Chloral hydrate

Absorption

Rapidly absorbed in the GI tract following oral or rectal administration. Chloral hydrate and its active metabolite, trichloroethanol, have been detected in CSF, umbilical cord blood, fetal blood, and amniotic fluid.

Description

Chloral hydrate is one of the oldest sedatives used for dental sedation. It was first synthesized in 1832 by Justus von Liebig and was the first synthetic central nervous system (CNS) depressant. It was used to treat delirium tremens, insomnia, and anxiety, although it is considered an unapproved drug by the US Food and Drug Administration. Initially considered to be a safer alternative to opium, it was noted to produce rapid unconsciousness when combined with ethanol. Physical dependence can occur with chronic use.
Chloral hydrate is classified as a sedative-hypnotic and is known to induce sleep in children. It has been very popular in pediatric dentistry since the mid-1950s. Chloral hydrate is rapidly absorbed following oral administration and is converted through its first pass in the liver to trichloroethanol，its active form. Trichloroethanol is conjugated in the liver and excreted in the urine. Like other agents that are metabolized in the liver, chloral hydrate may interact with other drugs, herbs, or foods resulting in clinically significant alterations of the agents (e.g.,warfarin).

Chemical properties

Chloral is a combustible, oily liquid with a pungent irritating odor.

The Uses of Chloral hydrate

Trichloroacetaldehyde Hydrate is a useful chemical reagent used as a sedative/hypnotic agent for the short-term treatment of insomnia. First developed in 1832, chloral hydrate is the oldest sleep medication still in use today. This medication is also used to calm you just before surgery or other procedures. It works by affecting certain parts of the brain to cause calmness.
Studies have shown that when used in pediatric sedation side effects such as hallucination, excessive sleep and seizures were observed. Drowsiness and trouble waking up in the morning, nausea, vomiting, stomach pain, diarrhea, and headache may occur. Stomach problems can be reduced by taking chloral hydrate with a full glass of water. It is sometimes administered to patients being treated with cyclophosphamide and it is known to inhibit some aldehyde dehydrogenases.
Besides, 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.

The Uses of Chloral hydrate

Chloral hydrate is used as an intermediate in the production of insecticides, herbicides and hypnotic drugs. It has also been widely used as a sedative or hypnotic drug in humans at oral doses of up to about 750-1000 mg/day. Chloral hydrate is used as a sedative hypnotic, more commonly in pediatrics. With the advent of newer sedative hypnotics, its use has significantly decreased. It is also a drug of abuse, particularly in combination with ethanol to produce an amnestic effect in an individual who ingests it unknowingly.

Background

A hypnotic and sedative used in the treatment of insomnia. The safety margin is too narrow for chloral hydrate to be used as a general anesthetic in humans, but it is commonly used for that purpose in animal experiments. It is no longer considered useful as an anti-anxiety medication.

Indications

Mainly used as a hypnotic in the treatment of insomnia; however, it is only effective as a hypnotic for short-term use. May be used as a routine sedative preoperatively to decrease anxiety and cause sedation and/or sleep with respiration depression or cough reflex.

Definition

ChEBI: Chloral hydrate is an organochlorine compound that is the hydrate of trichloroacetaldehyde. It has a role as a sedative, a general anaesthetic, a mouse metabolite and a xenobiotic. It is an organochlorine compound, an aldehyde hydrate and an ethanediol.

Biological Functions

Chloral hydrate (Noctec, Somnos) was developed in the late 1800s and is still used as a sedative–hypnotic agent. It is a hydrated aldehyde with a disagreeable smell and taste that is rapidly reduced in vivo to trichloroethanol, which is considered to be the active metabolite. It produces a high incidence of gastric irritation and allergic responses, occasionally causes cardiac arrhythmias, and is unreliable in patients with liver damage.

General Description

Chloral hydrate, trichloroacetaldehydemonohydrate, CCl₃CH(OH)₂ (Noctec), is analdehyde hydrate stable enough to be isolated. The relativestability of this gem-diol is largely a result of an unfavorabledipole–dipole repulsion between the trichloromethyl carbonand the carbonyl carbon present in the parent carbonylcompound.
Chloral hydrate is unstable in alkaline solutions, undergoingthe last step of the haloform reaction to yield chloroformand formate ion. In hydroalcoholic solutions, it formsthe hemiacetal with ethanol. Whether or not this compoundis the basis for the notorious and potentially lethal effect of the combination of ethanol and chloral hydrate (the “MickeyFinn”) is controversial. Synergism between two differentCNS depressants also could be involved. Additionally,ethanol, by increasing the concentration of nicotinamideadenine dinucleotide (NADH), enhances the reduction ofchloral to the more active metabolite trichloroethanol, andchloral can inhibit the metabolism of alcohol because it inhibitsalcohol dehydrogenase. Chloral hydrate is a weak acidbecause its CCl₃ group is very strong electron withdrawing.A 10% aqueous solution of chloral hydrate has pH 3.5 to4.4, which makes it irritating to mucous membranes in thestomach. As a result, GI upset commonly occurs for thedrug if undiluted or taken on an empty stomach. Chloral hydrateas a capsule, syrup, or suppository is currently available.

