Sodium thiopental


Sodium thiopental
Sodium thiopental
1:1 mixture (racemate)
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
Pregnancy cat.  ?
Legal status Schedule III (US)
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
SMILES eMolecules & PubChem
 N(what is this?)  thiopental (verify)

Sodium thiopental, better known as Sodium Pentothal (a trademark of Abbott Laboratories), thiopental, thiopentone sodium, or Trapanal (also a trademark), is a rapid-onset short-acting barbiturate general anaesthetic. 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 is also usually the first of three drugs administered during most lethal injections in the United States.

Contents

Barbiturates

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 alcohol 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.[4]

Further, barbiturates are relatively "promiscuous" (i.e. 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 anaesthetics), 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 anaesthetic concentrations of both thiopental and pentobarbital.[5] 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.[6]

Uses

Anesthesia

Thiopental is an ultra-short-acting barbiturate and has been used commonly in the induction phase of general anesthesia. Its use in the United States and elsewhere has been largely replaced with that of propofol. 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 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]

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. 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.[7]

In veterinary medicine, thiopental is used to induce anesthesia in animals. Since thiopental is redistributed to fat, certain breeds of dogs – primarily the sight hounds – can have prolonged recoveries from thiopental due to their lack of body fat and their lean body mass. 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.

Medically induced coma

In addition to anesthesia induction, thiopental was historically used to induce medical comas. It has now been superseded by drugs such as propofol.

Thiopental has a long Context Sensitive Half Time (CSHT), meaning infusions saturate peripheral compartments (fat, muscle etc.). When the infusion is stopped, the drug redistributes from the peripheral tissues back into the blood, prolonging the effect.

Thiopental also exhibits zero order kinetics at higher doses. The rate of elimination becomes constant.

Patients with brain swelling, causing elevation of the intracranial pressure, either secondary to trauma or following surgery, may benefit from this drug. 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[8] in reducing intracranial pressure.This phenomena is also termed as Reverse steal Effect.

Euthanasia

Thiopental is used intravenously for the purposes of euthanasia. The Belgians and the Dutch have created a protocol that recommends sodium thiopental as the ideal agent to induce coma, followed by pancuronium bromide.[9]

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.[9]

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.[10] 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. Death was pronounced at 11:47 a.m., about ten minutes after the single-dose injection was administered. Including the time required to insert the IV lines and prepare the inmate, the entire process lasted 43 minutes.[11][12] Ohio executed a second man using sodium thiopental on January 7, 2010. Vernon Smith was pronounced dead eight minutes after the time of injection.[13] A third man was executed using the single-drug method on April 20, 2010. Daryl Durr was pronounced dead at 10:36 am.[14] Most recently, William Garner was executed in Ohio with sodium thiopental.[15]

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. His 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.[16]

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, expressed strong reservations about the use of thiopental in the lethal injection procedure. "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."[17] 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.[18]

States such as Nebraska and South Dakota have turned to an Indian supplier of the drug but this move has been criticized on the grounds the chemical may deteriorate in transit to the United States.[19]

A request from Gary Locke to export thiopental for lethal injections was denied by the German government.[20]

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.[21] 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 chatty and cooperative with interrogators; however, the reliability of confessions made under thiopental is questionable.[22]

Psychiatry

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]

Metabolism

Thiopental rapidly and easily crosses the blood brain barrier as it is a lipophillic 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,[26] 5-ethyl-5-(1'-methyl-3'-hydroxybutyl)-2-thiobarbituric acid, and 5-ethyl-5-(1'-methyl-3'-carboxypropyl)-2-thiobarbituric acid.[27]

Dosage

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, 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.

Side effects

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, emergence delirium, 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

Thiopental should not be given in case of liver disease, Addison's disease, myxedema, severe heart disease, severe hypotension, a severe breathing disorder, or a history of porphyria.[28]

Co-administration of pentoxifylline and thiopental causes death by acute pulmonary oedema in rats. This pulmonary oedema was not mediated by cardiac failure or by pulmonary hypertension but was due to increased pulmonary vascular permeability.[29]

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[30] in an investigation of its properties, which were short-term anesthesia and surprisingly little analgesia.[31] Three months later,[32] Dr. John S. Lundy started a clinical trial of thiopental at the Mayo Clinic at the request of Abbott.[33] 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 substance's discovery, were due to excessive doses given to shocked trauma patients. Evidence has become available through freedom of information legislation and has been reviewed in the "British Journal of Anaesthesia".[34] Thiopental anaesthesia was in its early days, but nevertheless 13 of 344 wounded admitted to the Tripler Army Hospital did not survive.

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.

