Dextromethorphan

Structural formula
General
Non-proprietary name	Dextromethorphan
other names	(9 S , 13 S , 14 S ) -3-methoxy-17-methylmorphinan ( IUPAC ) (all- S ) -3-methoxy-17-methylmorphinane D -methorphan
Molecular formula	C 18 H 25 NO (dextromethorphan) C 18 H 25 NO HBr (dextromethorphan hydrobromide ) C 18 H 25 NO HBr H 2 O (dextromethorphan hydrobromide monohydrate )
Brief description	white crystalline powder
External identifiers / databases
CAS number 125-71-3 (dextromethorphan) 125-69-9 (dextromethorphan hydrobromide) 6700-34-1 (dextromethorphan hydrobromide monohydrate) EC number 204-752-2 ECHA InfoCard 100.004.321 PubChem 5360696 ChemSpider 13109865 DrugBank DB00514 Wikidata Q407781
Drug information
ATC code	R05 DA09 , N07 XX59 .
Drug class	Psychotropic , antitussive
properties
Molar mass	271,40 g · mol -1
Physical state	firmly
Melting point	109.5-112.5 ° C
pK s value	8.3
solubility	practically insoluble in water; easily soluble in chloroform
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances no GHS pictograms H and P phrases H: no H-phrases P: no P-phrases
Toxicological data	210 mg kg −1 ( LD 50 ,  mouse ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Dextromethorphan (abbreviated often: DXM ) is a drug that acts on the nervous system. The active ingredient was developed as a centrally (in the brain) effective antitussive (cough blocker). Today we know that the substance is a potent psychotropic that influences numerous brain functions. Since 2013, dextromethorphan has been approved in the USA in a fixed combination with quinidine for the treatment of neurological diseases caused by damage to the brain.

history

Dextromethorphan was one of three substances (along with dextropropoxyphene and diphenoxylate ) discovered in research funded by the CIA and the US Navy that could be used as a non-addictive cough drug to replace codeine and dihydrocodeine . The patent for dextromethorphan was applied for in 1954; in September of that year, the FDA ( Food and Drug Administration ) recognized it as an antitussive. It became available without a prescription three years later. Approval for the treatment of pseudobulbar affect disorder was only expanded in 2011 (USA) and 2013 (European Union). In the USA there has since been an expansion of the indications, in the EU the manufacturer has not applied for an extension of the approval.

Use as a medicine

application areas

Since 1954, dextromethorphan has been marketed as a centrally active (on the nervous system) antitussive agent against dry coughs and dry coughs. In addition, it shows effectiveness in the treatment of neuropathic pain and is approved in the USA in a fixed combination with quinidine for the treatment of neurological symptoms in the context of severe brain diseases.

Side effects

Side effects occur relatively rarely with dextromethorphan in low doses. In a certain percentage of the population (1–10% depending on the source), however, there is a pharmacogenetic weakness of the cytochrome P450 enzyme CYP2D6, so that hallucinations , loss of reality and psychotic episodes can occur even at therapeutic doses . Occasionally, tiredness, dizziness, nausea, and vomiting are observed. An overdose can lead to hallucinations and psychotic episodes.

Interactions

The simultaneous use of certain antidepressants ( MAO inhibitors , serotonin-reuptake-inhibiting antidepressants ) is contraindicated , as this can lead to serotonin syndrome (nausea, high blood pressure, fever, death).

Dextromethorphan should not be combined with alcohol, as this can lead to interactions such as nausea.

Dextromethorphan should not be combined with the antihistamine terfenadine , as this can lead to life-threatening interactions. In addition, occasional fatal interactions with antihistamines have also been observed, particularly at higher doses.

The plasma half-life is around 3.5 hours. However, there is a small percentage of people who break down the active ingredient dextromethorphan very slowly (pharmacogenetic weakness of the cytochrome P450 enzyme CYP2D6 ). This extends the plasma half-life of dextromethorphan, so that even at therapeutic doses, a strong state of intoxication can be triggered that is similar to that of other dissociatives . The mechanism of a quinidine- induced blockade of metabolism by means of CYP2D6 is used therapeutically with the fixed drug combination dextromethorphan / quinidine (brand name Nuedexta ). Quinidine is said to maintain the active substance level of dextromethorphan in the blood for longer by blocking CYP2D6.

