出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/01/22 02:55:38」(JST)
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| Systematic (IUPAC) name | |
|---|---|
| 4,5-α-epoxy-3-hydroxy-17-methyl morphinan-6-one | |
| Clinical data | |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a682013 |
| Pregnancy cat. | C |
| Legal status | Controlled (S8) (AU) Class A—Non-Clinical use—and Schedule II—Clinical use (UK), DEA Schedule II (USA) |
| Routes | oral, intramuscular, intravenous, subcutaneous, intranasal, rectal, sublingual, transmucosal, buccal, transdermal (experimental) |
| Pharmacokinetic data | |
| Bioavailability | Oral: 30–35%, Intranasal: 52–58%[1] |
| Protein binding | 20% |
| Metabolism | Hepatic |
| Half-life | 2–3 hours[2] |
| Excretion | Renal |
| Identifiers | |
| CAS number | 466-99-9 Y |
| ATC code | N02AA03 |
| PubChem | CID 5284570 |
| DrugBank | DB00327 |
| ChemSpider | 4447624 Y |
| UNII | Q812464R06 Y |
| KEGG | D08047 Y |
| ChEBI | CHEBI:5790 Y |
| ChEMBL | CHEMBL398707 Y |
| Synonyms | dihydromorphinone |
| Chemical data | |
| Formula | C17H19NO3 - HCL |
| Mol. mass | 321.8g/mol |
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| Physical data | |
| Solubility in water | HCl: 333 mg/mL (20 °C) |
| Y (what is this?) (verify) | |
Hydromorphone, a more common synonym for dihydromorphinone (not to be confused by dihydromorphine, which is a different derivative of the morphine family), commonly a hydrochloride (brand names Palladone, Dilaudid, and numerous others) is a very potent centrally acting analgesic drug of the opioid class. It is a derivative of morphine; to be specific, a hydrogenated ketone thereof, and it can be said that hydromorphone is to morphine as hydrocodone is to codeine and, therefore, a semi-synthetic drug. It is in medical terms an opioid analgesic and in legal terms a narcotic. Hydromorphone is commonly used in the hospital setting, mostly intravenously (IV) because its bioavailability orally, rectally, and intranasally is very low. Sublingual administration is usually superior to swallowing for bioavailability and effects.
Hydromorphone is much more soluble in water than morphine and therefore hydromorphone solutions can be produced to deliver the drug in a smaller volume of water. The hydrochloride salt is soluble in three parts of water whereas a gramme of morphine hydrochloride dissolves in 16 ml of water; for all common purposes the pure powder for hospital use can be used to produce solutions of virtually arbitrary concentration. When the powder has appeared on the street, this very small volume of powder needed for a dose means that overdoses are likely for those who mistake it for heroin or other powdered narcotics, especially those that have been cut or stepped on already.
Very small quantities of hydromorphone are detected in assays of opium on rare occasions; it appears to be produced by the plant under circumstances and by processes which are not understood at this time and may include the action of bacteria. A similar process and/or other metabolic processes in the plant may very well be responsible for the very low quantities of hydrocodone also found on rare occasions in opium and alkaloid mixtures derived therefrom; dihydrocodeine, oxymorphol, oxycodone, oxymorphone, metopon and possibly other derivatives of morphine and/or hydromorphone also are found in trace amounts in opium.
Hydromorphone was first synthesized and researched[by whom?] in Germany in 1924; Knoll introduced it to the mass market in 1926 under the brand name Dilaudid,[3] indicating its derivation and degree of similarity to morphine (by way of laudanum)—compare Dicodid (hydrocodone), Dihydrin (dihydrocodeine) and Dinarkon (oxycodone). The brand name Dilaudid is more widely known than the generic term hydromorphone, and because of this, Dilaudid is often used generically to mean any form of hydromorphone.
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Hydromorphone, a semi-synthetic μ-opioid agonist, is a hydrogenated ketone of morphine and shares the pharmacologic properties typical of opioid analgesics. Hydromorphone and related opioids produce their major effects on the central nervous system and gastrointestinal tract. These include analgesia, drowsiness, mental clouding, changes in mood, euphoria or dysphoria, respiratory depression, cough suppression, decreased gastrointestinal motility, nausea, vomiting, increased cerebrospinal fluid pressure, increased biliary pressure, pinpoint constriction of the pupils, increased parasympathetic activity and transient hyperglycemia.
