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International Congress Series 1242 (2002) 57 69

The intravenous barbiturates


R.N. Westhorpe *, C. Ball
Geoffrey Kaye Museum of Anaesthetic History and Australian and New Zealand College of Anaesthetists
Melbourne, Melbourne, Australia

Abstract
Adolf von Baeyer synthesised barbituric acid in 1864 by reacting malonic acid with urea.
Barbituric acid is clinically inert, and it was not until the synthesis of diethyl barbituric acid in 1882
that a clinically useful sedative became available. Named Veronal by Fischer, he and von Mering
first described its use in 1903. There followed many derivatives of the basic barbiturate molecule,
and the development of intravenous anaesthesia. Although many had brief periods of popularity, it
was sodium thiopentone which outlasted them all.
D 2002 Elsevier Science B.V. All rights reserved.
Keywords: Barbiturate; Barbituric acid; Thiobarbiturate; Thiopentone; Methohexitone

In the latter half of the 19th century, the medical climate was poised, waiting for the
introduction of an intravenous anaesthesia, except that no suitable drug existed.
Pierre-Cyprien Ore experimented with intravenous chloral hydrate in 1872, but slow
recovery and high mortality delayed further development of the method. In the early 20th
century, several drugs achieved limited popularity, including Hedonal, Paraldehyde,
Magnesium Sulphate and intravenous 5% ether. However, it was not until the introduction
of barbiturates that a true alternative to inhalation anaesthesia became available.
Adolf Johann von Baeyer first synthesised barbituric acid in 1864 by reacting malonic
acid with urea (Fig. 1). He later received the Nobel Prize in chemistry for his subsequent
work in organic chemistry and organic dyes. It is said that he named the new compound
barbituric acid after celebrating his discovery in a local Ghent tavern, where some artillery
officers were celebrating the day of their patron saint, St. Barbara. The amalgamation of
Barbara and urea thus gave rise to the name barbiturate.

Corresponding author.
E-mail address: westhorpe@netspace.net.au (R.N. Westhorpe).

0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved.


PII: S 0 5 3 1 - 5 1 3 1 ( 0 2 ) 0 0 7 5 8 - 6

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Fig. 1.

Barbituric acid is clinically inert and aroused little interest for many years. It was not
until the turn of the century when Hermann Emil Fischer, Professor of Chemistry in Berlin,
and his assistant Dilthey, undertook further research on diethyl barbituric acid which had
first been prepared in 1882. Fischer named the chemical Veronal after traveling near Mt.
Verona in Italy. It was also known later as barbital or barbitone (Fig. 2). Fischer teamed up
with Josef von Mering, a physician from Halle, to research oral administration, writing in
1903 that because of the slow onset, prolonged effect and insolubility, the drug would be
unsuitable for intravenous use. As an oral sedative, Veronal was popular for many years,
and was used by a number of celebrities for oblivion or suicide.
The first intravenous barbiturate was a combination, in equal parts, of Veronal and dial,
or diallylbarbituric acid (Fig. 2). The agent was created at the University of Zurich by T.A.
Redonnet in 1920, and named Somnifene (also known as Somnifen or Somnifaine). The
barbituric acid derivatives do not dissolve readily in water, and Somnifene was prepared as
a solution in water, glycerine and alcohol. First used in a labour ward by Cerne, and
shortly afterwards in Paris, by Fredet and Perlis for surgical procedures, Somnifene was
then used for many years in France and Germany despite its tendency to cause hyperactivity. It was not used widely outside Europe although J.H. Fjelde reported its use in
Dakota in 1929 for surgery and obstetrics.

Fig. 2.

