Colourless, transparent or white crystals with a pungent
odour. It volatilises slowly on exposure to air and melts at
about 55Β°. Soluble 1 in 0.25 of water, 1 in 1.3 of alcohol. 1 in
2 of chloroform, and 1 in 1.5 of ether: very soluble in olive oil.
A 10% solution has a pH of 3.5 to 5.5. Store in airtight con-
tainers.
Incompatible with alkalis, alkaline earths, alkali carbonates,
soluble barbiturates, borax, tannin, iodides, oxidising agents.
permanganates, and alcohol (chloral alcoholate may crystal-
lise out). It forms a liquid mixture when triturated with many
organic compounds, such as camphor, menthol, phenazone,
phenol, thymol, and quinine sails.
Dependence and Withdrawal, Adverse Effects, and Treatment :
Chloral hydrate has an unpleasant taste and is corrosive to
skin and mucous membranes unless well diluted. The most
frequent adverse effect is gastric irritation: abdominal disten-
sion and flatulence may also occur. CNS effects such as drow-
siness, light-headedness. ataxia, headache, and paradoxical
excitement, hallucinations, nightmares, delirium, and confu-
sion (sometimes with paranoia) occur occasionally. Hyper-
sensitivity reactions include skin rashes. Ketonuria may
occur,
The effects of acute overdosage resemble acute barbiturate in-
toxication . In addition the irritant effect may cause initial vomiting, and gastric necrosis leading to strictures. Cardiac arrhythmias have been reported.
Jaundice may follow liver damage, and albuminuria may follow kidney damage.
Tolerance may develop and dependence may occur. Features
of dependence and withdrawal are similar to those of barbiturates
Adverse effects should be managed in a similar way to those
of barbiturates.
In a drug surveillance programme, 1618 patients received
chloral hydrate as a hypnotic, usually in doses of 0.5 to 1 g. In
1130 patients evaluated, side-effects, which were reversible.
occurred in 2.3% of patients and included gastro-intestinal
symptoms (10 patients). CNS depression (20), and skin rash
(5). In 1 patient the prothrombin time was increased: in 1 patient hepatic encephalopathy seemed to worsen: and bradycardia developed in 1 patient.
In a Boston Collaborative Drug Surveillance Program side-
effects occurred in approximately 2% of 5435 patients who
received chloral hydrate, Three reactions were described as
life-threatening.
Carcinogenicity. Chloral hydrate has been widely used as a
sedative, especially in children. Concern over warnings that
chloral hydrate was carcinogenic in rodents has prompted
some experts, including the American Academy of Pediat-
rics, to review the relative risks of the medical use of this
agent. The original warnings appear to have been based in
part on the assumption that chloral hydrate was a reactive me-
tabolite of trichloroethylene and was responsible for its carci-
nogenicity but there is evidence to suggest that the
carcinogenicity of trichloroethylene is due to a reactive inter-
mediate epoxide metabolite. Studies in vitro indicate that cho-
ral hydrate can damage chromosomes in some mammalian
test systems but there have been no studies of the carcino-
genicity of chloral hydrate in humans. Some long-term stud-
ies in mice have linked chloral hydrate with the development
of hepatic adenomas or carcinomas. However, it was noted
that chloral hydrate was not the only sedative that had been
shown to be a carcinogen in experimental animals. The Amer-
ican Academy of Pediatrics considered chloral hydrate to be
an effective sedative with a low incidence of acute toxicity
when administered orally in the recommended dosage for
short-term sedation and although the information on carcino-
genicity was of concern it was not sufficient to justify the risk
associated with the use of less familiar sedatives. There was
no evidence in infants or children demonstrating that any of
the available alternatives were safer or more effective. How-
ever, the use of repetitive dosing with chloral hydrate to main-
tain prolonged sedation in neonates and other children was of
concern because of the potential for accumulation of drug
metabolites and resultant toxicity.
Effects on the CNS. Report' of a 2-year-old child who ex-
perienced the first of 2 seizures 60 minutes after receiving
chloral hydrate 70 mg per leg body-weight for sedation,
Hyparbilirubinaemia Small retrospective studies have
suggested that prolonged administration of chloral hydrate in
neonates may be associated with the development of hyperbi-
lirubinaemia. This may possibly be related to the prolonged
half-life of the metabolite trichloroethanol in neonates.
Overdosage Of 76 cases of chloral hydrate poisoning re-
ported to the UK National Poisons Information Service, 47
were severe.' Of 39 adults, 12 had cardiac arrhythmias in-
cluding 5 with cardiac arrest. Antiarrhythmic drugs were rec-
ommended unless obviously contra-indicated.
