnant woman for operative delivery (caesarean section) rapidly makes her unconscious, but the baby in her uterus remains conscious. However, larger or repeated doses can depress the baby's consciousness.[10]

Sodium thiopental is not used to maintain anesthesia in surgical procedures because, in infusion, it displays zero-order elimination pharmacokinetics, leading to a long period before consciousness is regained. Instead, anesthesia is usually maintained with an inhaled anesthetic (gas) agent. Inhaled anesthetics are eliminated relatively quickly, so that stopping the inhaled anesthetic will allow rapid return of consciousness. Sodium thiopental would have to be given in large amounts to maintain unconsciousness during anaesthesia due to its rapid redistribution throughout the body (as it has a high volume of distribution). Since its half-life of 5.5 to 26 hours is quite long, consciousness would take a long time to return.[2]

In veterinary medicine, sodium thiopental is used to induce anesthesia in animals. Since it is redistributed to fat, certain lean breeds of dogs such as sighthounds will have prolonged recoveries from sodium thiopental due to their lack of body fat and their lean body mass. Conversely, obese animals will have rapid recoveries, but it will take much longer for the drug to be entirely removed (metabolized) from their bodies. Sodium thiopental is always administered intravenously, as it can be fairly irritating to tissue and is a vesicant; severe tissue necrosis and sloughing can occur if it is injected incorrectly into the tissue around a vein.[11]

Medically-induced coma

In addition to anesthesia induction, sodium thiopental was historically used to induce medical comas.[12] It has now been superseded by drugs such as propofol because their effects wear off more quickly than thiopental. Patients with brain swelling, causing elevation of intracranial pressure, either secondary to trauma or following surgery, may benefit from this drug. Sodium thiopental, and the barbiturate class of drugs, decrease neuronal activity thereby decreasing cerebral metabolic rate of oxygen consumption (CMRO2), decrease the cerebrovascular response to carbon dioxide, which in turn decreases intracranial pressure. Patients with refractory elevated intracranial pressure (RICH) due to traumatic brain injury (TBI) may have improved long term outcome when barbiturate coma is added to their neurointensive care treatment.[13] Reportedly, thiopental has been shown to be superior to pentobarbital in reducing intracranial pressure.[14] This phenomenon is also called an inverse steal or Robin Hood effect as cerebral perfusion to all parts of the brain is reduced (due to the decreased cerebrovascular response to carbon dioxide) allowing optimal perfusion to ischaemic areas of the brain which have higher metabolic demands, since vessels supplying ischaemic areas of the brain would already be maximally dilated because of the metabolic demand.[15]

Status epilepticus

In refractory status epilepticus, thiopental may be used to terminate a seizure.

Euthanasia

Sodium thiopental is used intravenously for the purposes of euthanasia. In both Belgium and the Netherlands, where active euthanasia is allowed by law, the standard protocol recommends sodium thiopental as the ideal agent to induce coma, followed by pancuronium bromide to paralyze muscles and stop breathing.[16]

Intravenous administration is the most reliable and rapid way to accomplish euthanasia. Death is quick. A coma is first induced by intravenous administration of 20 mg/kg thiopental sodium (Nesdonal) in a small volume (10 mL physiological saline). Then, a triple dose of a non-depolarizing neuromuscular blocking drug is given, such as 20 mg pancuronium bromide (Pavulon) or 20 mg vecuronium bromide (Norcuron). The muscle relaxant should be given intravenously to ensure optimal bioavailability but pancuronium bromide may be administered intramuscularly at an increased dosage level of 40 mg.[16]

Lethal injection

Along with pancuronium bromide and potassium chloride, thiopental is used in 34 states of the US to execute prisoners by lethal injection. A very large dose is given to ensure rapid loss of consciousness. Although death usually occurs within ten minutes of the beginning of the injection process, some have been known to take longer.[17] The use of sodium thiopental in execution protocols was challenged in court after a study in the medical journal The Lancet reported autopsies of executed inmates showed the level of thiopental in their bloodstream was insufficient to cause unconsciousness although this is dependent on different factors and not just on the drug itself.

