Dextromethorphan: Wikis

  

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Dextromethorphan
Systematic (IUPAC) name
((+)-3-methoxy-17-methyl- (9α,13α,14α)-morphinan)
Identifiers
CAS number 125-71-3
ATC code R05DA09
PubChem 15978238
DrugBank APRD00655
ChemSpider 13109865
Chemical data
Formula C18H25NO 
Mol. mass 271.4 g/mol
SMILES eMolecules & PubChem
Physical data
Melt. point 111 °C (232 °F)
Pharmacokinetic data
Bioavailability 11%[1]
Metabolism Hepatic (liver) enzymes: major CYP2D6, minor CYP3A4, and minor CYP3A5
Half life 1.4–3.9 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat. A(AU) C(US)
Legal status Pharmacy Only (S2) (AU) OTC (US)
Routes Oral
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Dextromethorphan (DXM or DM) is an antitussive (cough suppressant) drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, 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.

DXM 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 the controlled substances ketamine and phencyclidine (PCP).[2]

Contents

History

Dextromethorphan was first patented under U.S. Patent 2,676,177. The U.S. Food and Drug Administration (FDA) approved dextromethorphan for over-the-counter sale as a cough suppressant in 1958. This filled the need for a cough suppressant lacking the sedative side-effects, stronger potential for abuse, and physically addictive properties of codeine phosphate, the most widely-used cough medication at the time.[3] In the United States, codeine phosphate syrup is still available in small quantities without a prescription in some states, but requires a signature and ID to purchase, similar to rules for sale of pseudoephedrine. As with most cough suppressants, studies show that dextromethorphan's effectiveness is highly debatable,[4] especially in children.[5]

During the 1960s and 1970s, dextromethorphan became available in an over-the-counter tablet form by the brand name Romilar. In 1973, Romilar was taken off the shelves after a burst in sales because of frequent abuse, and was replaced by cough syrup in an attempt to cut down on abuse.[3]

More recently (the early 1990s), gel capsule forms began reappearing in the form of Drixoral Cough Liquid Caps and later Robitussin CoughGels as well as several generic forms of that preparation.

Uses

The primary use of dextromethorphan is as a cough suppressant, for the temporary relief of cough caused by minor throat and bronchial irritation (such as commonly accompanies the flu and common cold), as well as those resulting from inhaled irritants.

In addition, a combination of dextromethorphan and quinidine has been shown to alleviate symptoms of easy laughing and crying (pseudobulbar affect) in patients with amyotrophic lateral sclerosis and multiple sclerosis.[6] Dextromethorphan is also being investigated as a possible treatment for neuropathic pain and pain associated with fibromyalgia.[7]

Recreational use

Robitussin Cough Gels which contain DXM solely

Since their introduction, over-the-counter preparations containing dextromethorphan have been used in a manner inconsistent with their labeling, often as a recreational drug.[3] At doses higher than medically recommended, dextromethorphan is classified as a dissociative psychedelic drug, with visible effects that are similar to those of ketamine and phencyclidine (PCP). It can produce distortions of the visual field, feelings of dissociation, distortions of bodily perception, excitement, as well as a loss of comprehension of time.[8][9]

Chemistry

Dextromethorphan is the dextrorotatory enantiomer of the methyl ether of levorphanol, an opioid analgesic. It is also a stereoisomer of levomethorphan, an opioid analgesic. It is named according to IUPAC rules as (+)-3-methoxy-17-methyl-9α,13α,14α-morphinan. As the pure free base, dextromethorphan occurs as an odorless, white to slightly yellow crystalline powder. It is freely soluble in chloroform 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. Dextromethorphan's specific rotation in water is +27.6° (20°C, Sodium D-line).

Pharmacology

Pharmacodynamics

Dextromethorphan has relatively low affinity for the NMDAR, with most of its actions on this receptor being mediated by its 8-fold more potent metabolite dextrorphan.[21] Additionally, dextromethorphan's affinity for the NET and μ-opioid receptor are very low and likely insignificant even at recreational doses.

