Opioid analgesics

Pratik Khanal
 Classification:-
A. NARCOTIC ANALGESICS
H O

1. Naturally Occuring:-
Morphine, Codeine, Thebaine

O H

H
N
C H 3

H O

M o rp h in e
 O
H3C

O H

H
N
CH3

HO

Codeine
2. Semisynthetic opioids:-
Heroin (diacetyl morphine), Oxymorphone, Buprenorphine
A
c
O

OH

H
N
C
H3

A
c
O

H
e
r
o
i
n(
D
i
ac
e
t
y
lm
o
rp
h
i
n
e
)
HO

H N

O OH

Buprenorphine
3. Synthetic Opioids
Meperidine (Pethidine), Fentanyl, Pentazocine, Tramadol

N N

F e n ta n y l
HO

P e n ta z o c in e

Pethidine (Meperidine)
 N

H
O

O
H
3C T
rama
dol
B. NARCOTIC ANTAGONISTS
Naloxone, Naltrexone, Nalmefene
H
O

O O
H

N
a
lo
xo
ne
H
O H
O

O O
H
O O
H

N
N
O
H
2C N
a
lt
rex
on
e
N
al
m e
fe
ne
C. ANTITUSSIVE AGENTS:-
Noscapine (Narcotine, Anarcotine), Dextromethorphan, Terpin
Hydrate
O

H
N
O
CH3

O
H 3C O
H

O
H 3C
O
O N o s c a p in e
CH3
 OCH3
O H

H 2O H3C N

Dextromethorphan
O H

T e rp in H y d ra te
1. NOCICEPTIVE ANALGESICS:-

a) Multicyclic Full μ Agonists

Codeine, Morphine, Hydrocodone, Hydromorphone, Oxycodone

b) Multicyclic Partial μ Agonists

Buprenorphine

c) Multicyclic κ Agonists/ μ Agonists

Nalbuphine, Pentazocine

d) Multicyclic Opioid antagonists

Nalmefene, Naloxone, Naltrexone

e) Flexible Full μ Agonists

Fentanyl, Meperidine, Methadone, Sufentanil
f) Dual Action Analgesics:-
Tapentadol, Tramadol

2. NEUROPATHIC ANALGESICS:-

a) First Line Agents:-

Desipramine, Duloxetine, Lidocaine, Nortriptyline

b) Second Line Agents:-

Methadone, Morphine, Oxycodone, Tramadol

c) Third Line Agents:-

Bupropion, Carbamazepine, Oxcarbazepine, Paroxetine
Morphine:- 2
HO 3
1
A
4 11
10
12
O B
E 13 9
5 14 D 17
C 16 N
15 CH3
6 8
HO
7
Morphine
Physicochemical and Metabolic Properties of Opoids:-

1. All opoids require a cationic amine for anchoring to the

conserved Asp residue of the G-protein coupled opoid
receptors.
2. Naturally occuring levorotatory (-) morphine has the 5R, 6S,
9R, 13S, 14R absolute configuration.
3. Ring C of pentacyclic (morphines) and tetracyclic
(morphinans) opoids is forced into a pseudoboat
conformation due to the presence of the 7,8-double bond and
the restraining furan (E) ring.
4. The aromatic A ring can be viewed as a substituent on the 4-
position of the piperidine (D) ring.
5. The 4-phenyl piperidine structure structure is considered the
pharmacophore for opoid analgesic action.
6. Many μ agonists have an N-methyl group that is readily N-
dealkylated by CYP3A4.

7. Nor-metabolites have limited clinical relevance due to a

decrease in distribution enhancing lipophilicity and the loss of an
agonist promoting hydrophobic interaction with the receptor.

8. In contrast, CYP2D6-mediated O-dealkylation of the 3-

methoxy group of codeine analogs is required to generate the
phenolic OH group essential for μ-receptor binding.

