Codeine
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| Surname | Codeine | |||||||||||||||||||||
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| Molecular formula | C 18 H 21 NO 3 | |||||||||||||||||||||
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| Molar mass | 299.36 g · mol -1 | |||||||||||||||||||||
| Physical state |
Solid |
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| density |
1.32 g cm −3 |
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| Melting point |
154–156 ° C (codeine monohydrate) |
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| pK s value |
8.21 (25 ° C) |
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | ||||||||||||||||||||||
Codeine or codeine (Latin Codeinum ; from ancient Greek κώδεια kốdeia , German ' Mohnkopf , Köpfchen or capsule of the poppy plant' , Latin codia ) is a naturally occurring chemical compound from the group of opiates . Codeine is used as a medicinal substance in medicine . It is used as a pain reliever mostly in combination with paracetamol and as a cough suppressant .
Codeine was isolated from opium by Pierre Jean Robiquet in 1832 . The first German patent for the economic preparation of methylmorphine (codeine) was registered by Albert Knoll in 1886 and granted in 1887.
Occurrence
The proportion of codeine in opium juice , the natural source of this substance, is 0.3–3%.
Chemical and physical properties
Codeine is the 3-monomethyl ether of morphine . The solubility in water for codeine monohydrate is 8 mg / ml at 20 ° C, 17 mg / ml at 80 ° C, for codeine hydrochloride 50 mg / ml at 20 ° C, 1000 mg / ml at 100 ° C, for codeine sulfate 35 mg / ml at 20 ° C, 150 mg / ml at 80 ° C and for codeine phosphate hemihydrate 400 mg / ml.
Analytics
Reliable qualitative and quantitative detection in pharmaceutical preparations and various body fluids such as blood serum , urine , saliva and others is possible after suitable sample preparation by coupling gas chromatography or HPLC with mass spectrometry .
Pharmacological properties
Codeine is a prodrug ; it develops its analgesic effect through the action of the active metabolite morphine , about 10% of which is produced in the liver by demethylation with the participation of the enzyme CYP2D6 . Codeine itself also has an effect by binding to opioid receptors (μ-receptors), but its affinity for the receptor is low. When 400 mg of codeine is taken, the maximum metabolism is reached, since the corresponding enzyme capacity of CYP2D6 is exhausted. As a result , the effect no longer increases , but only lasts longer. Regarding the antitussive effect, codeine is said to have the same effectiveness as morphine.
Due to a genetic CYP2D6 polymorphism , the effects of codeine can vary in strength : About 10% of Americans with white skin can only metabolize codeine slowly, so that the effect is less pronounced due to insufficient morphine formation. In contrast to this, rapid metabolisers, which make up an estimated 1–5.5% of the white US population, can experience elevated plasma morphine concentrations with the risk of morphine-related side effects, including intoxication.
Codeine has a pain relieving effect of four to six hours. About 10% of it is excreted unchanged and otherwise in the form of morphine and codeine conjugates via the kidneys (renally).
Clinical information
Like dihydrocodeine, codeine is approved for the symptomatic treatment of irritable cough (suppression of the cough stimulus in the case of an unproductive cough). The maximum daily dose is 184 mg for adults. The effectiveness of low prescription-free doses available in the US has not been proven. The analgesic potency of the single dose compared to morphine is around 0.1. The cough suppressant effectiveness of codeine in COPD is questionable.
In combination with paracetamol , acetylsalicylic acid, or diclofenac , codeine is used as a pain reliever (in doses of around 30 to 100 mg in adults) to treat moderate to severe pain.
Until 1999, codeine was a regular substitute for heroin addiction in Germany , which doctors preferred for reasons of compliance and the relative simplicity of initiating and overcoming withdrawal syndrome . It has been supplanted by substances with longer half-lives such as methadone .
Side effects
The most common adverse drug effects from codeine are fatigue, nausea, vomiting, and constipation . Codeine has a potential for dependence .
Codeine and its metabolite, morphine, are excreted in breast milk. In 2007, the Federal Institute for Drugs and Medical Devices (BfArM) therefore ordered a warning to be included in the product information texts, to watch out for side effects such as poor drinking, sleepiness ( somnolence ) and lethargy in infants and to interrupt breastfeeding when repeatedly taking codeine-containing preparations. This was preceded by a case report of the death of an infant who died of a breastfeeding-acquired morphine overdose after his mother took codeine-containing pain relievers.
