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Morphine O HO H N H CH 3 HO 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 M orphine (Astram orph) H O - G roup isneeded foractivity H O -G roup notim portantto activity
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Morphine
O
HOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Morphine (Astramorph)
HO- Group is needed for activity
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?
• http://www.thirteen.org/closetohome/animation/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
There are three known types of receptors for opioid analgesics: , , and .
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
O
HOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16 O
AcOH
NH
CH3
AcO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Morphine (Astramorph)Heroin (Diamorphine)(2X as potent as morphine)(Conversion of two -OH groups to -OAcfacilitates crossing of the BBB)
Easily enzymatically hydrolyzed to AcOH and HO-ArHO- Group is needed for activity
HO- Group not important to activity
Codeine
O
HOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Morphine (Astramorph)
HO- Group is needed for activity
HO- Group not important to activity
O
HOH
NH
CH3
CH3O
Codeine (5X LESS potent than morphine)
Inefficiently converted to HO group in the liver
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
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.
O
HOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Morphine (Astramorph)
O
HOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Dihydromorphine
H2 / Pd
However, this led to a cmpd with improved activity
O
HOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Dihydromorphine
O
H
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Hydromorphone(7X more potent than morphine)
O
[O]
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
O
H
NH
CH3
CH3O1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Hydrocodone(much more potent than codeine)
O
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
O
HOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Morphine (Astramorph)
HO- Group is needed for activity
HO- Group not important to activity
O
OOH
NH
CH3
CH3O
-OH group increases potencyOxycodone (Percocet)(equal to morphine in potency)
CH3 group reduces potency
Reduced C=C
oxidized OH
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.'
O
HOH
NH
CH3
HO1
23
4
5
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7
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9
10
11
12
1314
15 16
Morphine (Astramorph)
HO- Group is needed for activity
HO- Group not important to activity
O
OOH
NH
CH3
CH3O
-OH group increases potencyOxycodone (Percocet)(equal to morphine in potency)
CH3 group reduces potency
Reduced C=C
oxidized OH
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
O
HOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Morphine (Astramorph)
HO- Group is needed for activity
HO- Group not important to activity
O
OOH
NH
CH3
HO
-OH group increases potency
Oxymorphone ((Opana, Numorphan))(8X more potent than morphine)
Reduced C=C
oxidized OH
HO- Group is needed for activity
Oxymorphone
• Oxymorphone (Opana, Numorphan) or 14-Hydroxydihydromorphinone 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
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.
O
CH3O
NH
CH3
CH3O
Changing substitutents on nitrogen can either improve agonist activity…or create
antagonists!
O
HOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Morphine (Astramorph)
O
HOH
NH
CH2
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
H2C
Ph
More potent than morphine.
O
HOH
NH
CH2
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
HC
NalorphineAn antagonist at the morphine receptor!!!
CH2
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
O
OH
NH
CH2
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
HC
Naloxone
CH2O
O
HOH
NH
CH2
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
HC
Nalorphine
CH2
O
OH
NH
CH2
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Naltrexone
O
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
• 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.
O
OH
NH
CH2
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
HC
Naloxone
CH2O
O
HOH
NH
CH2
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
HC
Nalorphine
CH2
O
OH
NH
CH2
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Naltrexone
O