Chemistry

Thiopental, 5-ethyl-5-(1-methylbutyl)2-thiobarbituric acid, 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.png

References

  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. http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf. Retrieved 2006-03-12. 
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  7. ^ 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. 
  8. ^ Pérez-Bárcena J, Barceló B, Homar J et al. (February 2005). "[Comparison of the effectiveness of pentobarbital and thiopental in patients with refractory intracranial hypertension. Preliminary report of 20 patients"] (in Spanish; Castilian). Neurocirugia (Astur) 16 (1): 5–12; discussion 12–3. PMID 15756405. http://www.revistaneurocirugia.com/web/artics/v16n1/1.pdf. Retrieved 2008-07-18. 
  9. ^ a b Royal Dutch Society for the Advancement of Pharmacy (1994). "Administration and Compounding of Euthanasic Agents". The Hague. http://wweek.com/html/euthanasics.html. Retrieved 2008-07-18. 
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  11. ^ Martinez, Edecio (8 December 2009). "Kenneth Biros Execution: Ohio Man First to Die Under 1-Drug Thiopental Sodium Method". CBS News. http://www.cbsnews.com/blogs/2009/09/24/crimesider/entry5334823.shtml. 
  12. ^ "Ohio executes inmate with 1-drug lethal injection". Associated Press. Google. 9 December 2009. Archived from the original on 23 December 2009. http://www.webcitation.org/5mEkZTdUI. 
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  17. ^ McKinley, Jesse (28 September 2010). "Judges Question California's Motivation on Execution". New York Times. http://www.nytimes.com/2010/09/29/us/29execute.html. 
  18. ^ "U.S. Drug Maker Discontinues Key Death Penalty Drug". Fox News. 21 January 2011. http://www.foxnews.com/us/2011/01/21/drug-maker-discontinues-key-death-penalty-drug/#ixzz1BhqUFIxP. 
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  24. ^ "Drugged Future?". TIME. February 24, 1958. http://www.time.com/time/magazine/article/0,9171,863001,00.html. 
  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. http://www.maps.org/news-letters/v08n1/08118sne.html. 
  26. ^ 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. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=13243246. Retrieved 2008-07-18. [dead link]
  27. ^ Bory C, Chantin C, Boulieu R et al. (1986). "[Use of thiopental in man. Determination of this drug and its metabolites in plasma and urine by liquid phase chromatography and mass spectrometry]" (in French). C. R. Acad. Sci. III, Sci. Vie 303 (1): 7–12. PMID 3093002. 
  28. ^ "Pentothal (thiopental)". eMedicineHealth. April 12, 2009. http://www.emedicinehealth.com/drug-thiopental/article_em.htm. 
  29. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1978439. 
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  31. ^ Steinhaus, John E (September 2001). "The Investigator and His 'Uncompromising Scientific Honesty'". Asa Newsletter (American Society of Anesthesiologists) 65 (9): 7–9. http://www.asahq.org/~/media/For%20Members/Publications/Periodicals/ASA%20Newsletter/NL%20Archives/2001/09%20Sept%2001.ashx. 
  32. ^ 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. http://www.aana.com/Resources.aspx?id=1811. 
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  34. ^ Bennetts FE (September 1995). "Thiopentone anaesthesia at Pearl Harbor". Br J Anaesth 75 (3): 366–8. PMID 7547061. http://bja.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=7547061. Retrieved 2008-07-18. 

External links


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Look at other dictionaries:

  • Sodium thiopental — Thiopental Thiopental Général Nom IUPAC …   Wikipédia en Français

  • sodium thiopental — Pharm. See sodium pentothal. * * * …   Universalium

  • sodium thiopental — noun a long acting barbiturate used as a sedative • Syn: ↑phenobarbital, ↑phenobarbitone, ↑Luminal, ↑purple heart • Hypernyms: ↑barbiturate * * * Pharm. See sodium pentothal …   Useful english dictionary

  • sodium thiopental — noun The drug phenobarbitone. Syn: phenobarbital, phenobarbitone, purple heart …   Wiktionary

  • Thiopental — Général …   Wikipédia en Français

  • sodium pentothal — noun : the sodium salt of thiopental * * * Pharm. the sodium salt of thiopental sodium. Also called sodium thiopental. [Pentothal a trademark] * * * sodium pentothal, = thiopental sodium. (Cf. ↑thiopental sodium) …   Useful english dictionary

  • sodium pentothal — Pharm. the sodium salt of thiopental sodium. Also called sodium thiopental. [Pentothal a trademark] * * * …   Universalium

  • thiopental — noun A particular barbiturate drug. Syn: sodium thiopental, thiopentone sodium …   Wiktionary

  • Thiopental sodique — Thiopental Thiopental Général Nom IUPAC …   Wikipédia en Français

  • thiopental sodium — or thiopental [thī΄ō pen′təl] n. [ THIO + PENT(A) + AL] a yellowish white, hygroscopic powder, C11H17N2O2SNa, injected intravenously in solution as a general anesthetic and hypnotic …   English World dictionary


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