Oxymorphone
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| Non-proprietary name | Oxymorphone | ||||||||||||||||||
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| Molecular formula | C 17 H 19 NO 4 | ||||||||||||||||||
| Brief description |
whitish, odorless powder (hydrochloride) |
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| Mechanism of action |
Supraspinal analgesia by binding to µ-opioid receptors |
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| Molar mass | 301.34 g · mol -1 | ||||||||||||||||||
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| pK s value |
8.17 |
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | |||||||||||||||||||
Oxymorphone is a strong pain reliever drug ( analgesic ). The substance is a semi-synthetically produced opioid and is about ten times as powerful as morphine .
Oxymorphone is used in acute and long-term pain therapy for severe to very severe pain. Oxymorphone was discovered by MJ Lewenstein and U. Weiss and on 10 September 1957 under the number US 2,806,033 in the United States patent and the 1995 Food and Drug Administration FDA approved.
Dosage forms
Finished medicinal products are only approved in the USA; oral (tablets) as well as parenteral administration (injection solution) are possible. The hydrochloride of oxymorphone is used medicinally (1 mg oxymorphone hydrochloride corresponds to 0.89 mg oxymorphone base ) with 5 mg and 10 mg in fast and 5 mg to 40 mg in slowed-release tablets. The latter release the active ingredient evenly over about twelve hours.
In Germany, the drug falls under Annex II of the BtMG , so it is marketable but not prescribable.
Medical use
Oxymorphone is used to treat severe to very severe pain in acute and long-term pain therapy. It is also administered intravenously as an anesthetic during surgical interventions . Like all other opioids, oxymorphone has primary addiction potential. In addition to its strong analgesic effect, it also has a strong euphoric and calming effect.
Retarded tablets are used in the treatment of chronic pain because the active ingredient is released evenly for about 12 hours. As a result, the patient only has to take a defined dose twice a day. Oxymorphone is suitable for treating both tumor pain and non-tumor pain, such as chronic back pain .
Non-retarded oxymorphone is used as a fast-acting drug to treat so-called breakthrough pain in patients who are treated with the retard form. Like other opioids, oxymorphone should only be used when non-opioid analgesics or weaker opioids are no longer effective. Like morphine, levomethadone and hydromorphone , it is also used in veterinary medicine to treat pain.
Intravenous application causes pain relief within 10–60 seconds. After subcutaneous or intramuscular administration, analgesia occurs after about 5–8 minutes. The non-retarded tablet form brings about freedom from pain after about 30 minutes and the retard form after about 60 minutes. The duration of analgesia is around 3–4 hours for the non-retarded forms and around 12 hours for the retarded form. Oxymorphone has an analgesic potency of 10: 1–1.5 mg of oxymorphone, 10 mg of morphine are equipotent.
Physical Properties
Oxymorphone hydrochloride is an odorless, crystalline white powder. If it is exposed to direct light for longer, its white color becomes dark. However, this effect has no effect on analgesic potency. One gram of oxymorphone hydrochloride dissolves in 4 ml of water. It is sparingly soluble in ethanol and diethyl ether . The injection solution has a pH of 2.7-4.5.
structure
Oxymorphone is a morphine - derivative ; it is derived from the reference opioid morphine. The oxymorphone molecule has - like morphine - five rings, whereby the C7-C8 double bond of morphine (ring C) is omitted in the case of oxymorphone.
Nomenclature of the rings :
- Ring A, aromatic ring
- Ring B, cyclohexane ring
- Ring C, cyclohexane ring
- Ring D, piperidine ring
- Ring E, tetrahydrofuran ring
From a chemical point of view, oxymorphone is, like its analogue hydromorphone , a morphine ketone. Like morphine, it has a hydroxyl group on the 3rd carbon atom. The difference in the molecular structure is that oxymorphone has an additional OH group on the 14th carbon atom and a keto group on the 6th carbon atom. Furthermore, the double bond between the 7th and 8th carbon atom is reduced compared to morphine. These modifications to the morphine backbone lead to an increase in the analgesic potency from 1 for morphine to 10 for the resulting oxymorphone. As with morphine and hydromorphone, a methyl group is attached to the nitrogen of the piperidine ring.
Manufacturing
Oxymorphone is produced on a large scale from the opiate thebaine . Since this occurs in only about 0.2-0.5% in the black opium poppy (Papaver somniferum) , thebaine is extracted from the oriental opium poppy (Papaver orientale) because it contains about 3% of it.
Oxymorphone can also be synthesized from morphine and oxycodone. It is an active metabolite in the metabolism of the opioid oxycodone. Here, the oxygen is demethylated at the 3rd carbon atom of the oxycodone. However, oxymorphone is only present in low concentrations in the blood after ingestion of oxycodone. Important derivatives of oxymorphone are the opioid antagonists naloxone and naltrexone .
