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Chloral hydrate is a geminal diol with the chemical formula . It was first used as a sedative and hypnotic in Germany in the 1870s. Over time it was replaced by safer and more effective alternatives but it remained in use in the United States until at least the 1970s. It sometimes finds usage as a laboratory chemical reagent and precursor. It is derived from chloral (trichloroacetaldehyde) by the addition of one equivalent of water.
Chloral hydrate was used for the short-term treatment of insomnia and as a sedative before minor medical or dental treatment. It was largely displaced in the mid-20th century by and subsequently by . It was also formerly used in veterinary medicine as a general anesthetic but is not considered acceptable for anesthesia or euthanasia of small animals owing to adverse effects. It is also still used as a sedative prior to EEG procedures, as it is one of the few available sedatives that do not suppress epilepsy discharges.
In therapeutic doses for insomnia, chloral hydrate is effective within 20 to 60 minutes. In humans it is Metabolism within 7 hours into trichloroethanol and trichloroethanol glucuronide by erythrocytes and plasma esterases and into trichloroacetic acid in 4 to 5 days. It has a very narrow therapeutic window making this drug difficult to use. Higher doses can depress respiration and blood pressure. Tolerance to the drug develops after a few days of use.
Notably, it is used to synthesize isatin. In this synthesis, chloral hydrate reacts with aniline and hydroxylamine to give a condensation product which cyclicizes in sulfuric acid to give the target compound:
Moreover, chloral hydrate is used as a reagent for the deprotection of acetals, dithioacetals and tetrahydropyranyl ethers in organic solvents.
The compound can be crystallized in a variety of polymorphs.
Because of its status as a regulated substance, chloral hydrate can be difficult to obtain. This has led to chloral hydrate being replaced by alternative reagents in microscopy procedures.
Acute overdosage is often characterized by nausea, vomiting, confusion, , slow and irregular breathing, cardiac arrhythmia, and coma. The Blood plasma, Blood serum or blood concentrations of chloral hydrate and/or trichloroethanol, its major active metabolite, may be measured to confirm a diagnosis of poisoning in hospitalized patients or to aid in the forensic investigation of fatalities. Accidental Drug overdose of young children undergoing simple dental or surgical procedures has occurred. Hemodialysis has been used successfully to accelerate clearance of the drug in poisoning victims. It is listed as having a "conditional risk" of causing torsades de pointes.
In basic conditions the haloform reaction takes place and chloral hydrate is decomposed by hydrolysis to form chloroform.
Chloral hydrate inhibits liver alcohol dehydrogenase in vitro. This could be an explanation of the synergeric effect seen with alcohol.
Chloral hydrate is structurally and somewhat pharmacodynamics similar to ethchlorvynol, a pharmaceutical developed during the 1950s that was marketed as both a sedative and a hypnotic under the trade name Placidyl. In 1999, Abbott, the sole manufacturer of the drug in the United States at the time, decided to discontinue the product. After Abbott ceased production, the drug remained available for about a year. Despite the fact that it could have been manufactured generically, no other company in the United States chose to do so.
TCA is cleared by the kidneys at a rate slower than the expected filtration rate, suggesting that efficient reabsorption of filtered-out TCA happens.
The compound achieved wide use in both Lunatic asylum and the homes of those socially refined enough to avoid asylums. Upper- and middle-class women, well-represented in the latter category, were particularly susceptible to chloral hydrate addiction. After the 1904 invention of barbital, the first of the barbiturate family, chloral hydrate began to disappear from use among those with means. It remained common in asylums and hospitals until the Second World War as it was quite cheap. Chloral hydrate had some other important advantages that kept it in use for five decades despite the existence of more advanced . It was the safest available sedative until the middle of the twentieth century, and thus was particularly favored for children. It also left patients much more refreshed after a deep sleep than more recently invented sedatives. Its frequency of use made it an early and regular feature in The Merck Manual.
