Chloral hydrate is ageminal diol with theformulaCl3C−CH(OH)2. It was first used as asedative andhypnotic 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.[4] It sometimes finds usage as a laboratorychemical reagent and precursor. It is derived fromchloral (trichloroacetaldehyde) by the addition of oneequivalent of water.
Chloral hydrate has not been approved by theFDA in theUnited States nor theEMA in theEuropean Union for anymedical indication and is on the FDA list of unapproved drugs that are still prescribed by clinicians.[5] Usage of the drug as a sedative or hypnotic may carry some risk given the lack ofclinical trials. However, chloral hydrate products, licensed for short-term management of severe insomnia, are available in the United Kingdom.[6] Chloral hydrate was voluntarily removed from the market by all manufacturers in the United States in 2012.[citation needed] Prior to that, chloral hydrate may have been sold as a "legacy" or "grandfathered" drug; that is, a drug that existed prior to the time certain FDA regulations took effect and therefore, some pharmaceutical companies have argued, has never required FDA approval. New drugs did not have to be approved for safety until Congress passed the Federal Food, Drug, and Cosmetic Act (the "FD&C Act") in 1938. Further, a new drug did not have to be proven effective until 1962, when Congress amended the Act. Manufacturers contend that such "legacy drugs", by virtue of the fact that they have been prescribed for decades, have gained a history of safety and efficacy.
Chloral hydrate was used for the short-term treatment ofinsomnia and as a sedative before minor medical or dental treatment. It was largely displaced in the mid-20th century bybarbiturates[7] and subsequently bybenzodiazepines. It was also formerly used in veterinary medicine as ageneral anesthetic but is not considered acceptable for anesthesia or euthanasia of small animals owing to adverse effects.[8] It is also still used as a sedative prior toEEG procedures, as it is one of the few available sedatives that do not suppressepileptiform discharges.[9]
In therapeutic doses for insomnia, chloral hydrate is effective within 20 to 60 minutes.[10] In humans it ismetabolized within 7 hours intotrichloroethanol and trichloroethanol glucuronide by erythrocytes and plasma esterases and intotrichloroacetic acid in 4 to 5 days.[11] It has a very narrowtherapeutic window making this drug difficult to use. Higher doses can depressrespiration andblood pressure. Tolerance to the drug develops after a few days of use.[4]
Chloral hydrate is a starting point for the synthesis of other organic compounds. It is the starting material for the production ofchloral, which is produced by the distillation of a mixture of chloral hydrate andsulfuric acid, which serves as thedesiccant.
Notably, it is used to synthesizeisatin. In this synthesis, chloral hydrate reacts withaniline andhydroxylamine to give a condensation product which cyclicizes insulfuric acid to give the target compound:[12]
Moreover, chloral hydrate is used as a reagent for the deprotection of acetals, dithioacetals and tetrahydropyranyl ethers in organic solvents.[13]
The compound can be crystallized in a variety ofpolymorphs.[14]
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[15][16] in microscopy procedures.
Chloral hydrate is an ingredient used to makeMelzer's reagent, anaqueous solution that is used to identify certain species offungi. The other ingredients arepotassium iodide, andiodine. Whether tissue or spores react to this reagent is vital for the correct identification of some mushrooms.
Chloral hydrate was routinely administered in gram quantities. Prolonged exposure to its vapors is unhealthy, with anLD50 for 4-hour exposure of 440 mg/m3. Long-term use of chloral hydrate is associated with a rapid development of tolerance to its effects and possible addiction as well as adverse effects including rashes, gastric discomfort and severe kidney, heart, and liver failure.[17]
Acute overdosage is often characterized bynausea, vomiting, confusion,convulsions, slow and irregular breathing,cardiac arrhythmia, andcoma. Theplasma,serum orblood 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. Accidentaloverdosage 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.[18] It is listed as having a "conditional risk" of causingtorsades de pointes.[19]
Chloral hydrate inhibits liveralcohol dehydrogenasein vitro. This could be an explanation of the synergeric effect seen with alcohol.[23]
Chloral hydrate is structurally and somewhatpharmacodynamically similar toethchlorvynol, 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.
