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OPIOID ANALGESICS
by MANKARAN SINGH
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History contd
Used medicinally and recreationally fromearly Greek and Roman times
Opium and laudanum (opium combined
with alcohol) were used to treat almost allknown diseases
Morphine was isolated from opium in the
early 1800s and since then has been themost effective treatment for severe pain
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Terminology
opium is a Greek word meaning juice,
or the exudate from the poppy
opiate is a drug extracted from theexudate of the poppy
opioid is a natural or synthetic drug that
binds to opioid receptors producing
agonist effects
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Natural opioids occur in 2 places:
1) In the juice of the opium poppy (morphine
and codeine)
2) As endogenous endorphins
All other opioids are prepared from either
morphine (semisynthetic opioids such as
heroin) or they are synthesized from
precursor compounds (synthetic opioids suchas fentanyl)
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Pharmacological Effects
Sedation and anxiolysis Drowsiness and lethargy
Apathy
Cognitive impairment
Sense of tranquility
Depression of respiration Main cause of death from opioid overdose
Combination of opioids and alcohol is especially dangerous
Cough suppression Opioids suppress the cough center in the brain
Pupillary constriction pupillary constriction in the presence of analgesics is characteristic of opioid use
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Pharmacological effects contd.
Nausea and vomiting Stimulation of receptors in an area of the medulla called the
chemoreceptor trigger zone causes nausea and vomiting
Unpleasant side effect, but not life threatening
Gastrointestinal symptoms Opioids relieve diarrhea as a result of their direct actions on the
intestines
Other effects Opioids can release histamines causing itching or more severe
allergic reactions including bronchoconstriction Opioids can affect white blood cell function and immune function
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Mechanism of action
Activation of peripheral nociceptive fiberscauses release of substance P and other pain-signaling neurotransmitters from nerve terminalsin the dorsal horn of the spinal cord
Release of pain-signaling neurotransmitters isregulated by endogenous endorphins or byexogenous opioid agonists by acting
presynaptically to inhibit substance P release,causing analgesia
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Mu-Receptor: Two Types
Mu-1
Located outside spinal
cord
Responsible forcentral interpretation
of pain
Mu-2
Located throughout
CNS
Responsible forrespiratory depression,
spinal analgesia,
physical dependence,
and euphoria
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AGONISTS
*Morphine
*Heroin
*Hydromorphone
*Fentanyl*Codeine
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General Pharmacokinetics
LATENCY TO ONSET
*oral (15-30 minutes)
*intranasal (2-3 minutes)
*intravenous (15 30 seconds)
*pulmonary-inhalation (6-12 seconds)
DURATION OF ACTION anywhere between 4 and 72hours depending on the substance in question.
Metabolism hepatic via phase 1 and phase 2
biotransformations to form a diverse array of metabolites( eg., morphine to morphine-6-glucuronide).
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O
HO
H
NH
CH3
HO1
2
3
4
5
6
7
8
9
10
11
12
1314
15 16
N-CH2CH2Ph increases
N-CH2CH=CH2 creates antagonist
Reduction increases activity
Oxidation, coupled with reduction of 7,8 C=C, increases activityAcetylation increases activity
Removal increases activity
Removal of OH reduces activity
Introduction of OH increases activity
Summary of structure-activity relationships (SARs)
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What structural elements are
necessary for activity?
O
HO
H
NH
CH3
HO1
23
4
5
67
8
9
10
11
12
1314
15 16
R3R1
N
CH3
Basic NitrogenQuaternary Carbon Center
Spacer
R2
Aromatic Ring
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Removing the oxide bridge (and hydrogenating double bond,
removing one alcohol) produces levorphanol, which hasenhanced analgesic properties over morphine.
O
HO
H
NH
CH3
HO1
23
4
5
6
7
8
9
1011
12
1314
15 16
H
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Levorphanol
Levorphanol is used to treat severe pain and has several brand names.
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Surprisingly, its mirror image still has antitussive
properties, but no analgesic properties
H
NH
CH3
HO1
2
3
4
5
6
7
8
9
10
11
12
1314
15 16
Levorphanol
H
NH
H3C
OH1
23
4
5
6
7
8
9
10
11
12
1314
1516
dextrorphan
Mirror
analgesic + antitussiveAntitussive only
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Methylating the phenolic hydroxyl group improves
this antitussive activity
H
NH
H3C
OCH31
2
3
4
5
6
7
8
9
10
11
12
1314
1516
Dextromethorphan (DM)
Antitussive only
Dextromethorphan (DM or DXM) is
an antitussive drug that is found inmany over-the-countercold and
cough preparations, usually in the
form of dextromethorphanhydrobromide. It is also commonly
taken above the recommendeddosage by users seeking itsdissociative effect.