The chemical modification of the morphine molecule to produce hydromorphone results in a drug with higher lipid solubility and ability to cross the blood–brain barrier and, therefore, more rapid and complete central nervous system penetration. The results show hydromorphone to be somewhat faster-acting and about eight to ten times more potent than morphine and about three to five times more potent than heroin on a per milligram basis[citation needed]. The effective morphine to hydromorphone conversion ratio can vary from patient to patient by a significant amount with relative levels of some liver enzymes being the main cause; the normal human range appears to be of 8:1. It is not uncommon, for example, for the 2-mg tablet to have an effect similar to that of 30 mg of morphine sulfate or a similar morphine preparation.
Patients with kidney problems must exercise caution when dosing hydromorphone. In those with renal impairment, the half-life of hydromorphone can increase to as much as 40 hours. This could cause an excess buildup of the drug in the body, and result in fatality. The typical half-life of intravenous hydromorphone is 2.3 hours.[4] Peak plasma levels usually occur between 30 and 60 minutes after oral dosing.[5]
Hydromorphone is metabolized to hydromorphone-3-glucoronide which has no analgesic effects. Like the morphine metabolite, morphine-3-glucoronide, if levels of hm-3-glucoronide build up in ones system, it can produce excitatory neurotoxic effects such as restlessness, myoclonus and hyperalgesia. Metabolite build up can occur in patients with compromised kidney function, or sometimes in older patients.[6]
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CNS depressants, such as other opioids, anesthetics, sedatives, hypnotics, barbiturates, phenothiazines, chloral hydrate, dimenhydrinate and glutethimide may enhance the depressant effects of hydromorphone. MAO inhibitors (including procarbazine), first-generation antihistamines (brompheniramine, promethazine, diphenhydramine, chlorpheniramine), beta-blockers, and alcohol may also enhance the depressant effect of hydromorphone. When combined therapy is contemplated, the dose of one or both agents should be reduced.
Adverse effects of hydromorphone are similar to those of other potent opioid analgesics, such as morphine and heroin. The major hazards of hydromorphone include dose-related respiratory depression and sometimes circulatory depression.[7] More common side effects include light-headedness, dizziness, sedation, itching, constipation, nausea, vomiting, and sweating.[7] Massive overdoses are rarely observed in opioid-tolerant individuals, but, when they occur, they may lead to circulatory system collapse. A particular problem that may occur with hydromorphone is accidental administration in place of morphine due to a mix-up between the similar names, either at the time the prescription is written or when the drug is dispensed. This has led to several deaths and calls for hydromorphone to be distributed in distinctly different packaging from morphine to avoid confusion.[8][9] The effects of overdose can be exaggerated by dose dumping if the medication is taken with alcohol or benzodiazepines.[10]
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Like other opiates, hydromorphone can be used recreationally. Its reinforcing effects are mediated via its strong affinity for the μ-opioid receptor, inducing euphoria, sedation, reduced anxiety, respiratory depression, and other prototypical morphinian effects. Although such effects make it particularly susceptible to abuse, many patients using it for analgesia are able to use it for extended periods of time without developing drug-seeking behavior. Although users of hydromorphone will develop a physical dependence on the drug from extended use, this is not considered true addiction unless they are psychologically dependent on the drug and are compelled to continue taking it against the instructions of the prescribing doctor. In abusers, there can be a strong psychological dependence, thus creating an addiction with repeated use. While physical dependence causes withdrawal, psychological dependence can create strong compulsions to use the drug which can persist for days or weeks after the physical dependence is broken, and has been known to induce anxiety, insomnia, depression, and a range of other persistent mental illnesses. For this reason, psychotherapy is often included in detox programs, sometimes augmented with pharmacological therapies. Despite producing similar effects, hydromorphone is more expensive on the illicit market than heroin is,[citation needed] causing the abuse rates of hydromorphone to be lower than heroin and similar opiates in many areas. Even in the medical community, hydromorphone is quite scarce; opiates like hydrocodone, oxycodone, and fentanyl are typically prescribed more often, due in part to the fact that most doctors are more familiar with those medications and the side effects and interactions thereof[citation needed].