Air & Water Reactions

Water soluble.

Reactivity Profile

Chloral hydrate is incompatible with alkalis, alkaline earth metals, alkali carbonates and soluble barbiturates. Chloral hydrate is decomposed by sodium hydroxide. Chloral hydrate reduces ammoniacal silver nitrate. Chloral hydrate liquefies when triturated with an equal quantity of menthol, camphor or thymol. . Reaction of Chloral hydrate with hydroxylamine produces toxic hydrogen cyanide gas, Org. Synth., 1941, Vol. 1, 377.

Hazard

Overdose toxic, hypnotic drug, dangerous to eyes. Probable carcinogen.

Fire Hazard

Flash point data for Chloral hydrate are not available; however, Chloral hydrate is probably combustible.

Flammability and Explosibility

Non flammable

Biochem/physiol Actions

Chloral hydrate is a sedative/hypnotic.

Clinical Use

Although it is suggested that chloral hydrate per semay act as a hypnotic,chloral hydrate is very quickly convertedto trichloroethanol, which is generally assumed toaccount for almost all of the hypnotic effect. Thetrichloroethanol is metabolized by oxidation to chloral andthen to the inactive metabolite, trichloracetic acid, which is also extensively metabolized to acylglucuronidesvia conjugation with glucuronic acid. It appears tohave potent barbiturate-like binding to GABA_Areceptors.Although an old drug, it still finds use as a sedative in nonoperatingroom procedures for the pediatric patient.

Safety Profile

A human poison by ingestion and possibly other routes. Poison experimentally by ingestion, intravenous, and rectal routes. Moderately toxic by subcutaneous, parenteral, and intraperitoneal routes, Experimental reproductive effects. Human systemic effects by ingestion: general anesthetic, cardiac arrhythmias, blood pressure depression, eye effects, coma, pulse rate increase, arrhythmias. Human mutation data reported. Questionable carcinogen with experimental carcinogenic and tumorigenic data by skin contact. A sedative, anesthetic, and narcotic. Combustible when exposed to heat or flame. When heated to decomposition it emits toxic fumes of Cl-.

Synthesis

Chloral hydrate, 2,2,2-trichloro-1,1-ethandiol (4.3.1), is synthesized either by chlorination of ethanol or chlorination of acetaldehyde and the subsequent addition of water molecules to the resulting trichloroacetic aldehyde [31].

Potential Exposure

Chloral is used as an intermediate in the manufacture of such pesticides as DDT, methoxychlor, DDVP, naled, trichlorfon, and TCA. Chloral is also used in the production of chloral hydrate; used as a therapeutic agent with hypnotic, sedative, and narcotic effects; used in a time prior to the introduction of barbiturates

Drug interactions

Potentially hazardous interactions with other drugs
Anticoagulants: may transiently enhance effect of coumarins.
Antipsychotics: enhanced sedative effects.
Antivirals: concentration possibly increased by ritonavir.

Carcinogenicity

Chloral hydrate has not been adequately tested for teratogenicity, reproductive effects, or chronic toxicity. Similarly, no histological evaluations have been conducted.

Environmental Fate

Chloral hydrate is a CNS depressant, but its mechanism of action is not well known. Coingestion with ethanol produces enhanced effects by several mechanisms. First, ethanol competes for alcohol and aldehyde dehydrogenase, which then prolongs the half-life of ethanol. The metabolism of ethanol generates the reduced form of NADH, which is a cofactor for the metabolism of chloral hydrate to its active metabolite trichloroethanol. Finally, ethanol inhibits the conjugation of trichloroethanol to its inactive form urochloralic acid. This results in enhanced CNS depression.

Metabolism

Metabolized by the liver and erythrocytes to form trichloroethanol, an active metabolite. This reaction is catalyzed by alcohol dehydrogenase and other enzymes. Oxidation of chloral hydrate and trichloroethanol to trichloroacetic acid in the liver and kidneys also occurs to a lesser extent. Trichloroethanol also undergoes glucuronidation to produce an inactive metabolism.

Metabolism

Chloral hydrate is rapidly metabolised to trichloroethanol (the active metabolite) and trichloroacetic acid in the erythrocytes, liver, and other tissues. It is excreted partly in the urine as trichloroethanol and its glucuronide (urochloralic acid) and as trichloroacetic acid. Some is also excreted in the bile.

Shipping

UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required.

Toxicity evaluation

Chloral hydrate has been detected at 5 mg l^-1 in the US drinking water supply. Although chloral hydrate does not exist naturally, it can be produced as a by-product of chlorination of water at water treatment facilities, specifically in exposed water with high amounts of humic and fulvic substances.

Incompatibilities

Chloral hydrate reacts with strong bases forming chloroform. Contact with acids, or exposure to light may cause polymerization. Reacts with water, forming chloral hydrate. Reacts with oxidizers, with a risk of fire or explosions.

Waste Disposal

Incineration after mixing with another combustible fuel; care must be taken to assure complete combustion to prevent phosgene formation; an acid scrubber is necessary to remove the halo acids produced.