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History of Opium
http://opioids.com/timeline/index.html
Constituents of Opium
• Opium poppy contains over 40 opium alkaloids,
including morphine (up to 20%), narcotine (about
5%), codeine (about 1%), and papaverine (about
1%).
2
HO
3
1
11
4
12
O
13
5
HO
CH3O
10
15
9
14
O
H
8
6
16
H
N
H
CH3
7
Morphine (Astramorph)
H
N
CH3
HO
Codeine (5X LESS potent than morphine)
The History of Morphine
• http://opioids.com/morphine/200anniv.html
History of Morphine
• Doctors had long hunted for effective
ways to administer drugs without
ingesting them. Taken orally, opium is
liable to cause unpleasant gastric sideeffects. The development of the
hypodermic syringe in the midnineteenth century allowed the injection
of pure morphine. Both in Europe and
America, members of high society and
middle-class professionals alike would
jack up daily; poor folk couldn't afford
to inject drugs.
The History of Morphine
• Morphinism became rampant in the USA after its
extensive use by injured soldiers on both sides of
the Civil War. In late nineteenth-century America,
opiates were cheap, legal and abundant. In the
judgement of one historian, America became "a
dope fiend's paradise". Moreover it was believed
that injecting morphine wasn't addictive. Quitting
habitual opium use can cause malaise, flu-like
symptoms, and depression; morphine seemed an
excellent cure. In China, for instance, early
twentieth century missionaries handed out antiopium remedies in such profusion that the pills
became known as "Jesus Opium"; their active
ingredient was morphine.
Side effects of morphine
• Morphine has many side effects. The most
dangerous is respiratory depression. Minor degrees
of respiratory depression may be detected following
standard doses of morphine, but this is not clinically
important. With higher doses or in frail patients, the
respiratory rate decreases, the patient becomes
increasingly sedated, and the pupils very small.
Common side effects are nausea and vomiting due
to a central action of morphine stimulating one of
the centres in the brain concerned with vomiting
called the chemotactic trigger zone. Other central
nervous system side effects of morphine are cough
suppression, sedation, and dependence leading to
addiction.
Side effects of morphine
• Morphine also has an effect on the
muscle of the bowel and urinary tract,
causing the sphincter to contract and
reduce the peristalsis (the wavelike
movements of the bowel muscle that
propel its contents forwards). This
results in a delayed emptying of the
stomach, constipation, and may also
lead to urinary retention.
Structure of Morphine
HO- Group is needed for activity
2
HO
3
1
11
4
O
13
5
HO
10
15
12
9
14
H
8
6
16
H
N
CH3
7
Morphine (Astramorph)
HO- Group not important to activity
‘Tinkering’ with the structure of
morphine produced heroin
HO- Group is needed for activity
2
AcO
2
HO
Easily enzymatically hydrolyzed to AcOH and HO-Ar
3
3
1
1
11
4
11
4
12
O
13
5
HO
10
15
O
9
14
H
8
6
16
12
H
13
5
N
CH3
AcO
10
15
9
14
H
8
6
16
H
N
CH3
7
7
Morphine (Astramorph)
HO- Group not important to activity
Heroin (Diamorphine)
(2X as potent as morphine)
(Conversion of two -OH groups to -OAc
facilitates crossing of the BBB)
From aspirin to heroin?
• The father of modern medicine was
Hippocrates, who lived sometime between
460 B.C and 377 B.C. Hippocrates left
historical records of pain relief treatments,
including the use of powder made from the
bark and leaves of the willow tree to help
heal headaches, pains and fevers.
• By 1829, scientists discovered that it was
the compound called salicin in willow plants
which gave you the pain relief.
From aspirin to heroin?
• According to "From A Miracle Drug" written
by Sophie Jourdier for the Royal Society of
Chemistry: "It was not long before the
active ingredient in willow bark was
isolated; in 1828, Johann Buchner, professor
of pharmacy at the University of Munich,
isolated a tiny amount of bitter tasting
yellow, needle-like crystals, which he called
salicin.
From aspirin to heroin?
