Morphine

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of morphine
General
Surname Morphine
other names
  • (5 R , 6 S , 9 R , 13 S , 14 R ) -4,5- epoxy- N -methylmorphinan-7-en-3,6-diol ( IUPAC )
  • (-) - morphine
Molecular formula C 17 H 19 NO 3
External identifiers / databases
CAS number
  • 57-27-2 (free base)
  • 52-26-6 ( hydrochloride )
  • 6211-15-0 (sulfate salt pentahydrate)
PubChem 5288826
DrugBank DB00295
Wikidata Q81225
Drug information
ATC code

N02 AA01

Drug class

Opioid - analgesic

properties
Molar mass 285.34 g · mol -1
Physical state

Solid

Melting point

253-254 ° C

pK s value

8.21 (25 ° C)

solubility

H 2 O: 40 g l −1 (20 ° C, as hydrochloride)

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
07 - Warning

Caution

H and P phrases H: 302
P: no P-phrases
Toxicological data

335 mg kg −1 ( LD 50 ,  rat ,  oral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Morphine or morphine is a main alkaloid of opium and is one of the opiates . It belongs to the group of strong-acting opioids of stage III in the WHO stage scheme (classification of pain therapy) and is approved as a pain reliever for severe and severe pain . Morphine is the first alkaloid to be isolated in its pure form . It is a drug and is subject to narcotics regulations in accordance with the standard convention on narcotics .

History and naming

Morphine was first isolated from opium in 1804 by the German pharmacist's assistant Friedrich Wilhelm Adam Sertürner in Paderborn ; the correct sum formula was only determined in 1848 by Auguste Laurent . Sertürner initially called the alkaline substance , which is soporific (narcotic) in animal experiments, morphine , later the term morphine , which is predominant in technical terms today, came up, both of which are derived from Morpheus , the name of the Greek god of dreams . A further 77 years passed before the final structural formula was drawn up. Morphine was discovered by Armand Séguin and Bernard Courtois before 1804 , but initially only presented at their own institute and only published in 1816.

Occurrence and synthesis

Opium poppy, Papaver somniferum .
Milky juice of Papaver somniferum obtained by scratching immature seed pods provides opium when dried.

Morphine is made from opium, i.e. H. obtained from the dried milky sap of the opium poppy ( Papaver somniferum ); the morphine content in opium is around twelve percent, but fluctuates significantly depending on the origin and pretreatment of the milky juice.

The biosynthesis of morphine - and all other naturally occurring opium alkaloids - takes place from the isoquinoline alkaloid reticulin .

The total synthesis , which Marshall D. Gates and Gilg Tschudi succeeded in 1956 , is complex and delivers only low yields - in the case of the Fuchs synthesis it is around ten percent. The starting materials for this are phenylalanine and 4-hydroxyphenyl acetaldehyde . It is norcoclaurine an important intermediate. The morphinan alkaloids, to which morphine belongs, are then formed via reticulin.

The Rice synthesis achieves yields of 30% over 14 steps:

Rice morphine synthesis

Extraction

A calcium chloride solution is added to the aqueous opium extract . After the calcium methacrylate has been separated off , the solution is evaporated, with morphine and codeine separating out as hydrochlorides. The hydrochlorides are again brought into an aqueous solution, from which the morphine can be precipitated by adding ammonia .

Heroin is a derivative of morphine: 3,6-diacetylmorphine. It is obtained from morphine through a chemical reaction ( acetylation ).

Chemical properties

Morphine is sparingly soluble in water (1: 5000), slightly more soluble in hot water, soluble in ethanol (1: 250), sparingly soluble in ether (1: 7500), in carbon tetrachloride (1: 6400), slightly soluble in alkaline Water.

Morphine is unstable in a strongly acidic and in an alkaline environment. Strong acids rearrange it to apomorphine .

Due to the poor solubility of morphine in water, mainly sulfate (e.g. as morphine sulfate tablets, MST ) and the hydrochloride of morphine are used medicinally . H. about 300 times, better than that of the pure base. After the discovery of the analgesic effect of morphine, the poor solubility of morphine posed a serious problem for a long time, since an aqueous solution is required for injection purposes.

Analytics

In the skin of the cane toad ( Bufo marinus L.) a considerable amount of morphine was found.

For the reliable qualitative and quantitative determination of morphine in different test items such as B. urine , blood , blood serum , blood plasma , hair or plant material are adequate sample preparation methods such. B. Extraction procedure or SPE required. The extracts obtained can by using the coupling of chromatographic separation processes such. B. gas chromatography or HPLC can be analyzed with mass spectrometry . The procedures are also suitable for use in special forensic issues such as B. the influence of the consumption of poppy-containing products.

pharmacology

Pharmacodynamics

Morphine acts centrally as an agonist on opioid receptors . This prevents the transmission of pain and reduces the patient's perception of pain. The focus is on the activation of the μ-receptors. Morphine has a lower affinity for κ receptors. Presynaptically, morphine leads, mediated via the opioid receptor G-protein, to a decrease in the cellular calcium influx and thus to hyperpolarization. Post-synaptically there is a G-protein-mediated activation of potassium channels with subsequent potassium outflow. The potassium outflow also leads to hyperpolarization and effective prevention of pain transmission.