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His technique involved giving the intravenous component in the ward prior to an
ethylene anaesthetic. We are now using a 3 cc dose in most cases. This does several
things. In the first place the patient is put to sleep right in his room, a distinct
advantage which relieves him of further thoughts of the coming operation. Patients
appreciate this feature. . . .When awakening they are back in their own bed and have no
recollection of having been to the operating room at all. A wonderful feature! Its use
in obstetrics seemed to delight him further In the average sized woman, the injection
of 6 cc will last 6 h, as a rule. . . On awakening they do not even remember me having
taken out the needle. He stated that labour was not unduly affected, that the child may
be somnolent but otherwise unaffected, and that there was no risk of haemorrhaging or
altered reflexes. When commenting on the drowsiness afterwards he states that I do
not regard this as a drawback, as the rest does the patient good. He also adds,
Should it be desirable to awaken the patient shortly after delivery, an ampoule of
caffeine sodium benzoate will usually accomplish this in one-half to one hour. The
patient will then recognize relatives and talk rationally, but later may not remember
this phase.
Sodium amytal, sodium iso-amyl ethyl barbiturate, was first described in 1923. In
1928, a soluble form of sodium amytal was described in the US which was trialed and
reported on by Zerfas et al. in 1929. Despite having to be used within 30 min of
preparation, it soon became extremely popular, and over the next 4 years it was the most
common intravenous anaesthetic used in North America. Like other barbiturates, it
remained regional and was seldom used elsewhere. John Lundy at the Mayo clinic was
one of the first to use this drug. Slow recovery and restlessness were disadvantages of
sodium amytal.
Nembutal, also known as Pentobarbital sodium (among many other names), sodium
ethyl methyl butyl barbiturate, largely replaced sodium amytal as a basal narcotic, but
was similarly unstable in solution and caused restlessness and occasional skin reactions.
In 1927, the German obstetrician, Rudolph Bumm, introduced Pernocton, sodium secbutyl (2-bromoallyl)-barbiturate. Also known as Pernoston, this drug became very
popular, especially in Germany. Pernocton showed less postoperative hyperactivity and
restlessness than other barbiturates, and was stable in solution. Marketed as a 10% aqueous
solution, it did not require mixing.
Sodium soneryl, Butobarbitone, or Butobarbital sodium, sodium butyl ethyl barbiturate, was primarily an oral sedative which was used briefly intravenously as a 5% solution.
Prolonged recovery was a problem.
Helmuth Weese (1897 1954) graduated in medicine from Munich University but soon
changed direction to become a pharmacologist. By 1928 he was head of the department of
pharmacology at the Bayer works in Wuppertal-Elberfeld. He later became Professor of
Pharmacology in Cologne, and then Dusseldorf. It should be noted that these Bayer works
were the original site of what is now a worldwide chemical industry. However, although
they did significant work into the development of intravenous barbiturates, the company
has no connection with Adolf von Baeyer.
Considerable research into barbiturates began at this time, with many compounds being
tested. By changing the side chains on the basic molecule, certain predictable effects could
be achieved (Fig. 3). If the alkyl sides chain at C5 are too long, hypnotic activity is

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Fig. 3.

reduced, and convulsant activity may increase. Increasing lipid solubility leads to
increased hypnotic potency, together with decreased duration of action and latency of
onset, as well as more rapid metabolism.
The first truly short acting barbiturate, hexobarbitone (Evipan, Evipal), sodium
5-cyclohexenyl 1,5-dimethyl barbiturate, was synthesized under the direction of Weese,
and its first clinical use was reported by Weese and W. Scharpff in July 1932. The addition
of a methyl group onto one of the nitrogen atoms resulted in increased lipid solubility.
Thus, hexobarbitone soon became extremely popular as an induction agent due to its rapid
induction and short action, and by 1944 it was estimated that it had been used on over
10 million patients. It was prepared fresh from a white powder and the main side effect
was excitatory muscle movement on induction, a feature common to all methylated
barbiturates. Several other short-acting intravenous barbiturates appeared around this time.
Eunarcon, sodium 1-methyl 5-5-isopropyl-h-bromallyl barbiturate, also known as
Eunarkon was available as a stable 10% solution in ampoules. Rapid injection was
accompanied by muscle twitching, otherwise it was very similar to hexobarbitone apart
from a lower incidence of postoperative headache (Fig. 4).
Narconumal, 1-methyl-5-5-allyl isopropyl barbituric acid, had to be freshly prepared
and injected slowly (less than 1 cm3/min). It was very similar to hexobarbitone in action,
with a reputedly high safety factor. None of these other barbiturates could compete with
hexobarbitone however, which remained extremely popular, especially in Europe, long
after the introduction of thiopentone.

1. The thiobarbiturates
Substituting oxygen at C2 with a sulphur atom created thiobarbiturates. Although not
true barbiturates, they are commonly included in the generic class. Thiobarbiturates are
more lipid soluble, and are therefore shorter acting and more potent.

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Fig. 4.

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Fig. 4 (continued).

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Fig. 4 (continued).

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Fig. 4 (continued).

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Fig. 4 (continued).

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Fig. 4 (continued).