Pharmacokinetics

Following oral administration, dextromethorphan is rapidly absorbed from the gastrointestinal tract, where it enters the bloodstream and crosses the blood-brain barrier.

At therapeutic doses, dextromethorphan acts centrally (meaning that it acts on the brain) as opposed to locally (on the respiratory tract). It elevates the threshold for coughing, without inhibiting ciliary activity. Dextromethorphan is rapidly absorbed from the gastrointestinal tract and converted into the less active metabolite, dextrorphan in the liver by the cytochrome P450 enzyme CYP2D6. The average dosage necessary for effective antitussive therapy is between 10 mg and 45 mg, depending on the individual. The International Society for the Study of Cough recommend "an adequate first dose of medication ie 60 mg in the adult and repeat dosing should be infrequent rather than the qds recommended."[22]

The duration of action after oral administration is approximately three to eight hours for dextromethorphan-hydrobromide, and ten to twelve hours for dextromethorphan-polistirex. Approximately 1 in 10 of the caucasian population has little or no CYP2D6 enzyme activity leading to long lived high drug levels.[23]

Because administration of dextromethorphan can trigger a histamine release (an allergic reaction), its use in atopic children is very limited.

Metabolism

The first-pass through the hepatic portal vein results in some of the drug's being metabolized by O-demethylation into an active metabolite of dextromethorphan called dextrorphan (DXO). DXO is the 3-hydroxy derivative of dextromethorphan. The therapeutic activity of dextromethorphan is believed to be caused by both the drug and this metabolite. Dextromethorphan also undergoes N-demethylation (to 3-methoxymorphinan or MEM),[24] and partial conjugation with glucuronic acid and sulfate ions. Hours after dextromethorphan therapy, (in humans) the metabolites (+)-3-hydroxy-N-methylmorphinan, (+)-3-morphinan, and traces of the unchanged drug are detectable in the urine.[25]

A major metabolic catalyst involved is the cytochrome P450 enzyme known as 2D6, or CYP2D6. A significant portion of the population has a functional deficiency in this enzyme and are known as poor CYP2D6 metabolizers. O-demethylation of DXM to DXO contributes to at least 80% of the DXO formed during DXM metabolism.[24] As CYP2D6 is a major metabolic pathway in the inactivation of dextromethorphan, the duration of action and effects of dextromethorphan can be increased by as much as three times in such poor metabolizers.[26] In one study on 252 Americans, 84.3% were found to be "fast" (extensive) metabolizers, 6.8% to be "intermediate" metabolizers, and 8.8% were "slow" metabolizers of DXM.[27] There are a number of known alleles for CYP2D6, including several completely inactive variants. The distribution of alleles is uneven amongst ethnic groups; see also CYP2D6 - Ethnic factors in variability.

A large number of medications are potent inhibitors of CYP2D6. Some types of medications known to inhibit CYP2D6 include certain SSRI and tricyclic antidepressants, some antipsychotics, and the commonly-available antihistamine diphenhydramine -- also known as Benadryl. There exists, therefore, the potential of interactions between dextromethorphan and medications that inhibit this enzyme, particularly in slow metabolizers. See also CYP2D6 - Ligands.

DXM is also metabolized by CYP3A4. N-demethylation is primarily accomplished by CYP3A4, contributing to at least 90% of the MEM formed as a primary metabolite of DXM.[24]

A number of other CYP enzymes are implicated as minor pathways of DXM metabolism. CYP2B6 is actually more effective than CYP3A4 at N-demethylation of DXM, but, since the average individual has a much lower CYP2B6 content in his/her liver relative to CYP3A4, most N-demethylation of DXM is catalyzed by CYP3A4.[24]

Side effects

Side-effects of dextromethorphan use can include:[25]

Dextromethorphan can also cause other gastrointestinal disturbances. Dextromethorphan had been thought to cause Olney's Lesions when administered intravenously; however, this was later proven not to be true.[28][29] In some rare documented cases, dextromethorphan has produced psychological dependence in some people who used it recreationally. However, it does not produce physical addiction, according to the WHO Committee on Drug Dependence.[30]