Pharmacokinetics

Morphine is well resorbed after oral administration, but bioavailability is relatively low at 20–40% due to the high first-pass effect . After intravenous or intramuscular administration, on the other hand, bioavailability is almost 100%, with maximum analgesia being reached after 20 minutes with intravenous administration, after 30-60 minutes with intramuscular administration and after 45-90 minutes with subcutaneous administration. The duration of action after intravenous or intramuscular administration is four to five hours and is usually and naturally extended significantly (to 8 to 24 hours) with the (oral) administration of retarded dosage forms (retard capsules or retard tablets). The analgesic duration of action with rectal administration of a suppository (10–30 mg) is about four hours. Metabolites are e.g. B. the inactive morphine-3-glucuronide and the active (analgesic) morphine-6-glucuronide, which shows a significantly longer duration of action than the morphine itself. Other metabolites include a. Normorphine and codeine . Elimination takes place mainly renally using hydrophilic conjugates. Morphine does not have a so-called ceiling effect .

Therapeutic use

A local response to intravenous administration of morphine, triggered by the release of histamine in the veins.
Two immediate-release capsules of morphine sulfate (5 mg and 10 mg).

application areas

Pain therapy

Morphine is used to treat severe and severe acute and chronic pain and is the reference substance with an analgesic equivalence of the single dose of 1 for information on effectiveness in pain .

Treatment with morphine or other opioids for chronic pain should be based on the WHO grading scheme, i.e. H. according to a graduated plan: if possible, oral administration of a morphine preparation with a long-lasting effect in individually adapted dosage (single doses of around 2.5 to 30 mg at the beginning of treatment in adults) and at fixed time intervals. Since morphine alone does not completely eliminate all types of pain, a combination with other drugs is necessary in these cases. So-called coanalgesics and adjuvant therapeutic agents (including antidepressants , bisphosphonates , corticosteroids , neuroleptics ) support the effect of morphine. Other medicines reduce possible side effects, such as laxatives , which are used to counteract the frequent indolence of the bowel and prevent constipation.

Acute peaks of pain can require the additional administration of a fast-acting morphine.

With longer treatment, even with appropriate doses of morphine or other opioids, as with various other drugs, physical habituation arises. An opioid withdrawal , therefore, upon termination of the pain has tapered off effected (dose reduction per week by 30%). When using morphine in the dying phase to relieve breathlessness or pain, this aspect is negligible. Highly effective drugs such as morphine are not used for active euthanasia , but for the treatment of complaints that can occur in the dying phase. The medical obligation to provide adequate pain relief includes the use of such medications when indicated.

Symptomatic therapy for shortness of breath, cough and anxiety

Since morphine also has a dampening effect on the respiratory center , it is used in particular in palliative medicine for the symptomatic treatment of shortness of breath. It reduces the respiratory drive, thus lowering the patient's stress level, breathing becomes calmer and more economical by reducing the dead space ventilation caused by high-frequency but shallow breathing . Morphine has not been approved for this therapy, so it is carried out in off-label use . Morphine suppresses the urge to cough ( antitussive effect); Another opium alkaloid, codeine (from a chemical point of view methylmorphine), is therefore used as an active ingredient against coughs. In acute medicine, morphine is also used to alleviate symptoms in acute myocardial infarction (see there) in order to stop the vicious circle of pain, shortness of breath, fear, psychological and physical stress with an increase in the heart's oxygen consumption. In addition, by dilating the venous capacity vessels, morphine lowers the preload and, through slight arterial dilatation, also the afterload of the heart. Morphine also causes increased histamine release , which can lower blood pressure.

Substitution treatment

Morphine is also used in the substitution treatment (maintenance therapy) of adults with opioid dependence. The administration takes place within the scope of medical and comprehensive psychosocial measures with an orally effective preparation that releases the active ingredient with a delay, so that a long-lasting effect (delayed effect) results.

In Germany, morphine was launched in this indication in April 2015 (trade name Substitol ). The registration study was carried out from 2008 to 2010 at centers in Switzerland and Germany; DL - methadone was used as a comparison substance . In Austria, retarded oral morphine has been used in substitution treatment for a long time. Oral retarded morphine ( Sevre-Long ) has been approved in Switzerland since 2013.

Side effects

Bottle for morphine hydrochloride solution, around 1900

As with all potent opioid analgesics, constipation (constipation), nausea, and vomiting may occur. It can also lead to drowsiness , mood changes and changes in the hormonal system and the autonomic nervous system . Overdosing can lead to miosis , hypoventilation and low blood pressure .