Haemoperfusion through charcoal or haemodialysis was rec-
ommended for patients in prolonged coma. Cardiac arrhyth-
mias and CNS depression were also major features of 12
cases of chloral hydrate overdosage reported from Australia.2
Lignocaine was not always successful in controlling arrhyth-
mias, but propranolol was successful in all 7 patients in whom
it was used. It was noted that resistant arrhythmias, particular-
ly ventricular fibrillation, ventricular tachycardia, and su-
preventricular tachycardia were the usual cause of death in
patients who had taken an overdosage of chloral hydrate. Al-
though there had been no controlled studies of antiarrhythmic
therapy in overdosage with chloral hydrate, the successful use
of beta blockers appeared to be a recurring feature in reports
in the literature.
Administration of flumazenil produced an increased level of
consciousness, pupillary dilatation, and return of respiratory
rate and blood pressure towards normal in a patient who had
taken an overdosage of chloral hydrate.'
Precautions
Chloral hydrate should not be used in patients with marked
hepatic or renal impairment or severe cardiac disease and oral
administration is best avoided in the presence of gastritis. It
should be used with caution in patients susceptible to porphy-
ria or, as with all sedatives, in those with respiratory insuffi-
ciency.
Chloral hydrate may cause drowsiness: affected patients
should not drive or operate machinery. Prolonged administra-
tion and abrupt withdrawal of chloral hydrate should be
avoided to prevent precipitation of withdrawal symptoms,
Repeated administration in infants and children may lead to
accumulation of metabolites and thereby increase the risk of
adverse effects.
Chloral hydrate may interfere with tests for urinary glucose or
17-hydroxycorticosteroids,
Neonates. The half-life of trichloroethanol, an active me
tabolite of chloral hydrate, is prolonged in neonates; values
of up to 66 hours have been reported in some studies. Short
term sedation in the neonate with single oral doses of 25
50 mg per kg body-weight of chloral hydrate is considered'
be probably relatively safe, but repeated administration car-
ries the risk of accumulation of metabolites which may rest
in serious.. toxicity. Toxic reactions may occur even after the
drug has been discontinued since the metabolites may ace
mulate for several days.
Obstructive sleep apnoea Children with obstructive
sleep apnoea could be at risk: from life-threatening respiratory
obstruction if chloral hydrate is used for sedation. Details
2 such children who suffered respiratory failure following se-
dation with chloral hydrate for lung function studies have
been reported by Biban et al.'
Interaction
The sedative effects of chloral hydrate are enhanced by the
simultaneous administration of depressant! of the CNS such
as alcohol (the 'Mickey Finn' of detective fiction), barbitu-
rates, and other sedatives.
Chloral hydrate may enhance the effects of coumarin antico-
agulants. A hypermetabolic state, apparently due to displacement of thyroid
hormones from their
binding proteins, has been reported in patients given an intra-
venous dose of frusemide subsequent to chloral hydrate.
Pharmacokinetics
Chloral hydrate is rapidly absorbed from the gastro-intestinal
tract and starts to act within 30 minutes of oral administration.
It is widely distributed throughout the body. It is rapidly me-
tabolised to trichloroelhanol and trichloroacetic acid
in the erythrocytes, liver, and other tissues and excreted partly
in the urine as trichloroethanol and its glucuronide (urochlo-
ralic acid) and as trichloroacetic acid. Some is also excreted
in the bile.
Trichloroethanol is the active metabolite. and passes into the
cerebrospinal fluid, into breast milk, and across the placenta.
The half-life of trichloroethanol in plasma is reported to range
from about 7 to 11 hours but is considerably prolonged in the
Uses and Administration
Chloral hydrate is a hypnotic and sedative with properties
similar to those of the barbiturates. It is used in the short-term
management of insomnia and has been used as a sed-
ative for premedication . In the USA some authori-
ties consider chloral hydrate to be the drug of choice for
sedation of children before diagnostic, dental, or medical pro-
cedures (but see under Carcinogenicity above).
Externally, chloral hydrate has a rubefacient action and has.
been employed as a counter-irritant.
Chloral hydrate is administered by mouth as an oral liquid or
as gelatin capsules with chloral hydrate dissolved in a suitable
vehicle. It has also been dissolved in a bland fixed oil and
given by enema or as suppositories,
It should not be given as tablets because of the risk of damage
to the mucous membrane of the alimentary tract,
The usual hypnotic dose by mouth is 0.5 to 2 g at night and as
a sedative 250 mg can be given three times daily, to a maxi-
mum single or daily dose of 2 g. Oral dosage forms should be
taken well diluted or with plenty of water or milk. Children
may be given 30 to 50 mg per kg body-weight to a maximum
single dose of 1 g as a hypnotic, A suggested sedative dose for
premedication in children is 25 to 50 mg per kg to a maxi-
mum single dose of 1 g.
A reduction in dosage may be appropriate in frail elderly pa-
tients.
Derivatives of chloral hydrate, such as acetylglycinamide-
chloral hydrate, chloral betaine. chloralose, chlorhexadol, and
dichloralphenazone. which break down in the body to yield
chloral hydrate, have been used similarly.