J R Soc Med 2004;97:594-598
doi:10.1258/jrsm.97.12.594
© 2004 Royal Society of Medicine
One hundred years of barbiturates and their saint
Dimitri A Cozanitis MD DTM&H
Department of Anaesthesiology & Intensive Care Medicine, Institute of
Clinical Medicine, Helsinki University, Finland
Correspondence to: Department of Anaesthesiology & Intensive Care
Medicine, Helsinki University Hospital, Meilahti Hospital, FIN-00290 HUS,
Finland E-mail:
dcozanitis{at}yahoo.com
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INTRODUCTION
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Soporifics were limited to alcohol and opium until 1869, when
chloral
hydrate was first used as a sedative and hypnotic. Urethane,
bromides,
chlorbutanol, sulphones, hederal and chloralose then
followed. In 1863, Johan
Adolf Baeyer discovered malonylurea,
a substance that would become the parent
compound of the barbiturates.
The date of this discovery is believed to have
been 4 December,
and on that same day Baeyer visited a tavern frequented by
artillery
officers. 4 December is the feast day of Saint Barbara, patron
saint
of artillery-men as well as tunnellers and firemen; thus
he designated his
malonylurea barbituric acid (
Figure
1).
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THE SAINT
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Saint Barbara (
Figure 2) was
born in the latter part of the
third century in Heliopolis in what was then
Syria. Her father
Dioscurus, a Greek, was a fanatical idolater. In order to
shield
his daughter, whose beauty drew all eyes upon her, he confined
Barbara
to a tower having two windows. During one of her father's
travels, she
secretly embraced Christianity and had a third
window added through which the
sun would shine and honour the
Holy Trinity. When Dioscurus returned and
learned of Barbara's
conversion, he drew his sword to kill her but she
was miraculously
saved. Dioscurus offered Barbara to the pagan Roman Governor,
Marcianus,
who was taken by her beauty. Unable to win her to his will (for
she
had devoted her life to God), Marcianus ordered that the
maiden be flogged and
have her breasts cut off. That night Barbara
armed herself with prayer and, by
God's grace, her wounds were
healed. She escaped and hid in a cave but a
wicked shepherd
betrayed her to Dioscurus who beheaded his own daughter.
Immediately
thereafter loud thunder was heard; Dioscurus was struck by
lightning
and was
pulverized.
1
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Figure 2. Icon of St Barbara (in pearl and metal), Uspenski Cathedral,
Helsinki. [Photo: Mariamne Purmonen]
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THE FIRST BARBITURATES
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In 1903, a former assistant of the now von Baeyer in Strasbourg,
Emil
Fischer, along with a friend since their student days,
Josef von
Mering,
2 published
their paper on a new hypnotic,
barbital.
3 von
Mering having visited Verona earlier thought it appropriate
to name a compound
after the city; thereby barbital became
Veronal.
4 It was
manufactured by E Merck in Darmstadt and was even available
as scored soluble
cocoa-flavoured
tablets.
5 The
barbiturate
era had begun.
Emil Fischer (Figure 3) came
from an affluent family. His father, a lumber merchant, owned 1800 acres of
prime oak forest. Rather than following in his father's footsteps, the
young Fischer was drawn to chemistry. He became independently wealthy at the
age of 21 and developed into an eminent scientist receiving the Nobel Prize in
Chemistry, three years before his mentor von Baeyer was similarly honoured,
for his studies on sugar and purine chemistry. In his autobiography Fischer
mentions Veronal only in passing, since it was the synthesis of enzymes that
most interested
him.2 Seven of his
pupils became Nobel laureates.
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Figure 3. Emil Fischer (1852-1919). [Courtesy: Medical Historical Institute
and Museum,University of Zurich]
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It was Josef von Mering (Figure
4), later to earn fame as a physiologist and pharmacologist, who
persuaded Fischer to synthesize barbital. In 1886, von Mering created
experimental diabetes by injecting phloridzin into dogs. Along with Oskar
Minkowski in 1890 he demonstrated, by pancreatectomy, that the pancreas was
the seat of insulin production.