9. Opoids are also subject to Phase-II metabolism prior to

excretion. Phenols conjugate either with glucuronic acid or
sulphate, and both conjugates are found in the urine of patients
taking multicyclic opoids.
10. Morphine exists as cation at physiologic pH, and readily
forms salts with appropriate acids (commercial products are
sulfate and HCl.
 HO

Acid
Morphine O H

H
N
CH3

HO H

Conjugate Acid

Base O

O H

H
N
CH3

HO

Conjugate Base
11. Metabolism:- 3- and 6-O glucuronides, N-demethylation and
O-methylation to codeine (minor).
OH
O

O
HO OH
HO
OH

Glucuronic acid
H O G lu c - O

O H O H
M o rp h in e
H H
N H N
C H 3

H O H O
N o rm o rp h in e
M o rp h in e -3 -g lu c u ro n id e

C o d e in e
Peripheral and Nuclear Modifications of Morphine:-

A. Peripheral
I. Ring A and its 3-hydroxyl group is an important structural
feature for analgesic activity. Removal of 3-OH group reduces its
analgesic activity by 10-fold.

M o rp h in e O H

H
N
CH3

HO

3 -D e o x y m o rp h in e
II. Altering C-3 OH by etherification reduces narcotic analgesic
activity, the larger the ether group, the lower the analgesic activity.
With less active as analgesics, compounds such as codeine possess
very useful antitussive activity. O
H 3C

O H
M o rp h in e

H
N
C H 3

H O

C o d e in e
R P = 0 .1 5
 H 3 C

M o rp h in e O H

H
N
C H 3

H O

E th y lm o rp h in e
R P = 0 .1
 O
N

O H
Morphine
H
N
CH3

HO

Pholcodeine
RP=0.01
III. Derivatization of the C-3 OH by esterification generally only
modestly increases activity.
H 3C O

M o rp h in e O H

H
N
C H 3

H O

3 -A c e ty lm o rp h in e

R P > 1 .0
 H 3C O

O H
M o rp h in e

O H
N
CH 3

H 3C O

D ia c e ty lm o rp h in e (H e ro in )

R P = 2 .0
 IV. 6-OH of morphine are not required for analgesic activity as
indicated by relative potencies of the following morphine
analogues.

HO

M o rp h in e O H

H
N
CH 3

6 -D e o x y m o rp h in e

R P = 10
M o rp h in e 6 -M e th o x y m o rp h in e

RP = 5
H O

O H

O H
N
C H 3

H 3C O

M o rp h in e -6 -a c e ta te

R P = 4 .2
V. The 7,8 double bond of morphine also is not required for
analgesic activity as indicated by the relative analgesic potency of
dihydromorphine.
HO

Morphine O H

H
N
CH3

HO
Dihydromorphine

RP = 1.2
 VI Simple E ring opened analogues of morphine such as the
compound below are less active.
HO

Morphine HO H

N
CH3

HO

RP = 0.13
VII. Replacement of morphine’s N-methyl group by a hydrogen
atom as in normorphine reduces analgesic activity of that analog.
Much of this decrease is due to increased polarity resulting in
reduced BBB translocation to the CNS.
HO

Morphine O H

H
NH

HO
Normorphine

RP = 0.05
B. Nuclear
Annelation – adding a sixth ring across carbons 6 and 14 of the C
ring of morphine – yields compounds such as etorphine,
buprenorphine which are extremely potent analgesics. Etorphine
is typically used to immobilize large animals (elephants).
 HO
The lethal dose of etorphine
in humans is reported to be
as low as 30 μg (0.03mg).

Etorphine has a potency of as O

much as 3,000-4,000 times
that of morphine. N

Etorphine is a full agonist of

μ, κ and δ – opioid receptors. O

OH

Etorphine
HO

H N

O OH

Buprenorphine
Despite the presence of the N-cyclopropyl methyl group, which
normally promotes therapeutically useful μ antagonist action,
buprenorphine is a very potent but partial, agonist with an
analgesic potency between 25- and 40-fold that of morphine. A
0.3 to 0.4 mg dose of this oripavine-based analgesic is equipotent
with 10mg of morphine.
 Mechanism of Action:-

OVERVIEW OF PAIN :-

1. Pain is defined as an unpleasant sensory and emotional

experience associated with actual or potential tissue damage, or
described in terms of such damage.
2. Pain is the most common reason for visiting the emergency
department in more than 50% of cases and for 30% of family
practice visits.
3. Examples of Clinical pain include pain following surgery and
pain associated with injury.
4. Pain management becomes more important as people approach
death.
Pain:-

Acute pain is defined as the normal, predicted physiologic

response to an adverse chemical, thermal, or mechanical stimulus
associated with surgery, trauma, or acute illness.