In March 2013, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) issued a warning that codeine should not be given as a pain reliever in children after tonsillectomy or adenectomy . Serious and sometimes fatal cases of respiratory depression have been reported. In some affected children it could be proven that they were “ultra-fast metabolisers” due to a genetic variation of the enzyme cytochrome P450 2D6 , whereby the administered codeine was converted very quickly into the much more effective morphine. In 2017, the FDA further restricted the use of codeine so that the substance could no longer be given to children under the age of twelve in the United States. Breastfeeding mothers are cautioned against taking codeine.
Pharmaceutical information
In addition to codeine monohydrate, codeine phosphate hemihydrate is also used medicinally. Because of the flexible dosage, liquid presentations such as drops or juice are common for coughing, but tablets or capsules can also be used. Codeine has a plasma half-life of around 2 to 4 hours, while prolonged- release drugs offer a longer duration of action . The effect of codein is retarded in liquid dosage forms by binding to a cation exchanger (codeine poly (styrene, divinylbenzene) sulfonate).
Narcotics regulations
Germany
In Germany, the Narcotics Act classifies codeine as a marketable and prescribable narcotic, and handling it without a permit or prescription is generally a criminal offense. Low doses or quantities (ie "... without another substance from Annexes I to III up to 2.5 per cent or up to 100 mg of codeine per divided form, calculated as a base") are exempt from narcotics regulations as long as they are not applicable narcotics or alcohol addicts.
Austria
The use of codeine requires a prescription and is regulated by the Narcotics Ordinance. In concentrations of up to 2.5% in undivided formulations or up to 100 mg in divided formulations (based on the free base), no drug prescription is required.
Switzerland
In Switzerland too, codeine is a narcotic within the meaning of the Narcotics Act . However, preparations which do not contain more than 2.5% in the preparation or divided form 100 mg codeine are excluded.
Trade names
Bronchial lozenges VA (CH), Bronchicum mono (D), Capitole (CH), Codeinum phosphoricum (forte) Compren, Codicaps mono (D), Codicompren (D), Codipertussin (D, A), Iropect (CH), Longtussin (D ), Makatussin Codeine (D, A, CH), Optipect (D), Pharmacieplusd (CH), Rotpunkt Apotheke Bronchialpastillen with Codeine (CH), Tryasol (D), Tiamon (D), Tussoret (D), numerous generics (D , CH)
- with Paracetamol : Azur compositum SC (D), Contraneural Paracetamol / Codeine (D), Gelonida (D), Nedolon (D), Optipyrin (D), Talvosilen (D), Titretta (D)
- with paracetamol and caffeine : Azur compositum (D)
- with paracetamol and acetylsalicylic acid : Dolomo N (D)
- with acetylsalicylic acid: Dolviran N (D)
- with Diclofenac : Combaren (D), Voltaren plus (D)
- with diphenhydramine : Benylin (CH)
- with guaifenesin : resyl with codeine (A), resyl plus (A, CH)
- with Drofenine and Propyphenazon : Spasmoplus (A)
See also
Web links
Individual evidence
- ↑ a b c d Entry on Codeine. In: Römpp Online . Georg Thieme Verlag, accessed on July 31, 2013.
- ^ The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. 9th edition. Merck & Co., Whitehouse Station, NJ, USA 1976, ISBN 0-911910-26-3 , p. 316.
- ↑ a b c d Entry on codeine in the ChemIDplus database of the United States National Library of Medicine (NLM) .
- ↑ a b Codeine data sheet at Sigma-Aldrich , accessed on October 9, 2016 ( PDF ).
- ^ Henry George Liddell, Robert Scott: A Greek-English lexikon. 9th edition. Oxford 1940, p. 1016.
- ↑ Patent DE39887A : Process for the preparation of methylmorphine (codeine) and ethylmorphine. Registered August 7, 1886, published June 4, 1887, applicant: Dr. phil. A. Knoll.
