Tilidine
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| 1: 1 mixture of stereoisomers : (1 S , 2 R ) -isomer (left) and (1 R , 2 S ) -isomer (right) |
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| Non-proprietary name | Tilidine | ||||||||||||||||||
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| Molecular formula | C 17 H 23 NO 2 | ||||||||||||||||||
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| Molar mass | 273.37 g · mol -1 | ||||||||||||||||||
| Physical state |
firmly |
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| Melting point |
159 ° C (tilidine hydrochloride) |
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| boiling point |
95.5-96 ° C at 1 Pa |
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | |||||||||||||||||||
Tilidine is an active pain reliever drug from the group of opioids .
The synthetically produced substance is used for the treatment of severe and very severe pain. As a prodrug , tilidine has hardly any analgesic effect and it is only metabolized in the liver to the metabolites nortilidine and bisnortilidine , of which nortilidine shows the main effects.
In order to prevent misuse as an intoxicant , tilidine is usually combined with the drug naloxone in finished drugs . The combination of tilidine and naloxone is said to reduce the potential for abuse while maintaining the analgesic effect. Naloxone has a negligible effect after oral administration of therapeutic doses, but abolishes the effect of tilidine after high oral doses or intravenous administration. For the treatment of chronic pain, tilidine is classified as a pain reliever in level 2 according to the WHO level scheme.
chemistry
history
Tilidin was patented by Gödecke (Valoron) in 1967 and is commercially available as a generic.
Manufacturing
The chemical synthesis of tilidine starts with dimethylaminobuta-1,3-diene, which is obtained from crotonaldehyde and dimethylamine , and atropic acid ethyl ester , which form the target compound in a Diels-Alder reaction .
The diastereomers can be separated using chiral zinc complexes.
Stereoisomerism
2- (Dimethylamino) -1-phenylcyclohex-3-en-carboxylic acid ethyl ester contains two stereogenic centers. The following four stereo isomers exist : (1 R , 2 S ) form and the corresponding enantiomeric (1 S , 2 R ) form as well as the (1 R , 2 R ) form and the (1 S , 2 S ) -Shape. The drug tilidine is used as a racemate (1: 1 mixture) of the (1 R , 2 S ) and the (1 S , 2 R ) enantiomers. The importance of the enantiomeric purity of the synthetically produced drugs is being given increasing attention, because the two enantiomers of a chiral drug almost always show a different pharmacology and pharmacokinetics . In the past, this was often ignored due to ignorance of stereochemical relationships. The (1 S , 2 R ) form [(+) - trans form] is more effective than the (1 R , 2 S ) form [(-) - trans form]. When used subcutaneously , the ED 50 values of these two enantiomers are 1:23.
In addition, the racemic trans form [tilidine = 1: 1 mixture of (1 R , 2 S ) and (1 S , 2 R ) form] is about twice as active as the racemic cis that is not used in commercial drugs Form [1: 1 mixture of (1 R , 2 R ) - and (1 S , 2 S ) form]. The cis form is included to more than 0.5 percent as an impurity from the synthesis process in tilidine.