On December 8, 2009, Ohio became the first state to use a single dose of sodium thiopental for its capital execution, following the failed use of the standard three-drug cocktail during a recent execution, due to inability to locate suitable veins. Kenneth Biros was executed using the single-drug method.[18]

Washington State became the second state in the US to use the single-dose sodium thiopental injections for executions. On September 10, 2010, the execution of Cal Coburn Brown was the first in the state to use a single-dose, single-drug injection. His death was pronounced approximately one and a half minutes after the intravenous administration of five grams of the drug.[19]

After its use for the execution of Jeffrey Landrigan in the US, the United Kingdom introduced a ban on the export of sodium thiopental in December 2010,[20] after it was established that no European supplies to the US were being used for any other purpose.[21] The restrictions were based on "the European Union Torture Regulation (including licensing of drugs used in execution by lethal injection)".[22] From 21 December 2011, the EU extended trade restrictions to prevent the export of certain medicinal products for capital punishment, stating that "the Union disapproves of capital punishment in all circumstances and works towards its universal abolition".[23]

Truth serum

Further information: Social:Truth serum

Thiopental is still used in some places as a truth serum to weaken the resolve of a subject and make the individual more compliant to pressure.[24] Barbiturates decrease both higher cortical brain function and inhibition. It is hypothesized that because lying is a more mentally involving process than telling the truth, suppression of the higher cortical functions may lead to the uncovering of the truth. The drug tends to make subjects verbose and cooperative with interrogators; however, the reliability of confessions made under thiopental is questionable.[25]

Psychiatry

Psychiatrists have used thiopental to desensitize patients with phobias[26] and to "facilitate the recall of painful repressed memories."[27] One psychiatrist who worked with thiopental is Jan Bastiaans, who used this procedure to help relieve trauma in surviving victims of the Holocaust.[28]

Mechanism of action

Main page: Chemistry:Barbiturate

Sodium thiopental is a member of the barbiturate class of drugs, which are relatively non-selective compounds that bind to an entire superfamily of ligand-gated ion channels, of which the GABAA receptor channel is one of several representatives. This superfamily of ion channels includes the neuronal nicotinic acetylcholine receptor (nAChR), the 5-HT3 receptor, the glycine receptor and others. Surprisingly, while GABAA receptor currents are increased by barbiturates (and other general anesthetics), ligand-gated ion channels that are predominantly permeable for cationic ions are blocked by these compounds. For example, neuronal nAChR are blocked by clinically relevant anesthetic concentrations of both sodium thiopental and pentobarbital.[29] Such findings implicate (non-GABAergic) ligand-gated ion channels, e.g. the neuronal nAChR, in mediating some of the (side) effects of barbiturates.[30] The GABAA receptor is an inhibitory channel that decreases neuronal activity, and barbiturates enhance the inhibitory action of the GABAA receptor.[31]

Controversies

Following a shortage that led a court to delay an execution in California, a company spokesman for Hospira, the sole American manufacturer of the drug, objected to the use of thiopental in lethal injection. "Hospira manufactures this product because it improves or saves lives, and the company markets it solely for use as indicated on the product labeling. The drug is not indicated for capital punishment and Hospira does not support its use in this procedure."[32] On January 21, 2011, the company announced that it would stop production of sodium thiopental from its plant in Italy, because it could not provide Italian authorities with guarantees that exported doses would not be used in executions. According to a company spokesperson, Italy was the only viable place where it could produce the drug, leaving the US without a supplier.[33]

In October 2015 the U.S. Food and Drug Administration confiscated an overseas shipment of thiopental destined for the states of Arizona and Texas. FDA spokesman Jeff Ventura said in a statement, "Courts have concluded that sodium thiopental for the injection in humans is an unapproved drug and may not be imported into the country".[34]

Metabolism

Thiopental rapidly and easily crosses the blood–brain barrier as it is a lipophilic molecule. As with all lipid-soluble anaesthetic drugs, the short duration of action of sodium thiopental is due almost entirely to its redistribution away from central circulation into muscle and fatty tissue, due to its very high lipid–water partition coefficient (approximately 10), leading to sequestration in fatty tissue. Once redistributed, the free fraction in the blood is metabolized in the liver by zero-order kinetics. Sodium thiopental is mainly metabolized to pentobarbital,[35] 5-ethyl-5-(1'-methyl-3'-hydroxybutyl)-2-thiobarbituric acid, and 5-ethyl-5-(1'-methyl-3'-carboxypropyl)-2-thiobarbituric acid.[36]

