Sodium thiopental

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Sodium thiopental
1:1 mixture (racemate)
Sodium-thiopental-3D-vdW-2.png
Systematic (IUPAC) name
(RS)-[5-ethyl-4,6-dioxo-5-(pentan-2-yl)-1,4,5,6-tetrahydropyrimidin-2-yl]sulfanide sodium
Clinical data
AHFS/Drugs.com monograph
Legal status
Routes Oral, intravenous
Pharmacokinetic data
Half-life 5.5[1]-26 hours[2]
Identifiers
CAS number 71-73-8 YesY (sodium salt)
76-75-5 (free acid)
ATC code N01AF03 N05CA19
PubChem CID 3000714
DrugBank DB00599
ChemSpider 2272257 YesY
UNII 49Y44QZL70 N
KEGG D00714 YesY
ChEBI CHEBI:9561 YesY
ChEMBL CHEMBL738 YesY
Chemical data
Formula C11H17N2NaO2S 
Mol. mass 264.32 g/mol
 N (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 that is an analogue of thiobarbital. Sodium thiopental is a core medicine in the World Health Organization's "Essential Drugs List", which is a list of minimum medical needs for a basic healthcare system.[3] 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 and the EU banned the export of the drug for this purpose.[4]

Synthesis[edit]

Thiopental is synthesized by the alkylation of ethylmalonic ester with 2-bromopentane in the presence of sodium ethoxide. The product ethyl-(1-methylbutyl)malonic ester undergoes heterocyclization with thiourea, using sodium ethoxide as a base.

Sodium thiopental synthesis: E.H. Volwlier, D.L. Tabern, U.S. Patent 2,153,729 (1939); G.H. Donaldson, W. Bay, U.S. Patent 2,876,225 (1959).

Barbiturates[edit]

Main article: Barbiturate

Barbiturates are a class of drugs that act on the GABAA receptor in the brain and spinal cord. The GABAA receptor is an inhibitory channel that decreases neuronal activity, and barbiturates enhance the inhibitory action of the GABAA receptor. Barbiturates, benzodiazepines, and alcohols all bind to the GABAA receptor. Barbiturates that act on the barbiturate binding site of the GABAA receptor directly gate the chloride ion channel of the GABAA receptor, whereas benzodiazepines acting on the benzodiazepine site on the GABAA receptor increase the opening frequency of the chloride ion channel. This explains why overdoses of barbiturates may be lethal whereas overdoses of benzodiazepines alone are typically not lethal. Another explanation is that barbiturates can activate GABA receptors in the absence of the GABA molecule, whereas benzodiazepines need GABA to be present to have an effect: this may explain the more widespread effects of barbiturates in the central nervous system. Barbiturates have anesthetic, sedative, anxiolytic, anticonvulsant, and hypnotic properties. Barbiturates do not have analgesic effects.[5]

Further, barbiturates are relatively non-selective compounds that bind to an entire superfamily of ligand-gated ion channels, of which the GABAA receptor channel is only one of several representatives. This superfamily of ion channels includes the neuronal nACHR channel, the 5HT3R channel, the GlyR channel 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 channels are blocked by clinically relevant anesthetic concentrations of both sodium thiopental and pentobarbital.[6] Such findings implicate (non-GABA-ergic) ligand-gated ion channels, e.g. the neuronal nAChR channel, in mediating some of the (side) effects of barbiturates.[7]

Uses[edit]

Anesthesia[edit]

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.[citation needed] 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 such that consciousness returns.[citation needed]

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

Sodium thiopental is not used to maintain anesthesia in surgical procedures because, in infusion, it displays zero-order elimination kinetics, 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 an anesthetic plane, and because of its 11.5–26 hour half-life, consciousness would take a long time to return.[8]

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 sight hounds 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 be sometime before it is entirely removed (metabolised) from their bodies. Sodium thiopental is always administered intravenously, as it can be fairly irritating; severe tissue necrosis and sloughing can occur if it is injected incorrectly into the tissue around a vein.[citation needed]

Medically induced coma[edit]

In addition to anesthesia induction, sodium thiopental was historically used to induce medical comas.[9] It has now been superseded by drugs such as propofol because their effects wear off more quickly than thiopental. However, extended use of propofol risks the onset of propofol infusion syndrome.

