Narcotic and Non-Narcotic Analgesics

Narcotic and Non-Narcotic
Analgesics
Opioid Analgesics / Prof. Yogita Ozarde

TERMINOLOGY
• “opium” is a Greek word meaning “juice,” or the exudate
from the poppy
• “opiate” is a drug extracted from the exudate of the poppy
• “opioid” is a natural or synthetic drug that binds to opioid
receptors producing agonist effects

HISTORY OF OPIOIDS
• Morphine is obtained from opium, which is the partly dried
latex from incised unripe capsules of Papaver somniferum
• Used medicinally for thousands of years to produce Euphoria,
Analgesia, Sedation, Cough suppression and to treat diarrhea
• Morphine was isolated from opium in the early 1800’s and
since then has been the most effective treatment for pain
• Opium and laudanum (opium combined with alcohol) were
used to treat almost all known diseases

HISTORY OF OPIOIDS
• Alkaloids - Morphine, Codeine, Noscapine and Papavarine
• Controlling the widespread use of opioids has been
unsuccessful because of the euphoria, respiratory depression,
tolerance and physiological dependence

PHARMACOLOGICAL EFFECTS
• Sedation and anxiolysis

• Depression of respiration
• Cough suppression
• Pupillary constriction
• Nausea and vomiting
• Gastrointestinal symptoms
• Bronchoconstriction

MODIFICATIONS OF MORPHINE
Modification of morphine (Therapeutic usefulness & toxicity)

• Early changes on morphine nucleus before 1930s
• Morphine modification initiated by Small, Eddy, and co-
workers
• Morphine modification initiated by Eisleb and Schaumann
• Morphine modification initiated by Grewe

EARLY MORPHINE MODIFICATIONS
• Morphine: Analgesic CH3
10 9 17
N
1 11 8
14 16
13 15
2 7
12
3 6
4 5
O
HO OH
Morphine
• Codeine: Analgesic and to depress cough reflex

CH3
10 9 17
N
1 11 8
14 16
13 15
2 7
12
3 6
4 5
O
H3CO OH
Codeine

• Dihydromorphine : Analgesic
CH3
10 9 17
N
1 11 8
14 16
13 15
2 7
12
3 6
4 5
O
HO OH
Dihydromorphine
• Dihydrocodeine : Depress cough reflex

CH3
10 9 17
N
1 11 8
14 16
13 15
2 7
12
3 6
4 5
O
H3CO OH
Dihydrocodeine

• Ethyl morphine : Ophthalmology

CH3
10 9 17
N
1 11 8
14 16
13 15
2 7
12
3 6
4 5
O
C2H5O OH
Ethyl Morphine
• Heroin : Analgesic
CH3
10 9 17
N
1 11 8
14 16
13 15
2 7
12
3 6
4 5
O
H3COCO OCOCH3
Heroin

• Dihydromorphinone : Analgesic
CH3
10 9 17
N
1 11 8
14 16
13 15
2 7
12
3 6
4 5
O
HO O
Dihydromorphinone
• Dihydrocodeinone : Analgesic and to depress cough reflex

CH3
10 9 17
N
1 11 8
14 16
13 15
2 7
12
3 6
4 5
O
H3CO O
Dihydrocodeinone

• Oxymorphone : Analgesic
CH3
10 9 17
N
1 8
11 HO 14 16
13 15
2 7
12
3 6
4 5
O
HO O
Oxymorphone
• Oxycodone : Analgesic and to depress cough reflex

CH3
10 9 17
N
1 8
11 HO 14 16
13 15
2 7
12
3 6
4 5
O
H3CO O
Oxycodone

MODIFICATIONS BY SMALL & EDDY
The modifications done with the purpose
• To separate chemically the addiction property of morphine from its
other more salutary attributes

• To find other synthetic molecules without this undesirable property
Principle targets were chosen for modification in morphine structure

1. The peripheral groups and simple skeletal modifications on
alicyclic ring,
2. The peripheral groups and simple skeletal modifications on
aromatic ring,
3. The tertiary nitrogen.
PERIPHERAL GROUPS ON MORPHINE
CH 3
10 9 17
N Tertiary nitrogen
1 11 8
14 16
15
Allicyclic double bond
2 13
7
12
3 6
4 5 Ether linkage
O
HO OH Alcoholic hydroxy group
Phenolic hydroxy group