Contraindications

Because dextromethorphan can trigger a histamine release (allergic reaction), atopic children, who are especially susceptible to allergic reactions, should be administered dextromethorphan only if absolutely necessary, and only under the strict supervision of a health care professional.[25]

Drug interactions

Dextromethorphan should not be taken with either of the following:

See also

References

  1. ^ "Plasma profile and pharmacokinetics of dextromethorphan after intravenous and oral administration". Journal of Veterinary Pharmacology and Therapeutics. http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2885.2004.00608.x?cookieSet=1&journalCode=jvp. 
  2. ^ DEXTROMETHORPHAN (Street Names: DXM, CCC, Triple C, Skittles, Robo, Poor Man’s PCP)
  3. ^ a b c Dextromethorphan (DXM) | CESAR
  4. ^ Cough medicines "have no benefit" BBC News: Health, Tuesday, July 6, 2004. Accessed July 28, 2007.
  5. ^ "Kids' cough medicine no better than placebo" San Francisco Chronicle, July 8, 2004
  6. ^ Brooks B, Thisted R, Appel S, Bradley W, Olney R, Berg J, Pope L, Smith R (2004). "Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial". Neurology 63 (8): 1364–70. PMID 15505150. 
  7. ^ "Cough Drug May Help Fibromyalgia Pain". WebMD. http://www.webmd.com/content/article/106/108142. 
  8. ^ AJ Giannini. Drugs of Abuse--Second Edition. Los Angeles, Practice Management Information Corp, 1997.
  9. ^ [1]
  10. ^ Wong BY, Coulter DA, Choi DW, Prince DA (February 1988). "Dextrorphan and dextromethorphan, common antitussives, are antiepileptic and antagonize N-methyl-D-aspartate in brain slices". Neuroscience Letters 85 (2): 261–6. PMID 2897648. 
  11. ^ Church J, Jones MG, Davies SN, Lodge D (June 1989). "Antitussive agents as N-methylaspartate antagonists: further studies". Canadian Journal of Physiology and Pharmacology 67 (6): 561–7. PMID 2673498. 
  12. ^ Kamel IR, Wendling WW, Chen D, Wendling KS, Harakal C, Carlsson C (October 2008). "N-methyl-D-aspartate (NMDA) antagonists--S(+)-ketamine, dextrorphan, and dextromethorphan--act as calcium antagonists on bovine cerebral arteries". Journal of Neurosurgical Anesthesiology 20 (4): 241–8. doi:10.1097/ANA.0b013e31817f523f. PMID 18812887. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0898-4921&volume=20&issue=4&spage=241. 
  13. ^ "British Journal of Pharmacology — The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via [sigma1 receptor activation: comparison with the effects of dextromethorphan"]. http://www.nature.com/bjp/journal/v144/n7/full/0705998a.html. Retrieved 2007-07-16. 
  14. ^ Damaj MI, Flood P, Ho KK, May EL, Martin BR (February 2005). "Effect of dextrometorphan and dextrorphan on nicotine and neuronal nicotinic receptors: in vitro and in vivo selectivity". The Journal of Pharmacology and Experimental Therapeutics 312 (2): 780–5. doi:10.1124/jpet.104.075093. PMID 15356218. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15356218. 
  15. ^ Hernandez SC, Bertolino M, Xiao Y, Pringle KE, Caruso FS, Kellar KJ (2000). "Dextromethorphan and its metabolite dextrorphan block alpha3beta4 neuronal nicotinic receptors". J. Pharmacol. Exp. Ther. 293 (3): 962–7. PMID 10869398. 
  16. ^ a b c Codd EE, Shank RP, Schupsky JJ, Raffa RB (September 1995). "Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception". The Journal of Pharmacology and Experimental Therapeutics 274 (3): 1263–70. PMID 7562497. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7562497. 
