Introduction, classification, Structure activity relationship, mechanism of action, synthesis and uses of narcotic analgesics

1. Narcotic Analgesicsg
Dr Gopal Krishna PadhyDr. Gopal Krishna Padhy
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2. Definition
Analgesics are defined as drugs that selectively relieve paing g y p
by acting in the central nervous system or on peripheral pain
mechanism without disturbing consciousness.
These are mainly divided into two types.
o Narcotic analgesicso Narcotic analgesics
o Non-narcotic analgesics
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3. N ti l iNarcotic analgesics
oNarcotic analgesics are also known as opoid analgesicoNarcotic analgesics are also known as opoid analgesic.
o They relieve severe pain by acting mainly on the central
nervous system.y
o The oldest and the best narcotic analgesics are opium
alkaloids.
Th i l i i ll ddi io The narcotic analgesics are potentially addictive.
o If intake of the drug is stopped, very undesirable withdrawal
effects like sever pain sweating salvation hyperventilationeffects like sever pain, sweating, salvation, hyperventilation,
restlessness and confusion are observed
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4. ClassificationClassification
Morphine analoguesp g
3
Morphine Heroinp
Codeine 4/8/2020

5. Morphinan analoguesMorphinan analogues
Levorphanol Dextromethorphan
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6. Morphan analoguesp g
CH3
N
H3C
OH
H3C
M t i
N
CH2CHC
H3C
P t i MetazocinePentazocine
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7. 4 Phenylpiperidine analogues4-Phenylpiperidine analogues
N
COOC2H5
CH2CH2CNC
Meperidine / Pethidine Diphenoxylatep y
Anileridine
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8. 4-anilinopiperidine analoguesp p g
2 22 5
Fentanyl
Sufentanyl
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9. Diphenyl Propylamine derivativesDiphenyl Propylamine derivatives
2
33
2 5
3
Methadone Propoxyphene
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10. Mechanism of action of Narcotic analgesics
Narcotic analgesics produce their actions at a cellular level
b b ti ti opioid receptorsby by activating on opioid receptors.
e.g. Morphine and its derivatives act as agonists of the mu and
kappa opioid receptorskappa opioid receptors.
These receptors are distributed throughout the (CNS) and
also been found on peripheral afferent nerve terminalsalso been found on peripheral afferent nerve terminals .
Opioid receptors are coupled with inhibitory G- proteins
and their activation has number of actions like closing ofand their activation has number of actions like closing of
voltage sensitive calcium channels, stimulation of
potassium efflux leading to hyperpolarization which causespotassium efflux leading to hyperpolarization which causes
reduction in neuronal cell excitability.
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11. 4/8/2020

12. Structure activity relationship of morphine
• The structure of morphine is composed of five fusedThe structure of morphine is composed of five fused
rings and have 5 chiral centers.
• the levo (-) rotary form is the active form while dextro (+)the levo ( ) rotary form is the active form while dextro (+)
morphine is inactive.
•TheA ring and the basic nitrogen are the two necessaryTheA ring and the basic nitrogen are the two necessary
component in every potent opoid receptor agonist.
•The aromaticA ring and the tertiary nitrogen may beThe aromaticA ring and the tertiary nitrogen may be
connected by an ethylene/propelene linkage.
2
HO
1
2
3
10
11
A
Phenolic OH
O
N CH3
4
5
9
10
12
13
14
17BD
E
Ether bridge Tertiary Nitrogen
HO 6
7
8
14
15 16
C
Alcoholic OH 4/8/2020

13. Tertiary nitrogen atom
•The substituent on nitrogen of morphine and morphine
like structure is critical to degree and type of activitylike structure is critical to degree and type of activity.
• N-methyl substituents generally results in compound with
good agonist proportiesgood agonist proporties.
• Increasing the size of the N-substituent results in
antagonist e g naloxoneantagonist e.g. naloxone
Naloxone 4/8/2020

14. Hydroxyl Group
• Masking the phenolic hydroxyl group by etherification to
methyl ether decrease the analgesic activity about ten fold.
e.g. Codeine
CodeineCodeine
• Esterification of hydroxyl group leads to more active
compound than morphine. e.g. Heroin
• introduction of hydroxyl group at 14th position lead to
increase in activity e.g. oxymorphone
OxymorphoneOxymorphone
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15. Ring C
• Change in the C-ring chemistry of morphine can lead to
compounds with increased activity. e.g. Hydromorphone is 8-10p y g y p
times more potent than morphine.
HO
O
N CH3
O
C
Hydromorphone
O
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16. 4,5-Epoxide bridge
• Removal of 4,5-epoxide bridge in the morphine structure
results in mophinans.p
• only levo isomer of morphinan possess opoid analgesic
activity while dextro isomer have antitussive actvity.y y
• levorphanol is 8 times more potent than morphine.
Levorphanol
•Compound that lack both epoxide bridge and the C ring of
morphine retain opoid analgesic activity e gmorphine retain opoid analgesic activity. e.g.
Benzomorphans. 4/8/2020

