Summary of

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Summary of Structure-Activity Relationships
(SARs)
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What structural elements are necessary for
activity?
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Removing the oxide bridge (and hydrogenating
double bond, removing one alcohol) produces
levorphanol, which has enhanced analgesic
properties over morphine.
Levorphanol is used to treat severe pain and has
several brand names.
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Generic Name Levorphanol Brand Names/Synonyms Ant
algin Aromarone Cetarin Dea No. 9220 Dea No.
9733 Dromoran Lemoran Levo-Dromoran Levorfanol
Inn-Spanish Levorfanolo Dcit Levorphan Levorph
anal Levorphanol Dl-Form Levorphanol
Tartrate Levorphanolum Inn-Latin Methorfinan
Czech Methorphinan Orphan Racemethorphanum Racem
ic Dromoran Racemorfano Inn-Spanish Racemorphan
Racemorphan BanInn Racemorphane
Inn-French Racemorphanum Inn-Latinanum
Inn-Latin
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Surprisingly, its mirror image still has
antitussive properties, but no analgesic
properties
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Methylating the phenolic hydroxyl group improves
this antitussive activity(and increase oral
bioavailability)
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Dextromethorphan (DM or DXM) is an antitussive
drug that is found in many over-the-counter cold
and cough preparations, usually in the form of
dextromethorphan hydrobromide. It is also
commonly taken above the recommended dosage by
users seeking its dissociative effect.
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Meperidine

• Pethidine (INN) or meperidine (USAN) (also
  referred to as Demerol) is a fast-acting opioid
  analgesic drug.
• In the United States, it is more commonly known
  as meperidine or by its brand name Demerol.
• Pethidine is indicated for the treatment of
  moderate to severe pain, and is delivered as its
  hydrochloride salt in tablets (oral), as a syrup,
  or by intramuscular or intravenous injection.

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Meperidine (Pethidine, Demerol)

• For much of the 20th century, pethidine was the
  opioid of choice for many physicians in 1983 60
  of doctors prescribed it for acute pain and 22
  for chronic severe pain.
• Compared to morphine, pethidine was supposed to
  be safer and carry less risk of addiction, and to
  be superior in treating the pain associated with
  biliary spasm or renal colic due to its putative
  antispasmodic effects.
• It has fallen out of favor in recent years.

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Opioids to treat diarrhea?
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Diphenoxylate

• Diphenoxylate is an opioid agonist used for the
  treatment of diarrhea that acts by slowing
  intestinal contractions.
• It was discovered at Janssen Pharmaceutica in
  1956.

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Diphenoxylate

• It is a congener to the narcotic Meperidine of
  which the common brand name is Demerol.
• This being the case, this medication is
  potentially habit-forming, particularly in high
  doses or when long-time usage is involved.

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Lomotil(Diphenoxylate Atropine)

• To avoid potential abuse, diphenoxylate is
  manufactured and marketed as a combination drug
  with atropine (Lomotil).
• Atropine is a competitive antagonist of the
  muscarinic acetylcholine receptors
• Due to the presence of atropine, ingestion of too
  much Lomotil thus causes nausea and muscle
  weakness.

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Lomotil(Diphenoxylate Atropine)
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Loperamide (Imodium)

• Loperamide is an opioid receptor agonist and acts
  on the µ-opioid receptors in the myenteric plexus
  large intestines
• it does not affect the central nervous system
  like other opioids.

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myenteric plexus
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Loperamide (Imodium)

• Loperamide works by decreasing the activity of
  the myenteric plexus which decreases the motility
  of the circular and longitudinal smooth muscles
  of the intestinal wall.
• This increases the amount of time substances stay
  in the intestine, allowing for more water to be
  absorbed out of the fecal matter.
• Loperamide also decreases colonic mass movements
  and suppresses the gastrocolic reflex

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Loperamide (Imodium)

• Loperamide does not cross the blood-brain barrier
  and has no analgesic properties. Tolerance in
  response to long-term use has not been
  reported.However, loperamide can cause physical
  dependence. Symptoms of opiate withdrawal have
  been observed in patients abruptly discontinuing
  long-term therapy with loperamide.

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Fentanyl
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Fentanyl

• Fentanyl is an opioid analgesic, first
  synthesized by Janssen Pharmaceutica (Belgium) in
  the late 1950s, with an analgesic potency of
  about 80 times that of morphine.
• Fentanyl was introduced into medical practice in
  the 1960s as an intravenous anesthetic under the
  trade name of Sublimaze.

