Chloral hydrate is used in the medical field as a sedative/hypnotic. It is one of the oldest sedative/hypnotic still on the US market and has been used as such for 150 years. It has potential for abuse, thus is controlled by scheduling it as a schedule IV controlled substance.
[top]Introduction to Chloral Hydrate
Chloral hydrate was first synthesized by Justus von Liebig in 1832. Liebig also invented the Liebig condenser and has a University named after him in Giessen, Germany. He accomplished the synthesis by chlorination of ethanol
in an acidic medium followed by hydration of chloral (trichloroacetaldehyde). Its chemical formula is C2
.. Its sedative properties were first published in 1869,. It is still on the market, however it has largely been replaced by barbiturates, benzodiazepines, and the Z-drugs
), (zopliclone, Immovane), and (eszopliclone, Lunesta.)
[top]Using Chloral Hydrate
Chloral hydrate is now rarely prescribed, however it is still on the pharmaceutical market in many countries. It is still used in some surgical procedures, as a building block for more complex molecules and in Hoyer's mounting medium, which will be covered later in this text. It is used for the short-term treatment of insomnia and it can be used for alcohol
The usual lethal dose is 10g. However, fatalities have occurred with as little as 4g and survival has been documented after the ingestion of 30g of chloral hydrate.
Hypnotic: Adults: 500 to 1000mg, 15 to 30 minutes before bedtime.
Geriatrics: Initial: 250mg, 15 to 30 minutes before bedtime.
Sedative: Adults: 250mg 3 times daily after meals, maximum 2000mg/day
Premedicant: Adults: 500 to 1000mg, 30 minutes prior to procedure.
Ethanol Withdrawal: For management of withdrawal
symptoms a dose of 500mg to 1000mg, repeated at 6-hour intervals, has been used. Single or daily dose should not exceed 2000mg.
[top]Ways of administration
Chloral hydrate can be administered orally in gel caps or in a syrup form. It is also administered rectally via suppository. Since chloral hydrate is readily soluble in water, it can be injected intravenously. This method of administration is rarely performed, but has been documented. It is not recommended due to the irritation chloral hydrate will cause to the veins. A typical oral or rectal dose is between 500mg and 1000mg.
[top]Combinations with Chloral Hydrate
Combinations of chloral hydrate with other drugs that can create major drug
interactions are propoxyphene (Darvon, which has been taken off the U.S. market), GHB
, other sedatives
, and alcohol. In some individuals a disulfiram
(or flushing) reaction will occur when alcohol is mixed with chloral hydrate. Chloral hydrate has been involved in the deaths of Anna Nicole Smith and Marilyn Monroe in combination with other depressants
. Chloral hydrate when taken as prescribed alone rarely causes death. Death occurs mainly when chloral hydrate is combined with other depressants and opiates.
[top]Different Uses for Chloral Hydrate
Chloral hydrate is a cheaply available building block chemical. It is the starting material for the production of chloral, which is produced by the distillation of chloral hydrate and sulfuric acid. Chloral is then used as a desiccant.
Chloral is also used to synthesize isatin, or 1H-indole-2,3-dione, which is an indole derivative and is found in many plants. It was first synthesized in 1841 by Erdman and Laurent. Schiff bases of isatin are investigated for their pharmaceutical properties.
Hoyers mounting medium also uses chloral hydrate, a more biological use of this chemical, as a clearing agent of chitin (and fibers). Chiten is then used for slide-mounted observation of organisms such as bryophytes, ferns, seeds, and small arthropods (especially mites) under the microscope.
The anhydrous form of chloral hydrate, or chloral is an intermediate in insecticide and herbicide manufacture (including DDT, dichlorvos, and naled).
Mixed with alcohol it was the first "Mickey Finn" (a mixture to render a person unconscious or in a black out state).
[top]Pharmacology of Chloral Hydrate
Chloral hydrate's pharmacology properties enhance the GABAA receptor complex.It is believed that chloral hydrate has general CNS depressant effects due to its active metabolite, trichloroethanol. It accomplishes this by rapid and extensive metabolization in the liver and erythrocytes by alcohol dehydrogenase. A small amount of chloral hydrate and a larger portion of trichloroethanol are oxidized to a minor, less active metabolite, trichloroacetic acid, in one's liver and kidneys. This metabolite is excreted in the urine and bile together with trichloroethanol in free or conjugated form.
The complete metabolism can be found in the following table:
In doses used for hypnosis, chloral hydrate produces mild cerebral depression and quiet , deep sleep, usually with little or no hangover effects. Chloral hydrate decreases nighttime awakening with minimal effects on REM sleep. REM rebound does not occur with drug withdrawal. Tolerance to chloral hydrate may develop over a 5-14 day period of continued use.
The average half-life
of trichloroethanol in adults is 8 hours, ranging from 4 to 12 hours.
[top]Chemistry of Chloral Hydrate
Chloral hydrate's IUPAC name is 2,2,2-trichloralethane-1,1-diol. From the IUPAC name one can see that is it a geminol diol
, or any organic compound having two functional groups (-OH) bound to the same carbon atom. Geminol diols are notoriously unstable, however chloral hydrate is not. This has puzzled organic chemists for sometime and this will be discussed later. Another common name for chloral hydrate is trichloroacetaldehyde monohydrate. For every one mole of chloral there is one mole of water.
