morphine. 3d structure of morphine the ‘t-shape’ of this molecule is difficult to visualize from...
TRANSCRIPT
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
3D Structure of Morphine
• The ‘T-shape’ of this molecule is difficult to visualize from the 2D representation
• http://www.3dchem.com/molecules.asp?ID=186#
O
HOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
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, constipation, 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
• http://thebrain.mcgill.ca/flash/d/d_03/d_03_cr/d_03_cr_que/d_03_cr_que.html
There are three known types of receptors for opioid analgesics: , , and .
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 mu Receptor
• The main endogenous ligands for the mu receptor are the endorphins, peptides having 31 amino acids, with Tyr at the N-terminal end (note that the phenolic -OH group of tyrosine resembles that of morphine)
Tyrosine and Morphine
O
HOH
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
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
• Activation of the δ-Opioid receptor produces some analgesia, although not as much as activation of the mu receptor
• The natural ligands for this receptor are the enkephalins, pentapeptides with the structures: Tyr-Gly-Gly-Phe-Met or Tyr-Gly-Gly-Phe-Leu
• There is a recent interest in using delta agonists as antidepressants.
Overview: Opioid Receptors
• κ-Opioid receptors are also involved with analgesia, but activation also produces marked nausea and dysphoria (sadness, irritability, anxiety)
• The main endogenous ligands of the k receptor are the dynorphins, another class of endogenous peptide
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).
Commercial Products Containing Codeine
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.
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
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 name, "Dilaudid”.
• Another extended-release version called Hydromorph Contin, manufactured as controlled release capsules, continues to be produced.
O
H
NH
CH3
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Hydromorphone(Dilaudid)
(7X more potent than morphine)
O
Oxidized -OHReduced C=C
Hydromorphone
• Compared to morphine and heroin, hydromorphone has superior solubility and speed of onset and less troublesome side effect and dependence liability profile.
• 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
• Hydrocodone (marketed as Vicodin, Lortab, Dicodin, others)
• Usually sold mixed with other milder analgesics, such as acetaminophen (Tylenol, paracetamol)
• Such combination products are more effective analgesics and also limit the potential for abuse.
O
H
NH
CH3
MeO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
Hydrocodone(Vicodin, Lortab, Dicodin)
(7X more potent than morphine)
O
Oxidized -OHReduced C=C
Methylated OH, thus belongs to codein class
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 potency
Oxycodone (Percocet = mix with acetaminophen)
(Percodan = mix with aspirin)(OxyContin = with binders, continuous release)
(OxyNorm = immediate release, inert fillers)(equal to morphine in potency)
(orally bioavailable)
CH3 group reduces potency
Reduced C=C
oxidized OH
Oxycodone: Uses
• Percocet tablets (Oxycodone with acetaminophen) are routinely prescribed for post-operative pain control.
• 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
• Unlike Percocet, whose potential for abuse is limited by the presence of acetaminophen (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 (Numorphan = injectable, suppository)
Opana = tablet, OpanaER = extended release(8X more potent than morphine)
(poorly orally bioavailable, necessitating the inclusion of large amounts
of drug in Opana tablets)
Reduced C=C
oxidized OH
HO- Group is needed for activity
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
• 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.
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
HC
NalorphineAn antagonist at the morphine receptor!!!
CH2
N-allyl group changes biological activity from agonist to antagonist.
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.
O
OH
NH
CH2
HO1
23
4
5
6
7
8
9
10
11
12
1314
15 16
HC
Naloxone
CH2O
Naltrexone
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
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.