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Figure 4. Josef von Mering (1849-1908). [Courtesy: Medical Historical
Institute and Museum, University of Zurich]
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In 1919, Heinrich Hörlein at Bayer introduced phenobarbital (Luminal).
Patent rights were granted to Bayer in 1916 for yet more barbiturates,
including
pentobarbitone.6
When the United States entered the Great War in 1917, a serious difficulty
arose since German products were now considered enemy property. To overcome
this obstacle the American Government passed the Trading with The Enemy Act,
which permitted the Federal Trade Commission to grant licences to American
firms to manufacture German
products.7
In 1923, Horace Shonle at Lilly synthesized amylobarbitone, Amytal, and six
years later Amytal sodium became the first ever barbiturate to be used as an
intravenous anaesthetic. The sodium ion at the C2 position of the barbituric
acid molecule makes the barbiturates soluble for intravenous therapy as well
as affording greater absorption after oral dosage. This product however,
hydrolysed within thirty minutes of its preparation and its effects were
undesirably long lasting.
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SHORT-ACTING AGENTS
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Again in 1923, Shonle as well as Volviler and Tabern at Abbott,
working
independently, created pentobarbitone. Abbott was denied
patent rights since
these belonged to
Bayer.
6 Despite
this,
they offered their product 844 to John Lundy, anaesthetist at
the Mayo
Clinic, for oral clinical evaluation. The first recipients
were Lundy's
wife, Charles Mayo (co-founder of the Clinic) and
Jack Dempsey, former world
heavyweight boxing
champion.
7 The
compound
was launched as Nembutal and achieved outstanding clinical and
commercial
success. An intravenous preparation was also available, but
had
prolonged action.
The quest for an ultra-short-acting barbiturate ended in 1932 when the
chemists Walther Kropp and Ludwig Taub and the pharmacologist Hellmuth Weese
at IG Farben-industrie introduced hexobarbitone
(Evipan).8 Under
orders of the Allied Control Council in 1945 this firm, whose scientists had
discovered among other compounds the first sulfonamide (Prontosil) and
methadone, ceased to exist and its executives faced trial at Nurenberg. Evipan
and Evipan sodium became the property of the new Bayer company until the
product was finally withdrawn from the market in mid-1992.
In 1934, Volviler and Tabern created their ultra-short-acting barbiturate
thiopentone (Pentothal) by replacing the oxygen atom in the pentobarbitone
molecule for one of sulphur. For their achievement they were inducted into the
Inventors Hall of Fame, joining such earlier luminaries as Henry Ford, Thomas
Edison, and the Wright
brothers.7 A sad
note is that misuse of Pentothal and Evipan was the cause of deaths in
casualties of the Pearl Harbor attack in
1941.9
Lilly began trials with their ultra-short-acting counterpart 22451 in 1954.
These were soon abandoned after reports of excessive muscular activity and
even convulsions. In 1957, after further development, Lilly's now
acceptable preparation emerged; methohexitone (Brietal) entered the field,
having an even shorter duration of action than either Pentothal or Evipan.
Lundy again was the first to use Pentothal, in 1934. The effect of the dose
of the drug was gauged by paying attention to 'respiratory
exchange', rather than to respiratory movements by placing a wisp of
cotton over the nose and mouth of the patient and observing its motion. Lundy
also noted that morphine given subcutaneously along with a small dose of
Nembutal before injecting Pentothal would enable a patient to answer questions
truthfully without ever remembering being questioned. Thus he suggested that
this be used 'for obtaining information from insane persons or
criminals'.10
Tatum, however, was sceptical about any 'truth
serum'.11
Arthur L Tatum, with degrees in chemistry, physiology, and pharmacology
before qualification in medicine, joined Abbott to evaluate Nembutal. He
attempted to negotiate to receive a 2.5% royalty for his efforts from all of
Abbott's Nembutal sales, without
success.12
Barbiturates were classified according to their duration of action—long,
intermediate, short and ultra-short. Tatum advocated the use of analeptics,
specifically picrotoxin, in the treatment of acute barbiturate toxicity; this
became accepted practice until later refutation. He also discovered that
barbiturates were an effective antidote for cocaine
intoxication.11
The ease of substituting various groups onto the C 5-5 position of the
parent molecule yielded over 2500 barbiturates worldwide. Some 60 of these
were marketed, although five or six would have probably sufficed. Despite the
advent of the benzodiazepines in 1961 and newer types of anticonvulsants,
there remains a considerable demand for barbiturates. The 2002 edition of the
American Drug Index lists single and combination barbiturate
preparations in addition to an array of barbiturates combined with other drugs
for a wide spectrum of medical
conditions13 (Box
1).