Sulphur barbiturates were first described by Fisher and von Mering in 1903. They
administered a single dose to a dog that promptly died. This led them to conclude that the
sulphur had toxic properties and they discontinued their research. Sulphur barbiturates
were not studied again until early 1930s. At a meeting of the American Chemical Society
in August 1935, chemists Ernest Volwiler and Donalee Tabern, from Abbott laboratories,
described their work with several sulphur barbiturates. Ellis Miller and colleagues also
described the thiobarbiturates the same year. (Volwiler was later to become Vice President
of Abbott laboratories in 1940, President in 1950 and Chairman in 1958.)
According to Adams, the first clinical trials resulted from unreported experimental
work on rabbits by Spruth and Tabern. Sodium allyl-sec-butyl-thiobarbiturate and sodium
ethyl methyl butyl thiobarbiturate were then presented to John Lundy by Abbott for
further investigative work. The latter of these two drugs is the sulphur derivative of
pentobarbitone (Nembutal) and was known at the time as thiobarbiturate 8064. Lundy
later named it Thionembutal and it was given the trade name Pentothal sodium. This drug,
which we now know as thiopentone, was preferred by Lundy because of its rapid action
and short duration. The other drug was known as Thiosebutal.

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Reports indicate that Ralph Waters was the first to use thiopentone clinically, but John
Lundy was responsible for much of the early clinical research and reporting. He published
his experience with 2207 patients in December 1936 in the American Journal of Surgery.
His technique involved giving an average of 15 ml of a 5% solution over about 15 min.
His principal observation was that rapid injection led to respiratory depression and he
guarded against this by taping a piece of cotton wool to the patients upper lip which
monitored continuing respiration. This device was referred to as Lundys butterfly and was
widely used for many years.
These early days of intravenous anaesthetic agents were a time of great change in
anaesthesia. Not only were these anaesthetists experimenting with new drugs, but with
entirely new techniques. Sir Ivan Magill describing intravenous agents in 1931 claimed
that they provided a pleasant method of bridging the gap between consciousness and
unconsciousness before general anaesthesia. Initially, they were mostly used this way, as
induction agents, but anaesthetists were quick to see other potential advantages of
intravenous anaesthesiaalmost to the detriment of the technique.
In 1943, F.J. Halford wrote While intravenous anaesthesia would seem to be ideal for
war injuries because of its compactness, ease of preparation and nonexplosive characteristics, it should be clearly recognized that under war conditions anaesthetics cannot be
administered by highly skilled anaesthesiologists, but have instead to be given by doctors,
nurses and orderlies, to whom the art is strange . . . He goes on to describe a number of
patients anaesthetized with barbiturates on 7 December 1941 in Honolulu. Many of these
patients were badly shocked and a number died on induction. There was very little
equipment, a minimum of intravenous fluids, and a lack of oxygen. Whilst intravenous
barbiturates seemed a good solution, this was obviously not the case. The author
concludes, As Admiral Gordon-Taylor of the British Navy has so aptly said, Spinal
anaesthesia is the ideal form of euthanasia in war surgerythen let it be said that
intravenous anaesthesia is also an ideal method of euthanasia. It was the consensus of all
civilian surgeons concerned that, considering all the hazards of patient, anaesthetist and
anaesthetic, open drop ether still retains the primacy!
Fortunately for thiopentone, the editors published another article in the same journal
where a woman was successfully anaesthetized with thiopentone after a gunshot wound.
This case was obviously different, in that it was not a war injury, and the patient was
adequately transfused. The anaesthetic consisted of 1 cm3 increments of 2.5% thiopentone given 1 min apart. After 5 cm3, she was intubated and continued to breathe
spontaneously for the rest of the 90-min operation on a mixture of 50% oxygen/nitrous
oxide. A further 11 cm3 of thiopentone was given in total throughout the anaesthetic and
the patient eventually recovered, despite extensive abdominal and thoracic trauma. The
authors of this article, Charles Adams and Howard Gray, concluded that thiopentone
could safely be administered in shocked patients where adequate resuscitation was
available.
While earlier barbiturates enjoyed some popularity, it was thiopentone that became
universally acceptable. First used as a 10% solution, it was noted as the cause of
respiratory depression and perivascular irritation. It was later used as a 5% solution and
eventually recommended as a 2.5% solution. After preparation it remained stable for
several days.

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A number of other thiobarbiturates were introduced. They include the following.