MODIFICATIONS ON ALICYCLIC RING
• Modifications at C-6 position: Methylated, esterified,

oxidized , removed or replaced by halogen (More potent
analgesics & more toxic)
e.g. Heroin, Chloromorphine
CH3 CH3
10 9 17 10 9 17
N N
1 11 8 1 8
14 16 11 14 16
13 15 13 15
2 7 2 7
12 12
3 6 3 6
4 5 4 5
O O
H3COCO OCOCH3 HO Cl
Heroin Chloromorphine

• Modifications at C-8 position: Catalytic hydrogenation gives

dihydrocodeine and dihydromorphine which are the precursors
of more potent ketones, the dihydrocodeinone and
dihydromorphinone.
CH3
CH3
10 9 17
10 9 17 N
N
1 11 8
14 16
1 11 8
14 16
13 15
2 7
13 15 12
2 7
12
3 6
4 5
3 6
4 5 O
O HO O
HO OH
Dihydromorphine Dihydromorphinone

CH3 CH3
10 9 17 17
10 9
N N
1 11 8 1 8
14 16 11 14 16
13 15 13 15
2 7 2 7
12 12
3 6 3 6
4 5 4 5
O O
H3CO OH H3CO O
Dihydrocodeine Dihydrocodeinone
• C-8 β-halo derivatives are found to be more potent analgesics

than morphine.

• Modifications at C-14 position: introduction of 14-OH group

increases potency
• E.g. 14-hydroxydihydromorpninone
14-hydroxydihydrocodeinone
CH3 CH3
10 9 17 17
10 9
N N
1 8 1 8
11 HO 14 16 11 HO 14 16
13 15 13 15
2 7 2 7
12 12
3 6 3 6
4 5 4 5
O O
HO O H3CO O
14-hydroxydihydromorphinone 14-hydroxydihydrocodeinone

• Bridging of C-6 and C-14 through an ethylene linkage is also

tried e.g. Etorphine.
• It is about 200 times more potent than morphine in man.
CH3
CH3
C C3H7
OH
O
HO OCH3
Etorphine

• Introduction of any new substituent further does not enhance

the activity. 5-methyl dihydromorphine and azidomorphines
may be the exceptions.
CH 3 CH 3
17 10 9 17
10 9
N N
1 8 1 8
11 14 16 11 R 14 16
13 15 13 15
2 7 2 7
12 12
3 6 3 6
4 5 4 5
O O
HO CH 3 OH HO N3
5-methyl dihydromorphine Azidomorphines

R= H; R= OH

MODIFICATIONS ON AROMATIC RING
• An intact benzene ring is essential for activity.
• Modification of C-3 phenolic hydroxyl group causes a
decrease in analgesic activity.
• Any further substitution in phenyl ring generally diminishes
the activity. The only exception is 1-fluoro codeine, which
possesses same analgesic activity as that of codeine.
CH 3
10 9 17
F N
1 11 8
14 16
13 15
2 7
12
3 6
4 5
O
H 3CO CH 3 OH
1-Fluoro Codeine

THE TERTIARY NITROGEN
• Methyl , n-pentyl, or n-hexyl substitution gives opioid agonists

• The N-phenylethyl group enhances the analgesic activity in
desmorphine, codeine and heterocodeine
• N-allyl and N-cycloalkylmethyl functions impart narcotic
antagonistic properties to the molecule
H
CH3 H 2C C H2C
10 9 17 10 9 17 CH 2
N N N
1 11 HO 8 1 11 HO 14 8 16 HO
14 16
13 15 2 13 15
2 7 7
12 12
6 3 5 6
3 4 5 4
O O
O HO O HO O
HO O
Naloxone Naltrexone
Oxymorphone

NALORPHINE
• Nalorphine was the first clinically useful narcotic antagonist.
• Its unpleasant psychomimetic and hallucinogenic properties
preclude its use as analgesic, though it is a potentially valuable
non-addict drug with partial agonistic features.
H
C
H2C
10 9 17 CH2
N
1 11 14 8 16
2 13 15
7
12
3 5 6
4
O
HO OH
N-allylmorphine
(Nalorphine)