| Box 1 Examples of available preparations containing
barbiturates in 2002 (Source: American Drug Index)
Amylobarbitone+d–amphetamine
Butabarbitone+aspirin, caffeine
Butabarbitone+nitroglycerin
Phenobarbitone+propanthaline
Phenobarbitone+ephedrine, theophylline
Phenobarbitone+pepsin, atropine, pancreatin, hyoscyamine
Phenobarbitone+homatropine, aluminium hydroxide, magnesium trisilicate
|
The barbiturates seemed a godsend to both patients and physicians because
of their apparent freedom from harmful side-effects. They endowed sleep to
those deprived of it, and for others relieved the intolerable anxiety of
everyday living. But these blessings came with a price; the Achilles'
heel of these drugs was the development of tolerance, noted first in
19035 and the
physiological dependence on them which could lead to their misuse or
abuse.
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CLASSIFICATION AND CONTROL
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Barbiturates were greatly sought after and easily obtainable.
In 1939, 100
tonnes of barbiturates were sold in the USA. Annual
production there reached
2000 tonnes by the mid-1960s. As early
as 1920, a notice by the Lilly sales
department disclosed that
'some jobbers were ordering barbital in lots of
1000 dollars
each'.
14
Between
the World Wars, a Canadian physician remarked, 'I bought Luminal
tablets
in 5000 lots every few
months'.
15
Such statements were portents.
From 1928 to 1937, of just over one million
hospital admissions
from ten centres, 143 000 were in consequence of
barbiturate
intoxication; the corresponding figure from 1940 to 1945 was
200
000. New York City hospitals were reporting that one death
every 36 hours was
related to barbiturate misuse or
abuse.
16 The number
of suicides involving barbiturates was second only
to that resulting from
carbon monoxide poisoning. Warnings were
sounded by medical and pharmaceutical
associations but they
fell on deaf ears. If some action was taken, it was more
symbolic
than substantial. The American legislative process for barbiturate
control
was posing difficulties. In 1945, a Bill was put before Congress
(HR
6178) that would place barbiturates in the category of narcotics—a
move
adamantly opposed by the American Pharmaceutical
Association.
17
Uniform
State laws were believed to be less complex and drastic than
Federal
legislation. Unfortunately, disagreements arose among
the States regarding the
record-keeping, prescription renewals,
manufacturing and distribution of these
compounds.
The legal aspects aside, the greatest evil was illegitimate use. For
reasons of frustration, desperation, or simple foolishness, the American
public was gulping barbiturates, which on the streets were easily found and
cheap. They had names such as 'red birds', 'red dogs' and
'yellow jackets' (based on the colour of the capsules) or
'Nebbies', 'goof pills' or 'downers'. The
gratification offered by these drugs was oblivion. Lilly's
quinalbarbitone, 'Seconal' (in red capsules), was particularly
popular. Lilly apart, there were some 60 providers of this substance, and tens
of millions of 'reds' were imported illegally from Mexico. Lilly was
accused in the press of blanketing the country with their barbiturates. The
company fought back, limiting the number, colour, and size of the empty
capsules that were sold to wholesalers. Every single item, whether capsule,
tablet, box or package, would carry the Lilly identification label. Various
barbiturate awareness programmes were initiated by Lilly for both health and
law enforcement
agencies.18
Barbiturates differ in their capacity to become habit-forming and Dutta
proposed a classification according to their potential for abuse.