- ↑ S. Chericoni, F. Stefanelli, V. Iannella, M. Giusiani: Simultaneous determination of morphine, codeine and 6-acetyl morphine in human urine and blood samples using direct aqueous derivatisation: validation and application to real cases. In: J Chromatogr B Analyt Technol Biomed Life Sci. 949-950, Feb 15, 2014, pp. 127-132. PMID 24491926 .
- ↑ V. Milovanović, B. Cirić, J. Milenković, V. Kilibarda, M. Curcić, S. Vucinić, B. Antonijević: Determination of morphine, codeine and 6-monoacetylmorphine in saliva of substance abuse patients using HPLC / MS methods . In: Vojnosanit Pregl. 69 (2), Feb 2012, pp. 141-146. PMID 22500367 .
- ↑ SS Barsegian, EA Purvina, EM Salomatin, TA Sviridova, TN Fedorova: Determination of morphine and codeine in forensic chemical studies with the use of a single quadrupole mass-selective detector coupled to the HPLC system. In: Sud Med Ekspert. 55 (6), Nov-Dec 2012, pp. 33-37. PMID 23405467 .
- ↑ KA Rees, PA McLaughlin, MD Osselton: Validation of a gas chromatography-ion trap-tandem mass spectrometry assay for the simultaneous quantification of cocaine, benzoylecgonine, cocaethylene, morphine, codeine, and 6-acetylmorphine in aqueous solution, blood, and skeletal muscle tissue. In: J Anal Toxicol. 36 (1), Jan-Feb 2012, pp. 1-11. PMID 22290746 .
- ^ Y. Caraco, T. Tateishi, FP Guengerich, AJJ Wood: Microsomal codeine N-demethylation: Cosegregation with cytochrome P4503A4 activity. In: Metab Dispos. 24 (7), 1996, pp. 761-764. PMID 8818573
- ↑ Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline information for codeine and CYP2D6. In: PharmGKB . May 5, 2016. Retrieved November 20, 2016 .
- ↑ Eberhard Klaschik : Pain therapy and symptom control in palliative medicine. In: Stein Husebø , Eberhard Klaschik (ed.): Palliative medicine. 5th edition, Springer, Heidelberg 2009, ISBN 3-642-01548-4 , pp. 207-313, here: p. 232.
- ↑ Red List online drug directory , accessed March 9, 2014.
- ↑ SM Smith, K. Schroeder, T. Fahey: Over-the-counter medications for acute cough in children and adults in ambulatory settings . In: Cochrane Database Syst Rev . No. 1 , 2008, p. CD001831 , doi : 10.1002 / 14651858.CD001831.pub3 , PMID 18253996 .
- ↑ J. Smith, E. Owen, J. Earis, A. Woodcock: Effect of codeine on objective measurement of cough in chronic obstructive pulmonary disease. In: J Allergy Clin Immunol . 117 (4), Apr 2006, pp. 831-835. Epub 2006 Feb 7. PMID 16630941 .
- ↑ Eberhard Klaschik : Pain therapy and symptom control in palliative medicine. 2009, p. 232.
- ↑ G. Coren et al .: Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. In: Lancet. 368, 2006, p. 704.
- ↑ Pharm. Ztg. 152, 2007, p. 125.
- ↑ Rheinisches Ärzteblatt. 11/2007.
- ↑ Safety review update of codeine use in children; new boxed warning and contraindication on use after tonsillectomy and / or adenoidectomy. (PDF; 118 kB) FDA, February 20, 2013, accessed on June 8, 2013 (English).
- ↑ FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. In: FDA. April 20, 2017. Retrieved April 25, 2017 .
- ↑ USA: Stricter restrictions on tramadol and codeine. In: Deutsche Apothekerzeitung online. April 24, 2017. Retrieved April 25, 2017 .
- ↑ Michael Freissmuth, Stefan Offermanns, Stefan Böhm: Pharmacology and toxicology: From the molecular basis for pharmacotherapy . 2nd Edition. Springer, Heidelberg, Berlin 2016, ISBN 978-3-662-46689-6 , pp. 264 ( limited preview in Google Book search).
- ↑ gesetze-im-internet.de: Annex III (to § 1 Paragraph 1) marketable and prescription narcotics to the Narcotics Act.
- ↑ Narcotics Ordinance, Section 20, Paragraph 4 1 .
- ↑ Narcotics Directory Ordinance (BetmVV-EDI), Appendix 4, Directory c .
