Morphine

HO- Group is needed for activity

2
HO 3
1

4 11

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

Morphine (Astramorph)

HO- Group not important to activity

 Brand Names
• AstramorphTM PF; DuramorphTM;
InfumorphTM; KadianTM; MS ContinTM;
MSIRTM; Oramorph SRTM; RMSTM;
RoxanolTM; Roxanol RescudoseTM;
RoxanolTM
• EpimorphTM (Canada); Morphine-HPTM
(Canada); MST-ContinusTM (Mexico);
MS-IRTM (Canada); StatexTM (Canada)
• Morphine is a highly potent opiate analgesic drug
and is the principal active agent in opium and the
prototypical opiate.

• Like other opioids, e.g. Diamorphine (heroin),

morphine acts directly on the
central nervous system (CNS) to relieve pain, and
at synapses of the nucleus accumbens in
particular.

• Morphine is highly addictive when compared to

other substances, and tolerance and physical and
psychological dependences develop very rapidly.
 Administration of Morphine
• Parenterally as subcutaneous, intravenous,
or epidural injections. When injected,
particularly intravenously, morphine produces
an intense contraction sensation in the
muscles due to histamine release and also
produces a very intense 'rush' which is
mediated by several different receptors in the
CNS. The military sometimes issues
morphine loaded in an autoinjector.
 Administration
• Orally, it comes as an elixir, concentrated
solution, powder (for compounding) or in tablet
form. Morphine is rarely supplied in suppository
form. Due to its poor oral bioavailability, oral
morphine is only one-sixth to one-third of the
potency of parenteral morphine. Morphine is
available in extended release capsules for
chronic administration, as well as immediate-
release formulations.
 Side Effects
• Morphine has many side effects. The most
dangerous is respiratory depression. With higher
doses or in frail patients, the respiratory rate
decreases, the patient becomes increasingly
sedated, and the pupils very small.
• Common side effects are nausea and vomiting
due to a central action of morphine stimulating
one of the centres in the brain concerned with
vomiting called the chemotactic trigger zone.
 Side Effects
• Other central nervous system side effects of
morphine are cough suppression, sedation, and
dependence leading to addiction.
• Morphine also has an effect on the muscle of
the bowel and urinary tract, causing the
sphincter to contract and reduce the peristalsis
(the wavelike movements of the bowel muscle
that propel its contents forwards). This results in
a delayed emptying of the stomach, constipa
tion, and may also lead to urinary retention.
 Side Effects

• Morphine can also cause histamine

release, which causes itching of the
skin and nose and a mild flushing of the
skin.
How do opioid analgesics work?
There are three known types of receptors
for opioid analgesics: , , and .

• http://www.thirteen.org/closetohome/ani
mation/opi-anim2-main.html

• http://thebrain.mcgill
.ca/flash/i/i_03/i_03_m/i_03_m_par/i_03
_m_par_heroine.html#drogues
 The  receptor seems to be the major
opioid target
• Activation of the μ receptor by an agonist such as
morphine causes analgesia, sedation, reduced blood
pressure, itching, nausea, euphoria, decreased
respiration, miosis (constricted pupils) and decreased
bowel motility often leading to constipation.
• Some of these effects, such as sedation, euphoria
and decreased respiration, tend to disappear with
continued use as tolerance develops. Analgesia,
miosis and reduced bowel motility tend to persist; little
tolerance develops to these effects.
 The  receptor
• Tolerance develops to different effects at
different rates largely because these effects
are caused by activation of different μ-
receptor subtypes.

• Stimulation of μ1-receptors blocks pain while

stimulation of μ2-receptor causes respiratory
depression and constipation.
 Overview: Opioid Receptors
• Opioid receptors are a group of
G-protein coupled receptors with
opioids as ligands. The endogenous
opioids are dynorphins, enkephalins
and endorphins. The opioid receptors
are ~40% identical to somatostatin
receptors (SSTRs).
 Overview: Opioid Receptors
• δ-Opioid receptor activation produces analgesia. Some research
suggests that they may also be related to seizures. The endogenous
ligands for the δ receptor are the enkephalins. Until quite recently,
there were few pharmacological tools for the study of δ receptors. As
a consequence, our understanding of their function is much more
limited than those of the other opioid receptors.Recent work indicates
that exogenous ligands which activate the delta receptors mimic the
phenomenon known as 'ischemic preconditioning'. Experimentally, if
short periods of transient ischemia (restriction in the blood supply) are
induced the downstream tissues are robustly protected if permanent
interruption of the blood supply is then effected.Opiates and opioids
with delta activity mimic this effect. In the rat model introduction of
delta active ligands results in significant cardioprotection.
 Overview: Opioid Receptors
• κ-Opioid receptors are also involved with
analgesia, but activation also produces
marked nausea and dysphoria (sadness,
irritability, anxiety)
 Heroin
HO- Group is needed for activity Easily enzymatically hydrolyzed to AcOH and HO-Ar