MODIFICATION OF MORPHINE
• Bentley and Hardy postulated that it might be a more rigid
structure which is important to act with a single pain relieving
receptor and not with other side effects evoking centers. This
led to the synthesis of thebaine derivatives.
N R N R
CH 3 CH 3
R R
OH OH
H 3 CO OCH 3 HO OCH 3
Thebaine Oripavine

• The compound I is about 700 times more potent than
morphine.
• Buprernorphine is about 100 times active as morphine (as
agonist) and four times as active as Nalorphine (as antagonist)
and is therefore non-addicting and without psychotomimetic
effects. N CH 3
N
Ph
CH 3
C(CH 3)3
OH
O OH
HO OH O
HO OCH 3
Compound I
Buprenorphine

• Diprenorphine is a 100 times more potent narcotic antagonist
than Nalorphine.
CH 3
CH 3
OH
O
HO OCH 3
Diprenorphine

• Replacement of the N-methyl group in morphine by larger
alkyl groups not only lowers the analgesic activity, but also
confers morphine antagonistic properties on the molecule.
(Except N-phenethyl derivative, with 14 times more analgesic
activity than morphine)
10 9 17
N
1 11 14 8 16
2 13 15
7
12
3 5 6
4
O
HO OH
N-Phenethyl Morphine

• Unfortunately, these studies on morphine did not provide the
answer to the elimination of addiction potentialities from these
compounds.
• In fact, the studies suggested that any modification bringing
about an increase in the analgesic activity caused a
concomitant increase in addiction liability.

MODIFICATIONS BY EISLEB & SCHAUMANN
• Pharmacological testing of meperidine for antispasmodic
property
• Peculiar erection of the tail (Straub reaction)in mice
• Meperidine (piperidine derivative) active as analgesic agent
• Schumann spot the segment in morphine structure similar to
CH 3
meperidine by molecular dissection.

10 9 17
CH 3
9 N 17
COOC 2H 5
N 11
1
14 16
1 11 8
14 16 12 13
2 15
13 15
2 7
12
3 4 5 O N
3 5 6 O
4
O
HO OH CH 3
C 2H 5
Meperidine Meperidine
Morphine

STRUCTURAL NECESSITY FOR ACTIVITY
N CH 3
C2H 5 O
O
Meperidine

STRUCTURE ACTIVITY RELATIONSHIP
• Replacement of 4-phenyl group by hydrogen, alkyl, other aryl,
aralkyl and heterocyclic groups reduced analgesic activity.
• Many N-substituted analogues of meperidine have been
prepared. Anileridine is employed clinically.
COOC2H 5
CH 2CH 2 R
Anileridine: R = -NH 2
Pheneridine: R = -H

• Replacement of carbethoxy group (-COOC2H5) by acyloxy
group (-OCOC2H5) results in better analgesic activity.
• The replacement of N-methyl group by various aralkyl groups

can increase the analgesics property markedly.
COOC 2 H 5
CH 2CH 2CH 2 NH
Piminodine

• Piperidine is enlarged to 7-membered azepine ring
• Proheptazine is among the more active analgesic agents in
higher ring homologue of meperidine
• Substitution of the piperidine ring with 5-membered
pyrrolidine ring is also successful.
OCOC 2H 5
OCOC 2H 5
H 3C H3C
H 3C
N
N
H 3C
CH 3 Prodilidene
Proheptazine

• The presence of m-hydroxyl group in the phenyl ring resembles
that of C-3 phenolic hydroxyl group in the morphine. Bemidone
represents the class.
• Replacement of the ester moiety by ketone function in the
bemidone yielded a new series of compounds, ketobemidone.
COOC2H5 COC2H5
HO HO
N N
CH3
CH3
Bemidone Ketobemidone

• Prodines are the reverse esters of meperidines. here the ester
of meperidine (-COOC2H5 ) is replaced by (-OCOC2H5)
OCOC2H5
propionoxy function CH3
CH3
Prodine
• In all above structures, phenyl ring and acyl group are directly
attached to the piperidine ring.

