Chloral hydrate is a
geminal diol with the
formulaCl3C−C
H(
OH)2. 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 usage in the United States until at least the 1970s.[4] 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.
Uses
Hypnotic
Chloral hydrate has not been approved by the
FDA in the
United States nor the
EMA in the
European Union for any
medical 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 of
clinical 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. 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 of
insomnia and as a sedative before minor medical or dental treatment. It was largely displaced in the mid-20th century by
barbiturates[7] and subsequently by
benzodiazepines. It was also formerly used in veterinary medicine as a
general anesthetic but is not considered acceptable for anesthesia or euthanasia of small animals due to adverse effects.[8] It is also still used as a sedative prior to
EEG procedures, as it is one of the few available sedatives that does not suppress
epileptiform discharges.[9]
In therapeutic doses for insomnia, chloral hydrate is effective within 20 to 60 minutes.[10] In humans it is
metabolized within 7 hours into
trichloroethanol and trichloroethanol glucuronide by erythrocytes and plasma esterases and into
trichloroacetic acid in 4 to 5 days.[11] 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.[4]
In organic synthesis
Chloral hydrate is a starting point for the synthesis of other organic compounds. It is the starting material for the production of
chloral, which is produced by the distillation of a mixture of chloral hydrate and
sulfuric acid, which serves as the
desiccant.
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:[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 of
polymorphs.[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.
Melzer's reagent
Chloral hydrate is an ingredient used to make
Melzer's reagent, an
aqueous solution that is used to identify certain species of
fungi. The other ingredients are
potassium iodide, and
iodine. Whether tissue or spores react to this reagent is vital for the correct identification of some mushrooms.
Safety
Chloral hydrate was routinely administered in gram quantities. Prolonged exposure to its vapors is unhealthy, with an
LD50 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 by
nausea, vomiting, confusion,
convulsions, slow and irregular breathing,
cardiac arrhythmia, and
coma. The
plasma,
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
overdosage 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 causing
torsades de pointes.[19]
Production
Chloral hydrate is produced from
chlorine and
ethanol in acidic solution.
Chloral hydrate is metabolized in vivo to
trichloroethanol, which is responsible for secondary physiological and psychological effects.[21]
Chloral hydrate is structurally and somewhat
pharmacodynamically 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. The metabolite of chloral hydrate exerts its pharmacological properties via enhancing the
GABA receptor complex[22] and therefore is similar in action to
benzodiazepines,
nonbenzodiazepines and
barbiturates. It can be moderately
addictive, as
chronic use is known to cause
dependency and
withdrawal symptoms. The chemical can potentiate various
anticoagulants and is weakly
mutagenicin vitro and in vivo.[citation needed]
Legal status
In the United States, chloral hydrate is a
schedule IVcontrolled substance and requires a physician's prescription. Its properties have sometimes led to its use as a
date rape drug.[23][24] 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.[25][26][27] Its
sedative properties were observed by
Rudolf Buchheim in 1861, but described in detail and published only in 1869 by
Oscar Liebreich;[28] subsequently, because of its easy synthesis, its use became widespread.[29] Through experimentation, physiologist
Claude Bernard clarified that the chloral hydrate was
hypnotic as opposed to an
analgesic.[30] It was the first of a long line of sedatives, most notably the
barbiturates, manufactured and marketed by the German pharmaceutical industry.[27] 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.[31][30] Chloral hydrate had certain advantages over
morphine for this application, as it worked quickly without injection and had a consistent strength.
The compound achieved wide use in both
asylums 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.[27] 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
barbiturates. It was the safest available sedative until the middle of the twentieth century, and thus was particularly favored for children.[30] 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.[32]
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.[33] 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
lipidsolubility. 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.[34]
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.[35]
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.
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.[36]
I cannot but think of Lucy, and how different things might have been. If I don't sleep at once, chloral, the modern
Morpheus — 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.[37]
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:
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.[38]
Notable users
King
Chulalongkorn of
Thailand (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.[39]
André Gide (1869–1951) was given chloral hydrate as a boy for sleep problems by a physician named Lizart. Gide states in his autobiography If It Die... that "all my later weaknesses of will or memory I attribute to him."[41]
William James (1842–1910), psychologist and philosopher, used the drug for insomnia and sedation due to chronic neurosis.
Mary Todd Lincoln (1818–1882), wife of American president
Abraham 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 to Lou Salome and other associates. Whether the drug contributed to his insanity is a point of controversy.[45]
Dante Gabriel Rossetti (1828–1882) became addicted to chloral, with whisky chasers, after the death of his wife
Elizabeth Siddal from a
laudanum 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.[46]
John Tyndall (1820–1893), an Irish physicist, died of an accidental overdose of chloral administered by his wife.[48]
Evelyn Waugh (1903–1966), insomniac for much of his adult life, for which "in later life ... he became so deleteriously dependent on chloral".[49] 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 biographer
Christopher Sykes observed that Waugh's description of
D. 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".[50]
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
micrograms 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.[54]
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