Dosage

The usual dose range for induction of anesthesia using thiopental is from 3 to 6 mg/kg; however, there are many factors that can alter this. Premedication with sedatives such as benzodiazepines or clonidine will reduce requirements due to drug synergy, as do specific disease states and other patient factors. Among patient factors are: age, sex, and lean body mass.[37] Specific disease conditions that can alter the dose requirements of thiopentone and for that matter any other intravenous anaesthetic are: hypovolemia, burns, azotemia, liver failure, hypoproteinemia, etc.[38]

Side effects

As with nearly all anesthetic drugs, thiopental causes cardiovascular and respiratory depression resulting in hypotension, apnea, and airway obstruction. For these reasons, thiopental should only be administered by suitably trained medical personnel, who should give thiopental in an environment equipped to provide (respiratory) support, such as mechanical ventilation. Other side-effects include headache, agitated emergence, prolonged somnolence, and nausea. Intravenous administration of sodium thiopental is followed instantly by an odor and/or taste sensation, sometimes described as being similar to rotting onions, or to garlic. Residual side-effects may last up to 36 hours.

Although each molecule of thiopental contains one sulfur atom, it is not a sulfonamide, and does not show the allergic reactions of sulfa/sulpha drugs.

Contraindications

Thiopental should be used with caution in cases of liver disease, Addison's disease, myxedema, severe heart disease, severe hypotension, a severe breathing disorder, or a family history of porphyria.[39][40]

Co-administration of pentoxifylline and thiopental causes death by acute pulmonary edema in rats. This pulmonary edema was not mediated by cardiac failure or by pulmonary hypertension but was due to increased pulmonary vascular permeability.[41]

History

Sodium thiopental was discovered in the early 1930s by Ernest H. Volwiler and Donalee L. Tabern, working for Abbott Laboratories. It was first used in human beings on March 8, 1934, by Dr. Ralph M. Waters[42] in an investigation of its properties, which were short-term anesthesia and surprisingly little analgesia.[43] Three months later,[44] Dr. John S. Lundy started a clinical trial of thiopental at the Mayo Clinic at the request of Abbott.[45] Abbott continued to make the drug until 2004, when it spun off its hospital-products division as Hospira.

Thiopental is famously associated with a number of anesthetic deaths in victims of the attack on Pearl Harbor. These deaths, relatively soon after the drug's introduction, were said to be due to excessive doses given to shocked trauma patients. However, recent evidence available through freedom of information legislation was reviewed in the British Journal of Anaesthesia,[46] which has suggested that this story was grossly exaggerated. Of the 344 wounded that were admitted to the Tripler Army Hospital, only 13 did not survive, and it is unlikely that thiopentone overdose was responsible for more than a few of these.