The CAS number for chloral hydrate is 302-17-0. The molecular mass of chloral hydrate is 165.40 g/mol. It is a colorless crystalline solid and has a melting point of 57 C and a boiling point of 98 C. The reaction of the chlorination of ethanol in acidic solution is:
OH + H2
Chloral hydrate is a geminol diol which is very stable, however this is not the norm. Geminol diols are extremely unstable compounds, so why is chloral hydrate so stable yet other geminol diols are not? In chloral hydrates case, the trichloro- group on the adjacent carbon stabilizes the geminol diol thermodynamically rather than kinetically. If one would like to find out more about the reason chloral hydrate, a geminol diol, is very stable, it is explained in the following footnote. It can get rather complex, and a good knowledge of Organic Chemistry is required to grasp the thermodynamic and kinetic properties involved.
[top]The Dangers of Chloral Hydrate
First developed in 1832 and the sedative/hypnotics
properties discovered in 1869, chloral hydrate is one of the oldest sleep medications still in use today. Chloral hydrate when taken by itself and as prescribed is a rather safe medication to use as a premedicant, sedative and hypnotic. Having been in use in medicine for about 150 years attests to the fact than when used properly, chloral hydrate is a safe medication. However, even when taking chloral hydrate as prescribed, side effects
can arise when taken by itself in certain people. When abused, it can cause dependence and serious side effects.
[top]Central Nervous System
Occasionally a patient taking chloral hydrate may become disoriented and incoherent and show paranoid behavior. Rarely, paradoxical reactions occur with chloral hydrate. Paradoxical reactions are usually accompanied by excitement, violent behavior and a walking blackout, this does not happen with chloral hydrate, usually. This mainly occurs with taking a large dose of benzodiazepines.
Rarely, excitement, tolerance, addiction
, delirium, staggering gait, ataxia
, lightheadedness, vertigo, dizziness, nightmares, malaise, mental confusion and hallucinations have been reported.
Leukopenia and eosinophilia have occasionally occurred. Leukopenia is a lower than normal amount of white blood cells and eosinophilia being an abnormally high number of eosinophils in the blood. Eosinophils are white blood cells that specifically combat multicellular parasites and certain infections in vertebrates. This is a rare side effect
of some adverse effects of certain drugs, one rarely being chloral hydrate.
Allergic skin rashes including hives, erythema, and eczematoid dermatitis have occasionally been reported when taking chloral hydrate. When combined with alcohol a disulfiram reaction (flushing) can occur of the skin.
Some patients experience gastric irritation and occasionally nausea and vomiting, flatulence (gas), diarrhea, and unpleasant taste can occur. This may be due to the pH of chloral hydrate which has a pH of 3.5-5.5 in a 10% solution in water, which would be considered somewhat acidic for a medication. That is why it is recommended that at least 240ml of water or ginger ale be taken with chloral hydrate gel caps. Most medications are salts in some form or another. An are closer to a pH of 7. Thus irritation of the stomach lining can occur in some people who use chloral hydrate frequently or at times sparingly.
[top]Drug Abuse and Dependence on Chloral Hydrate
Drug dependence on chloral hydrate can occur when the drug is abused or taken for an extended period of time. If a person chronically abuses chloral hydrate they can face liver damage as well as severe withdrawal symptoms. Because chloral hydrate has potential for abuse and dependence, it should only be used on a short term basis.
If chloral hydrate is used for a prolonged period of time and then suddenly stopped, there are withdrawal symptoms the user will probably experience. Hallucinations along with symptoms that are similar to delirium tremens. It is important to note that the delirium tremens are fatal sometimes. It's very important that chloral hydrate is not abused.
In this day and age, chloral hydrate abuse has given way first to barbiturate abuse and now mainly benzodiazepine
abuse and Z-drug
abuse (for Z-drugs, see introduction of this article.)
[top]Chloral Hydrate overdose Symptoms
An overdose of chloral hydrate is quite similar to overdosing on barbiturates. These symptoms include: hypothermia
, cardiac arrhythmias, respiratory depression, hypotension and coma.
Miosis (severe eye pupil constriction), vomiting, areflexia (nerve problems) and muscle flaccidity (bad muscle tone) could occur also. Due to the result of respiratory failure or hypertension
an overdose of chloral hydrate could result in death.
The usually overdose amount is 10g as an average. Persons who are tolerant may be able to withstand or survive a larger amount. Other people without a tolerance, children or neophytes possibly could overdose at 4g. If you know someone who has overdosed on chloral hydrate, call 911 and proceed with CPR until the paramedics arrive.
[top]Industrial Production of Chloral Hydrate
Chloral hydrate is made by hydration of purified chloral. Chloral is typically produced by the chlorination of ethanol or aldehyde. Specifically during the chlorination of aldehydes, the raw materials acetaldehyde or paraldehyde may be used. Due to loss of ethanol via formation of ethyl chloride and ethyl acid sulfate as well as enviromental and waste disposal problems associated with production of these materials, the ethanol process has been largely replaced by aldehyde chlorination, with acetaldehyde being the aldehyde of choice. Acetaldehyde chlorination is carried out via the reaction:
CH3CH=O + 3Cl2 ---> CCl3CH=O + 3HCl
Chloral itself is an unstable compound, making it highly reactive such that it may combine with many chemical substances, including itself, or decompose.
