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| Clinical data | |
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| Trade names | Pentothal, Trapanal |
| Other names | Truth serum, thiopentone, thiopental |
| AHFS/Drugs.com | Monograph |
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| Routes of administration | Intravenous (most common),by mouth,rectal |
| Drug class | Barbiturate |
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| Pharmacokinetic data | |
| Protein binding | 80% |
| Metabolism | Liver |
| Metabolites | Pentobarbital, others |
| Onset of action | 30–45 seconds |
| Eliminationhalf-life | 5.5[2]–26 hours[3] |
| Duration of action | 5–10 minutes |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.000.694 |
| Chemical and physical data | |
| Formula | C11H17N2NaO2S |
| Molar mass | 264.32 g·mol−1 |
| 3D model (JSmol) | |
| Chirality | Racemic mixture |
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Sodium thiopental, also known asSodium Pentothal (a trademark ofAbbott Laboratories),thiopental,thiopentone, orTrapanal (also a trademark), is a rapid-onset short-actingbarbiturategeneral anesthetic. It is the thiobarbiturateanalog ofpentobarbital, and an analog ofthiobarbital. Sodium thiopental was a core medicine in theWorld Health Organization's List of Essential Medicines,[4] but was supplanted bypropofol.[5][6][7] Despite this, thiopental is listed as an acceptable alternative to propofol, depending on local availability and cost of these agents.[7] It was the first of three drugs administered during mostlethal injections in the United States until the US division ofHospira objected and stopped manufacturing the drug in 2011, and theEuropean Union banned the export of the drug for this purpose.[8] Although thiopental abuse carries a dependency risk, its recreational use is rare.[9]
Sodium thiopental is well-known inpopular culture, especially under the name "sodium pentothal," as a "truth serum," although its efficacy in this role has been questioned.[10][11]
Sodium thiopental is an ultra-short-actingbarbiturate and has been used commonly in the induction phase ofgeneral anesthesia. Its use has been largely replaced with that ofpropofol, but may retain some popularity as an induction agent forrapid-sequence induction andintubation, such as inobstetrics.[12] Followingintravenous injection, the drug rapidly reaches the brain and causesunconsciousness 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 heruterus remains conscious. However, larger or repeated doses can depress the baby's consciousness.[13]
Sodium thiopental is not used to maintain anesthesia in surgical procedures because, in infusion, it displayszero-order eliminationpharmacokinetics, leading to a long period before consciousness is regained. Instead, anesthesia is usually maintained with aninhaled 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 highvolume of distribution). Since itshalf-life of 5.5 to 26 hours is quite long, consciousness would take a long time to return.[3]
Inveterinary medicine, sodium thiopental is used to induceanesthesia in animals. Since it is redistributed to fat, certain lean breeds of dogs such assighthounds 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 avesicant; severetissue necrosis and sloughing can occur if it is injected incorrectly into the tissue around a vein.[14]
In addition to anesthesia induction, sodium thiopental was historically used to inducemedical comas.[15] It has now been superseded by drugs such as propofol because their effects wear off more quickly than thiopental.Patients withbrain swelling, causing elevation ofintracranial 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 totraumatic brain injury (TBI) may have improved long term outcome whenbarbiturate coma is added to their neurointensive care treatment.[16] Reportedly, thiopental has been shown to be superior topentobarbital in reducing intracranial pressure.[17] 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.[18]
In refractorystatus epilepticus, thiopental may be used to terminate a seizure.