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

Heroin (Diamorphine)
Morphine (Astramorph) (2X as potent as morphine)
(Conversion of two -OH groups to -OAc
facilitates crossing of the BBB)
HO- Group not important to activity
 Codeine
HO- Group is needed for activity
Inefficiently converted to HO group in the liver
2
HO 3
1 CH3 O

4 11

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

Morphine (Astramorph) Codeine (5X LESS potent than morphine)

HO- Group not important to activity

 Uses of Codeine
• Approved indications for codeine include:
• ･Cough, though its efficacy in low dose over the counter
formulations has been disputed.
• Diarrhea
• Moderate to severe pain･Irritable bowel syndrome
• Codeine is sometimes marketed in combination
preparations with paracetamol (acetaminophen) as
co-codamol (best known in North America as Tylenol 3),
with aspirin as co-codaprin or with ibuprofen. These
combinations provide greater pain relief than either agent
(drug synergy; see synergy).
 Codeine
• Codeine is considered a prodrug, since it is metabolised
in vivo to the principal active analgesic agent morphine. It
is, however, less potent than morphine since only about
10% of the codeine is converted. It also has a
correspondingly lower dependence-liability than morphine.
• The conversion of codeine to morphine occurs in the liver
and is catalysed by the cytochrome P450 enzyme
CYP2D6. Approximately 6 ﾐ 10% of the Caucasian
population have poorly functional CYP2D6 and codeine is
virtually ineffective for analgesia in these patients (Rossi,
2004).
 Hydrogenation of morphine’s C=C
produced dihydromorphine

2
2
HO 3
1 HO 3
1

4 11
4 11
15 10 16 10
O
12 H2 / Pd 12
15 16
9 O
14 9
13 N 13
14
N
5 H 5 H
H CH3 H CH3
6 8
HO HO 6 8
7
7

Morphine (Astramorph) Dihydromorphine

Dihydromorphine is slightly stronger than morphine as an analgesic with a nearly identical side-
effect profile, and is a somewhat more active euphoriant -- therefore making it theoretically a bit
superior in alleviating suffering -- and perhaps in a way subjectively closer to that of morphine
than hydromorphone, other morphine derivatives, the codeine-based series, or the synthetics.
Like metopon, dihydromorphine may be less addictive overall and have better bioavailability
after oral administration than morphine. The onset of action is more rapid than morphine and it
also tends to have a longer duration of action, generally 4-7 hours.
 However, this led to a cmpd with
improved activity
2 2
HO 3
1 HO 3
1

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

Dihydromorphine Hydromorphone
(7X more potent than morphine)

Hydromorphone is a drug developed in Germany in the 1920s and introduced to the mass
market beginning in 1926. It is used to relieve moderate to severe pain and severe, painful
dry coughing. Hydromorphone is known by the trade names Hydal, Sophidone, Hydrostat,
and most famously, "Dilaudid ｨ ", though an extended-release version called Palladone ｨ
SR was available for a short time in the United States before being voluntarily withdrawn
from the market after an FDA advisory released in July 2005 warned of a high overdose
potential when taken with alcohol; it is still available in the United Kingdom as of March
2007. Another extended-release version called Hydromorph Contin ｨ , manufactured as
controlled release capsules, continues to be produced and distributed in Canada by Purdue
Pharma Inc. in Pickering, Ontario.
 Hydromorphone
• Hydromorphone is becoming more popular in the
treatment of chronic pain in many countries, and it is
used as a substitute for heroin and morphine where
these two drugs are not marketed on account of
hydromorphone's superior solubility and speed of onset
and less troublesome side effect and dependence
liability profile as compared to morphine and heroin.
Many chronic pain patients find that hydromorphone has
a spectrum of actions which suit them just as well as
morphine, and better than synthetics like methadone or
levorphanol in alleviating suffering, as contrasted with
simple pain of equal objective intensity.
 Similar synthetic manipulations make
hydrocodone more potent than codeine
2
CH3O 3
1