| Overview of the stereoisomers of 2-dimethylamino-1-phenylcyclohex-3-ene carboxylic acid ethyl ester | ||||
| Isomeric form | (1 S , 2 R ) - trans | (1 R , 2 S ) - trans | (1 R , 2 R ) - cis | (1 S , 2 S ) - c sharp |
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-trans-Tilidin.svg)
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-trans-Tilidin.svg)
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-cis-Tilidin.svg)
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-cis-Tilidin.svg)
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| Names | Dextilidine (INN) (+) - trans -Tilidine, (+) - Tilidine, (1 S , 2 R ) - trans -Tilidine |
(-) - trans -tilidine, (-) - tilidine, (1 R , 2 S ) - trans -tilidine |
cis -tilidine (INNvm) |
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Tilidine ( INN v) trans -Tilidine, (±) - trans -Tilidine, D, L - trans -Tilidine, Tilidate ( BAN 1999), rac -ethyl [(1 RS , 2 SR ) -2- (dimethylamino) -1 -phenylcyclohex-3-ene carboxylate] |
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| Ethyl [2- (dimethylamino) -1-phenylcyclohex-3-enecarboxylate] | ||||
| CAS number | 32447-90-8 | 38690-93-6 | 112244-09-4 (racemate cis form) 20380-56-7 |
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| 51931-66-9 20380-58-9 (racemate trans form) |
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| 17243-69-5 (not specified / mixture of isomers) |
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| Database links |
PubChem : 30131 |
PubChem: 12546498 |
PubChem: 44150542 |
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PubChem: 98526 |
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PubChem: 32329 |
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Pharmaceutical information
Tilidine is medicinally in the form of the hydrochloride - hemihydrate and phosphate used. The dosage forms are drops (20 drops = 50 mg) for oral use and prolonged-release tablets (50–200 mg). In Germany, tilidine is combined with naloxone in the preparations (4 mg naloxone per 50 mg tilidine).
Clinical information
application areas
Tilidine is indicated for the treatment of severe and very severe pain. The potency is 0.16-0.19 compared to morphine (about one fifth of the analgesic potency) - according to other information, the analgesic equivalence of the single dose is only 1/10 (one tenth).
Side effects
In principle, all of the side effects typical of opioids apply to tilidine (see opioids, section “Other effects” ). However, because of the addition of naloxone, the constipation ( constipation ) can be much less pronounced. Naloxone also reduces the respiratory depressive effect. The rapid onset of action promotes nausea and vomiting.
Use with impaired liver and kidney function
In patients with pre-existing liver damage, there is a risk of loss of effectiveness, since the hepatic metabolism to the active metabolites can be impaired. Renal insufficiency does not require dose adjustment.
Contraindications
Tilidine is contraindicated in case of hypersensitivity to the substance, opiate addiction (see section pharmacology ), as well as porphyria , respiratory depression , intestinal obstruction , acute abdomen , traumatic brain injury , increased intracranial pressure and in combination with certain drugs ( benzodiazepines or MAO inhibitors ) .
pharmacology
Tilidine itself has hardly any opioid-typical effect and is only metabolized during its first passage through the liver by demethylation to nortilidine - the actual opioid active ingredient. Nortilidine is on the one hand a µ- agonist , on the other hand it is converted into the again active bisnortilidine, which also mediates opioid effects. After taking tilidine, the opioid effect builds up comparatively quickly (about 10–20 minutes). The enzymes involved in this step belong to the class of cytochrome P450 . In detail, the enzymes CYP3A4 and CYP2C19 seem to be involved in the breakdown of tilidine to nortilidine and also in the further breakdown to bisnortilidine and polar substances that have not been investigated further. This could be demonstrated by inhibition with naloxone and specific antagonists inhibiting these enzymes. Two thirds of the dose of tilidine is metabolized to nortilidine, of which half is further metabolized to bisnortilidine through demethylation. This means that around 33% of the effective form nortilidine is available.
In the usual dosages, which can vary depending on the patient, the analgesic effect sets in after about 5 to 10 minutes (injection, oral drops) or about 15 to 20 minutes (capsules), the duration of action is about 4 to 6 hours. In the case of sustained-release drugs, i.e. dosage forms that gradually release the active ingredient, the duration of action is correspondingly longer at 6 to 12 hours. The analgesic active metabolite nortilidine has a terminal plasma half-life of 3 to 5 hours.
After oral administration of therapeutic doses, the naloxone added to tilidine is almost completely broken down and inactivated during its first passage through the liver ( first-pass effect ). Only after ingestion of large amounts or after parenteral administration are sufficient concentrations of naloxone to develop an antagonistic effect and to inhibit or destroy the effect of the ingested tilidine. In the case of opiate addicts , the most severe withdrawal symptoms can occur even after oral administration .
Tilidine does not have an antitussive effect .