Amylobarbitone, pentobarbitone and quinalbarbitone are in the category with
the highest abuse potential rating, while the ultra-short-acting compounds
(e.g. hexobarbitone, thiopentone, methohexitone) possess little or no
potential for
abuse.19 In 1971,
the US Controlled Substances Act went into effect. Under the Act, barbiturates
and other drugs including narcotics are divided into five schedules according
to their potential for abuse along with their application in medical
practice.
Although America bore the brunt of the barbiturate issue, 1968 saw 24 700
000 prescriptions for barbiturates in the UK. Physicians were obviously
catering more to the public's wants than to their
needs.20 The
Campaign for the Use and Restriction of Barbiturates (CURB) was formed by a
group of determined individuals who used teaching and commercial promotional
techniques to inform and educate physicians of the hazards associated with
barbiturates. The Medicines Act of 1968 provided legal control over
barbiturate products.
The measures taken to contain the barbiturate problem have borne fruit. The
2002 annual report of the American Association of Poison Control Centers
recorded 3573 cases of barbiturate poisoning with 21
deaths.21 In 1997,
there was an unusually high number of fatalities (54) involving barbiturates,
with phenobarbitone and alcohol implicated in the mass suicide of 42 members
of a cult.
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PHENOBARBITONE
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Phenobarbitone is considered a sedative rather than a hypnotic
substance
and according to the Controlled Substances Act grouping
it has low abuse
potential. In 1912, phenobarbitone (Luminal)
was found effective for the
treatment of epilepsy by Hauptmann
in Hoche's clinic in Freiburg. It
replaced the bromides which
had been used for this purpose since 1857.
Certainly, tolerance
in patients treated with phenobarbitone did develop, but
the
factor of addiction was questioned. Tatum was of the opinion
that
addiction to barbiturates does not
occur
11 but others
disagreed.
In any case, the signs and symptoms of abstinence clearly differ
between
chronic users of barbiturates and those of opioids. Over time,
phenobarbitone
therapy for epilepsy, particularly in children, causes
hyperactivity,
troubles with school and sleep and impaired memory
performance.
22
Barbiturates
are best known for their effect on the central nervous system
but
a peripheral effect is that provided by phenobarbitone for
the treatment of
physiological jaundice of the newborn. The
mode of action is the induction of
glucuronyl transferase and
other hepatic enzymes that can be functionally
immature in these
infants.
23
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CONCLUSION
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The century of barbiturates has brought benefit to some and
troubles to
others but still their namesake remains a source
of veneration. In 1988,
French tunnellers set up a statue of
St Barbara at the Sangatte access shaft
when work began on the
Euro-tunnel. Austrian tunnellers, in 2000, working
alongside
British and French colleagues, placed a statuette of their patron
saint
in the 3.2 km tunnel under the North Downs and the Thames as
part of the
new line from the Channel coast to London. Sadly,
on 31 May 2002 the cave
where Barbara had been beheaded near
Aboud in Palestine, and the tunnel
leading to it, were severely
damaged by military action. The cave had been a
pilgrimage site
since her death in 306. In England there are two churches
dedicated
to St Barbara; the older one, in Ashton under Hill, Worcestershire,
is
more than 1000 years old.
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Acknowledgments
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Sincere thanks for help in preparing this article are due to
Christopher C
J Jones; Archivist Lisa Bayne, Eli Lilly &
Company, Indianapolis;
Archivist Walter Fuchs, Medical Historical
Institute and Museum, University of
Zurich; and Katja Glock,
Merck KGaA, Darmstadt. The reading of the manuscript
by my medical
colleagues is gratefully appreciated.
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REFERENCES
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|---|
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- Report of the Advancements of Pharmaceutical Chemistry
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- Kaiserliches Patentamt. Patent No. 293163. Issued to Farbenfabriken
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INTRODUCTION
THE SAINT
