- Sodium thiopental
Sodium thiopental 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 Pregnancy cat. ? Legal status Schedule III (US) Routes Oral, intravenous Pharmacokinetic data Half-life 5.5-26 hours Identifiers CAS number (sodium salt)
76-75-5 (free acid)
ATC code N01 N05 PubChem DrugBank ChemSpider UNII KEGG ChEBI ChEMBL Chemical data Formula C11H17N2NaO2S Mol. mass 264.32 g/mol SMILES & (what is this?)
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. It is also usually the first of three drugs administered during most lethal injections in the United States.
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.
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. 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.
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.
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.
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.
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
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 in reducing intracranial pressure.This phenomena is also termed as Reverse steal Effect.
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.
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.
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. 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. Ohio executed a second man using sodium thiopental on January 7, 2010. Vernon Smith was pronounced dead eight minutes after the time of injection. A third man was executed using the single-drug method on April 20, 2010. Daryl Durr was pronounced dead at 10:36 am. Most recently, William Garner was executed in Ohio with sodium thiopental.
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.
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." 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.
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.
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. 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.
Psychiatrists have used thiopental to desensitize patients with phobias, and to "facilitate the recall of painful repressed memories." 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.
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, 5-ethyl-5-(1'-methyl-3'-hydroxybutyl)-2-thiobarbituric acid, and 5-ethyl-5-(1'-methyl-3'-carboxypropyl)-2-thiobarbituric acid.
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.
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.
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.
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 in an investigation of its properties, which were short-term anesthesia and surprisingly little analgesia. Three months later, Dr. John S. Lundy started a clinical trial of thiopental at the Mayo Clinic at the request of Abbott. 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". 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.
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.
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