• In Fentanyl series, phenyl ring and acyl group are separated
from the ring by nitrogen. Fentanyl, alfentanyl, sufentanyl and
carfentanyl are more potent than pethidine.
O O
N C2H5 N C2H5
R2 CH2OCH3 CH2OCH3 COOC2H5
C2H5 N C2H5 N
R1 N N O O
S O
CH2CH2 CH2CH2 N N
C2H5
N
CH2CH2 N CH2CH2
Fentanyl : R1 = -H ; R2 = -H
Sufentanyl Alfentanyl N
Lofentanyl : R1 = -CH3 ; R2 = -COOC2H5 N Carfentanyl

METHADONE SERIES
• Modifications of morphine nucleus by opening of the nitrogen
ring resulted into methadone series of compounds. Methadone
possesses analgesic as well as spasmolytic properties.
COC2 H 5
CH 3
CH 3 CH 3
Methadone

METHADONE SERIES
• Resemblance of methadone structure with meperidine
COC2H5 COC2H5 COOC2H5
CH3
C6H5 C6H5
H3C H3C
N CH3 N N
CH3 CH3 CH3

Methadone Isomethadone Meperidine
• The methadone derivatives are generally more potent

analgesics than the isomethadone analogues.

• The insertion of m-hydroxyl group in one of the phenyl rings
of methadone causes a marked decrease in analgesic activity.
• The replacement of propionyl group by hydrogen, hydroxyl or
acetoxy, led to decrease in activity.
• Similarly replacement of the propionyl group by amide group
gives more active compound methadone e.g. Racemoramide
O
COC2 H 5 N
CH 3
H H2
N C C N O
CH 3 CH 3 CH 3
Racemoramide
Methadone

• Removal of any of the two phenyl rings results into decreased
activity.
• The dimethylamino group is replaced by heterocyclic rings
like morpholine and piperidine retains analgesic activity.
O O
COC2H5 C 2H 5 C 2H 5
CH3
H H2 H H2
N C C N O C C N
CH3 CH3 CH3 CH3
Methadone Phenadoxone Dipanone

• N-methylated derivatives (metabolites of methadone
analogues) retains analgesic activity.
C 2H 5 HO
OCOCH 3 H C2H 5 H
N N
CH 3 CH 3 CH 3
CH 3
Metabolite of methadone Metabolite of alphacetylmethadol
• Molecular modifications of methadone include homologation

and cyclization of dimethylamino group, reduction of CO to –
CHOH, removal and relocation of CH3 branching, isosteric
replacement of one or both phenyls by thienyl etc.
MODIFICATION BY GREWE
• Synthetic tetracyclic compounds N-methyl-morphinan
• N-methylmorphinan differs from the morphine nucleus in the
lack of the ether bridge between C-4 and C-5
• These are analgesic (i.e. ether bridge is not essential)
CH 3
10 9 17
N
1 11 8
14 16
13 15
2 7
12
3 6
4 5
N-methyl morphinan

• The levo-form of morphinan possesses the analgesic activity
while dextro possesses cough suppressant activity
• Introduction of –OH group at C-3 enhances analgesic activity
(ethers and esters also active)
• The 14-hydroxylation results in potent derivatives with
antagonist properties e.g. Oxilorphan, Butorphanol
CH 2CH CH 2CH
10 9 17 17
10 9
N N
1 8 1 8
11 HO 14 16 11 HO 14 16
13 15 13 15
2 7 2 7
12 12
3 6 6
4 5 3 5
4
HO Oxilophan HO Butorphanol
• N-substitution may results into either agonist or antagonist
e.g. N-phenylethyl, N-p-amino phenylethyl, N-furylethyl or N-

acetophenone derivative gives potent analgesics.
• N-allyl derivative (Levallorphan) possesses antagonistic
properties.
CH 2CH=CH 2
10 9 17
N
1 11 8
14 16
13 15
2 7
12
3 6
4 5
HO Levallorphan

• Removing the oxide bridge (and hydrogenating double bond,
removing one alcohol) produces levorphanol, which has
enhanced analgesic properties over morphine.