Venesetic, sodium iso-amyl ethyl thiobarbiturate, the sulphur homologue of sodium
amytal. It was said to act in a very similar way to thiopentone.
Kemithal sodium, sodium cyclohexenyl-5-allyl-2-thiobarbiturate, also used as a 10%
solution, was stable in solution for 4 to 5 h. Kemithal was noted to cause less respiratory
depression than thiopentone, and to be less likely to cause laryngospasm, or result in the
emergence of hyperactivity. However, it was noted as producing arrhythmias more
frequently. Thiamylal (thioquinalbarbitone, Surital sodium), sodium 5-allyl-5 (1methyl
butyl) thiobarbiturate, was described by Volwiler and Tabern in 1935. A number of studies
suggested that Surital was as safe and as effective as thiopentone, with slightly less
cumulative effect.
Buthalitone sodium, sodium 5-allyl-5-iso-butyl thiobarbiturate, was first synthesised by
Miller and introduced by Helmuth Weese and Ferdinad Koss in 1954. It was also known as
Baytenal or Baytinal, and later, Transithal and Ulbreval. It was stable for 36 h in solution
with 6% sodium carbonate. It reportedly had a faster recovery time than hexobarbitone,
but was eventually abandoned, once again because of a high incidence of muscle
movements. Thiobutobarbitone, sodium 5-ethyl-5-secbutyl-thiobarbiturate, was first introduced by Karl Horatz and Fritz Sturtzbecher in 1952 after it had first been described by
Volwiler and Tabern in 1935. It is slightly less potent than thiopentone but is otherwise
very similar. It was widely used on the continent, and was particularly popular in Germany
where it was marketed as Inaktin. Elsewhere it was known as Inactin. Thionarcex, sodium
5-ethyl-5-butyl ethyl thiobarbiturate, was slightly more potent than thiopentone, with a
slightly shorter recovery time.
Zima, von Werder and Hotovy introduced a methyl thioethyl group at the 5 position of
the barbiturate chain in an attempt to accelerate breakdown and prevent liver damage due
to toxic doses. This research led to the development of methitural, sodium methyl
thioethyl-2 pentyl thiobarbiturate, which was very short acting. It was used briefly in
the USA, as Nereval, and Germany, as Thiogenal, but it was not as effective as other
agents and possessed greater parasympathomimetic properties. It was soon abandoned.
The methyl group in hexobarbitone was responsible for the rapid onset of action and
further research into the methylated barbiturates continued for this reason. Eventually,
research by Chernish et al. at the Lilly Research Laboratories led to the development in
1956 of Lilly 22,451, a drug more potent than thiopentone, with a more rapid recovery
rate, but with unfortunate convulsive properties. Sodium 1-methyl, 5-5-allyl (1-methyl, 2pentynyl) barbiturate was shown to have four isomers, due to the two asymmetrical carbon
atoms. It could be fractionated into pairs with either high and low melting points.
Separation of the high melting point isomers led to the development of Lilly 25,398, or
methohexitone, first used clinically by Dundee and Moore in 1960 [1 12].
References
[1] R.C. Adams, Intravenous Anaesthesia, Harper and Brothers, London, 1944.
[2] R.C. Adams, H.K. Gray, Intravenous anaesthesia with pentothal sodium in the case of gunshot wound
associated with accompanying severe traumatic shock and loss of blood: report of a case, Anesthesiology 4
(1943) 70 73.

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[3] C. Ball, R.N. Westhorpe, The history of intravenous anaesthesia: the barbiturates. Part 1, Anaesth. Intensive
Care 29 (2001) 97.
[4] C. Ball, R.N. Westhorpe, The history of intravenous anaesthesia: the barbiturates. Part 2, Anaesth. Intensive
Care 29 (2001) 219.
[5] C. Ball, R.N. Westhorpe, The history of intravenous anaesthesia: the barbiturates. Part 3, Anaesth. Intensive
Care 29 (2001) 323.
[6] J. Dundee, Intravenous anaesthesia, Churchill Livingstone, 1988.
[7] J. Dundee, P. McIlroy, The history of the barbiturates, Anaesthesia 37 (1982) 726 734.
[8] Editorial, The question of intravenous anaesthesia in war surgery, Anesthesiology 4 (1943) 74 77.
[9] F.J. Halford, A critique of intravenous anaesthesia in war surgery, Anesthesiology 4 (1943) 67 69.
[10] J. Schulte am Esch, M. Goerig, Anaesthetic Equipment in the History of German Anaesthesia, Drager
Druck, Lubeck, 1997.
[11] P. White, Textbook of Intravenous Anaesthesia, Williams and Wilkins, 1997.
[12] W.D. Wylie, H.C. Churchill Davidson, A Practice of Anaesthesia, Lloyd Luke, London, 1972.