Chloral hydrate was also a significant object of study in various early pharmacological experiments. In 1875, Claude Bernard tried to determine if chloral hydrate exerted its action through a metabolic conversion to chloroform. This was not only the first attempt to determine whether different drugs were converted to the same metabolite in the body but also the first to measure the concentration of a particular pharmaceutical in the blood. The results were inconclusive. In 1899 and 1901 Hans Horst Meyer and Ernest Overton respectively made the major discovery that the general anaesthetic action of a drug was strongly correlated to its lipid solubility. However, chloral hydrate was quite polar but nonetheless a potent hypnotic. Overton was unable to explain this mystery. Thus, chloral hydrate remained one of the major and persistent exceptions to this breakthrough discovery in pharmacology. This anomaly was eventually resolved in 1948, when Claude Bernard's experiment was repeated. While chloral hydrate was converted to a different metabolite than chloroform, it was found that it was converted into the more lipophilic molecule 2,2,2-trichloroethanol. This metabolite fit much better with the Meyer–Overton correlation than chloral had. Prior to this, it had not been demonstrated that general anesthetics could undergo chemical changes to exert their action in the body.
Chloral hydrate was the first hypnotic to be used intravenously as a general anesthetic. In 1871, Pierre-Cyprien Oré began experiments on animals, followed by humans. While a state of general anesthesia could be achieved, the technique never caught on because its administration was more complex and less safe than the oral administration of chloral hydrate, and less safe for intravenous use than later general anesthetics were found to be.
Chloral hydrate is soluble in both water and ethanol, readily forming concentrated solutions. A solution of chloral hydrate in ethanol called "knockout drops" was used to prepare a Mickey Finn.
In 1897, Bram Stoker's epistolary novel Dracula, one of its characters, Doctor John Seward, recorded his use and his molecular formula in his diary:
In the conclusion of Edith Wharton's 1905 novel The House of Mirth, Lily Bart, the novel's heroine, becomes addicted to chloral hydrate and overdoses on the substance:
Notes
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Legal status
In the United States, chloral hydrate is a schedule IV controlled substance and requires a physician's prescription. Its properties have sometimes led to its use as a date rape drug. The phrase, "slipping a mickey," originally referred specifically to adding chloral hydrate to a person's (alcoholic) drink without the person's knowledge.
History
Chloral hydrate was first synthesized by the chemist Justus von Liebig in 1832 at the University of Giessen. Liebig discovered the molecule when a chlorination (halogenation) reaction was performed on ethanol. Its sedative properties were observed by Rudolf Buchheim in 1861, but described in detail and published only in 1869 by Oscar Liebreich; subsequently, because of its easy synthesis, its use became widespread. Through experimentation, physiologist Claude Bernard clarified that the chloral hydrate was hypnotic as opposed to an analgesic. It was the first of a long line of sedatives, most notably the , manufactured and marketed by the German pharmaceutical industry. Historically, chloral hydrate was utilized primarily as a psychiatric medication. In 1869, German physician and pharmacologist Oscar Liebreich began to promote its use to calm anxiety, especially when it caused insomnia. Chloral hydrate had certain advantages over morphine for this application, as it worked quickly without injection and had a consistent strength.
Society and culture
Chloral hydrate was used as one of the earliest synthetic drugs to treat insomnia. In 1912, Bayer introduced the drug phenobarbital under the brand name Luminal. In the 1930s, pentobarbital and secobarbital (better known by their original brand names Nembutal and Seconal, respectively) were synthesized. Chloral hydrate was still prescribed, although its predominance as a sedative and a hypnotic was largely eclipsed by barbiturates.
I cannot but think of Lucy, and how different things might have been. If I don't sleep at once, chloral, the modern Morpheus — ! I should be careful not to let it grow into a habit. No I shall take none to-night! I have thought of Lucy, and I shall not dishonor her by mixing the two.
She put out her hand and measured the soothing drops into a glass; but as she did so, she knew they would be powerless against the supernatural lucidity of her brain. She had long since raised the dose to its highest limit, but to-night she felt she must increase it. She knew she took a slight risk in doing so; she remembered the chemist's warning. If sleep came at all, it might be a sleep without waking.
In the James Bond films From Russia With Love and The Living Daylights, chloral hydrate is used as a knockout drug.
Notable users
Environmental
It is, together with chloroform, a minor side-product of the chlorination of water when organic residues such as humic acids are present. It has been detected in drinking water at concentrations of up to 100 per litre (μg/L) but concentrations are normally found to be below 10 μg/L. Levels are generally found to be higher in surface water than in ground water.
See also
External links
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