• Surprisingly, its mirror image still has antitussive properties,
but no analgesic properties
• Methylation of the phenolic hydroxyl group improves the
antitussive activity
2 2
3 OH HO 3
1
1
11 4 4 11
10 15 10 16
16 15
12 12
9 9
14 14
N 13 13 N
H 5 5 H
H3C H H CH3
8 6 8
6
7 7
dextrorphan Levorphanol
Antitussive only analgesic + antitussive

Mirror
BENZOMORPHANS
• Removal of Ether Bridge and peripheral groups in the alicyclic
ring of the morphine did not destroy its analgesic activity
• May and Murphy synthesized benzomorphans in which
alicyclic ring was replaced by one or two methyl groups
CH 3
8 1
N2
4' 3
7 9 H
6
3' 5 4
2' 1' H
HO Benzomorphan

CH 3
8 1
N2
4' 3
7 9 R2
6
3' 5 4
2' 1' R1
HO
• Substitutions at 2’-position - OH ≥ H ≥ NH2, NO2, F and Cl
• The trimethyl compound (R1= R2 = CH3) is about three times
more potent than the dimethyl analogue (R1 = H; R2 = CH3)
• Insertion of methyl group at C-9 increases analgesic activity

• Insertion of hydroxyl group at C-9 (which is equivalent to 14-
hydroxylation in morphine series) decreases the activity.
• The N-phenyl ethyl analogues always posses greater potency
over N-methyl analogues
• Analgesic activity and addiction liability can be observed in
two isomeric forms (Cis and Trans) of the same compound
• Enantiomers: (-) isomer is a stronger analgesic without
addiction, while (+) isomer is a weak analgesic with high
physical dependence capacity. CH 3
8 1
N 2
4' CH3 3
7 9
6
3' 5 4
2' 1' CH 2 CH 2CH 3
HO

• Pentazocine and cyclazocine are the classic antagonists from
benzomorphan series.
CH 3 CH 2CH=C(CH 3)2 CH 2CH

8 1 8 1 1
N 2 N 2 8
N 2
4' CH3 3 4'
7 9 7 9 CH3 3 4'
7 9 CH3 3
6 6 6
3' 5 4 3' 4 3'
5 5 4
2' 1' CH 3 2' CH 3 2' CH 3
1' 1'
HO HO
Metazocine Pentazocine HO Cyclazocine
• Cyclazocine (hallucinogenic properties) and pentazocine are

useful mixed agonist-antagonists

• An N-allyl (Pentazocine) or N-cyclopropylmethyl
(Cyclazocine) group frequently confers antagonistic activity
• Exceptions E.g. Tonazocine and 4-phenylpiperidine derivative
are potent antagonist
CH3
N
CH3
CH2CH2
HO CH3
CH3
N
CH3
CH3
HO
Tonazocine 4-Phenylpiperidine
derivative

• Within the morphine skeleton, a C-14 hydroxy or alkoxy
group and a C-6 ketone are necessary for pure antagonist
activity. e.g. Naloxone
• Xorphanol is found to be a partial agonist at the κ-receptor and
antagonist at the μ-receptor.
H
C
H2C N
10 9 17 CH2
N CH3
1 11 HO 14 8 16
2 13 15
7
12
3 5 6
4
O
HO O HO Xorphanol CH2
Naloxone

• Steric effect of C-14 –OH group of Naloxone makes the N-
allyl substituent equatorial and this stabilizes the receptor in an
antagonist rather than in an agonist conformation
• The oripavine derivative, 16-methyl Cyprenorphine is the
most selective non-peptide δ antagonist.
N
CH 3
OH
CH 3
O
HO OCH 3
Cyprenorphine

• Benzomorphans provides powerful κ-agonists with long
duration of addictive properties and respiratory depressant
activity. e.g. Bremazocine
• Etonitazene can be related to morphine. It is a benzimidazole
derivative and is highly potent, having about 1000 times
activity of morphine
O 2N
N
OC 2 H 5
(CH 2)N(C2 H 5)2
Etonitazine

OPIOID RECEPTORS
• Distributed throughout brain, spinal cord & peripheral tissues
• All of the opioid receptors (μ, κ and δ) are G-protein-coupled
receptors, composed of seven TM domains
• Opiates cause respiratory depression which is attributed to the
stimulation of μ and δ receptors present in areas of the brain
stem associated with control of respiration
• μ and δ agonists alters the respiratory function by reducing the
responsiveness of chemoreceptor in brain stem and carotid
body to carbon dioxide

