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Names | |||
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Preferred IUPAC name 2,2,2-Trichloroethane-1,1-diol | |||
Other names
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Identifiers | |||
3D model (JSmol) | |||
1698497 | |||
ChEBI | |||
ChEMBL | |||
ChemSpider | |||
DrugBank | |||
ECHA InfoCard | 100.005.562 | ||
EC Number |
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101369 | |||
KEGG | |||
PubChem CID | |||
RTECS number |
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UNII | |||
UN number | 2811 | ||
CompTox Dashboard (EPA) | |||
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Properties [2] | |||
CCl3CH(OH)2 | |||
Molar mass | 165.39 g·mol−1 | ||
Appearance | Colorless solid | ||
Odor | Aromatic, slightly acrid | ||
Density | 1.9081 g/cm3 | ||
Melting point | 57 °C (135 °F; 330 K) | ||
Boiling point | 98 °C (208 °F; 371 K) (decomposes) | ||
660 g/(100 ml) | |||
Solubility | Very soluble in benzene, ethyl ether, ethanol | ||
log P | 0.99 | ||
Acidity (pKa) | 9.66, 11.0 [3] | ||
Structure | |||
Monoclinic | |||
Pharmacology | |||
N05CC01 ( WHO ) | |||
Oral syrup, rectal suppository | |||
Pharmacokinetics: | |||
Well absorbed | |||
Hepatic and renal (converted to trichloroethanol) | |||
8–10 hours | |||
Bile, feces, urine (various metabolites not unchanged) | |||
Legal status |
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Hazards | |||
GHS labelling: | |||
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Danger | |||
H301, H315, H319 | |||
P264, P270, P280, P301+P310, P302+P352, P305+P351+P338, P321, P330, P332+P313, P337+P313, P362, P405, P501 | |||
Lethal dose or concentration (LD, LC): | |||
LD50 (median dose) | 1100 mg/kg (oral) | ||
Safety data sheet (SDS) | External MSDS [ dead link ] | ||
Related compounds | |||
Related compounds | Chloral, chlorobutanol | ||
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
Chloral hydrate is a geminal diol with the formula Cl 3 C−CH(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.
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]
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]
Chloral hydrate is also an ingredient used for Hoyer's solution, a mounting medium for microscopic observation of diverse plant types such as bryophytes, ferns, seeds, and small arthropods (especially mites). Other ingredients may include gum arabic and glycerol. An advantage of this medium includes a high refractive index and clearing (macerating) properties of small specimens (especially advantageous if specimens require observation with differential interference contrast microscopy).[ citation needed ]
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 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.
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]
Chloral hydrate is produced from chlorine and ethanol in acidic solution.
In basic conditions the haloform reaction takes place and chloral hydrate is decomposed by hydrolysis to form chloroform. [20]
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 mutagenic in vitro and in vivo.[ citation needed ]
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. [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.[ citation needed ]
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 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. [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]
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]
In 1897, Bram Stoker's epistolary novel Dracula , one of its characters, Doctor John Seward, recorded his use and his molecular formula in his phonographic diary:
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]
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]
Hypnotic, or soporific drugs, commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to induce sleep and to treat insomnia (sleeplessness).
Chloroform, or trichloromethane, is an organochloride with the formula CHCl3 and a common solvent. It is a very volatile, colorless, strong-smelling, dense liquid produced on a large scale as a precursor to refrigerants and PTFE. Chloroform is a trihalomethane that serves as a powerful general anesthetic, euphoriant, anxiolytic, and sedative when inhaled or ingested, for this reason, Chloroform was used as an inhalational anesthetic between the 19th century and the first half of the 20th century. It is miscible with many solvents but it is only very slightly soluble in water.
A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but the majority of them affect the neurotransmitter gamma-aminobutyric acid (GABA). In spite of the fact that each sedative acts in its own way, most produce relaxing effects by increasing GABA activity.
Colloquially known as "downers", depressants or CNS depressants are drugs that lower neurotransmission levels, decrease the electrical activity of brain cells, or reduce arousal or stimulation in various areas of the brain. Some specific depressants do influence mood, either positively or negatively, but depressants often have no clear impact on mood. In contrast, stimulants, or "uppers", increase mental alertness, making stimulants the opposite drug class from depressants. Antidepressants are defined by their effect on mood, not on general brain activity, so they form an orthogonal category of drugs.
Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives. It possesses pharmacological properties similar to those of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia. In addition to the hypnotic properties, triazolam's amnesic, anxiolytic, sedative, anticonvulsant, and muscle relaxant properties are pronounced as well.
Hydroxyzine, sold under the brand names Atarax and Vistaril among others, is an antihistamine medication. It is used in the treatment of itchiness, insomnia, anxiety, and nausea, including that due to motion sickness. It is used either by mouth or injection into a muscle.