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The short length of action of hydromorphone and other metabolic factors mean that the abstinence syndrome, or withdrawal, is brief but intense. A low dosing user of hydromorphone opting or otherwise forced to quit "cold turkey" can expect the withdrawal syndrome to be at least as intense as morphine if not much more severe. It is compressed into a spike, peaking in 14 to 21 hours and resolving in 36 to 72 hours, provided the user is not taking other longer-acting opioids and has normal liver and kidney function. All of the effects of hydromorphone and its attendant withdrawal syndrome can be significantly lengthened by such factors. Possible but less common is the opposite: some patients require oral doses of hydromorphone as frequently as every 90 minutes, and the withdrawal syndrome can peak in as little as 9 hours. Users taking over 40 milligrams per day can experience painful withdrawal lasting up to two weeks with symptoms including constant shaking, cold sweats, diarrhea, vomiting, muscle pain, body cramps, and insomnia. Even after the withdrawal, long-term users of this drug can experience symptoms for months, even years after, however, those symptoms are usually psychological, including drug cravings, feelings of self-doubt, of "emptiness", moderate depression, mild anxiety, and sometimes slight insomnia, though these symptoms occurring after the initial withdrawal are usually much more prominent in users who use the drug (or other drugs) recreationally, likely because recreational users enjoy the effects that it has on their mood.
Opiate withdrawal is almost never life threatening in and of itself although it can result in behaviors which make a sufferer a danger to themselves and others. For this reason, enduring withdrawal is safer when under the care of a qualified physician. Mild psychological issues can be treated with therapy, while more severe symptoms of psychological distress (incessant crying, suicidal/homicidal thoughts/actions, severe mood swings, etc.) may be treated with antidepressants and/or anxiolytics. If (and only if) a patient is experiencing intense physical withdrawal symptoms such as hyperalgesia, diarrhea, and photosensitivity, doctors may consider prescribing a long acting opiate substitute (such as methadone) and then slowly tapering the down the dose (usually over a period of days or weeks) until the patient is on a low enough dose to discontinue the drug completely. Even after quiting the drug completely, most doctors will recommend that the patient continue to attend therapy and take all other prescribed medicines as instructed until the root cause of the patients drug abuse is identified and addressed, and the recovering addict has developed a healthy support network to prevent relapse.
Hydromorphone is known in various countries around the world by the brand names Hydal, Dimorphone, Sophidone LP, Dilaudid, Hydrostat, Hydromorfan, Hydromorphan, Hymorphan, Laudicon, Opidol, Palladone, Hydromorph Contin and others. An extended-release version of hydromorphone called Palladone was available for a short time in the United States before being voluntarily withdrawn from the market after a July 2005 FDA advisory warned of a high overdose potential when taken with alcohol. As of March 2010, it is still available in the United Kingdom under the brand name Palladone SR, Nepal under the brand name Opidol, and in most other European countries.
There is currently a newer extended-release (once-daily) version of Hydromorphone available (in the United States), marketed under the brand name EXALGO. EXALGO was FDA-approved for marketing in March, 2010. EXALGO is available in 8, 12, 16 and 32 mg controlled-release tablets. According to the distributor,[11] Mallinckrodt Inc., EXALGO does not have the same issue with 'Dose Dumping' as did Palladone SR and "Consuming alcohol does not significantly alter the release of EXALGO into the bloodstream. However, patients should not consume alcohol while taking EXALGO due to CNS depressant effect."[12]
An identical once-daily formulation, under the trade name JURNISTA, has been launched in several countries by Janssen-Cilag. JURNISTA was first launched in Germany in August 2006.
EXALGO and JURNISTA both employ the OROS PUSH-PULL osmotic delivery system designed to release hydromorphone at a controlled rate over an extended period of time allowing for once-daily administration.[11]
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Hydromorphone is most commonly detected via blood and urine testing. Hydromorphone is usually detectable via blood screen for up to 24 hours and via urine screen from 3 to 8 days. Urine screen depends on several factors such as age, frequency of use, weight and duration of use. Extremes: a 20-year-old patient with a normal BMI, who is administered a small dosage (<8 mg per day for <5 days) would screen positive for up to 3 days in 95% of clinical tests. Conversely, patients who are >35 years of age and have been administered a heavy dosage (>16 mg per day) with an overweight to obese BMI tend to test positive up to 7 to 8 days in 85% of clinical cases.
