Dextromethorphan
Clinical data | |
---|---|
Pronunciation | /ˌdɛk.stroʊ.məˈθɔːrˌfæn/ DEK-stroh-məth-OR-fan |
Trade names | Robitussin, Delsym, others |
Other names | DXM, 3-methoxy-N-methylmorphinan |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682492 |
License data | |
Pregnancy category |
|
ATC code | |
Legal status | |
Legal status |
|
poor metabolizers)[4] | |
Excretion | Kidney |
Identifiers | |
| |
JSmol) | |
Melting point | 111 °C (232 °F) |
| |
| |
(what is this?) (verify) |
Dextromethorphan (DXM) is a
It is in the morphinan class of medications with sedative, dissociative, and stimulant properties (at lower doses). Dextromethorphan does not have a significant affinity for the mu-opioid receptor activity typical of morphinan compounds and exerts its therapeutic effects through several other receptors.[7] In its pure form, dextromethorphan occurs as a white powder.[8]
When exceeding approved dosages, dextromethorphan acts as a
.It was patented in 1949 and approved for medical use in 1953.[12]
Medical uses
Cough suppression
The primary use of dextromethorphan is as a
Pseudobulbar affect
In 2010, the FDA approved the combination drug
Major depressive disorder
The combination medicine
Contraindications
Because dextromethorphan can trigger a
Adverse effects
Side effects of dextromethorphan at normal therapeutic doses can include:[4][14][19]
- body itching (see above)
- nausea
- vomiting
- drowsiness
- dizziness
- constipation
- diarrhea
- sedation
- confusion
- nervousness
- closed-eye hallucination
A rare side effect is
Neurotoxicity
Dextromethorphan was once thought to cause
Dependence and withdrawal
In many documented cases[citation needed], dextromethorphan has produced psychological dependence in people who used it recreationally. It is considered less addictive than other common cough suppressants, such as the weak opiate codeine.[4] Since dextromethorphan also acts as a serotonin reuptake inhibitor, users report that regular recreational use over a long period of time can cause withdrawal symptoms similar to those of antidepressant discontinuation syndrome. Additionally, disturbances have been reported in sleep, senses, movement, mood, and thinking.
Overdose
Adverse effects of dextromethorphan in
- mild nausea
- restlessness
- insomnia
- talking fast
- dilated pupils
- glassy eyes
- dizziness
At doses 11 to 75 times the recommended therapeutic dose:[22][failed verification][23]
- hallucinations
- dissociation
- vomiting
- blurred vision
- double vision
- bloodshot eyes
- dilated pupils
- sweating
- fever
- bruxia(teeth grinding)
- hypotension
- hypertension
- tachycardia
- shallow respiration
- diarrhea
- urinary retention
- muscle spasms
- sedation
- paresthesia
- blackouts
- inability to focus eyes
- skin rash
- severe itchiness
- acute psychosis
Episodic
Interactions
Serotonin syndrome may result from the combined use of dextromethorphan and serotonergic antidepressants such as selective serotonin reuptake inhibitor (SSRIs) or monoamine oxidase inhibitor (MAOIs).[24] Further research is needed to determine whether doses of dextromethorphan beyond those normally used therapeutically are needed to produce this effect.[9] In any case, dextromethorphan should not be taken with MAOIs due to the possibility of this complication.[19] Serotonin syndrome is a potentially life-threatening condition that can occur rapidly, due to a buildup of an excessive amount of serotonin in the body.