Use as an intoxicant
The use of tilidine as drugs is limited by the fact that it usually with the opioid antagonist naloxone combined fixed and is not retarded preparations and monopreparations only anesthetic recipe can be obtained. In Germany, 4 mg naloxone per 50 mg tilidine are added to all finished medicinal products .
Tilidine is not very common among users of highly potent opiates such as morphine , semi-synthetic opioids such as heroin or fully synthetic opioids such as methadone . According to press reports, however, counterfeit prescriptions are comparatively common in connection with Tilidin.
Narcotics regulations
Tilidin is subject to narcotics regulations. In Germany, trans -Tilidine as a marketable and prescription narcotic can only be prescribed on a narcotic prescription since January 1, 2013 . This does not apply to solid preparations with delayed release of active ingredients ( sustained-release medicinal products ) that contain the active ingredient below a specified dose limit and in combination with naloxone. cis -Tilidine is marketable, but not a prescription. In Switzerland, too, drugs containing tilidine ( trans- tilidine) must be prescribed on a narcotic prescription.
Tilidin is mainly sold in Germany, Belgium and Switzerland, in the USA Tilidin is subject to Schedule I ; The substances in this category (including heroin and cannabis ) are comparable to the substances in the BtMG in Annex I. Accordingly, no therapeutic or medical use is recognized for the pain reliever tilidine in the USA and it is prohibited.
Trade names
- Monopreparations
- Valoron (CH)
- Combination preparations
- Valoron N (D), Valtran (B), numerous generics (D)
Web links
- Stephan Orth: Unrestrained violence: trendy drug makes young people go crazy . In: Spiegel Online . January 23, 2008.
Individual evidence
- ↑ a b The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals. 14th edition. 2006, ISBN 0-911910-00-X , p. 1622.
- ↑ Registration dossier on ethyl 2- (dimethylamino) -1-phenylcyclohex-3-ene-1-carboxylate ( GHS section ) at the European Chemicals Agency (ECHA), accessed on January 3, 2020.
- ↑ There is not yet a harmonized classification for this substance . A labeling of ethyl 2- (dimethylamino) -1-phenylcyclohex-3-ene-1-carboxylate in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on January 3, 2020, is reproduced from a self-classification by distributors .
- ↑ a b c Gödecke, Berlin / Freiburg im Breisgau, 1974.
- ↑ Der Tagesspiegel: Without pain and understanding. Berlin Crimes (December 22, 2007).
- ↑ E. Mutschler, G. Geisslinger, HK Kroemer, S. Menzel, P. Ruth: Mutschler drug effects. Pharmacology - Clinical Pharmacology - Toxicology. 10th edition. Wissenschaftliche Verlagsgesellschaft, Stuttgart 2012. p. 225.
- ↑ Product information Valoron N retard prolonged-release tablets, Valoron N drops (Pfizer Pharma PFE). As of July 2017.
- ^ Römpp Lexikon Chemie. 10th edition. Georg Thieme-Verlag, Stuttgart / New York 1999, p. 4556.
- ↑ G. Satzinger: About Cyclohexene, I Synthesis and reactions of 4-phenyl-3-amino-cyclohexenen- (1), a new class of analgesics. In: Justus Liebig's Annals of Chemistry . 758, 1969, pp. 64-87, doi: 10.1002 / jlac.19697280111 .
- ↑ G. Satzinger: About Cyclohexene, II structure and properties of the stereoisomeric 3-dimethylamino-4-phenyl-4-ethoxycarbonyl-1-cyclohexene. In: Justus Liebig's Annals of Chemistry. 758, 1972, pp. 43-64, doi: 10.1002 / jlac.19727580105 .
- ↑ G. Satzinger: About Cyclohexene, III The absolute configuration of (+) - and (-) - 3r-dimethylamino-4c-phenyl-4t-ethoxycarbonyl-1-cyclohexene. In: Justus Liebig's Annals of Chemistry. 758, 1972, pp. 65-67, doi: 10.1002 / jlac.19727580106 .
