Opioid Analgesics

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Opioid Analgesics
Opioid Analgesics
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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).

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History of Morphine in the U.S.

• 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.

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History of Morphine Use in the U.S.

• 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.

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How Does Morphine Work?

• There are at least three different opioid
  receptors in the CNS mu, delta, and kappa
• Morphine is an agonist at all three receptors,
  but seems to prefer the mu receptor
• Thus, agonists of the mu receptor (which act as
  powerful analgesics) are classified as morphine
  like.

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Side effects of morphine

• Morphine has many side effects. The most
  dangerous is respiratory depression.
• Other central nervous system side effects of
  morphine are cough suppression, sedation, and
  dependence leading to addiction.
• 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.

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Structure of Morphine
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Tinkering with the structure of morphine
produced heroin
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Heroin

• The two hydroxyl groups of morphine are converted
  to acetate esters, producing diacetylmorphine, or
  heroin.
• Heroin crosses the blood-brain-barrier much more
  quickly than morphine,
• Once across the BBB, brain esterases rapidly
  cleave the acetate esters back to hydroxyl groups
• In particular the C3 hydroxyl group is needed for
  analgesic (and euphoric) activity.

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Heroin is addictive because it crosses the BBB
more quickly than morphine.
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Heroin Addiction

• Heroin use frequently leads to dependency.
• Ceasing heroin use after continuous use for as
  little as three days can cause withdrawal
  symptoms
• In repeat users, tolerance develops
• However, tolerance for the euphoric effect
  develops more rapidly than tolerance for the
  respiratory depression, thus leading to the
  (unanticipated) cessation of breathing in the
  user.

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How do these drugs work?

• http//thebrain.mcgill.ca/flash/i/i_03/i_03_m/i_03
  _m_par/i_03_m_par_heroine.htmldrogues

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Manufacture of codeine

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

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Codeine is demethylated back to morphine in the
liver

• To experience the painkilling properties of
  codeine the body must first convert it into
  morphine.
• (Unlike morphine), Codeine is readily absorbed by
  the gastrointestinal tract, becoming quickly
  transported to various tissues throughout the
  body.

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Codeine

• 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.

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The C3 hydroxyl group is necessary for activity.
(The methyl ether is only 0.1 as active)
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Codeine is a useful cough suppressant

• 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.

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Tinkering with the morphine structure can
produce useful painkillers