Pharmacodynamics
Analgesic effect
Oxymorphone acts like endogenous opioid peptides ( endorphins and enkephalins ) in the central nervous system. The effect is based on a binding to specific receptors, the opioid receptors , which occur both spinally (in the spinal cord) and supraspinally (in the brain). The difference to the endogenous opioids is that the effects of exogenous opioids, such as. B. morphine and oxymorphone, are many times stronger.
The µ-opioid receptors, but also the κ-opioid receptors, are primarily responsible for analgesia. Oxymorphone has a high receptor affinity (good fit to the receptor) as well as a high intrinsic activity at the µ-opioid receptor, which causes the high analgesic potency. By binding to the opioid receptors, oxymorphone, like other opioids, changes the conformation of the receptor, including the G proteins coupled to it . This results in an opening of postsynaptic potassium channels ( hyperpolarization of the cell membrane ) and a closure of the presynaptic calcium channels (lower release of exciting transmitters such as substance P and glutamate) with an inhibition of synaptic conduction of excitation.
Other effects / side effects
Like morphine , oxymorphone causes nausea , vomiting , constipation , sedation , euphoria and / or dysphoria , respiratory depression , muscle rigidity, inhibition of the cough center, miosis , hypotension , bradycardia , itchy skin and physical and psychological dependence . An overdose can be antagonized by intravenous administration of the antidote naloxone .
Pharmacokinetics
absorption
Oxymorphone is absorbed very well both subcutaneously and intramuscularly. The oral bioavailability is only about 10%, since oxymorphone is subject to a relatively high first-pass effect after oral administration . The poor oral bioavailability requires correspondingly high doses despite the high therapeutic potency.
metabolism
In spite of its structural similarity to morphine, oxymorphone is, unlike morphine, mainly metabolised by uridine diphosphate glucuronosyl transferase (UGT) , an enzyme produced in the liver. Like the analogues oxycodone and hydromorphone, it does not form any active metabolites. The main metabolite is conjugated oxymorphone, i. This means that about 45% of the metabolite oxymorphone-3-glucuronide is formed by coupling glucuronide to the phenolic OH group of the third carbon atom, followed by 6 α -oxymorphol (<5%), which is produced by reducing the keto -Group on the 6th carbon atom is caused. These metabolites are excreted through the kidneys. In addition, about 10% free oxymorphone is excreted in the urine.
Interactions
Oxymorphone increases the effects of substances that affect the central nervous system. These include alcohol, barbiturates, sedatives, anxiolytics and neuroleptics.
Others
Etherification of the 14-hydroxyl group increases the analgesic potency sharply. 14-methoxymorphone is up to 40 times more potent than oxymorphone and, depending on the species and test method, shows 130-800 times the potency of morphine in animal experiments . Introduction of a 14-phenylpropoxy group and an additional 5-methyl group leads to the 14 β- phenylpropoxymetopon, an extremely potent analgesic that is up to 24,000 times more potent than morphine and 2 times more potent than dihydroetorphine.
literature
- Mellar Davis, Paul Glare, Janet Hardy: Opioids in cancer Pain. Oxford University Press, 2005, ISBN 0-19-852943-0
- Freye: Opioids in Medicine. Springer, 6th edition, ISBN 3-540-40812-6
- Kurzweil, Pittrow: From Opium Poppy to Synthetic Opiates. Shaker Verlag, 1995, ISBN 3-8265-5080-3
- Helmut Schmidhammer, Mariana Spetea: Development of 5-Substituted N-Methylmorphinan-6-ones as Potent Opioid Analgesics with Improved Side-Effect Profile . In: International Journal of Medicinal Chemistry . tape 2012 , June 2012, p. 1–10 , doi : 10.1155 / 2012/208039 .
Individual evidence
- ↑ Opana Oxymorhone Hydrochloride Injection ( Memento of 29 July 2012 at the Internet Archive ).
- ↑ a b c Entry on oxymorphone in the ChemIDplus database of the United States National Library of Medicine (NLM)
- ↑ a b entry on oxymorphone. In: Römpp Online . Georg Thieme Verlag, accessed on July 10, 2011.
- ↑ a b Data sheet Oxymorphone solution 1.0 mg / mL in methanol from Sigma-Aldrich , accessed on August 26, 2016 ( PDF ).
- ↑ Patent US2806033 : Morphine derivative.
- ↑ Johannes Schütz, Mariana Spetea, Martin Koch, Mario D. Aceto, Louis S. Harris, Andrew Coop, Helmut Schmidhammer: Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 20. 14-Phenylpropoxymetopon: An Extremely Powerful Analgesic . In: Journal of Medicinal Chemistry . tape 46 , no. 19 , August 2003, p. 4182-4187 , doi : 10.1021 / jm030878b .
