OPIOID ANALGESICS

by MANKARAN SINGH
 History of Opioids
• Opium is extracted from poppy seeds
(Paper somniforum)
• Used for thousands of years to produce:
– Euphoria
– Analgesia
– Sedation
– Relief from diarrhea
– Cough suppression
 History cont’d
• Used medicinally and recreationally from
early Greek and Roman times
• Opium and laudanum (opium combined
with alcohol) were used to treat almost all
known diseases
• Morphine was isolated from opium in the
early 1800’s and since then has been the
most effective treatment for severe pain
 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
 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 such
as fentanyl)
 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
 Pharmacological effects cont’d.
• 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
 Mechanism of action
• Activation of peripheral nociceptive fibers
causes release of substance P and other pain-
signaling neurotransmitters from nerve terminals
in the dorsal horn of the spinal cord

• Release of pain-signaling neurotransmitters is

regulated by endogenous endorphins or by
exogenous opioid agonists by acting
presynaptically to inhibit substance P release,
causing analgesia
Three Opioid Receptors

• Mu

• Kappa

• Delta
 Delta Receptor
• It is unclear what delta’s responsible for.
• Delta agonists show poor analgesia and
little addictive potential
• May regulate mu receptor activity
 Mu-Receptor: Two Types
• Mu-1 • Mu-2
– Located outside spinal – Located throughout
cord CNS
– Responsible for – Responsible for
central interpretation respiratory depression,
of pain spinal analgesia,
physical dependence,
and euphoria
 Kappa Receptor

• Only modest analgesia

• Little or no respiratory depression
• Little or no dependence
 AGONISTS
*Morphine
*Heroin
*Hydromorphone
*Fentanyl
*Codeine
 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 72
hours 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).
 Summary of structure-activity relationships (SAR’s)

Removal of OH reduces activity

2
HO 3
1 N-CH2CH2Ph increases
4 11
N-CH2CH=CH2 creates antagonist
15 10 16
12
Removal increases activity O
9
14
5
13 N
H
H CH3
6 8
HO
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

4 11

15 10 16
12
O
9
14
13 N N
5 H R1 R2
H CH3 R3 CH3
6 8
HO
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.

2
2 HO 3
HO 3
1
1

4 11
4 11
15 10 16
15 10 16 12
12
O 9
9 14
14 13 N
5
13 N 5 H
H
H CH3
H CH3 6 8
6 8
HO 7
7

Levorphanol

Levorphanol is used to treat severe pain and has several brand names.
Surprisingly, its mirror image still has antitussive
properties, but no analgesic properties

2 2
3 OH HO 3
1
1

11 4 4 11

16 10 15 10 16
15 12
12
9 9
14 14
N 13
5
13 N
H 5 H
H3C H H CH3
8 6 6 8
7 7

dextrorphan Levorphanol

Antitussive only analgesic + antitussive

Mirror
Methylating the phenolic hydroxyl group improves
this antitussive activity

2
1
3 OCH3

Dextromethorphan (DM or DXM) is 11 4

an antitussive drug that is found in 16 10 15

12

many over-the-counter cold and 9

14
N 13
cough preparations, usually in the H 5
H3C H
form of dextromethorphan 8 6
hydrobromide. It is also commonly 7

taken above the recommended

dosage by users seeking its Dextromethorphan (DM)
dissociative effect.
Antitussive only
 Aromatic Ring
Spacer
2
HO 3
1

4 11

15 10 16
12
O
9
14
13 N N
5 H R1 R2
H CH3 R3 CH3
6 8
HO
7

Quaternary Carbon Center

Basic Nitrogen

O
N
CH3
O
Et
Meperidine
(DemerolTM)
(PethidineTM)
 Meperidine
• Pethidine or meperidine 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, as a syrup, or by intramuscular or
intravenous injection.
 Opioids to treat diarrhea?
Arom atic Ring
Spacer
2
HO 3
1

4 11

15 10 16
12
O
9
14
13 N N
5 H R1 R2
H CH3 R3 CH3
6 8
HO
7

Quaternary Carbon Center

Basic Nitrogen

Cl

O
N
N
HO
O CH3
CN N
O Et
N
O CH3
CH3
O
Et
M eperidine Diphenoxylate
(Dem erol TM ) (active ingredient of Lom otil) Loperam ide
(Pethidine TM ) (m ixture with atropine, to prevent abuse) (active ingredient of Imodium )
Does not cross BBB, thus no analgesic effect
 Fentanyl
Aromatic Ring
Spacer
2
HO 3
1

4 11

15 10 16
12
O
9
14
13 N N
5 H R1 R2
H CH3 R3 CH3
6 8
HO
7

Quaternary Carbon Center

Basic Nitrogen

O O N
N N
CH3 CH2CH2Ph
O
Et
Et
Meperidine Fentanyl
(DemerolTM) (80X more potent than morphine!)
(PethidineTM)
 Fentanyl

O N
N
CH2CH2Ph
Et

• Fentanyl is an opioid analgesic, 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
OCH3

O
O N O N N
N O N N
OCH3
CH2CH2Ph N N Et
Et Et
Fentanyl Alfentanil N N Remifentanil O

(80X more potent than morphine!) (Alfenta)

OCH3 O
OCH3

O N N
O N N
S
Et
Et
Sufentanil
(Sufenta) Carfentanil
5X more potent than Fentanil (100X more potent than Fentanil!)
 Methadone
Aromatic Ring
Spacer
2
HO 3
1

4 11

15 10 16
12
O
9
14
13 N N
5 H R1 R2
H CH3 R3 CH3
6 8
HO
7

Quaternary Carbon Center

Basic Nitrogen

CH3

O CH3
N

CH3

Methadone
 Methadone CH3

O CH3
N

CH3

• Methadone was best known for its use in treating

narcotic addiction.