OPIOID LIGAND BINDING SITE
• Binding site is an inner cavity formed by conserved residues
of the TM helices TM3, TM4, TM5, TM6 and TM7.
• Amino acid terminus is also an important determinant of
ligand binding affinity
• The ligand specificity is due to differences in the extracellular
loops or amino acids within the binding cavity
• Agonists bound to the cavity via interaction with a conserved
Asp from TM3 and a His from TM6

OPIOID LIGAND BINDING SITE
• Molecular modeling calculations show that -OH of the peptide
or nonpeptide opioid forms a H-bond with the His on TM6
• The Tyr charged nitrogen, or N+ of the nonpeptide agonist,
forms an ionic bond with the conserved Asp of TM3
• Antagonist ligands are thought to bind deeper in the binding
pocket but retain the ionic bond with the Asp of TM3
• The bulky substituent on the charged nitrogen of antagonists
insert itself between TM3 and TM6, preventing the shifts
required for activation resulting in functional antagonism

OPIOID RECEPTORS
The opioid receptors can be classifies as:
1. OP1 Receptors: Delta opioid receptors (δ)
2. OP2 Receptors: Kappa opioid receptors (κ)
3. OP3 Receptors: mu opioid receptors (μ)

MU OPIOID RECEPTORS (μ)
• Endogenous opioid peptides (endomorphin-1 and
endomorphin-2) are highly selective for mu opioid receptors
• Opioid alkaloids and their synthetic analogues are μ selective
agonists (morphine , normorphine and dihydromorphinone are
10-20 times more μ receptor selective)
• Naloxone & naltrexone are μ opioid receptors antagonists
• Activities by interaction with μ receptor are decreases gastric
motility, emesis, tolerance, analgesia, respiratory depression
euphoria, addiction and withdrawal symptoms

• Naloxone and naltrexone are pure antagonists at all opioid
receptor sites
• The 14β-OH moiety is most important characteristic feature
for attributing the pure antagonistic properties
H
H 2C C H2C
10 9 17 CH 2
N N
1 11 HO 14 8 16 HO
2 13 15
7
12
3 5 6
4
O O
HO O HO O
Naloxone Naltrexone

KAPPA OPIOID RECEPTORS (κ)
• κ receptor subspecies are involved in producing spinal analgesia,
euphoria and addiction.
• The 6,7-benzomorphan structural analogues (Ethylketazocine
and Bremazocine) exhibit Kappa opioid receptors selectivity
• More selective arylacetamide derivatives U50488 & PD117302
Cl
Cl S
CH 3
CH 3
N
N
O
O
N
N
U50488 PD117302

KAPPA OPIOID RECEPTORS (κ)
• U50488 is 50 times more selective for κ over μ receptors. Most
useful pharmacological tool in characterization of κ opioid receptor
activity
• PD117302 is 1000 times more selective for κ over μ & δ receptors
• (±) nor-binaltorphimine is the κ opioid receptor selective
antagonists
N N
OH HO
O N O
HO H OH
nor- Binaltrophimine

• κ receptor agonists have allyl, cyclopropylmethyl,
cyclobutylmethyl substitution on N-atom, but which are μ
receptor antagonists
Kappa agonist activity can be increased by two modifications
• Introduction of the O-atom placed strategically at the 8-
position (ethylketazocine)
• Introduction of the O-atom ring into the N-substituent
(bremazocine)

DELTA OPIOID RECEPTORS (δ)
• Modifications in structures of enkephalins (pentapeptides
produced in brain) to produce potent and selective δ opioid
receptor agonists
• But, their use is restricted due to less metabolic stability and
poor distribution properties. CH 3
H 2N H O CH 3
O CH 3
N
OH
HO N N
H H
O H CH 3 O O
DADLE
(D-Ala, D-Leu) enkephalin

• There are two highly selective nonpeptide delta opioid
receptor antagonists e.g. Natrindol, Naltiben
N N
OH OH
O N O O
HO H HO
Natrindol Naltiben
• Number of delta agonists are under clinical trials and may

drugs of future

MU AND KAPPA RECEPTOR ACTIVATION
Response Mu-1 Mu-2 Kappa
Analgesia
Respiratory
Depression
Euphoria
Dysphoria
Decrease GI
motility
Physical
Dependence
• It is unclear what delta’s responsible for