Patients with brain swelling, causing elevation of the 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 and therefore decrease the production of osmotically active metabolites, which in turn decreases swelling. Patients with significant swelling have improved outcomes following the induction of coma. Reportedly, thiopental has been shown to be superior to pentobarbital in reducing intracranial pressure.This phenomenon is also termed as Reverse steal Effect.[10]

Status epilepticus[edit]

In refractory status epilepticus, that is, status epilepticus that does not resolve with both benzodiazepines and anti-epileptic drugs, thiopental can be used as a third-line treatment. For this purpose, it can only be administered on an intensive care unit, as the required dose can lead to profound cardiorespiratory depression. The dose is titrated to a burst suppression pattern on the electroencephalogram.[11]

Euthanasia[edit]

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.[12]

Intravenous administration is the most reliable and rapid way to accomplish euthanasia. 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 skeletal muscle relaxant 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 availability but pancuronium bromide may be administered intramuscularly at an increased dosage level of 40 mg.[12]

Lethal injection[edit]

For more details on this topic, see Lethal injection.

Along with pancuronium bromide and potassium chloride, thiopental is used in 34 states of the U.S. 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.[13] 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.

On December 8, 2009, the State of Ohio became the first 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.[14]

The state of Washington is now the second state in the U.S. to use the single-dose sodium thiopental injections for death penalty executions. On September 10, 2010, Cal Coburn Brown was executed. This was the first execution 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.[15]

After its use for execution of Jeffrey Landrigan in the US, the United Kingdom introduced a ban on the export of sodium thiopental in December 2010,[16] after it was established that no European supplies to the US were being used for any other purpose.[17] The restrictions were based on "the European Union Torture Regulation (including licensing of drugs used in execution by lethal injection)".[18] From 21 December 2011 the European Union 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".[19]

Truth serum[edit]

For more details on this topic, see Truth serum.

Thiopental (Pentothal) is still used in some places as a truth serum to weaken the resolve of the subject and make them more compliant to pressure.[20] The barbiturates as a class decrease higher cortical brain functioning. Some psychiatrists hypothesize that because lying is more complex than telling the truth, suppression of the higher cortical functions may lead to the uncovering of the truth. The drug tends to make subjects loquacious and cooperative with interrogators; however, the reliability of confessions made under thiopental is questionable.[21] Sodium thiopental features as a truth serum in several Hollywood films, in comics and other literature, and even in popular music.[22]

Psychiatry[edit]

Psychiatrists have used thiopental to desensitize patients with phobias,[23] and to "facilitate the recall of painful repressed memories."[24] One psychiatrist who worked with thiopental is the Dutch Professor Jan Bastiaans, who used this procedure to help relieve trauma in surviving victims of the Holocaust.[25]

Controversies[edit]

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."[26] On January 21, 2011, the company announced that it would stop production of sodium thiopental from its plant in Italy because it could not guarantee Italian authorities that the drug would not be used in executions. Italy was the only viable place where the company could produce sodium thiopental, leaving the United States without a supplier.[27]

Metabolism[edit]

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 towards muscle and fat tissue, due to its very high fat:water partition coefficient (aprx 10), leading to sequestration in fat tissue. Once redistributed, the free fraction in the blood is metabolised in the liver. Sodium thiopental is mainly metabolized to pentobarbital,[28] 5-ethyl-5-(1'-methyl-3'-hydroxybutyl)-2-thiobarbituric acid, and 5-ethyl-5-(1'-methyl-3'-carboxypropyl)-2-thiobarbituric acid.[29]

Dosage[edit]

The usual dose range for induction of anesthesia using thiopental is from 3 to 7 mg/kg; however, there are many factors that can alter this. Premedication with sedatives such as benzodiazepines or clonidine will reduce requirements, as do specific disease states and other patient factors. Among patient factors are: age, sex, and lean body mass. Specific disease conditions that can alter the dose requirements of thiopentone and for that matter any other intravenous anaesthetic are: hypovolemia, burns, azotemia, hepatic failure, hypoproteinemia, etc.[citation needed]

Side effects[edit]

As with nearly all anesthetic drugs, thiopental causes cardiovascular and respiratory depression resulting in hypotension, apnea and airway obstruction. For these reasons, only suitably trained medical personnel should give thiopental in an environment suitably equipped to deal with these effects. 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. The hangover from the side effects may last up to 36 hours.

Although individual molecules of thiopental contain one sulfur atom, it is not a sulfonamide, and does not show allergic reactions of sulfa/sulpha drugs.

Contraindications[edit]

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.[30][31]

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.[32]

History[edit]

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[33] in an investigation of its properties, which were short-term anesthesia and surprisingly little analgesia.[34] Three months later,[35] Dr. John S. Lundy started a clinical trial of thiopental at the Mayo Clinic at the request of Abbott.[36] 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,[37] 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.