• Two Italians, Brugnatelli and Fontana, had in
fact already obtained salicin in 1826, but in a
highly impure form. By 1829, [French
chemist] Henri Leroux had improved the
extraction procedure to obtain about 30g from
1.5kg of bark. In 1838, Raffaele Piria [an
Italian chemist] then working at the Sorbonne
in Paris, split salicin into a sugar and an
aromatic component (salicylaldehyde) and
converted the latter, by hydrolysis and
oxidation, to an acid of crystallised colourless
needles, which he named salicylic acid."
From aspirin to heroin?
O
OH
OH
Salicylic Acid
• The problem was that salicylic acid was tough on
stomachs and a means of 'buffering' the compound
was searched for. The first person to do so was a
French chemist named Charles Frederic Gerhardt. In
1853, Gerhardt neutralized salicylic acid by buffering
it with sodium (sodium salicylate) and acetyl
chloride, creating acetylsalicylic acid. Gerhardt's
product worked but he had no desire to market it
and abandoned his discovery.
From aspirin to heroin?
• In 1899, a German chemist named Felix
Hoffmann, who worked for a German
company called Bayer, rediscovered
Gerhardt's formula. Felix Hoffmann made
some of the formula and gave it to his father
who was suffering from the pain of arthritis.
With good results, Felix Hoffmann then
convinced Bayer to market the new wonder
drug. Aspirin was patented on March 6,
1889.
From aspirin to heroin?
• The folks at Bayer came up with
the name Aspirin, it comes from
the 'A" in acetyl chloride, the "spir"
in spiraea ulmaria (the plant they
derived the salicylic acid from) and
the 'in' was a then familiar name
ending for medicines.
From aspirin to heroin?
O
O
O
OH
H3C
OH
Cl
O
OH
Salicylic Acid
O
CH3
O-Acetylsalicylic Acid
(ASA, aspirin)
O-Acetylsalicylic acid is a better pain reliever than
Salicylic acid. It is also less irritating to the stomach.
From aspirin to heroin?
• The following is taken from:
• http://opioids.com/heroin/heroinhistory.h
tml
• Source: Sunday TimesDate: 13
September 1998
From aspirin to heroin?
• Heinrich Dreser, chemist and opportunist, was
one of the most influential men of his age.
• Born in 1860, in Darmstadt, the son of a
physics professor, he showed promise as a
chemist from an early age. After receiving his
doctorate from Heidelberg University, he
worked in various laboratories before
becoming a professor at Bonn University in
1893. Four years later he joined the Bayer
Company, where he was in charge of testing
the efficacy and safety of new drugs.
From aspirin to heroin?
• Dreser was admired for his thorough,
methodical approach, and for his innovations
in testing (he was, for example, the first
chemist to use animal experiments on an
industrial scale). The credit for originating new
products for Bayer belonged, strictly speaking,
to the researcher Arthur Eichengruen, but
Dreser had the power to decide which new
products would be developed. He had also
negotiated a special deal which guaranteed
him a share of the profits from products he
launched.
From aspirin to heroin?
• In 1897 the Bayer chemist Felix
Hoffmann, acting on Eichengruen's
instructions, discovered a new
process for modifying salicyclic
acid (a remedy for fever and
inflammation which unfortunately
has excruciating digestive side
effects) to produce acetylsalicyclic
acid (ASA).
From aspirin to heroin?
• Eichengruen enthusiastically recommended
ASA to Dreser in 1898. Dreser, after
cursory consideration, rejected it.
Ostensibly, his objection was that ASA
would have an "enfeebling" action on the
heart. "The product has no value," he
pronounced confidently. But the real
problem was almost certainly that he had
another product on his mind whose
impending success he was anxious not to
jeopardise. This was heroin.
From aspirin to heroin?
• The drug that Bayer launched
under the trademark Heroin in
1898 was not an original discovery.
Diacetylmorphine, a white,
odourless, bitter, crystalline
powder deriving from morphine,
had been invented in 1874 by an
English chemist, C R Wright.
From aspirin to heroin?
