Dextromethorphan (DXM)

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Dextromethorphan (DXM) is an antitussive drug. It is one of the active ingredients in many over the-counter cold and cough medicines, including generic labels. Dextromethorphan has also found other uses in medicine, ranging from pain relief to psychological applications. It is sold in syrup, tablet, spray, and lozenge forms. In its pure form, dextromethorphan occurs as a white powder. 

Dextromethorphan is also used recreationally. When exceeding label-specified maximum dosages, dextromethorphan acts as a dissociative hallucinogen. Its mechanism of action is as an NMDA receptor antagonist, producing effects similar to those of ketamine and phencyclidine (PCP). 

Dextromethorphan (DXM)

Dextromethorphan produces a range of toxicities depending upon either the dose or the components of the specific formulation that was ingested. Cases of recreational abuse of dextromethorphan have been reported in United States, Sweden, Australia, Germany, and Korea primarily among adolescents and young adults. However, these reports are still relatively infrequent.  

At the time being, dextromethorphan is not listed in the Schedules of the United Nations 1961 Convention on Narcotic Drugs.

Chemical Name

IUPAC Name:   (+)-3-methoxy-17-methyl-(9α,13α,14α)-morphinan

CA Index Name:   (+)-3-methoxy-17-methyl-(9α,13α,14α)-morphinan

Molecular Formula:  C18H25NO (free base);     C18H26BrNO (hydrobromide salt);     C18H28BrNO2 (hydrobromide monohydrate)

Molecular Weight: 271.40g/mol (free base); 352.31 g/mol (hydrobromide salt); 370.32 g/mol (hydrobromide monohydrate)

Melting point:      111 °C (free base); 

                                122-12 4 °C (hydrobromide salt)

                                116-119 °C (hydrobromide monohydrate)

Boiling point:   Decomposes (free base)

Stereoisomers

Dextromethorphan is the dextrorotatory enantiomer of the methyl ether of levorphanol, an opioid analgesic. It is also a stereoisomer of levomethorphan, an opioid analgesic.

Synthesis

Dextromethorphan is considered a synthetic opiate. It has been synthesized from a benzylisoquinoline (with a planar structure) by a process known as Grewe’s cyclization (from the 1950’s) to give the corresponding morphinan (with a three dimensional structure). The isoquinoline is 1,2,3,4,5,6,7,8-octahydro-1-(4methoxybenzyl)isoquinoline (there is just one residual double bond at the fusion position of the two rings of the isoquinoline) is converted into the N-formyl derivative, cyclized to the N- formyl normorphinan, and the formyl group reduced to an N-methyl group, to give 3-methoxy-17-methylmorphinan, or Racemethorphan.

Chemical description

Dextromethorphan is a synthetic compound. Dextromethorphan is 3 methoxy-17 methylmorphinan monohydrate, which is the d isomer of levophenol, a codeine analogue and opioid analgesic.

Chemical properties

Dextromethorphan is freely soluble in ethanol 96% and essentially insoluble in water. Dextromethorphan is commonly available as the monohydrated hydrobromide salt. However, some newer extended-release formulations contain dextromethorphan bound to an ion exchange resin based on polystyrene sulfonic acid. Dextrometorphan’s specific rotation in water is + 27.6° (20°C, Sodium Dline).

Pharmacodynamics

Neuropharmacology and effects on central nervous system Dextromethorphan (d-3-methoxy-N-methylmorphinan) is the d-isomer of the codeine analogue methorphan; however, unlike the l-isomer, it does not act through opioid receptors.  Instead, dextromethorphan binds with high affinity to sites associated with sigma ligands and low affinity to the phencyclidine (PCP) channel of the N-methyl-D-aspartate (NMDA) receptor as seen in animal studies. Most NMDA receptors in the brain are thought to be pentametric or tetrametric complexes of the NR1 subunit and one or more of four NR2 subunits (NR2A-2D) (Fig. Kutsuwada et al., 1992). It is of interest to note that dextromethorphan is thought to be NR1/NR2A-containing NMDA receptor –preferred antagonist (Avenet et al., 1997).

Conversely, the active metabolite of dextromethorphan, dextrorphan (3-hydroxy-17-methylmorphinan) binds with low affinity to sites associated with sigma ligands and high affinity to the PCP-site (Klein et al., 1989; Murray et al., 1984); (Franklin et al., 1992). The relationship of these receptor binding sites to the pharmacological mechanism of the antitussive effects of dextromethorphan is not known; however, these observations, coupled with the ability of naloxone to antagonize the antitussive effects of codeine but not those of dextromethorphan, indicate that cough suppression can be achieved by a number of different mechanisms.

Interactions with other drugs and medicines

Dextromethorphan should not be taken with monoamine oxide inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs) because of an apparent serotonin syndrome (fever, hypertension, arrhythmias). Dextrometrophan shouldn’t be combined with terfenadine nor with diphenhydramine as life threatening interactions have been reported (Kintz P. und Mangin P. (1992)). Because administration of dextromethorphan can trigger a histamine release, its use in atopic for children is very limited. Additive CNS depressant effects may occur when co-administered with alcohol, antihistamines, psychotropics, and other CNS depressant drugs.

Routes of administration and dosage  

Dextrometorphan, an oral drug, is available as lozenges, capsules, tablets, and cough syrups, in a variety of prescription medications and over-the-counter cough and cold remedies. Products contain dextromethorphan alone or in combination with guaifenesin, brompheniramine, pseudoephedrine, phenylephrine, promethazine, codeine, acetaminophen, and/or chlorpheniramine. 