  17. ^ Henderson MG, Fuller RW (October 1992). "Dextromethorphan antagonizes the acute depletion of brain serotonin by p-chloroamphetamine and H75/12 in rats". Brain Research 594 (2): 323–6. http://linkinghub.elsevier.com/retrieve/pii/0006-8993(92)91144-4. 
  18. ^ Gillman PK (October 2005). "Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity". British Journal of Anaesthesia 95 (4): 434–41. doi:10.1093/bja/aei210. PMID 16051647. http://bja.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=16051647. 
  19. ^ Schwartz AR, Pizon AF, Brooks DE (September 2008). "Dextromethorphan-induced serotonin syndrome". Clinical Toxicology (Philadelphia, Pa.) 46 (8): 771–3. PMID 19238739. 
  20. ^ Zhang W, Wang T, Qin L, Gao HM, Wilson B, Ali SF, Zhang W, Hong JS, Liu B (20 January 2004). "Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase". The FASEB Journal. doi:10.1096/fj.03-0983fje. PMID 14734632. 
  21. ^ Chou YC, Liao JF, Chang WY, Lin MF, Chen CF (March 1999). "Binding of dimemorfan to sigma-1 receptor and its anticonvulsant and locomotor effects in mice, compared with dextromethorphan and dextrorphan". Brain Research 821 (2): 516–9. PMID 10064839. http://linkinghub.elsevier.com/retrieve/pii/S0006-8993(99)01125-7. 
  22. ^ Professor Alyn H Morice paper titled 'Cough' par. 'Dextromethorphan' http://www.issc.info/cough.html
  23. ^ Professor Alyn H Morice paper titled 'Cough' http://www.issc.info/cough.html
  24. ^ a b c d "Comparative Contribution to Dextromethorphan Metabolism by Cytochrome P450 Isoforms in Vitro: Can Dextromethorphan Be Used as a Dual Probe for Both CYP2D6 and CYP3A Activities?". http://dmd.aspetjournals.org/cgi/content/full/29/11/1514. Retrieved 2008-08-10. 
  25. ^ a b c d e f "Dextromethorphan". NHTSA. http://www.nhtsa.dot.gov/PEOPLE/injury/research/job185drugs/dextromethorphan.htm. 
  26. ^ "Clinical Pharmacology & Therapeutics — Abstract of article: The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans[ast"]. http://www.nature.com/clpt/journal/v60/n3/abs/clpt1996482a.html. Retrieved 2007-07-16. 
  27. ^ "The polymorphic metabolism of dextromethorphan (abstract)". http://jcp.sagepub.com/cgi/content/abstract/27/2/139. Retrieved 2008-08-10. 
  28. ^ Olney J, Labruyere J, Price M (1989). "Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs". Science 244 (4910): 1360–2. doi:10.1126/science.2660263. PMID 2660263. 
  29. ^ Hargreaves R, Hill R, Iversen L. "Neuroprotective NMDA antagonists: the controversy over their potential for adverse effects on cortical neuronal morphology". Acta Neurochir Suppl (Wien) 60: 15–9. PMID 7976530. 
  30. ^ WHO Expert Committee on Drug Dependence (1970) (PDF). Seventeenth Report. World Health Organization. http://whqlibdoc.who.int/trs/WHO_TRS_437.pdf. Retrieved 2008-12-29. 

Simple English

[[File:|right|thumb|Dextromethorphan]] Dextromethorphan (DXM or DM) is a drug. It is used to prevent coughs in many over-the-counter cold and cough medicines. Dextromethorphan can also be used for pain relief or for psychological conditions. It is sold in syrup, tablet, and lozenge forms, manufactured under several different brand names and generic labels. In its pure form, dextromethorphan is a white powder.

If more is taken than directed, dextromethorphan acts as a dissociative hallucinogenic drug. Its mechanism of action (how it works) is as an NMDA receptor antagonist (blocks a chemical in the brain), producing effects similar to those of the controlled substances ketamine and phencyclidine (PCP). [1]

References









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