http://en.wikipedia.org/wiki/Antitussivehttp://en.wikipedia.org/wiki/Over-the-counter_substancehttp://en.wikipedia.org/wiki/Common_coldhttp://en.wikipedia.org/wiki/Cough_syruphttp://en.wikipedia.org/wiki/Hydrobromidehttp://en.wikipedia.org/wiki/Hydrobromidehttp://en.wikipedia.org/wiki/Cough_syruphttp://en.wikipedia.org/wiki/Common_coldhttp://en.wikipedia.org/wiki/Over-the-counter_substancehttp://en.wikipedia.org/wiki/Antitussive -
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O
HO
H
NH
CH3
HO
1
23
4
5
6
7
8
9
10
11
12
1314
15 16
R3R1
N
CH3
Basic NitrogenQuaternary Carbon Center
Spacer
R2
Aromatic Ring
N
CH3
O
O
Et
Meperidine(DemerolTM)(PethidineTM)
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Meperidine
Pethidine or meperidine is a fast-acting opioidanalgesicdrug.
In the United States, it is more commonly known asmeperidine or by its brand name Demerol.
Pethidine is indicated for the treatment of moderate tosevere pain, and is delivered as its hydrochloride salt in
tablets, as a syrup, or by intramuscular or
intravenous injection.
http://en.wikipedia.org/wiki/Opioidhttp://en.wikipedia.org/wiki/Analgesichttp://en.wikipedia.org/wiki/Pain_and_nociceptionhttp://en.wikipedia.org/wiki/Hydrochloridehttp://en.wikipedia.org/wiki/Intramuscularhttp://en.wikipedia.org/wiki/Intravenous_injectionhttp://en.wikipedia.org/wiki/Intravenous_injectionhttp://en.wikipedia.org/wiki/Intramuscularhttp://en.wikipedia.org/wiki/Hydrochloridehttp://en.wikipedia.org/wiki/Pain_and_nociceptionhttp://en.wikipedia.org/wiki/Analgesichttp://en.wikipedia.org/wiki/Opioid -
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Opioids to treat diarrhea?
O
HO
H
NH
CH 3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
R3R 1
N
CH 3
Basic NitrogenQuaternary Carbon Center
Spacer
R 2
Aromatic Ring
N
CH3
O
O
Et
Meperidine(DemerolTM )(PethidineTM )
NO
O
Et
Diphenoxylate(active ingredient of Lom otil)
(mixture w ith atropine, to prevent abuse)
CN
HON
Loperamide(active ingredient of Imodium )
Does not cross BB B, thus no analgesic effect
O
N
CH 3
CH3
Cl
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Fentanyl
O
HO
H
NH
CH3
HO1
2
3
4
5
6
7
8
9
10
11
12
1314
15 16
R3R1
N
CH3
Basic NitrogenQuaternary Carbon Center
Spacer
R2
Aromatic Ring
N
CH3
O
O
Et
Meperidine(DemerolTM)
(PethidineTM
)
N
CH2CH2Ph
O
Et
Fentanyl(80X more potent than morphine!)
N
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Fentanyl
Fentanyl is an opioidanalgesic, with ananalgesic potency of about 80 times that ofmorphine. Fentanyl was introduced into
medical practice in the 1960s as anintravenous anesthetic under the trade name
of Sublimaze.
N
CH2CH2Ph
O
Et
N
http://en.wikipedia.org/wiki/Opioidhttp://en.wikipedia.org/wiki/Analgesichttp://en.wikipedia.org/wiki/Morphinehttp://en.wikipedia.org/wiki/1960shttp://en.wikipedia.org/wiki/Anesthetichttp://en.wikipedia.org/wiki/Anesthetichttp://en.wikipedia.org/wiki/1960shttp://en.wikipedia.org/wiki/Morphinehttp://en.wikipedia.org/wiki/Analgesichttp://en.wikipedia.org/wiki/Opioid -
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Fentanyl analogs
N
CH2CH2Ph
O
Et
Fentanyl(80X more potent than morphine!)
NNO
Et
Alfentanil(Alfenta)
N
OCH3
N
N N
N
ONO
Et
Remifentanil
N
OCH3
OCH3
O
O
NO
Et
Sufentanil(Sufenta)
5X more potent than Fentanil
N
OCH3
SNO
Et
Carfentanil(100X more potent than Fentanil!)
N
OCH3O
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Methadone
O
HO
H
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
R3R1
N
CH3
Basic NitrogenQuaternary Carbon Center
Spacer
R2
Aromatic Ring
NCH3
O
CH3
CH3
Methadone
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Methadone
Methadone was best known for its use in treatingnarcotic addiction.
N
CH3O
CH3
CH3
http://en.wikipedia.org/wiki/Narcotichttp://en.wikipedia.org/wiki/Narcotic