Chloral hydrate is metabolized to both2,2,2-trichloroethanol (TCE) andtrichloroacetic acid (TCA) byalcohol dehydrogenase. TCE is further converted to its glucoronide.Dichloroacetic acid (DCA) has been detected as a metabolite in children, but how it gets made is unknown.[24] TCE glucoronide, TCA, and a very small amount of free TCE are excreted in urine in male human adults. This study did not detect significant amounts of DCA; the authors noted that DCA can form during inappropriate sample preparation. Both TCA and DCA cause liver tumors in mice.[25]
TCA is cleared by the kidneys at a rate slower than the expected filtration rate, suggesting that efficientreabsorption of filtered-out TCA happens.[25]
In the United States, chloral hydrate is aschedule IVcontrolled substance and requires a physician's prescription. Its properties have sometimes led to its use as adate rape drug.[26][27] The phrase, "slipping a mickey," originally referred specifically to adding chloral hydrate to a person's (alcoholic) drink without the person's knowledge.[28]
Chloral hydrate was first synthesized by the chemistJustus von Liebig in 1832 at the University of Giessen. Liebig discovered the molecule when a chlorination (halogenation) reaction was performed onethanol.[29][30][31] Itssedative properties were observed byRudolf Buchheim in 1861, but described in detail and published only in 1869 byOscar Liebreich;[32] subsequently, because of its easy synthesis, its use became widespread.[33] Through experimentation, physiologistClaude Bernard clarified that the chloral hydrate washypnotic as opposed to ananalgesic.[34] It was the first of a long line of sedatives, most notably thebarbiturates, manufactured and marketed by the German pharmaceutical industry.[31] Historically, chloral hydrate was utilized primarily as apsychiatric medication. In 1869, German physician and pharmacologistOscar Liebreich began to promote its use to calm anxiety, especially when it caused insomnia.[35][34] Chloral hydrate had certain advantages overmorphine for this application, as it worked quickly without injection and had a consistent strength.[citation needed]
The compound achieved wide use in bothasylums 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 hydrateaddiction. After the 1904 invention ofbarbital, the first of thebarbiturate family, chloral hydrate began to disappear from use among those with means.[31] 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 advancedbarbiturates. It was the safest available sedative until the middle of the twentieth century, and thus was particularly favored for children.[34] 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 inThe Merck Manual.[36]
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 tochloroform. This was not only the first attempt to determine whether different drugs were converted to the samemetabolite in the body but also the first to measure the concentration of a particular pharmaceutical in the blood. The results were inconclusive.[37] In 1899 and 1901Hans Horst Meyer andErnest Overton respectively made the major discovery that thegeneral anaesthetic action of a drug was strongly correlated to itslipidsolubility. 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 morelipophilic molecule2,2,2-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.[38]
Chloral hydrate was the first hypnotic to be usedintravenously 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.[39]
Chloral hydrate was used as one of the earliest synthetic drugs to treatinsomnia. In 1912, Bayer introduced the drugphenobarbital under the brand name Luminal. In the 1930s,pentobarbital andsecobarbital (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.
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 aMickey Finn.[40]
I cannot but think of Lucy, and how different things might have been. If I don't sleep at once, chloral, the modernMorpheus —C2HCl3O·H2O! 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.[41]
In the conclusion ofEdith Wharton's 1905 novelThe House of Mirth, Lily Bart, the novel's heroine, becomes addicted to chloral hydrate and overdoses on the substance:
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.[42]
KingChulalongkorn ofThailand (1853–1910) used the drug for a period after 1893 to relieve what may have been a mix of depression and unspecified illnesses. He was reported by his doctor to have been taking one bottle per day during July 1894 although this was reduced after this time.[44]
André Gide (1869–1951) was given chloral hydrate as a boy for sleep problems by a physician named Lizart. Gide states in his autobiographyIf It Die... that "all my later weaknesses of will or memory I attribute to him."[46]
William James (1842–1910), psychologist and philosopher, used the drug for insomnia and sedation due to chronic neurosis.[citation needed]
Mary Todd Lincoln (1818–1882), wife of American presidentAbraham Lincoln, became addicted in the years after her husband's death and was committed to an asylum.
Friedrich Nietzsche (1844–1900) regularly used chloral hydrate in the years leading up to his nervous breakdown, according toLou Salomé and other associates. Whether the drug contributed to his insanity is a point of controversy.[50]
Dante Gabriel Rossetti (1828–1882) became addicted to chloral, with whisky chasers, after the death of his wifeElizabeth Siddal from alaudanum overdose in 1862. He had a mental breakdown in 1872. He lived out the last ten years of his life addicted to chloral and alcohol, in part to mask the pain of botched surgery to an enlarged testicle in 1877.
Oliver Sacks (1933–2015) abused chloral hydrate in 1965 as a depressed insomniac. He found himself taking fifteen times the usual dose of chloral hydrate every night before he eventually ran out, causing violent withdrawal symptoms.[51]
John Tyndall (1820–1893), an Irish physicist, died of an accidental overdose of chloral administered by his wife.[53]
Evelyn Waugh (1903–1966), insomniac for much of his adult life, for which "in later life ... he became so deleteriously dependent on chloral".[54] Waugh's novel,The Ordeal of Gilbert Pinfold, is largely a fictionalised account of an episode Waugh himself experienced as a result of excessive use of chloral in combination with bromide and alcohol. Waugh's friend and biographerChristopher Sykes observed that Waugh's description ofD. G. Rossetti's demise under the effects of excessive use of chloral in his 1928 biography of the artist "is a fairly exact description of how [Waugh's own] life ended in 1966".[55]
Chloral hydrate is, together withchloroform, a minorside-product of thechlorination of water when organic residues such ashumic acids are present. It has been detected in drinking water at concentrations of up to 100micrograms per litre (μg/L) but concentrations are normally found to be below 10 μg/L. Levels are generally found to be higher insurface water than inground water.[59]
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