See also

References

  1. ↑ "Pharmacokinetics of thiopental after single and multiple intravenous doses in critical care patients". European Journal of Clinical Pharmacology 49 (1–2): 127–37. 1995. doi:10.1007/BF00192371. PMID 8751034. 
  2. ↑ 2.0 2.1 "Pharmacokinetics and plasma binding of thiopental. II: Studies at cesarean section". Anesthesiology 54 (6): 474–80. June 1981. doi:10.1097/00000542-198106000-00006. PMID 7235275. 
  3. ↑ WHO Model List of Essential Medicines 16th list, March 2009. Geneva, Switzerland: World Health Organization. 2009. 
  4. ↑ The selection and use of essential medicines : report of the WHO Expert Committee, March 2011 (including the 17th WHO model list of essential medicines and the 3rd WHO model list of essential medicines for children). Geneva: World Health Organization. 2012. WHO technical report series; 965. ISBN 9789241209656. 
  5. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  6. ↑ 6.0 6.1 World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  7. ↑ "Death Penalty Opposition: EU Set to Ban Export of Drug Used in US Executions". Spiegel Online International. https://www.spiegel.de/international/europe/death-penalty-opposition-eu-set-to-ban-export-of-drug-used-in-us-executions-a-803238.html. 
  8. ↑ "The Abuse of Agents Used to Induce or Maintain General Anesthesia: Intravenous Hypnotics and the Halogenated Hydrocarbons". Substance abuse: inpatient and outpatient management for every clinician. New York: Springer. December 2014. p. 115. doi:10.1007/978-1-4939-1951-2_10. ISBN 978-1493919512. OCLC 897466425. 
  9. ↑ "Comparison of the Effects of Thiopental Sodium and Propofol on Haemodynamics, Awareness and Newborns During Caesarean Section Under General Anaesthesia". Turkish Journal of Anaesthesiology and Reanimation 43 (2): 106–112. April 2015. doi:10.5152/TJAR.2014.75547. PMID 27366476. 
  10. ↑ Avery's Diseases of the Newborn. Elsevier Health Sciences. 12 August 2011. p. 169. ISBN 9781455727148. http://www.us.elsevierhealth.com/averys-diseases-of-the-newborn-9781437701340.html. Retrieved 13 August 2016. [yes|permanent dead link|dead link}}]
  11. ↑ "Injury due to extravasation of thiopental and propofol: Risks/effects of local cooling/warming in rats". Biochemistry and Biophysics Reports 8: 207–211. December 2016. doi:10.1016/j.bbrep.2016.09.005. PMID 28955958. 
  12. ↑ "TRAUMA.ORG: Critical Care: Barbiturate Coma". http://www.trauma.org/archive/anaesthesia/barbcoma.html. 
  13. ↑ "ICP management in patients suffering from traumatic brain injury: a systematic review of randomized controlled trials". Acta Neurochirurgica 159 (12): 2279–2287. December 2017. doi:10.1007/s00701-017-3363-1. PMID 29058090. 
  14. ↑ "Barbiturates for acute traumatic brain injury". The Cochrane Database of Systematic Reviews 12 (12): CD000033. December 2012. doi:10.1002/14651858.CD000033.pub2. PMID 23235573. 
  15. ↑ "Anesthetic Management of Head-injured Patients". http://www.amcresidents.com/lectures/Dr_Trickey/Physiology_of_CBF_and_CSF.htm. 
  16. ↑ 16.0 16.1 Royal Dutch Society for the Advancement of Pharmacy (1994). "Administration and Compounding of Euthanasic Agents". The Hague. http://wweek.com/html/euthanasics.html. 
  17. ↑ "Ohio executes inmate with 1-drug lethal injection". Associated Press. December 2001. https://nypost.com/2009/12/08/ohio-executes-inmate-with-1-drug-lethal-injection/. 
  18. ↑ "Kenneth Biros Execution: Ohio Man First to Die Under 1-Drug Thiopental Sodium Method". CBS News. 8 December 2009. https://www.cbsnews.com/news/kenneth-biros-execution-ohio-man-first-to-die-under-1-drug-thiopental-sodium-method/. 
  19. ↑ "Killer on death row 16-1/2 years is executed". The Seattle Times. 10 September 2010. http://seattletimes.nwsource.com/html/localnews/2012856652_execution10m.html. 
  20. ↑ "Drug sold in UK to be used for execution in Georgia". BBC News. 24 January 2011. https://www.bbc.co.uk/news/uk-12263460. 
  21. ↑ "US lethal injection drug faces UK export restrictions". BBC News. 29 November 2010. https://www.bbc.co.uk/news/uk-11865881. 
  22. ↑ "Controls on torture goods - Detailed guidance - GOV.UK". https://www.gov.uk/controls-on-torture-goods. 
  23. ↑ "EU Council Regulation (EU) No 1352/2011". https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2011:338:0031:0034:EN:PDF. 
  24. ↑ "Truth serum used on 'serial child killers'". Sydney Morning Herald. Reuters. January 12, 2007. https://www.smh.com.au/world/truth-serum-used-on-serial-child-killers-20070113-gdp8d6.html. 
