Morphine HO- Group is needed for activity HO

Morphine
HO- Group is needed for activity
2
HO
3
1
11
4
O
10
15
12
9
13
5
14
H
H
HO
16
8
6
N
CH3
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 immediaterelease 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.ht
ml#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 μreceptor 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 Gprotein 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
2
AcO
2
HO
Easily enzymatically hydrolyzed to AcOH and HO-Ar
3
3
1
1
11
4
11
4
15
12
O
10
O
16
13
14
H
H
8
6
13
5
N
CH3
10
15
14
H
H
AcO
16
9
9
5
HO
12
8
6
N
CH3
7
7
Morphine (Astramorph)
HO- Group not important to activity
Heroin (Diamorphine)
(2X as potent as morphine)
(Conversion of two -OH groups to -OAc
facilitates crossing of the BBB)
Codeine
HO- Group is needed for activity
Inefficiently converted to HO group in the liver
2
HO
3
CH3O
1
11
4
O
10
15
12
O
9
13
5
14
H
H
HO
16
8
6
N
H
CH3
7
Morphine (Astramorph)
HO- Group not important to activity
H
N
CH3
HO
Codeine (5X LESS potent than morphine)
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
HO
3
11
4
O
5
14
H
H
HO
16
H2 / Pd
9
13
8
6
3
1
11
4
10
15
12
2
HO
1
12
O
10
15
9
N
13
5
14
H
CH3
7
Morphine (Astramorph)
16
N
H
HO
8
6
CH3
7
Dihydromorphine
Dihydromorphine is slightly stronger than morphine as an analgesic with a nearly identical sideeffect 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
HO
3
11
4
5
14
H
8
6
[O]
N
H
HO
1
11
16
9
13
3
4
10
15
12
O
2
HO
1
7
Dihydromorphine
12
O
10
15
9
13
5
14
H
CH3
H
O
16
8
6
N
CH3
7
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
11
4
12
O
10
15
9
13
5
14
H
H
O
16
8
6
N
CH3
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 semisynthetic 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
CH3O
2
HO
3
1
11
4
12
O
10
15
9
13
5
14
H
H
HO
O
16
8
6
oxidized OH
N
CH3
7
Morphine (Astramorph)
HO- Group not important to activity
H
OH
N
CH3
O
Reduced C=C
Oxycodone (Percocet) -OH group increases potency
(equal to morphine
in potency)
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
CH3O
2
HO
3
1
11
4
12
O
10
15
13
5
14
H
H
HO
O
16
9
8
6
oxidized OH
N
CH3
7
Morphine (Astramorph)
HO- Group not important to activity
H
OH
N
CH3
O
Reduced C=C
Oxycodone (Percocet) -OH group increases potency
(equal to morphine
in potency)
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
2
HO
3
1
11
4
10
15
12
O
O
16
9
13
5
14
H
H
HO
HO- Group is needed for activity
8
6
oxidized OH
N
CH3
7
H
OH
N
CH3
O
Reduced C=C
-OH group increases potency
Morphine (Astramorph)
HO- Group not important to activity
Oxymorphone ((Opana, Numorphan))
(8X more potent than morphine)
Oxymorphone
• Oxymorphone (Opana, Numorphan) or 14Hydroxydihydromorphinone 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
H
N
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
HO
12
10
15
16
11
12
O
14
H
H
8
6
N
13
5
CH3
7
Morphine (Astramorph)
14
H
H
HO
8
6
3
1
11
4
10
15
16
H2
C
9
9
13
2
HO
1
4
11
5
HO
3
1
4
O
2
HO
3
N
12
O
7
More potent than morphine.
14
H
Ph
H
HO
16
9
13
5
C
H2
10
15
8
6
H
C
N
C
H2
CH2
7
Nalorphine
An antagonist at the morphine receptor!!!
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
3
2
HO
1
3
1
11
4
10
15
12
O
13
14
H
H
8
6
H
C
N
C
H2
7
O
16
12
O
9
13
5
14
H
OH
CH2
O
Nalorphine
10
15
12
11
4
11
4
16
9
5
HO
2
HO
N
8
6
H
C
7
Naloxone
C
H2
O
16
9
13
5
CH2
10
15
14
H
OH
8
6
N
C
H2
7
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
3
2
HO
1
3
1
11
4
10
15
12
O
13
14
H
H
8
6
H
C
N
C
H2
7
O
16
12
O
9
13
5
14
H
OH
CH2
O
Nalorphine
10
15
12
11
4
11
4
16
9
5
HO
2
HO
N
8
6
H
C
7
Naloxone
C
H2
O
16
9
13
5
CH2
10
15
14
H
OH
8
6
N
C
H2
7
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.