Flurazepam is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It produces a metabolite with a long half-life, which may stay in the bloodstream for days. Flurazepam was patented in 1968 and came into medical use the same year. Flurazepam, developed by Roche Pharmaceuticals, was one of the first benzodiazepine hypnotic medications to be marketed.
Eszopiclone, sold under the brand name Lunesta among others, is a medication used in the treatment of insomnia. Evidence supports slight to moderate benefit up to six months. It is taken by mouth.
Xylazine is a structural analog of clonidine and an alpha-2 adrenergic receptor agonist, sold under many trade names worldwide, most notably the Bayer brand name Rompun, as well as Anased, Sedazine and Chanazine.
Nonbenzodiazepines, sometimes referred to colloquially as Z-drugs, are a class of psychoactive; depressant, sedative, hypnotic, anxiolytic drugs that are benzodiazepine-like in uses, such as for treating insomnia and anxiety.
The ventrolateral preoptic nucleus (VLPO), also known as the intermediate nucleus of the preoptic area (IPA), is a small cluster of neurons situated in the anterior hypothalamus, sitting just above and to the side of the optic chiasm in the brain of humans and other animals. The brain's sleep-promoting nuclei, together with the ascending arousal system which includes components in the brainstem, hypothalamus and basal forebrain, are the interconnected neural systems which control states of arousal, sleep, and transitions between these two states. The VLPO is active during sleep, particularly during non-rapid eye movement sleep, and releases inhibitory neurotransmitters, mainly GABA and galanin, which inhibit neurons of the ascending arousal system that are involved in wakefulness and arousal. The VLPO is in turn innervated by neurons from several components of the ascending arousal system. The VLPO is activated by the endogenous sleep-promoting substances adenosine and prostaglandin D2. The VLPO is inhibited during wakefulness by the arousal-inducing neurotransmitters norepinephrine and acetylcholine. The role of the VLPO in sleep and wakefulness, and its association with sleep disorders – particularly insomnia and narcolepsy – is a growing area of neuroscience research.
Quazepam, sold under brand name Doral among others, is a relatively long-acting benzodiazepine derivative drug developed by the Schering Corporation in the 1970s. Quazepam is used for the treatment of insomnia including sleep induction and sleep maintenance. Quazepam induces impairment of motor function and has relatively selective hypnotic and anticonvulsant properties with considerably less overdose potential than other benzodiazepines. Quazepam is an effective hypnotic which induces and maintains sleep without disruption of the sleep architecture.
Chloral, also known as trichloroacetaldehyde or trichloroethanal, is the organic compound with the formula Cl3CCHO. This aldehyde is a colourless liquid that is soluble in a wide range of solvents. It reacts with water to form chloral hydrate, a once widely used sedative and hypnotic substance.
Estazolam, sold under the brand name Prosom among others, is a tranquilizer medication of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. Estazolam is an intermediate-acting oral benzodiazepine. It is used for short-term treatment of insomnia.
2,2,2-Trichloroethanol is the chemical compound with formula Cl3C−CH2OH. Its molecule can be described as that of ethanol, with the three hydrogen atoms at position 2 replaced by chlorine atoms. It is a clear flammable liquid at room temperature, colorless when pure but often with a light yellow color.
Hexobarbital or hexobarbitone, sold both in acid and sodium salt forms as Citopan, Evipan, and Tobinal, is a barbiturate derivative having hypnotic and sedative effects. It was used in the 1940s and 1950s as an agent for inducing anesthesia for surgery, as well as a rapid-acting, short-lasting hypnotic for general use, and has a relatively fast onset of effects and short duration of action. Modern barbiturates have largely supplanted the use of hexobarbital as an anesthetic, as they allow for better control of the depth of anesthesia. Hexobarbital is still used in some scientific research.
A GABA receptor agonist is a drug that is an agonist for one or more of the GABA receptors, producing typically sedative effects, and may also cause other effects such as anxiolytic, anticonvulsant, and muscle relaxant effects. There are three receptors of the gamma-aminobutyric acid. The two receptors GABA-α and GABA-ρ are ion channels that are permeable to chloride ions which reduces neuronal excitability. The GABA-β receptor belongs to the class of G-Protein coupled receptors that inhibit adenylyl cyclase, therefore leading to decreased cyclic adenosine monophosphate (cAMP). GABA-α and GABA-ρ receptors produce sedative and hypnotic effects and have anti-convulsion properties. GABA-β receptors also produce sedative effects. Furthermore, they lead to changes in gene transcription.
tert-Amyl alcohol (TAA) or 2-methylbutan-2-ol (2M2B), is a branched pentanol.
Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as well as overdose potential among other possible adverse effects. They have been used recreationally for their anti-anxiety and sedative effects, and are thus controlled in most countries due to the risks associated with such use.
Somnifacient, also known as sedatives or sleeping pills, is a class of medications that induces sleep. It is mainly used for treatment of insomnia. Examples of somnifacients include benzodiazepines, barbiturates and antihistamines.
Notes
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