4 11

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

Hydrocodone
(much more potent than codeine)

Hydrocodone or dihydrocodeinone (marketed as Vicodin, Anexsia,

Dicodid, Hycodan, Hycomine, Lorcet, Lortab (or Loritab), Norco,
Novahistex, Hydroco, Tussionex, Vicoprofen, Xodol) is a semi-
synthetic opioid derived from two of the naturally occurring opiates,
codeine and thebaine. Hydrocodone is an orally active narcotic analgesic
and antitussive. Sales and production of this drug have increased
significantly in recent years, as have diversion and illicit use.
Hydrocodone is commonly available in tablet, capsule and syrup form.
 Oxycodone
HO- Group is needed for activity
CH3 group reduces potency

CH3 O
2
HO 3
1

4 11

15 10 16 O
12
O N
14
9
oxidized OH H
13 N OH CH3
5 H
H CH3 O
6 8
HO
7 Reduced C=C
Oxycodone (Percocet) -OH group increases potency
Morphine (Astramorph) (equal to morphine
in potency)

HO- Group not important to activity

 Oxycodone
• Oxycodone is a potent and potentially addictive
opioid analgesic medication synthesized from
thebaine. Its name is derived from codeine - the
chemical structures are very similar, differing
only in that the hydrogen on the codeine is
oxidised to a hydroxyl group, hence 'oxy' and the
hydroxyl group from the codeine becomes a
ketone group, hence 'oxycodone.'
HO- Group is needed for activity
CH3 group reduces potency

CH3 O
2
HO 3
1

4 11

15 10 16 O
12
O N
14
9
oxidized OH H
13 N OH CH3
5 H
H CH3 O
6 8
HO
7 Reduced C=C
Oxycodone (Percocet) -OH group increases potency
Morphine (Astramorph) (equal to morphine
in potency)

HO- Group not important to activity

 Oxycodone: Brand Names
• It is effective orally and is marketed in combination with
aspirin (Percodan, Endodan, Roxiprin) or
paracetamol/acetaminophen (Percocet, Endocet,
Roxicet, Tylox) for the relief of pain. More recently,
ibuprofen has been added to oxycodone (Combunox).

• It is also sold in a sustained-release form by Purdue

Pharma under the trade name OxyContin as well as
generic equivalents, and instant-release forms
Endone, OxyIR, OxyNorm, Percolone, OxyFAST,
and Roxicodone.
 Oxycodone: Uses
• Percocet tablets (Oxycodone with acetaminophen)
are routinely prescribed for post-operative pain
control. Oxycodone is also used in treatment of
moderate to severe chronic pain. When used at
recommended doses for any period of time it
provides effective pain control with manageable
side effects. Both immediate release oxycodone
(OxyNorm in the UK) and sustained-release
oxycodone (OxyContin in the UK) are prescribed for
pain due to cancer more than for any other
condition.
Oxycodone: Recreational Use
• The introduction of OxyContin in 1995 resulted
in increasing patterns of abuse. Unlike Percocet,
whose potential for abuse is limited by the
presence of paracetamol, OxyContin contains
only oxycodone and inert filler. Abusers simply
crush the tablets, then either ingest the resulting
powder orally, intranasally, via intravenous,
intramuscular or subcutaneous injection (by
dissolving the powder), or rectally to achieve
rapid absorption into the bloodstream.
 Oxycodone: Recreational Use
• Injection of OxyContin is particularly dangerous
since it contains binders which enable the time
release of the drug. Often mistaken as the time
release, the outside coating of the pill is merely
used as a color code for different dosage
amounts. The vast majority of OxyContin-related
deaths are attributed to ingesting substantial
quantities of oxycodone in combination with
another depressant of the central nervous system
such as alcohol or benzodiazepines.
 Oxymorphone
HO- Group is needed for activity
HO- Group is needed for activity

HO
2
HO 3
1

4 11

15 10 16 O
12
O N
14
9
oxidized OH H
13 N OH CH3
5 H
H CH3 O
6 8
HO
7 Reduced C=C
-OH group increases potency
Morphine (Astramorph)
Oxymorphone ((Opana, Numorphan))
HO- Group not important to activity (8X more potent than morphine)
 Oxymorphone

