History of Opium

1
History of Opium

• http//opioids.com/timeline/index.html

2
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).

3
The History of Morphine

• http//opioids.com/morphine/200-anniv.html

4
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 side-effects. The development of the
  hypodermic syringe in the mid-nineteenth 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.

5
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 anti-opium remedies in such profusion
  that the pills became known as "Jesus Opium"
  their active ingredient was morphine.

6
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.

7
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.

8
Structure of Morphine
9
Tinkering with the structure of morphine
produced heroin
10
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.

11
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.

12
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."

13
From aspirin to heroin?

• 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.

14
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.

15
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.

16
From aspirin to heroin?
O-Acetylsalicylic acid is a better pain reliever
than Salicylic acid. It is also less irritating
to the stomach.
17
From aspirin to heroin?

• The following is taken from
• http//opioids.com/heroin/heroinhistory.html
• Source Sunday TimesDate 13 September 1998

18
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.

19
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.

20
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).

21
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.

22
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.

23
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.

24
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.

25
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.

26
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.

27
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.

28
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.

29
From aspirin to heroin?

• So why not try the same chemical trick with a
  stronger pain killer, morphine?

30
Manufacture of codeine

• Up to 90 of the morphine isolated from opium is
  converted into codeine by methylation.

31
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.

32
The C3 hydroxyl group is necessary for
activity.(The methyl ether is only 0.1 as
active)
33
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, non-productive
  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.

34
Heroin is addictive because it crosses the BBB
more quickly than morphine.
35
Tinkering with the morphine structure can
produce useful painkillers
36
Tinkering with the nitrogen substituent can
produce opioid antagonists

• Opioid antagonists are used to treat heroin and
  morphine overdose

37
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 opioid-receptor
  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.