17. Methadone
MOA-In addition to opioid receptor agonist activity, methadone also act asMOA In addition to opioid receptor agonist activity, methadone also act as
antagonist of the N-methyl-D-aspartate (NMDA) receptor and it strongly
inhibits serotonin and norepinephrine uptake.
Uses-Methadone is indicated for the management of pain severe enough
to require an opioid analgesic and for which alternative treatment options
are inadequate. It is also used in treating drug addiction, since it replaces
other agonists on the receptor. 4/8/2020

18. Fentanyl
MOA: Similar to morphine
Uses: It is uses both independently and in combination with
droperidol for preanesthetic medication, in different forms of
narcosis, and in post-operational anesthesia.
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19. Morphine Codeine
h b dUses: Morphine is prescribed in
all cases when NSAID action is
not sufficient and requires the use
MOA S l h
not sufficient and requires the use
of strong opioid analgesics. It is
widely used in myocardial
MOA: Similar to morphine
Uses: This drug is very effective
in oral use and is used for average
y y
infarction to relieve pain and for
calming the patient. It is used in
l d d f in oral use and is used for average
to moderate pain. It is often used
as an antitussive drug. Codeine is
pulmonary edema and in few
forms of diarrhoea.
It is used in surgery as a g
used to treat mild to moderate
pain and also to reduce coughing.
It is used in surgery as a
preanesthetic medication before
the general anesthesia procedureg p
begins.
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20. Levorphanol Dextromethorphan
MOA: Levorphanol has a
similar mechanism of action
d h d
MOA: Levorphanol has a similar
mechanism of action compared
compared to methadone.
Uses: This drug is
recommended for relieving
p
to methadone.
Uses: For treatment and relief
recommended for relieving
moderate to high pain in
biliary colic, renal colic,
of dry cough.
y
myocardial infarction, cancer
and surgery.
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21. Meperidine Anileridine
MOA: Similar to morphine
Uses: Meperidine is used to
MOA: Similar to morphine
Uses: Anileridine is a syntheticUses: Meperidine is used to
help relieve moderate to
severe pain. Meperidine is
Uses: Anileridine is a synthetic
opioid and strong analgesic
medication. It is a narcotic pain
widely used as preanesthetic
medication. It is preferred in
b t t i l ti d t it
p
reliever used to treat moderate
to severe pain.
obstetrical practice due to its
quick onset and short-lasting
action..
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22. Diphenoxylate Loperamide
MOA: Diphenoxylate is an
opiate receptor agonist that
i l i GIstimulate mu receptors in GI to
decrease the peristalsis and
constrict the sphinctersconstrict the sphincters.
Diphenoxylate has a direct
effect on circular smooth MOA: Similar to diphenoxylate
muscle of the bowel, that
conceivably results in
i d l i
MOA: Similar to diphenoxylate
Uses: This medication is used to
treat sudden diarrhea (including
segmentation and prolongation
of gastrointestinal transit time.
Uses: it is mainly used for
traveler's diarrhea). Loperamide
is also used to reduce the
t f di h i ti tUses: it is mainly used for
treating diarrhea. It helps to
decrease the number and
amount of discharge in patients
who have undergone an
ileostomy.
frequency of bowel
movements.
y
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23. Propoxyphene
MOA: Similar to morphine
Uses: For the relief of mild toUses: For the relief of mild to
moderate pain.
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24. Narcotic antagonist
An opioid antagonist or opioid receptor antagonist is aAn opioid antagonist, or opioid receptor antagonist, is a
receptor antagonist that acts on one or more of the opioid
receptorsreceptors.
Examples: Naloxone and naltrexone
HO
OHO
O
N
OH
CH2
O
Naloxone NaltrexoneO Naloxone Naltrexone
MOA: They are competitive antagonists that bind to the opioid
receptors with higher affinity than agonists but do not activate thereceptors with higher affinity than agonists but do not activate the
receptors. This effectively blocks the receptor, preventing the body
from responding to opioids and endorphins.
Uses: Naltrexone is exploited in treatment of opioid addiction.
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25. BOOKS FOR FURTHER READING
Wil d Gi ld T b k f i M di i l
BOOKS FOR FURTHER READING
Wilson and Gisvold,Text book of organic, Medicinal
and Pharmaceutical Chemistry.
Foyes Principles of medicinal chemistry byWilliams
O. Foye.y
AText book of medicinal chemistry (Synthetic and
Biochemical Approach) vol I& II by SN PandeyaBiochemical Approach) vol. I& II by SN Pandeya.
Synthesis of Essential Drugs by R.S.Vardanyan and
VJ H bV.J. Hruby
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