The average adult dose approved of dextromethorphan for antitussive effects is 15-30 mg taken 3 to 4 times per day. It is a highly effective and safe agent in this dose range (Bem et al., 1992).

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Adverse reactions in humans

drowsiness,  dizziness,  coma,  respiratory depression, nausea,  gastrointestinal upset,  constipation,  abdominal discomfort, tachycardia,  warm sensations,  inability to concentrate,  dry mouth and throat 

At 5 to 10 times the recommended dose, adverse effects resemble those observed for ketamine or PCP, and these include: confusion, dreamy state, depersonalization, distortion of motor and speech, disorientation, stupor, somnolence, hyperexcitability, ataxia, nystagmus, impaired muscle tone, dissociative anaesthesia, visual hallucinations (closed eye hallucinations of sheets, swirls, and blobs of color), toxic psychosis (Schwartz, 2005; Siu et al., 2007). 

When cough and cold preparations that contain dextromethorphan are taken in doses 5 to 10 times the recommended dosage, additive toxicities with the additional ingredients are observed. The combination of dextromethorphan with high doses of guaifenesin causes intense nausea and vomiting; with chlorpheniramine causes flushed skin, mydriasis, tachycardia, delirium, respiratory distress, syncope, and seizures.

Reference

  1. Avenet P, Leonardon J, Besner F, Graham D, Depootere H, Scatton B (1997)  Antagonist properties of eliprodil and other  NMDA receptor antagonists at rat NR1/NR2A and NR1/NR2B receptors exposed in Xenopus oocytes. Neurosci Lett 223: 133-6 

2. Bem JL, Peck R (1992). Dextromethorphan. An overview of safety issues. Drug Saf 7(3): 190199. 

3. Carr BC (2006). Efficacy, abuse, and toxicity of over-the-counter cough and cold medicines in the pediatric population. Curr Opin Pediatr 18(2): 184-188. 

4. CEWG (2009). Epidemiologic Trends in Drug Abuse, NIDA. 

5. Chung H, Park M, Hahn E, Choi H, Choi H, Lim M (2004). Recent trends of drug abuse and drugassociated deaths in Korea. Ann N Y Acad Sci 1025: 458-464. 

6. Church J, Shacklock JA, Baimbridge KG (1991). Dextromethorphan and phencyclidine receptor ligands: differential effects on K(+)- and NMDA-evoked increases in cytosolic free Ca2+ concentration. Neurosci Lett 124(2): 232-234. 

7. Cornish JW, Herman BH, Ehrman RN, Robbins SJ, Childress AR, Bead V, et al. (2002). A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients. Drug Alcohol Depend 67(2): 177-183. 

8. DEA (2003). Dextromethorphan Tablets in Ballston Spa, New York  edn, vol. XXXVI. Drug Enforcement Administration: Washington, DC. 

9. Drachtman RA, Cole PD, Golden CB, James SJ, Melnyk S, Aisner J, et al. (2002). Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity. Pediatr Hematol Oncol 19(5): 319-327. 

10. Franklin PH, Murray TF (1992). High affinity [3H]dextrorphan binding in rat brain is localized to a noncompetitive antagonist site of the activated N-methyl-D-aspartate receptor-cation channel. Mol Pharmacol 41(1): 134-146. 

11. Hollander D, Pradas J, Kaplan R, McLeod HL, Evans WE, Munsat TL (1994). High-dose dextromethorphan in amyotrophic lateral sclerosis: phase I safety and pharmacokinetic studies. Ann Neurol 36(6): 920-924. 

12. Jasinski DR (2000). Abuse potential of morphine/dextromethorphan combinations. J Pain Symptom Manage 19(1 Suppl): S26-30. 

13. Klein M, Musacchio JM (1989). High affinity dextromethorphan binding sites in guinea pig brain. Effect of sigma ligands and other agents. J Pharmacol Exp Ther 251(1): 207-215. 

14. Kutsuwada T, Kashiwabuchi N, Mori H, Sakimura S, Kushiya E, Araki K, Meguro H, Kumanishi T, Arakawa M, Mishina M (1992) Molecular diversity of the NMDA receptor channel. Nature 358:36-41 

15. Lexi-CompONLINE (2008). Dextromethorphan. In: Lexi-Comp Online: Lexi-Comp, Inc. 

16. Logan BK (2009). Combined dextromethorphan and chlorpheniramine intoxication in impaired drivers. J Forensic Sci 54(5): 1176-1180. 

17. Logan BK, Goldfogel G, Hamilton R, Kuhlman J (2009). Five deaths resulting from abuse of dextromethorphan sold over the internet. J Anal Toxicol 33(2): 99-103. 

18. Manning BH, Mao J, Frenk H, Price DD, Mayer DJ (1996). Continuous co-administration of dextromethorphan or MK-801 with morphine: attenuation of morphine dependence and naloxonereversible attenuation of morphine tolerance. Pain 67(1): 79-88. 

19. Mansky P, Jasinski DR (1970). Effects of dextromethorphan (D) in man. Pharmacologist 12: 231. 

20. Mao J, Price DD, Caruso FS, Mayer DJ (1996). Oral administration of dextromethorphan prevents the development of morphine tolerance and dependence in rats. Pain 67(2-3): 361-368. 

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