Acute pain results from activation of the pain receptors

(nociceptors) at the site of tissue damage.

Acute pain provides a warning signal that something is wrong

and in need for further examination.

Pain can be divided into nociceptive pain and neuropathic pain.

Nociceptive pain is mediated by stimulation of nociceptors,
which are located in skin, bone, connective tissue, muscle, and
viscera and respond only to noxious stimuli approaching or
exceeding harmful intensity.

Nociceptors serve a biologically useful role at localizing noxious

chemical (alcohol in an open wound), thermal (heat or cold), and
mechanical (crusing, tearing, etc.) stimuli. Nociceptive pain
usually responds to NSAIDs and opoids.

Neuropathic pain is chronic pain due to direct central or

peripheral nerve damage. Common chronic pain complaints in
older adults include headache, low back pain, cancer pain,
arthritis pain, neurogenic pain (pain resulting from damage to
peripheral nerves or to the CNS itself).
Endogenous Opioid Peptides and Their Physiologic Functions:-

Hughes et al. used the electrically simulated contractions of

guinea pig ileum and the mouse of vas deferens, which are very
sensitive to inhibition by opioids, as bioassays to follow the
purification of compounds with morphine-like activity from
mammalian brain tissue.
These researchers were able to isolate and determine the
structures of two pentapeptides, Tyr-Gly-Gly-Phe-Met (Met-
enkephalin) and Tyr-Gly-Gly-Phe-Leu (Leu-enkephalin), that caused
the opioid activity. The compounds were named enkephalins after
the Greek word Kaphale, which translates as “from the head.”
The endogenous opioids exerts their analgesic action at
spinal and supraspinal sites. They also produce analgesia by a
peripheral mechanism of action associated with the inflammatory
process.
G-protein function and second messenger generation:-

When a GPCR becomes acivated by an agonist, the

associated heterotrimeric protein catalyses the exchange of GDP by
GTP, enabling both Gα-GTP and βγ-dimers to interact with a variety
of downstream effectors. There are four major families of Gα
proteins: Gs, Gi/o, Gq, and G12.
Mechanism of action:-

The signal transduction mechanism for μ, δ and κ receptors

is through Gi/o proteins. Activation of opioid receptors is linked
through the G-protein to an inhibition of adenylate cyclase activity.
The resultant decrease in cAMP production, efflux of potassium
ions, and closure of voltage-gated Ca2+ channels causes
hyperpolarisation of the nerve cell and a strong inhibition of nerve
firing.
Specific Drugs:-

Morphine Sulphate:- Morphine is the prototypical opioid

agonist, and all synthetic multicyclic analgesics are based on the
morphine nucleus to some degree. The presence of N-CH3
substituent, phenolic hydroxyl, and B/C cis configuration assure
potent and selective μ agonism. Morphine has very poor oral
bioavailability because of extensive prehepatic (GI) and first pass
(liver) metabolism to the inactive 3-glucuronide and 3-sulphate
conjugates.
Codeine Sulphate:-

Codeine is 3-methoxy analog of morphine. Codeine use for

longer than 6 months has recnetly been associated with an
increased risk of serious or fatal cardiovascular events, and an
increased risk of all cause of mortality has been noted when used
for more than 30 days.
Codeine must undergo CYP2D6- mediated activation to
the phenolic structure required for binding to μ receptors.
Naloxone Hydrochloride, Naltrexone Hydrochloride, and
Nalmefene Hydrochloride

The three opioid antagonists are marketed to reverse the central

actions of opioid agonists. They all have a classic antagonist-
directing nitrogen substituent on a pentacyclic scaffold and
contain the requisite 14β-OH and the 7,8-dihydro-6-one or 6-ene
C ring. With a four carbon N-cyclopropyl methyl substituent,
naltrexone is twice as potent as the allyl-substituted naloxone,
presumably due to enhanced didtribution to central sites of
action. With the replacement of the polar C6 – keto of Naltrexone
with a lipophilic methylene moiety, nalmefene shows the
anticipated rise in logP and should distribute to the CNS at least
as well as, if not better than, naltrexone. Naloxone is orally
inactive, while naltrexone and nalmefene have suficient
bioavailability for oral administration.