Dextromethorphan should not be taken during pregnancy as it is suspected of negatively affecting fetal brain development.

pharmacology

In its mechanism of action, dextromethorphan differs significantly from therapeutically used opioids and from its enantiomer levomethorphan . It also has a significantly reduced psychological and, in therapeutic doses, practically no physical addiction potential. Pharmacologically, dextromethorphan is no longer classified as an opioid because it is not bound to any opioid receptor. The earlier classification is related to the fact that it acts as an agonist on the sigma-1 receptor , which was previously wrongly counted among the opioid receptors. In addition, it acts as a non-competitive antagonist by blocking the channels on NMDA receptors . That explains the effectiveness in pain therapy. Furthermore it has u. a. a potency as dopamine, norepinephrine and serotonin reuptake inhibitors. It is therefore being researched or already used for use in depression , post- stroke conditions , brain injuries , seizure disorders , Parkinson's and autism .

chemistry

Stereochemistry

The structure of dextromethorphan is related to opioids such as codeine and morphine , but differs fundamentally from them in its stereochemistry . Its stereocenters in positions 9, 13 and 14 are inverted compared to those of the opioids with a morphine backbone. Dextromethorphan is the enantiomer of the opioid levomethorphan .

Chemical properties

The dextromethorphan hydrobromide [(9 S , 13 S , 14 S ) -3-methoxy-17-methylmorphinan · HBr] is hardly soluble in water. It is well soluble in ethanol , glycerol and chloroform .

synthesis

Dextromethorphan is produced synthetically . The resolution of (±) -3-methoxy- N -methylmorphinane [(9 S * , 13 S * , 14 S * ) -3-methoxy-17-methylmorphinane] takes place via the formation of diastereomeric salts with D - tartaric acid .

Use as an intoxicant

Dextromethorphan is sometimes taken as an intoxicant , as it has dissociative effects in higher doses , which can be similar to those of low-dose ketamine or even LSD / psilocybin. Regular consumption can lead to addiction. Like any psychotropic substance , dextromethorphan can lead to substance-induced psychosis . Although preparations with DXM are not subject to prescription in Germany, the active ingredient should not be underestimated. While deaths directly caused by dextromethorphan are not known, there have been deaths from other substances contained in combination preparations; especially by paracetamol , which is why special warnings are given against these combinations. Also from simultaneous use with other psychoactive substances; such as benzodiazepines, amphetamines (and their derivatives), opiates and opioids, are also warned in specialist publications.

Trade names

Monopreparations

• as an antitussive : Bexin (CH), Calmerphan (CH), Calmesin (CH), Dextro.Med (CH), Emedrin (CH), Hicoseen (CH), Hustenstiller-Ratiopharm (D), Irotussin (CH), NeoTussan (D ), Pulmofor (CH), Silomat DMP (D), Tossa-X (CH), Tussastopp (A), Vicks cough lozenges / cough syrup (CH), Wick formula 44 (A), Wick cough lozenges / cough syrup (D)

Combination preparations

• as an antitussive: Basoplex (D), Benical (CH), Contac Kaltungs-Trunk forte (D), Lindosan (A), Pretuval (CH), Vicks MediNait (CH), Wick DayMed capsules (D), Wick cold syrup (A) , Wick MediNait (D)
• as a psychotropic : Nuedexta (EU)

Web links

Commons : Dextromethorphan  - Collection of Images, Videos and Audio Files

• DXM . In: Erowid . (English)