• Diacetylmorphine was first
synthesised in the Bayer laboratory
in 1897 - by Hoffmann, two weeks
after he first synthesised ASA. The
work seems to have been initiated
by Dreser, who was by then aware of
Wright's discovery, even though he
subsequently implied that heroin
was an original Bayer invention.
From aspirin to heroin?
• In November 1898, Dreser presented the drug to the Congress
of German Naturalists and Physicians, claiming it was 10 times
more effective as a cough medicine than codeine, but had only a
tenth of its toxic effects. It was also more effective than
morphine as a painkiller. It was safe. It wasn't habit-forming. In
short, it was a wonder drug - the Viagra of its day.
• "What we don't recognise now," says David Muso, professor of
psychiatry and the history of medicine at Yale Medical School, "is
that this met what was then a desperate need - not for a
painkiller, but for a cough remedy".
• Tuberculosis and pneumonia were then the leading causes of
death, and even routine coughs and colds could be severely
incapacitating. Heroin, which both depresses respiration and, as
a sedative, gives a restorative night's sleep, seemed a godsend.
From aspirin to heroin?
• By 1899, Bayer was producing about a ton of heroin a year,
and exporting the drug to 23 countries. The country where it
really took off was the US, where there was already a large
population of morphine addicts, a craze for patent medicines,
and a relatively lax regulatory framework. Manufacturers of
cough syrup were soon lacing their products with Bayer
heroin.
• There were heroin pastilles, heroin cough lozenges, heroin
tablets, water-soluble heroin salts and a heroin elixir in a
glycerine solution. Bayer never advertised heroin to the public
but the publicity material it sent to physicians was
unambiguous. One flyer described the product thus: "Heroin:
the Sedative for Coughs . . . order a supply from your jobber.”
From aspirin to heroin?
• But worrying rumours were surfacing. As early
as 1899, researchers began to report patients
developing "tolerance" to the drug, while a
German researcher denounced it as "an
extremely dangerous poison". By 1902 - when
heroin sales were accounting for roughly five
percent of Bayer's net profits - French and
American researchers were reporting cases of
"heroinism" and addiction.
• Had heroin been his only pet project, this
disappointment could have spelt career
disaster.
From aspirin to heroin (and back)!
• Luckily, although his first "baby" was showing signs
of turning into a monster, Dreser had belatedly
adopted another: aspirin. Eichengruen, refusing to
accept Dreser's rejection of ASA, had continued to
investigate it and to lobby for its development.
Eventually, Dreser recognised which way the wind
was blowing, tested ASA on himself (as well as on his
laboratory of rabbits), and finally published an
enthusiastic scientific paper recommending it,
particularly for the treatment of rheumatism - but
omitting to mention the contributions of Eichengruen
and Hoffmann. In February 1899, the brand name
"Aspirin" was registered, and in June, Dreser
presided over its launch.
And Back!
• Like heroin, aspirin more or less sold itself.
As a painkiller without undesirable side
effects, it was - and remained for decades unique. By the end of 1899 it was being used
all over Europe and the US, and by the time
the heroin bubble burst, aspirin had more
than filled the gap. Bayer was on its way to
becoming an industrial giant. Hoffman and
Eichengruen do not seem to have received
any special compensation for their efforts.
For Dreser, though, the rewards were
spectacular.
From aspirin to heroin?
• So why not try the same chemical trick
with a stronger pain killer, morphine?
HO
AcO
O
Cl
O
H
H
HO
O
N
H
CH3
N
H
AcO
Morphine
Heroin
Diacetylmorphine
Diamorphine
CH3
Manufacture of codeine
• Up to 90% of the morphine isolated from
opium is converted into codeine by
methylation.
2
HO
3
1
11
4
12
O
13
5
HO
CH3O
10
15
CH3I
9
14
H
8
6
16
H
N
O
Base
H
CH3
7
Morphine (Astramorph)
H
N
CH3
HO
Codeine (5X LESS potent than morphine)
Codeine is demethylated back
to morphine in the liver
• To experience the painkilling properties of codeine the
body must first convert it into morphine. Codeine is
readily absorbed by the gastrointestinal tract, becoming
quickly transported to various tissues throughout the
body. Codeine does not accumulate in body tissues
because it is metabolised by the liver and its metabolic
products are excreted by the kidneys. The process by
which codeine is metabolised is known as glucuronidation.