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Fentanyl analogs
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Fentanyl and analogs

• Fentanyls are extensively used for anesthesia and
  analgesia, most often in the operating room and
  intensive care unit.
• Duragesic, by Janssen Pharmaceutica, is a
  fentanyl transdermal patch used in chronic pain
  management.
• Duragesic patches work by releasing fentanyl into
  body fats, which then slowly release the drug
  into the blood stream over 72 hours, allowing for
  long lasting relief from pain.

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Carfentanil

• Carfentanil was discovered by Janssen
  Pharmaceutica.
• It has a quantitative potency approximately
  10,000 times that of morphine and 100 times that
  of fentanyl, activity in humans starting at about
  1 µg.

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Carfentanil

• Carfentanil is marketed under the trade name
  Wildnil as a tranquilizer for large animals. It
  is intended for animal use only as its extreme
  potency makes it inappropriate for use in humans.

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Carfentanil

• It is thought that in the 2002 Moscow theater
  hostage crisis, the Russian military made use of
  an aerosol form of carfentanil to subdue Chechen
  hostage takers.
• Its short action, easy reversibility and
  therapeutic index (10600 vs. 300 for fentanyl)
  would make it a near-perfect agent for this
  purpose.

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Carfentanil

• Wax et al. surmise from the available evidence
  that the Moscow emergency services had not been
  informed of the use of the agent, and therefore
  did not have adequate supplies of naloxone or
  naltrexone (opioid antagonists) to prevent
  complications in many of the victims.
• Assuming that carfentanil was the only active
  constituent (which has not been verified by the
  Russian military), the primary acute toxic effect
  to the theatre victims would have been
  opioid-induced apnea in this case mechanical
  ventilation and/or treatment with opioid
  antagonists would have been life-saving for many
  or all victims.

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Methadone
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Methadone

• Methadone/dolophine, was first synthesized in
  1937 by German scientists Max Bockmuhl and Gustav
  Ehrhart at IG Farben (Hoechst-Am-Main, now part
  of Frankfurt, Germany) during their search for an
  analgesic that would be easier to use during
  surgery (and less potentially addictive, post-op)
  than morphine.

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Methadone

• Methadone was introduced into the United States
  in 1947 by Eli Lilly and Company as an analgesic
  (They gave it the trade name Dolophine, which is
  now registered to Roxane Laboratories).
• Since then, it has been best known for its use in
  treating narcotic addiction, although such a use
  never became widespread and common until the
  early 1990's when public policy sought to find
  ways to reduce the spread of HIV and AIDS.

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Scheduling of Drugs

• The Controlled Substances Act was introduced into
  law in 1970
• According to the CSA, drugs are classified or
  scheduled depending on their potential for
  abuse and whether or not there is a medical need
  for a particular drug.

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Schedule I drugs

• Findings required
• (A) The drug or other substance has a high
  potential for abuse.
• (B) The drug or other substance has no currently
  accepted medical use in treatment in the United
  States.
• (C) There is a lack of accepted safety for use of
  the drug or other substance under medical
  supervision.
• Examples include Heroin, Cannabis, and LSD

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Schedule II drugs

• Findings required
• The drug or other substance has a high potential
  for abuse.
• The drug or other substance has a currently
  accepted medical use in treatment in the United
  States or a currently accepted medical use with
  severe restrictions.
• Abuse of the drug or other substances may lead
  to severe psychological or physical dependence.
• Examples include Morphine, Cocaine,
  Methylphenidate (Ritalin)

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Schedule III drugs

• Findings required
• (A) The drug or other substance has a potential
  for abuse less than the drugs or other substances
  in schedules I and II.
• (B) The drug or other substance has a currently
  accepted medical use in treatment in the United
  States.
• (C) Abuse of the drug or other substance may lead
  to moderate or low physical dependence or high
  psychological dependence.
• Examples include anabolic steroids, hydrocodone,
  and codeine.

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Schedule IV drugs

• Findings required
• (A) The drug or other substance has a low
  potential for abuse relative to the drugs or
  other substances in schedule III.
• (B) The drug or other substance has a currently
  accepted medical use in treatment in the United
  States.
• (C) Abuse of the drug or other substance may lead
  to limited physical dependence or psychological
  dependence relative to the drugs or other
  substances in schedule III.
• Examples include benzodiazepines and barbituates.

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Schedule V drugs

• Findings required
• (A) The drug or other substance has a low
  potential for abuse relative to the drugs or
  other substances in schedule IV.
• (B) The drug or other substance has a currently
  accepted medical use in treatment in the United
  States.
• (C) Abuse of the drug or other substance may lead
  to limited physical dependence or psychological
  dependence relative to the drugs or other
  substances in schedule IV.
• Examples include cough syrups containing a small
  amount of codeine, or anti-diarrheals containing
  small amounts of diphenoxylate.