Conventionally, the commercial practice of manufacturing chloral from acetaldehyde involves adding water to the material undergoing chlorination to inhibit decomposition of dichloroaldehyde and chloral by their reactions with chlorine. Chloroform and carbon tetrachloride result from decomposition. The decomposition reactions are inhibited by the formation of hydrates.
The hydrates are much more stable and therefore production of crude chloral containing only trace amounts of dichloroaldehyde, without significant chloroform and carbon tetrachloride co-production, can be accomplished. The chlorination reaction in addition generates significant amounts of by product hydrogen chloride gas (HCl), some of which tends to be absorbed by the wet crude chloral. To produce the purified chloral from the wet crude product, water and HCl must be removed.
Once the purified chloral is manufactured, pesticides, other chloral based hypnotics, i.e, chloral betaine and chloral hydrate can be produced.
Chloral hydrate is a Schedule IV controlled substance in the United States. Therefore the clandestine manufacture of chloral hydrate will not be discussed.
[top]Forms of Chloral Hydrate
Chloral hydrate comes in various forms in medicine. It is either in the form of a syrup 500mg/5ml, a suppository or in a gel cap either in a 500mg dose. In the U.S. the brand names of the gel caps is Somnote. The suppositories come in 325mg, 500mg and 650mg doses. The 325mg and 650mg suppositories are brand name and called Aquachloral supprettes. The 500mg suppository is a generic form of chloral hydrate and simply called chloral hydrate suppositories.
Chloral Hydrate in bulk form comes in large, monoclinic plates. Perfect 001 cleavage. It slowly volatilizes on exposure to air, so it is kept in dark airtight containers or bottles.
[top]Legal Status of Chloral Hydrate
The legal status of chloral hydrate with the United Nations and Europe, except the UK and Germany has no notations. Basically, chloral hydrate is considered a dangerous chemical, and that is about it. The UN classifies the danger of the drug as 6.1.
In the United States, chloral hydrate is considered a Schedule IV drug in the DEA scheduling of drugs. This is due, because it is a drug that is still sought after by addicts. Although, most sedatives/hypnotics sought after are either barbiturates and benzodiazepines, chloral hydrate is still on the market, thus is controlled by the DEA, because of it's addiction liability.
In the UK, chloral hydrate is not a controlled substance. However, a prescription is still needed for chloral hydrate from chemists and pharmacists about the UK.
Chloral hydrate is available by prescription in Germany in a product called "Chloraldurat".
In general, chloral hydrate is considered a dangerous chemical. It is basically considered in the class of Harmful (Xn) thus different countries have different laws on chloral hydrate, however individual countries, especially second world countries and third world countries it can probably be available without a prescription, if it is even available. Chloral hydrate is such an old sedative/hypnotic that many countries probably have discontinued it or may sell it OTC. Harmful Xn means harmful substance of preparations.
[top]History of Choral Hydrate
Sleeping potions were some of the earliest drugs discovered, and sleep aids are still among the most widely used drugs today. The ancient Greeks and Egyptians used the extract of the opium
poppy to induce sleep. The Greek god of sleep, Hypnos, was usually depicted holding a poppy
flower. Ancient Greeks and Romans knew of several other herbal sleep inducers. The bark of Mandrake
was used as a sleep aid, as were the seeds of an herb called Henbane
Two drugs used in the nineteenth century to induce sleep were bromides and chloral hydrate
. Chloral hydrate was synthesized in 1832 by a German scientist, Justus von Liebig, who is to organic chemistry as Elvis Presley was to rock and roll.
Chloral hydrate is a CNS depressant that acts very rapidly. Chloral hydrate could send a person into a deep sleep in about 30 minutes. Slipped into whiskey, it was the "knockout drops" of the underworld, also called a "Mickey Finn." Usually used back then to knock out an unsuspecting customer, and then robbed of his/her valuables.
[top]The latest Chloral Hydrate threads
 Liebig, Justus (1832). "On the Decomposition of Alcohol by Chlorine." Annalen der Pharmacie 1
(1):31-32 (translated from German)
 Liebreich, Oskar (1869). "The Chloral Hydrate; A new Hypnotic and Anesthetic and its Application in Medicine: A Drug Investigation." Berliner:Mueller (translated from German)
(drug & illness) then (pharmaceutical info) press C, scroll down to Chloral Hydrate, then press
 Anna Nicole Smith Autopsy Released. Coroner: Ex-Playmate died from accidental sedative overdose. The Smoking Gun (wikipedia/chloral hydrate)
 Lu, J, Greco, MA (2006)."Sleep circuitry and the hypnotic mechanism of GABAA drugs." . Journal of Clinical Sleep(B2)
 The Merck Index, Thirteenth Edition, 2001, Chloral Hydrate, chemical 2080
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