Individual evidence

1. ↑ ^{a b} entry on dextromethorphan. In: Römpp Online . Georg Thieme Verlag, accessed on July 7, 2014.
2. ↑ HCA Psychotropic Medication List ( Memento of July 14, 2014 in the Internet Archive ), accessed on March 26, 2014.
3. ↑ LA Zawertailo, HL Kapla, UE Busto, RF Tyndale, EM Sellers: Psychotropic effects of dextromethorphan are altered by the CYP2D6 polymorphism: a pilot study. In: J Clin Psychopharmacol. 18 (4), 1998, pp. 332-337.
4. ↑ J. Mutschler, A. Koopmann, M. Grosshans a. a .: Dextromethorphan Withdrawal and Dependence Syndrome. In: Dtsch Arztebl Int. 107 (30), 2010, pp. 537-540.
5. ↑ Lawrence A. Labbate, Maurizio Fava, Jerrold F. Rosenbaum: Handbook of Psychiatric Drug Therapy. Philadelphia 2010.
6. ↑ ^{a b} Sean Sweetman (Ed.): Martindale: The Complete Drug Reference. 35th edition. Book and CD-ROM. Pharmaceutical Press, 2006, ISBN 0-85369-704-3 .
7. ↑ Data sheet Dextromethorphan hydrobromide monohydrate from Sigma-Aldrich , accessed on May 9, 2017 ( PDF ).
8. ↑ Entry on dextromethorphan in the ChemIDplus database of the United States National Library of Medicine (NLM) .
9. ↑ Linda Nguyen, Kelan L. Thomas, Brandon P. Lucke-Wold, John Z. Cavendish, Molly S. Crowe, Rae R. Matsumoto: Dextromethorphan. An update on its utility for neurological and neuropsychiatric disorders. Pharmacology & Therapeutics 159 (2016) 1-22. http://dx.doi.org/10.1016/j.pharmthera.2016.01.016
10. ^ [Information from the Food and Drug Administration (FDA) of the United States of America. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021879s000lbl.pdf ]
11. ^ Memorandum for the Secretary of Defense. (PDF) Retrieved July 28, 2013 . 
12. ↑ Dextromethorphan for sensory incontinence. ( Memento from February 22, 2014 in the Internet Archive ) In: Apotheke ad hoc. May 1, 2013. Retrieved January 21, 2014.
13. ↑ M. Fink: Toxic serotonin syndrome or neuroleptic malignant syndrome? In: Pharmacopsychiatry . 29 (4), 1996, pp. 159-161. PMID 8858716 .
14. ↑ BP Skop u. a .: The serotonin syndrome associated with paroxetine, an over-the-counter cold remedy, and vascular disease. In: Am J Emerg Med. 12 (6), 1994, pp. 642-644. PMID 7945606 .
15. ↑ P. Kintz, P. Mangin: Toxicological findings in a death involving dextromethorphan and terfenadine. In: Am. J. Forensic Med. Pathol. 13 (4), 1992, pp. 351-352. PMID 1288270 .
16. ↑ Heinz Lüllmann, Klaus Mohr, Lutz Hein: Pharmacology and Toxicology. Understand drug effects - use drugs in a targeted manner; a textbook for students of medicine, pharmacy and life sciences, a source of information for doctors, pharmacists and health policymakers. Georg Thieme Verlag, 2010. Chapter 13.2.1., Page 188.
17. ↑ Swiss Compendium for Medical Substances and their Indications. Here: Dextromethorphan HBr. As of December 2019. Accessed December 15, 2019.
18. ↑ Linda Nguyen, Kelan L. Thomas, Brandon P. Lucke-Wold, John Z. Cavendish, Molly S. Crowe, Rae R. Matsumoto: Dextromethorphan. An update on its utility for neurological and neuropsychiatric disorders. Pharmacology & Therapeutics 159 (2016) 1-22. http://dx.doi.org/10.1016/j.pharmthera.2016.01.016
19. ^ Axel Kleemann , Jürgen Engel, Bernd Kutscher, Dietmar Reichert: Pharmaceutical Substances. 4th edition. 2 volumes. Thieme-Verlag, Stuttgart 2000, ISBN 1-58890-031-2 , pp. 615-616. (online since 2003 with biannual additions and updates)
20. ↑ Dextromethorphan: Withdrawal and Dependency Syndrome. In: Deutsches Ärzteblatt, Int. 107 (30), 2010, pp. 537-540.
21. ↑ https://erowid.org/chemicals/dxm/faq/dxm_general_info.shtml#toc.4.11.4 Section 4.11.4 of the DXM FAQ.

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