• Oxymorphone (Opana, Numorphan) or 14-Hydroxydihydro

morphinone is a powerful semi-synthetic opioid analgesic
that is derived from thebaine, and is approximately 6-8 times
more potent than morphine. Clinically, it is administered as
its hydrochloride salt via injection, or suppository; typically in
dosages of 1 mg (injected) to 5 mg (suppository).
Endo Pharmaceuticals markets oxymorphone in the United
States as Opana and Opana ER. Opana is available as 5
mg and 10 mg tablets; Opana ER, an extended-release form
of oxymorphone, is available as tablets in strengths of 5 mg,
10 mg, and 20 mg. As with other opioids, oxymorphone can
cause physical dependency, and may be abused.
 Thebaine
CH3O

O
N
H
CH3
CH3O

Thebaine (paramorphine) is an opiate alkaloid. A minor constituent of opium,

thebaine is chemically similar to both morphine and codeine, but produces
stimulatory, with strychnine-like convulsions, rather than depressant effects.
Thebaine is not used therapeutically, but is converted industrially into a
variety of compounds including oxycodone, oxymorphone, nalbuphine,
naloxone, naltrexone, buprenorphine and etorphine.
It is controlled in Schedule II of the Controlled Substances Act as well as
under international law. Thebaine is listed as a Class A drug under the
Misuse of Drugs Act 1971 in the United Kingdom.
 Changing substitutents on nitrogen can either
improve agonist activity…or create
antagonists!
2 2
2
HO 3 HO 3
1 HO 3
1 1

4 11 4 11
4 11
10 15 10 16
15 16 12 15 10 16
12
O O H2 O
12
9 9
9 H
14 13
14
N C 14
13 N 5 H 13 N C
5 H 5 H
H CH3 H C Ph H C
8 6 8 H2 H2 CH2
HO 6 HO HO 6 8
7 7
7

Morphine (Astramorph) More potent than morphine. Nalorphine

An antagonist at the morphine receptor!!!

Nalorphine , derivative of morphine that acts to reverse the effects of

morphine and other narcotics . It counteracts narcotic-induced nervous
system and respiratory system depression but is not effective against
depression induced by other sedatives such as barbiturates . Nalorphine
and other narcotic antagonists are useful in reversing the effects of narcotic
overdoses. Because nalorphine causes withdrawal symptoms in addicts, it
is administered to apparent ex-addicts to determine if they have returned to
drug use. Nalorphine is marketed under the trade name Nalline.
 Still more potent antagonists can be made by
incorporating the same structural changes used to
make morphine a more potent analgesic
2
HO 3
1 2 2
HO 3 HO 3
1
1
4 11
10 4 11 4 11
15 16
12 10 10
O 12
15 16 12
15 16

14
9 H O O
13 N C 9 H 14
9
5 H 14
13 N C 13 N
H C 5 H 5 H
H2 CH2 OH C
HO 6 8 OH C
8 H2 CH2 6 8 H2
7
O 6 O
7 7

Nalorphine
Naloxone Naltrexone

Naloxone is a drug used to counter the effects of opioid overdose, for

example heroin or morphine overdose. Naloxone is specifically used to
counteract life-threatening depression of the central nervous system
and respiratory system. It is marketed under various trademarks
including Narcan, Nalone, and Narcanti, and has sometimes been
mistakenly called "naltrexate." It is not to be confused with Naltrexone,
another opioid receptor antagonist with qualitatively different effects.
 Naltrexone
2
HO 3
1 2 2
HO 3 HO 3
1
1
4 11
10 4 11 4 11
15 16
12 10 10
O 12
15 16
12
15 16

14
9 H O O
13 N C 9 H 14
9
5 H 14
13 N C 13 N
H C 5 H 5 H
H2 CH2 C OH C
HO 6 8 OH CH2
8 H2 6 8 H2
7
O 6 O
7 7

Nalorphine
Naloxone Naltrexone

• Naltrexone is an opioid receptor antagonist used primarily in the

management of alcohol dependence and opioid dependence. It is
marketed in generic form as its hydrochloride salt, naltrexone
hydrochloride, and was formerly marketed using the trade name
Revia. In some countries, an extended-release formulation is
marketed under the trade name Vivitrol. It should not be confused
with naloxone, which is used in emergency cases of overdose rather
than for longer term dependence control.