Thiopental is still rarely used as a recreational drug, usually stolen from veterinarians or other legitimate users of the drug; however, more common sedatives such as benzodiazepines are usually preferred as recreational drugs, and abuse of thiopental tends to be uncommon and opportunistic.[citation needed]

See also[edit]

References[edit]

  1. ^ Russo H, Brès J, Duboin MP, Roquefeuil B (1995). "Pharmacokinetics of thiopental after single and multiple intravenous doses in critical care patients". Eur. J. Clin. Pharmacol. 49 (1–2): 127–37. doi:10.1007/BF00192371. PMID 8751034. 
  2. ^ Morgan DJ, Blackman GL, Paull JD, Wolf LJ (June 1981). "Pharmacokinetics and plasma binding of thiopental. II: Studies at cesarean section". Anesthesiology 54 (6): 474–80. doi:10.1097/00000542-198106000-00006. PMID 7235275. 
  3. ^ "WHO Model List of Essential Medicines" (PDF). World Health Organization. March 2005. Retrieved 2006-03-12. 
  4. ^ "Death Penalty Opposition: EU Set to Ban Export of Drug Used in US Executions". Spiegel Online International. Retrieved 23 January 2014. 
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  8. ^ Morgan, DJ; Blackman, GL; Paull, JD; Wolf, LJ (1981). "Pharmacokinetics and plasma binding of thiopental. II: Studies at cesarean section". Anesthesiology 54 (6): 474–80. doi:10.1097/00000542-198106000-00006. PMID 7235275. 
  9. ^ http://www.trauma.org/archive/anaesthesia/barbcoma.html
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  12. ^ a b Royal Dutch Society for the Advancement of Pharmacy (1994). "Administration and Compounding of Euthanasic Agents". The Hague. Retrieved 2008-07-18. 
  13. ^ "Ohio executes inmate with 1-drug lethal injection". Associated Press. December 2001. Retrieved 2009-12-08. 
  14. ^ Martinez, Edecio (8 December 2009). "Kenneth Biros Execution: Ohio Man First to Die Under 1-Drug Thiopental Sodium Method". CBS News. 
  15. ^ Sullivan, Jennifer (10 September 2010). "Killer on death row 16-1/2 years is executed". The Seattle Times. 
  16. ^ BBC: Drug sold in UK to be used for execution in Georgia, 14 January 2011
  17. ^ BC: US lethal injection drug faces UK export restrictions, 29 November 2010
  18. ^ UK government Web site: Controls on Torture Goods
  19. ^ EU Council Regulation (EU) No 1352/2011
  20. ^ "Truth serum used on 'serial child killers'". Sydney Morning Herald. Reuters. January 12, 2007. 
  21. ^ Anne Bannon; Stevens, Serita Deborah (2007). The Howdunit Book of Poisons (Howdunit). Cincinnati: Writers Digest Books. ISBN 1-58297-456-X. 
  22. ^ "Truth Serums". Television Tropes & Idioms. Retrieved 27 July 2012. 
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  24. ^ "Drugged Future?". TIME. February 24, 1958. 
  25. ^ Snelders, Stephen (1998). "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. 
  26. ^ McKinley, Jesse (28 September 2010). "Judges Question California's Motivation on Execution". New York Times. 
  27. ^ "U.S. Drug Maker Discontinues Key Death Penalty Drug". Fox News. 21 January 2011. 
  28. ^ WINTERS WD, SPECTOR E, WALLACH DP, SHIDEMAN FE (July 1955). "Metabolism of thiopental-S35 and thiopental-2-C14 by a rat liver mince and identification of pentobarbital as a major metabolite". J. Pharmacol. Exp. Ther. 114 (3): 343–57. PMID 13243246. Retrieved 2008-07-18. [dead link]
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  31. ^ M. F. M. James; R. J. Hift (July 1, 2000). "Porphyrias". bja.oxfordjournals.org. Retrieved September 25, 2013. 
  32. ^ Pereda J, Gómez-Cambronero L, Alberola A et al. (October 2006). "Co-administration of pentoxifylline and thiopental causes death by acute pulmonary oedema in rats". Br. J. Pharmacol. 149 (4): 450–5. doi:10.1038/sj.bjp.0706871. PMC 1978439. PMID 16953192. 
  33. ^ "This Month in Anesthesia History: March". Anesthesia History Association. 
  34. ^ Steinhaus, John E (September 2001). "The Investigator and His 'Uncompromising Scientific Honesty'". Asa Newsletter (American Society of Anesthesiologists) 65 (9): 7–9. 
  35. ^ Lundy, John S. (1966). "From this point in time: Some memories of my part in the history of anesthesia". Journal of the American Association of Nurse Anesthetists (American Association of Nurse Anesthetists) 24 (2): 95–102. 
  36. ^ Thatcher, Virginia S. (1953). "Chapter 7: Illegal or Legal?". History of Anesthesia with Emphasis on the Nurse Specialist. J.B. Lippincott. ISBN 0-8240-6525-5. 
  37. ^ Bennetts FE (September 1995). "Thiopentone anaesthesia at Pearl Harbor". Br J Anaesth 75 (3): 366–8. doi:10.1093/bja/75.3.366. PMID 7547061. Retrieved 2008-07-18. 

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