At the beginning of morphine therapy, nausea and vomiting can occur, as morphine acts directly on the vomiting center in the brain stem . After a while, this side effect usually subsides. Only the constipation does not require any habituation. With long-term use, a laxative should therefore be prescribed.

In principle, the ability to drive is considered restricted. A driving ban is to be pronounced, especially in the case of a new appointment or a change in therapy, however, after an appropriate setting with retarded opioids, the ability to drive does not seem to be significantly impaired.

Because of its euphoric effect, morphine is ascribed a high potential for addiction, especially when using rapidly flowing forms of medication (drops, non- retarded tablets, injection solutions ). Treatment of pain with opioids does not generally lead to the development of addiction. However, tolerance may develop which, if symptoms recur, require further dose adjustment.

Furthermore, with morphine (compared to fentanyl or sufentanil, for example) there is a risk of histamine release.

Overdose

The main danger of overdosing with morphine and other opioids is depression of the respiratory center ( respiratory depression ), which can lead to unconsciousness and ultimately to respiratory failure. Overdosage with morphine (and other opioids) may show up. a. deepened breathing with reduced frequency with only a few breaths per minute. For patients who are still responsive and have such reduced breathing, the repeated request to breathe regularly can be life-saving (so-called command breathing). If morphine poisoning is suspected , an emergency doctor must be called in, who is the most important measure to restore and maintain breathing. Morphine intoxication can be treated by administering naloxone (or the tartrate of 3-hydroxy-nor-allylmorphine with the preparation Lorfan ). Naloxone acts as a competitive antagonist , displaces morphine from the opioid receptors and thereby neutralizes its effect. The half-life of naloxone is well below that of morphine, so that although the patient is briefly symptom-free, after the effect of the naloxone has subsided, there is a risk of respiratory arrest due to the opiate overdose. If too much naloxone is given, a morphine dependent patient can go straight from the overdose to withdrawal .

The fatal dose of morphine for an average adult (without tolerance) is 200 mg for oral intake (up to 1500 mg for people with tolerance) and 100 mg for parenteral administration. However - especially with intravenous administration - significantly lower doses can be life-threatening. Two to three drops of tincture of opium can be fatal for infants.

A study published in 2013 showed that between 1999 and 2012 there was a four-fold increase in opioid-induced deaths from pain management overdose in the United States. In parallel, opioid prescriptions quadrupled as a result of efforts to improve pain management. Factors ranging from opioid abuse to overdosing include: a. on the part of the patient, a previously known tendency to abuse drugs or alcohol, on the part of the doctor, a long-term prescription of opioids that is too uncritical after surgery or in the case of non-tumor-related pain.

If opioids are used correctly, however, not a single death has been described in the literature; Opioids are considered safer in pain therapy compared to other analgesics such as ASA, metamizole, COX inhibitors and paracetamol.

Trade names and dosage forms

Morphine packaging with syringes from the 1950s

Morphine is used medicinally in the form of morphine sulfate - pentahydrate or as morphine hydrochloride - trihydrate .

Finished medicinal products
Capros (D), Compensan (A), Kapanol (D, CH), M-beta (D), M-long (D), Morixon (D), Morphanton (D), MSI (D), MSI Mundipharma Morphine Merck , MSR (D), MSR Mundipharma, MST (D), Mundidol (A), M-retard (CH), M-Stada (D), MST-Continus (D, CH), MST-Mundipharma, MST-Retardgranulat, Painbreak (D), Sevredol (D, CH), Sevre-Long (CH), Substitol (A, D), Vendal (A), and others.

The dosage forms are fast- and slow-releasing drugs in the form of capsules, tablets, effervescent tablets, drops, granules, suppositories (such as MSR : abbreviation for "morphine sulfate rectal") and injection solutions ( MSI = morphine sulfate per injection ). The colloquial term “morphine patches” refers to transdermal patches with other opioids ( fentanyl , buprenorphine ).

See also

literature

  • Waltraud Stammel, Helmut Thomas: Endogenous alkaloids in mammals. A contribution to the pharmacology of the body's own neurotoxins. Naturwissenschaftliche Rundschau (2007) 60 (3), pp. 117–124.
  • Heinz Lüllmann, Klaus Mohr, Hein: Pharmacology and Toxicology . Thieme, Stuttgart / New York 2006, ISBN 3-13-368516-3 .
  • Thomas Karow, Ruth Lang-Roth: General and special pharmacology and toxicology . 17th edition. Thomas Karow Verlag, Pulheim 2009, ISBN 978-1-00-002009-0 .

Web links

Commons : Morphine  - Collection of pictures, videos and audio files
Wiktionary: Morphine  - explanations of meanings, word origins, synonyms, translations
Wiktionary: Morphine  - explanations of meanings, word origins, synonyms, translations

Individual evidence

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  40. ↑ Medical abbreviations on the Internet: MSI. Med-Serv