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Another option for prolonged administration is an implantable pump loaded with 90 days' worth of hydromorphone; the device consists of two small titanium tubes arranged into a piston with a semi-permeable membrane on one end which operates the pump by means of osmotic pressure, as the device is placed in areas under the skin which have a salinity gradient. Like morphine—which also has an identical molecular weight—hydromorphone can be dissolved in DMSO and applied externally to allow the body to pull the solution into the bloodstream. Hydromorphone can also be made into an emulsion for IM or SC injection which can continue to release the drug into the system in sufficient quantities to maintain therapeutic concentrations for up to a week.
In the United States, the main drug control agency, the Drug Enforcement Administration, reports an increase in annual aggregate production quotas of hydromorphone from 766 kilograms in 1998 to 3,300 kilograms in 2006, and an increase in prescriptions in this time of 289%, from about 470,000 to 1,830,000.[citation needed]
Like all opioids used for analgesia, hydromorphone is potentially habit-forming and is listed in Schedule II of the United States' Controlled Substances Act of 1970 as well as in similar levels under the drugs laws of practically all other countries and is listed in the Single Convention On Narcotic Drugs.
In 2009, Ohio approved the use of an intramuscular injection of hydromorphone and midazolam as a backup means of carrying out executions when a suitable vein cannot be found for intravenous injection.[13] By 2014, after European manufacturers such as Lundbeck banned U.S. prisons from using their drugs in executions, Ohio used hydromorphone and midazolam to execute Dennis McGuire at the Southern Ohio Correctional Facility; according to witnesses, McGuire appeared to gasp and convulse for roughly 20 minutes before he died.[14]
Hydromorphone is made from morphine either by direct re-arrangement (made by reflux heating of alcoholic or acidic aqueous solution of morphine in the presence of platinum or palladium catalyst) or reduction to dihydromorphine (usually via catalytic hydrogenation), followed by oxidation with benzophenone in presence of potassium tert butoxide or aluminium tert butoxide (Oppenauer oxidation). The 6 ketone group can be replaced with a methylene group via the Wittig reaction to produce 6-Methylenedihydrodesoxymorphine, which is 80× stronger than morphine.[15]
Changing morphine into hydromorphone increases its activity and, therefore, makes hydromorphone about eight times stronger than morphine on a weight basis, all other things being equal.[citation needed] Changed also is lipid solubility, contributing to hydromorphone's having a more rapid onset of action and alterations to the overall absorption, distribution, metabolism, and elimination profile as well as the side effect profile (in general, less nausea and itching) versus that of morphine. The semi-synthetic opiates, of which hydromorphone and its codeine analogue hydrocodone are among the best-known and oldest, include a huge number of drugs of varying strengths and with differences among themselves both subtle and stark, allowing for many different options for treatment.
Hydromorphone is made from morphine via catalytic hydrogenation and is also produced in trace amounts by human and other mammalian metabolism of morphine and occasionally appears in assays of opium latex in very small quantities, apparently forming in the plant in an unknown percentage of cases under poorly understood conditions.
Some bacteria have been shown to be able to turn morphine into closely related drugs including hydromorphone and dihydromorphine among others. The bacterium Pseudomonas putida serotype M10 produces a naturally occurring NADH-dependent morphinone reductase that can work on unsaturated 7,8 bonds, with result that, when these bacteria are living in an aqueous solution containing morphine, significant amounts of hydromorphone form, as it is an intermediary metabolite in this process; the same goes for codeine being turned into hydrocodone.[16]
The process gave rise to various concentrations of hydromorphone, dihydromorphine, hydromorphinol, and oxymorphone during the experiments. Three paths were found: from morphine to hydromorphone with dihydromorphine as the penultimate step, from morphine to hydromorphone with morphinone as the penultimate step, and from morphine to hydromorphinol to hydromorphone.
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| 関連記事 | 「hydrochloride」「hydromorphone」 |