Transcript OpioidAnalgesics_3

Summary of
Structure-Activity Relationships (SAR’s)
Removal of OH reduces activity
2
HO
3
11
4
Removal increases activity
10
15
12
O
16
9
13
5
14
H
H
HO
N-CH2CH2Ph increases
N-CH2CH=CH2 creates antagonist
1
8
6
N
CH3
7
Introduction of OH increases activity
Oxidation, coupled with reduction of 7,8 C=C, increases activity
Acetylation increases activity
Reduction increases activity
What structural elements are
necessary for activity?
Aromatic Ring
Spacer
2
HO
3
1
11
4
12
O
10
15
9
13
5
14
H
H
HO
16
8
6
N
R1
CH3
R2
N
R3
CH3
7
Quaternary Carbon Center
Basic Nitrogen
Removing the oxide bridge (and hydrogenating
double bond, removing one alcohol) produces
levorphanol, which has enhanced analgesic
properties over morphine.
HO
3
1
10
15
12
11
4
11
13
H
8
6
7
16
9
14
H
10
15
12
16
9
5
HO
3
1
4
O
2
HO
2
N
13
5
CH3
14
H
N
H
8
6
CH3
7
Levorphanol
Levorphanol is used to treat severe pain and has several
brand names.
Generic Name
Levorphanol
Brand Names/Synonyms
Antalgin
Aromarone
Cetarin
Dea No. 9220
Dea No. 9733
Dromoran
Lemoran
Levo-Dromoran
Levorfanol [Inn-Spanish]
Levorfanolo [Dcit]
Levorphan
Levorphanal
Levorphanol Dl-Form
Levorphanol Tartrate
Levorphanolum [Inn-Latin]
Methorfinan [Czech]
Methorphinan
Orphan
Racemethorphanum
Racemic Dromoran
Racemorfano [Inn-Spanish]
Racemorphan
Racemorphan [Ban:Inn]
Racemorphane [Inn-French]
Racemorphanum [Inn-Latin]anum [Inn-Latin]
Surprisingly, its mirror image
still has antitussive properties,
but no analgesic properties
2
1
11
16
10
3
1
11
4
4
15
2
HO
OH
3
12
12
H3C
16
9
9
N
10
15
14
H
13
13
5
5
14
H
N
H
H
8
8
6
6
CH3
7
7
Levorphanol
dextrorphan
analgesic + antitussive
Antitussive only
Mirror
Methylating the phenolic hydroxyl group
improves this antitussive activity
(and increase oral bioavailability)
2
11
16
10
OCH3
3
1
4
15
12
9
N
H 3C
14
H
13
5
H
8
6
7
Dextromethorphan (DM)
Antitussive only
2
11
16
10
OCH3
3
1
4
15
12
9
N
H 3C
14
H
13
5
H
8
6
7
Dextromethorphan (DM)
Antitussive only
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.
Aromatic Ring
Spacer
2
HO
3
1
11
4
12
O
13
5
HO
10
15
9
14
8
6
16
H
H N
R1
CH3
R2
R3
N
CH3
7
Quaternary Carbon Center
O
N
O
CH3
=
Basic Nitrogen
O
N
Et
Meperidine
(DemerolTM)
(PethidineTM)
EtO
CH3
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.
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.
Opioids to treat diarrhea?
Aromatic Ring
Spacer
2
HO
3
1
11
4
12
O
10
15
16
9
13
5
14
N
H
R1
CH3
H
HO
8
6
R2
N
R3
CH3
7
Quaternary Carbon Center
Basic Nitrogen
Cl
O
N
HO
O
O
Et
N
O
N
CN
N
O
CH3
CH3
CH3
Et
Meperidine
(DemerolTM)
(PethidineTM)
Diphenoxylate
(active ingredient of Lomotil)
(mixture with atropine, to prevent abuse)
Loperamide
(active ingredient of Imodium)
Does not cross BBB, thus no analgesic effect
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.
Diphenoxylate
O
N
O
O
Et
N
O
CN
CH3
Et
Meperidine
(DemerolTM)
(PethidineTM)
Diphenoxylate
(active ingredient of Lomotil)
(mixture with atropine, to prevent abuse)
• 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 longtime usage is involved.
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.
Lomotil
(Diphenoxylate + Atropine)
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.
myenteric plexus
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
Loperamide (Imodium)
Cl
HO
N
N
O
CH3
CH3
• 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.
Fentanyl
Aromatic Ring
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HO
3
1
11
4
O
10
15
12
9
14
13
5
H
H
HO
16
8
6
N
R1
R2
CH3
N
R3
CH3
7
Quaternary Carbon Center
O
O
N
O
N
CH3
Basic Nitrogen
N
CH2CH2Ph
Et
Et
Meperidine
(DemerolTM)
(PethidineTM)
Fentanyl
(80X more potent than morphine!)
Fentanyl
N
O
N
CH2CH2Ph
Et
• 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.
Fentanyl analogs
O
OCH3
N
O
O
N
O
N
CH2CH2Ph
N
Et
N
Alfentanil
(Alfenta)
Fentanyl
(80X more potent than morphine!)
N
Et
Remifentanil
N
OCH3
O
O
N
S
Et
Sufentanil
(Sufenta)
5X more potent than Fentanil
N
OCH3
N
Et
N
O
N
OCH3
N
O
OCH3
N
Et
Carfentanil
(100X more potent than Fentanil!)
O
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.
Carfentanil
O
N
O
OCH3
N
Et
Carfentanil
(100X more potent than Fentanil!)
• 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.
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.
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.
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.
Methadone
Aromatic Ring
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HO
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O
10
15
9
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5
14
H
H
HO
16
8
6
N
R1
CH3
R2
N
R3
CH3
7
Quaternary Carbon Center
CH3
O
CH3
N
CH3
Methadone
Basic Nitrogen
Methadone
CH3
O
CH3
N
CH3
• 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.
Methadone
CH3
O
CH3
N
CH3
• 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.
‘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.
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
Schedule II drugs
Findings required:
(A) The drug or other substance has a high potential
for abuse.
(B) 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.
(C) Abuse of the drug or other substances may lead
to severe psychological or physical dependence.
Examples include Morphine, Cocaine,
Methylphenidate (Ritalin)
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.
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.
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-diarrheal’s containing
small amounts of diphenoxylate.