MECHANISM OF ACTION

MECHANISM OF ACTION
• All the opioid receptors are G-protein-coupled receptor
• Activation of receptor causes an inhibition of AC
Adenylate
ATP cyclase cAMP
• Camp is required for release of neurotransmitter

• Inhibition of opening of voltage-gated calcium influx channel
(simultaneously enhancing potassium ions efflux)
• Hyperpolarization of the nerve cell and decreased firing and
release of pain neurotransmitters (glutamate and substance P)
• Blockage of inter-neuronal transmission of pain impulses
CLINICAL USES OF OPIOID AGONISTS
• Management of acute pain, chronic pain, severe pain of acute
myocardial infarction, obstetric analgesia
• Cough suppression (codeine, dextromethorphan)
• Treatement of diarrhoea (Diphenoxylate, Loperamide)
• Management of acute pulmonary edema
• Preoperative medication and intraoperative adjunctive agents
in anesthesia (Fentanyl, alfentanyl, sufentanyl)
• Maintenance programmes for addicts

SIDE EFFECTS
• Respiratory depression
• Nausea
• Vomiting
• Constipation
• Increase blood pressure
• Urine retention
• Perspiration and itching
• Dependency and addiction

THERAPEUTIC USES OF ANTAGONISTS
• Treatement of opioid induced respiratory depression
• Prevention of development of dependence on morphine
(Nalorphine along with morphine)
• Treatement of compulsive users of opioids
• Reduction of intensity of untoward effects of opioids
(Euphoria, drowsiness, vomiting and muscular incoordination)

• Treatement of abstinence syndrome characterized by abnormal
pain, irritability, cold sweats, diarrhoea, nausea and vomiting
(Nalorphine precipitates the withdrawal symptoms)
NALORPHINE
• Nalorphine is partial narcotic antagonist
• It is used to reverse narcotic-induced respiratory depression.
• It precipitates withdrawal symptoms and produces behavioral
disturbances in addition to the antagonism action.
H
C
H 2C
10 9 17 CH 2
N
1 11 14 8 16
2 13 15
7
12
3 5 6
4
O
HO OH
N-allylmorphine
(Nalorphine)

NALOXONE
• Naloxone is pure narcotic antagonist at all opioid receptor
• It is used to reverse the respiratory depressant effects of opioid
overdoses
• Major metabolite found in the urine is Naloxone-3-
glucuronide H
C
H 2C
10 9 17 CH 2
N
1 11 HO 14 8 16
2 13 15
7
12
3 5 6
4
O
HO O
Naloxone

NALTREXONE
• Naltrexone is pure opioid antagonist at all opioid receptor
subtypes with the highest affinity for the μ receptor
• It is 17 times more potent than Nalorphine in morphine
dependent humans and twice as potent as Naloxone in
precipitating withdrawal symptoms
• It is orally bioavailable; duration of action is 24 hrs.
Naltrexone is reduced to the active antagonist 6-β-naltrexol by
dihydrodiol dehydrogenase, a cytosolic enzyme. It has dose
related hepatotoxicity.

NALTREXONE
• Methylnaltrexone is methylated quaternary form of
naltrexone.
• The permanently charged nitrogen prevents the drug from
crossing the BBB thus it only acts as antagonist at peripheral
opioid receptors.
H 2C H 2C
CH 3
N N
HO HO
O O
HO O HO CH 2
Naltrexone Methylnaltrexone

NALMEFENE
• Nalmefene is pure opioid antagonist i.e. 6-methylene analogue
of naltrexone.
• It is long acting than Naloxone but otherwise similar
pharmacodynamic and metabolic (3-glucuronidation) profile.
H 2C
HO
O
HO CH 2
Nalmefene