Sodium thiopental is used intravenously for the purposes ofeuthanasia. 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 bypancuronium bromide to paralyze muscles and stop breathing.[19]
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-depolarizingneuromuscular blocking drug is given, such as 20 mg pancuronium bromide (Pavulon) or 20 mgvecuronium bromide (Norcuron). The muscle relaxant should be given intravenously to ensure optimalbioavailability but pancuronium bromide may be administered intramuscularly at an increased dosage level of 40 mg.[19]
Along withpancuronium bromide andpotassium chloride, thiopental is used in 34 states of the US to execute prisoners bylethal 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.[20] The use of sodium thiopental in execution protocols was challenged in court after a study in the medical journalThe Lancet reportedautopsies 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 an execution, following the failed use of the standard three-drug cocktail during a prior execution, due to inability to locate suitable veins.Kenneth Biros was executed using the single-drug method.[21]
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 ofCal 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.[22]
After its use for theexecution of Jeffrey Landrigan in the US, the United Kingdom introduced a ban on the export of sodium thiopental in December 2010,[23] after it was established that no European supplies to the US were being used for any other purpose.[24] The restrictions were based on "the European Union Torture Regulation (including licensing of drugs used in execution by lethal injection)".[25] 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".[26]
Thiopental is still used in some places as atruth serum to weaken the resolve of a subject and make the individual more compliant to pressure.[27] Barbiturates decrease both higher cortical brain function and inhibition. It is thought that because lying is a more involved 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.[28]
Psychiatrists have used thiopental to desensitize patients withphobias[29] and to "facilitate the recall of painful repressed memories."[30] One psychiatrist who worked with thiopental isJan Bastiaans, who used this procedure to help relieve trauma in surviving victims of theHolocaust.[31]
Sodium thiopental is a member of thebarbiturate class of drugs, which are relatively non-selective compounds that bind to an entire superfamily ofligand-gated ion channels, of which theGABAA receptor channel is one of several representatives. This superfamily of ion channels includes the neuronalnicotinic acetylcholine receptor (nAChR), the5-HT3 receptor, theglycine 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.[32] Such findings implicate (non-GABAergic) ligand-gated ion channels, e.g. the neuronal nAChR, in mediating some of the (side) effects of barbiturates.[33] The GABAA receptor is an inhibitory channel that decreases neuronal activity, and barbiturates enhance the inhibitory action of the GABAA receptor.[34]
Following a shortage that led a court to delay an execution in California, a company spokesman forHospira, 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."[35] 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.[36]
In October 2015 theU.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".[37]
Thiopental rapidly and easily crosses theblood–brain barrier as it is alipophilic 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–waterpartition coefficient (approximately 10), leading to sequestration in fatty tissue. Once redistributed, the free fraction in the blood is metabolized in the liver byzero-order kinetics. Sodium thiopental is mainly metabolized topentobarbital,[38] 5-ethyl-5-(1'-methyl-3'-hydroxybutyl)-2-thiobarbituric acid, and 5-ethyl-5-(1'-methyl-3'-carboxypropyl)-2-thiobarbituric acid.[39]
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 withsedatives such asbenzodiazepines orclonidine will reduce requirements due todrug synergy, as do specific disease states and other patient factors. Among patient factors are: age, sex, and lean body mass.[40] 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.[41]
As with nearly allanestheticdrugs, thiopental causes cardiovascular andrespiratory depression resulting inhypotension,apnea, andairway 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 asmechanical ventilation. Other side-effects include headache,agitated emergence, prolongedsomnolence, andnausea. 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 eachmolecule of thiopental contains onesulfur atom, it is not asulfonamide, and does not show the allergic reactions of sulfa/sulpha drugs.
Thiopental should be used with caution in cases ofliver disease,Addison's disease,myxedema, severeheart disease, severehypotension, a severebreathing disorder, or a family history ofporphyria.[42][43]
Co-administration ofpentoxifylline and thiopental causes death by acutepulmonary edema in rats. This pulmonary edema was not mediated bycardiac failure or bypulmonary hypertension but was due to increased pulmonaryvascular permeability.[44]
Sodium thiopental was discovered in the early 1930s byErnest H. Volwiler and Donalee L. Tabern, working forAbbott Laboratories. It was first used in human beings on March 8, 1934, by Dr. Ralph M. Waters[45] in an investigation of its properties, which were short-term anesthesia and surprisingly little analgesia.[46] Three months later,[47] Dr. John S. Lundy started a clinical trial of thiopental at theMayo Clinic at the request of Abbott.[48] Abbott continued to make the drug until 2004, when it spun off its hospital-products division asHospira.
Thiopental is famously associated with a number of anesthetic deaths in victims of theattack 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 throughfreedom of information legislation was reviewed in theBritish Journal of Anaesthesia,[49] which has suggested that this story was grossly exaggerated. Of the 344 wounded that were admitted to theTripler Army Hospital, only 13 did not survive, and it is unlikely that thiopentone overdose was responsible for more than a few of these.