- ↑ European Pharmacopoeia. 6th edition. Deutscher Apotheker-Verlag, Stuttgart 2008, ISBN 978-3-7692-3962-1 , pp. 4160-4161.
- ^ EJ Ariëns: Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology. In: European Journal of Clinical Pharmacology . 26, 1984, pp. 663-668, doi: 10.1007 / BF00541922 .
- ^ Hermann J. Roth, Christa E. Müller, Gerd Folkers: Stereochemistry and Medicinal Products. Wissenschaftliche Verlagsgesellschaft, Stuttgart 1998, ISBN 3-8047-1485-4 , pp. 251-274.
- ^ Hermann J. Roth, Christa E. Müller, Gerd Folkers: Stereochemistry and Medicinal Products. Wissenschaftliche Verlagsgesellschaft, Stuttgart 1998, ISBN 3-8047-1485-4 , p. 120.
- ↑ European Pharmacopoeia, Edition 9.0 , European Directorate for the Quality of Medicines & HealthCare; 2018, p. 3788, monograph Tilidine hydrochloride hemihydrate .
- ^ Hager's Handbook of Pharmaceutical Practice. Volume 9, Springer Verlag, 1995, p. 934.
- ↑ a b 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. 234.
- ^ J. Sorge: Drug pain therapy - opioids. In: M. Zenz, I. Jurna: Textbook of pain therapy. Stuttgart 2001, p. 462.
- ↑ PharmaWiki - Tilidin. Retrieved June 7, 2019 .
- ↑ J. Weiss, E. Sawa, K.-D. Riedel, WE Haefeli, G. Mikus: In vitro metabolism of the opioid tilidine and interaction of tilidine and nortilidine with CYP3A4, CYP2C19, and CYP2D6. In: Naunyn-Schmiedeberg's Arch. Pharmacol. 378, 2008, pp. 275-282, doi: 10.1007 / s00210-008-0294-7 .
- ↑ a b K. Hardtke et al. (Ed.): Commentary on the European Pharmacopoeia. Ph. Eur. 7.0, tilidine hydrochloride hemihydrate. Loose-leaf collection, 39th delivery 2011, Wissenschaftliche Verlagsgesellschaft, Stuttgart.
- ↑ K. Aktories, U. Förstermann, FB Hofmann, K. Starke: General and special pharmacology and toxicology , 9th edition. Urban & Fischer in Elsevier, 2006, ISBN 3-437-44490-5 .
- ↑ Berlin wants to crack down on the fashion drug Tilidin. In: Der Spiegel. August 11, 2008, p. 131.
- ↑ gesetze-im-internet.de: Annex III (to § 1 Paragraph 1) marketable and prescription narcotics to the Narcotics Act.
- ↑ Rapid-release tilidine will soon be subject to BtM. In: pharmische-zeitung.de. January 1, 2013, accessed April 13, 2015 .
- ↑ "... except in solid preparations with delayed release of active ingredients which, without another substance from Annexes I to III, contain up to 300 mg of tilidine per divided form, calculated as a base, and, based on this amount, at least 7.5 per cent of naloxone hydrochloride" , Source: gesetze-im-internet.de: Annex III (to Section 1 Paragraph 1) marketable and prescription narcotics to the Narcotics Act.
- ↑ Annex II (to § 1 Paragraph 1) marketable but not prescription drugs , gesetze-im-internet.de
- ↑ Ordinance of the Swiss Agency for Therapeutic Products on Narcotic Drugs and Psychotropic Substances ( Memento of January 8, 2010 in the Internet Archive ) of December 12, 1996 (as of November 15, 2005).
- ↑ Nadia Kounang CNN: Kratom to join heroin, LSD on Schedule I drug list. Retrieved March 27, 2017 .
- ↑ US DEA (US drug control agency): Drug Scheduling ( memento of the original from January 29, 2012 on WebCite ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice.