  25. ↑ The Howdunit Book of Poisons (Howdunit). Cincinnati: Writers Digest Books. 2007. ISBN 978-1-58297-456-9. 
  26. ↑ "Behavioral desensitization of phobic anxiety using thiopental sodium". The American Journal of Psychiatry (American Psychiatric Association) 137 (12): 1580–2. December 1980. doi:10.1176/ajp.137.12.1580. PMID 6108082. 
  27. ↑ "Drugged Future?". TIME. February 24, 1958. http://content.time.com/time/magazine/article/0,9171,863001,00.html. 
  28. ↑ "The LSD Therapy Career of Jan Bastiaans, M.D". Newsletter of the Multidisciplinary Association for Psychedelic Studies (Multidisciplinary Association for Psychedelic Studies) 8 (1): 18–20. 1998. http://www.maps.org/news-letters/v08n1/08118sne.html. 
  29. ↑ "Intravenous anaesthetics inhibit nicotinic acetylcholine receptor-mediated currents and Ca2+ transients in rat intracardiac ganglion neurons". British Journal of Pharmacology 144 (1): 98–107. January 2005. doi:10.1038/sj.bjp.0705942. PMID 15644873. 
  30. ↑ "Which molecular targets are most relevant to general anaesthesia?". Toxicology Letters 100-101 (1–2): 1–8. November 1998. doi:10.1016/S0378-4274(98)00158-1. PMID 10049127. 
  31. ↑ "Anesthesia and Analgesia". University of Virginia School of Medicine. http://www.healthsystem.virginia.edu/internet/ccm/Anesth/aneshome.cfm. 
  32. ↑ "US executions delayed by shortage of death penalty drug" (in en). Guardian. 2010-09-28. http://www.theguardian.com/world/2010/sep/28/us-executions-delayed-drug-shortage. 
  33. ↑ "Key death penalty drug discontinued by U.S. maker" (in en). NBC News. January 21, 2011. http://www.nbcnews.com/health/health-news/key-death-penalty-drug-discontinued-u-s-maker-flna1C9467323. 
  34. ↑ "The FDA Confiscated A Supply Of Execution Drugs Texas Is Thought To Have Imported Illegally". Texas Monthly. October 27, 2015. https://www.texasmonthly.com/the-daily-post/the-fda-confiscated-a-supply-of-execution-drugs-texas-is-thought-to-have-imported-illegally/. 
  35. ↑ "Metabolism of thiopental-S35 and thiopental-2-C14 by a rat liver mince and identification of pentobarbital as a major metabolite". The Journal of Pharmacology and Experimental Therapeutics 114 (3): 343–57. July 1955. PMID 13243246. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=13243246. [|permanent dead link|dead link}}]
  36. ↑ "[Use of thiopental in man. Determination of this drug and its metabolites in plasma and urine by liquid phase chromatography and mass spectrometry]" (in fr). Comptes Rendus de l'Académie des Sciences, Série III 303 (1): 7–12. 1986. PMID 3093002. 
  37. ↑ "[The relationship of age to the pharmacokinetics of early drug distribution: the concurrent disposition of thiopental and indocyanine green.]" (in en). Anesthesiology 72 (3): 403–411. 1990. doi:10.1097/00000542-199003000-00002. PMID 2310019. 
  38. ↑ "PENTOTHAL". WebMD. 15 November 2021. https://www.rxlist.com/pentothal-drug.htm#description. 
  39. ↑ "Pentothal (thiopental)". eMedicineHealth. 12 April 2009. http://www.emedicinehealth.com/drug-thiopental/article_em.htm. 
  40. ↑ "Porphyrias". British Journal of Anaesthesia 85 (1): 143–53. July 2000. doi:10.1093/bja/85.1.143. PMID 10928003. https://academic.oup.com/bja/article/85/1/143/263924. 
  41. ↑ "Co-administration of pentoxifylline and thiopental causes death by acute pulmonary oedema in rats". British Journal of Pharmacology 149 (4): 450–5. October 2006. doi:10.1038/sj.bjp.0706871. PMID 16953192. 
  42. ↑ "This Month in Anesthesia History: March". Anesthesia History Association. http://www.anesthesia.wisc.edu/AHA/Calendar/March.html. 
  43. ↑ "The Investigator and His 'Uncompromising Scientific Honesty'". ASA Newsletter (American Society of Anesthesiologists) 65 (9): 7–9. September 2001. http://www.asahq.org/~/media/For%20Members/Publications/Periodicals/ASA%20Newsletter/NL%20Archives/2001/09%20Sept%2001.ashx. 
  44. ↑ "From this point in time: some memories of my part in the history of anesthesia". The Journal of the American Association of Nurse Anesthetists (American Association of Nurse Anesthetists) 34 (2): 95–102. April 1966. PMID 5175948. http://www.aana.com/Resources.aspx?id=1811. 
  45. ↑ "Chapter 7: Illegal or Legal?". History of Anesthesia with Emphasis on the Nurse Specialist. J.B. Lippincott. 1953. ISBN 0-8240-6525-5. http://www.aana.com/uploadedFiles/Resources/Archives_-_Library/Historical_Resources/Thatcher/0008CHP7.PDF. 
  46. ↑ "Thiopentone anaesthesia at Pearl Harbor". British Journal of Anaesthesia 75 (3): 366–8. September 1995. doi:10.1093/bja/75.3.366. PMID 7547061. 

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