METHADONE HYDROCHLORIDE
CH3
CH3 CH3
N
N NaH
CN Cl CH3 CH3
CN
CH3
2-dimethylamino- 4-dimethylamino-2, 2-
Diphenylacetonitrile 1-methyl ethyl chloride diphenylvaleronitrile
H C2H5MgBr
CH3 CH3
CH3 CH3
N HCl N
CH2 CH3
C2H5 HCl C2H5
O O
Methadone Hydrochloride
Opioid Analgesics / Prof. Yogita Ozarde Methadone
FENTANYL CITRATE
H
O H3C O
N
H 3C
Cl -HCl N NH
NH
Propanoyl chloride N-phenylpiperidin-4-amine
N-phenyl-N-(piperidin-4-yl)propionamide
Phenethyl Chloride Citric acid
CH2COOH
HO COOH N N
CH2COOH
H3C O
Thank you

Narcotic and Non-Narcotic Analgesics

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Narcotic and Non-Narcotic Analgesics

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Narcotic and Non-Narcotic

Opioid Analgesics / Prof. Yogita Ozarde

Opioid Analgesics / Prof. Yogita Ozarde

• Used medicinally for thousands of years to produce Euphoria,

Analgesia, Sedation, Cough suppression and to treat diarrhea

• Morphine was isolated from opium in the early 1800’s and

Opioid Analgesics / Prof. Yogita Ozarde

Opioid Analgesics / Prof. Yogita Ozarde

• Sedation and anxiolysis

Opioid Analgesics / Prof. Yogita Ozarde

Modification of morphine (Therapeutic usefulness & toxicity)

Opioid Analgesics / Prof. Yogita Ozarde

• Morphine: Analgesic CH3

• Codeine: Analgesic and to depress cough reflex

Opioid Analgesics / Prof. Yogita Ozarde

• Dihydrocodeine : Depress cough reflex

Opioid Analgesics / Prof. Yogita Ozarde

• Ethyl morphine : Ophthalmology

Opioid Analgesics / Prof. Yogita Ozarde

• Dihydrocodeinone : Analgesic and to depress cough reflex

Opioid Analgesics / Prof. Yogita Ozarde

• Oxycodone : Analgesic and to depress cough reflex

Opioid Analgesics / Prof. Yogita Ozarde

The modifications done with the purpose

• To separate chemically the addiction property of morphine from its

other more salutary attributes

Principle targets were chosen for modification in morphine structure

Opioid Analgesics / Prof. Yogita Ozarde

• Modifications at C-6 position: Methylated, esterified,

Opioid Analgesics / Prof. Yogita Ozarde

• Modifications at C-8 position: Catalytic hydrogenation gives

Opioid Analgesics / Prof. Yogita Ozarde

• C-8 β-halo derivatives are found to be more potent analgesics

Opioid Analgesics / Prof. Yogita Ozarde

• Modifications at C-14 position: introduction of 14-OH group

Opioid Analgesics / Prof. Yogita Ozarde

• Bridging of C-6 and C-14 through an ethylene linkage is also

Opioid Analgesics / Prof. Yogita Ozarde

• Introduction of any new substituent further does not enhance

5-methyl dihydromorphine Azidomorphines

Opioid Analgesics / Prof. Yogita Ozarde

Opioid Analgesics / Prof. Yogita Ozarde

• Methyl , n-pentyl, or n-hexyl substitution gives opioid agonists

Opioid Analgesics / Prof. Yogita Ozarde

Opioid Analgesics / Prof. Yogita Ozarde

Opioid Analgesics / Prof. Yogita Ozarde

Opioid Analgesics / Prof. Yogita Ozarde

Opioid Analgesics / Prof. Yogita Ozarde

Opioid Analgesics / Prof. Yogita Ozarde

Opioid Analgesics / Prof. Yogita Ozarde

meperidine by molecular dissection.

Opioid Analgesics / Prof. Yogita Ozarde

Opioid Analgesics / Prof. Yogita Ozarde

Opioid Analgesics / Prof. Yogita Ozarde

group (-OCOC2H5) results in better analgesic activity.

• The replacement of N-methyl group by various aralkyl groups

Opioid Analgesics / Prof. Yogita Ozarde

Opioid Analgesics / Prof. Yogita Ozarde

Opioid Analgesics / Prof. Yogita Ozarde

Opioid Analgesics / Prof. Yogita Ozarde

Opioid Analgesics / Prof. Yogita Ozarde

Opioid Analgesics / Prof. Yogita Ozarde

CH3 CH3 CH3