Through O-demethylation the codeine is converted into
morphine and through N-demethylation it becomes
norcodeine. The metabolism rate is approximately 30 mg
of codeine in an hour and about 90% of the drug will be
excreted from the body within a day. In most people, only
about 10% of codeine is transformed into morphine.
The C3 hydroxyl group is necessary for activity.
(The methyl ether is only 0.1% as active)
HO- Group is needed for activity
Inefficiently converted to HO group in the liver
2
HO
CH3O
3
1
11
4
Liver
O
H
H
O
13
5
N
CH3
HO
Codeine (5X LESS potent than morphine)
HO
10
15
12
9
14
H
8
6
16
H
N
CH3
7
Morphine (Astramorph)
HO- Group not important to activity
Codeine is a useful cough
suppresant
• The antitussive and analgesic attributes of
codeine also enable it to work as a cough
suppressant, especially with dry, nonproductive coughs. It does this by inhibiting
the receptor in the cough centre of the
medulla oblongata and acting on the brain
to reduce the cough reflex, without the
suppression of the respiratory centre.
Codeine increases the viscosity of bronchial
secretions and has a drying effect on the
respiratory tract.
Heroin is addictive because it
crosses the BBB more quickly
than morphine.
Easily enzymatically hydrolyzed to AcOH and HO-Ar
2
AcO
3
12
O
13
5
AcO
10
15
H
8
6
16
Esterases
9
14
H
3
1
11
4
11
4
2
HO
1
N
(in the brain)
Heroin (Diamorphine)
(2X as potent as morphine)
(Conversion of two -OH groups to -OAc
facilitates crossing of the BBB)
THIS IS A PRODRUG
13
5
CH3
7
12
O
AcO
10
15
9
14
H
8
6
16
H
7
ACTIVE DRUG
N
CH3
‘Tinkering’ with the morphine structure
can produce useful painkillers
CH3 group reduces potency
RO
HO
CH3O
O
oxidized OH
O
H
H
oxidized OH
N
CH3
O
Reduced C=C
R = H Hydromorphone (Dilaudid)
(5X MORE potent than morphine)
R = CH3 Hydrocodone
(approx. half as potent as morphine orally)
H
OH
O
N
CH3
oxidized OH
H
OH
O
Reduced C=C
-OH group increases potency
Oxymorphone
(10X MORE potent than morphine)
N
CH3
O
Reduced C=C
Oxycodone (Percocet) -OH group increases potency
(equal to morphine
in potency)
‘Tinkering’ with the nitrogen substituent
can produce opioid antagonists
• Opioid antagonists are used to treat heroin and
morphine overdose
HO
HO
O
O
H
OH
N
H
OH
CH2
N
CH2
O
O
Naloxone
Narcan , NaloneTM, and NarcantiTM
TM
Naltrexone
ReviaTM or VivitrolTM
These drugs may also be used to
treat recovering addicts
•
Naltrexone is sometimes used for rapid detoxification ("rapid detox") regimens
for opioid dependence. The principle of rapid detoxification is to induce opioidreceptor blockade while the patient is in a state of impaired consciousness so
as to attenuate the withdrawal symptoms experienced by the patient. Rapid
detoxification under general anaesthesia involves an unconscious patient and
requires intubation and external ventilation. Rapid detoxification is also possible
under sedation. The rapid detoxification procedure is followed by oral
naltrexone daily for up to 12 months for opioid dependence management. There
are a number of practitioners who will use a naltrexone implant placed in the
lower abdomen, and more rarely, in the posterior to replace the oral naltrexone.
This implant procedure has not been shown scientifically to be successful in
"curing" the subject of their addiction, though it does provide a better solution
than oral naltrexone for medication compliance reasons. Naltrexone implants
are made by at least three companies, though none are FDA approved. There
is currently scientific disagreement as to whether this procedure should be
performed under local or general anesthesia, due to the rapid, and sometimes
severe, withdrawal that occurs from the naltrexone displacing the opiates from
the receptor sites.