Patients who are taking dextromethorphan should exercise caution when drinking
Pharmacology
Pharmacodynamics
Site | DXM | DXO | Species | Ref |
---|---|---|---|---|
NMDAR (MK-801) |
2,120–8,945 | 486–906 | Rat | [16] |
σ1 | 142–652 | 118–481 | Rat | [16] |
σ2 | 11,060–22,864 | 11,325–15,582 | Rat | [16] |
MOR |
1,280 ND |
420 >1,000 |
Rat Human |
[16] [29] |
DOR |
11,500 | 34,700 | Rat | [16] |
KOR |
7,000 | 5,950 | Rat | [16] |
SERT | 23–40 | 401–484 | Rat | [16] |
NET | ≥240 | ≥340 | Rat | [16] |
DAT | >1,000 | >1,000 | Rat | [16] |
5-HT1A | >1,000 | >1,000 | Rat | [16] |
5-HT1B/1D | 61% at 1 μM | 54% at 1 μM | Rat | [16] |
5-HT2A | >1,000 | >1,000 | Rat | [16] |
α1 | >1,000 | >1,000 | Rat | [16] |
α2 | 60% at 1 μM | >1,000 | Rat | [16] |
β |
>1,000 | 35% at 1 μM | Rat | [16] |
D2 |
>1,000 | >1,000 | Rat | [16] |
H1 |
>1,000 | 95% at 1 μM | Rat | [16] |
mAChRs |
>1,000 | 100% at 1 μM | Rat | [16] |
nAChRs |
700–8,900 (IC50) |
1,300–29,600 (IC50) |
Rat | [16] |
VDSCs |
>50,000 (IC50) | ND | Rat | [30][31] |
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site. |
Dextromethorphan has been found to possess the following actions (<1 μM) using rat tissues:[16][32]
- SERT and NET blocker (cf. serotonin–norepinephrine reuptake inhibitor)
- Sigma σ1 receptor agonist
- Negative allosteric modulator of nicotinic acetylcholine receptors
Dextromethorphan is a
Pharmacokinetics
Following oral administration, dextromethorphan is rapidly absorbed from the
At therapeutic doses, dextromethorphan acts
Dextromethorphan has an
Metabolism
The first pass through the
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 dextromethorphan to dextrorphan contributes to at least 80% of the dextrorphan formed during dextromethorphan metabolism.[37] 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.[38] 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 dextromethorphan.[39] A number of alleles for CYP2D6 are known, including several completely inactive variants. The distribution of alleles is uneven amongst ethnic groups.
A large number of medications are potent
Dextromethorphan 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 dextromethorphan.[37]
A number of other CYP enzymes are implicated as minor pathways of dextromethorphan metabolism. CYP2D6 is more effective than CYP3A4 at N-demethylation of dextromethorphan, but since the average individual has a much lower CYP2D6 content in the liver compared to CYP3A4, most N-demethylation of dextromethorphan is catalyzed by CYP3A4.[37]
Chemistry
Dextromethorphan is the
Synthesis
Several routes exist for the synthesis of Dextromethorphan. Even though many of the syntheses have been known since the middle of the 20th century, researchers are still working today to further develop the synthesis of Dextromethorphan and, for example, to make it more environmentally friendly.
This includes the synthesis by means of ionic liquids.[citation needed]
Racemate separation
Since only one of the stereoisomers has the desired effect, the separation of a racemic mixture of hydroxy N- methyl morphinan using tartaric acid and subsequent methylation of the hydroxyl group is a suitable method. By using (D)-tartrate, the (+)-isomer remains as the product.
This synthetic pathway was patented by Roche in 1950.
Traditional synthesis
The traditional synthetic route uses Raney nickel and has been further improved over time, for example by the use of ibuprofen and AlCl3.
Overall, it is a cost-effective method with moderate reaction conditions that is easy to handle and suitable for industrial production.[citation needed]
Grewe's cyclization
Grewe's cyclization is easier to handle in terms of the chemicals used, produces higher yields and higher purity of the product.[41]
Improved Grewe's cyclization
Formylation of octabase prior to cyclization avoids ether cleavage as a side reaction and yields higher than without N-substitution or N-methylation. In this example, the purification was done by formation of a brucine salt.[citation needed]
This process has also been patented by Roche.
History
The
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 misuse. A few years later, products with an unpleasant taste were introduced (such as Robitussin, Vicks-44, and Dextrotussion), but later the same manufacturers began producing products with a better taste.[44] The advent of widespread internet access in the 1990s allowed users to rapidly disseminate information about dextromethorphan, and online discussion groups formed around use and acquisition of the drug. As early as 1996, dextromethorphan hydrobromide powder could be purchased in bulk from online retailers, allowing users to avoid consuming dextromethorphan in syrup preparations.[42]
FDA panels considered moving dextromethorphan to prescription status due to its potential for abuse, but voted against the recommendation in September 2010, citing lack of evidence that making it prescription-only would curb abuse.
In
Society and culture
Marketing
It may be used in
Recreational use
It may produce distortions of the visual field – feelings of dissociation, distorted bodily perception, excitement, and a loss of sense of time. Some users report stimulant-like euphoria, particularly in response to music. Dextromethorphan usually provides its recreational effects in a non-linear fashion, so that they are experienced in significantly varied stages. These stages are commonly referred to as "plateaus". These plateaus are numbered from one to four, with the first having the mildest effects to fourth being the most intense. Each plateau is said to come with different related effects and experiences.[52]
The first plateau is said to induce music euphoria and mild stimulation, likened to that of MDMA. The second plateau is likened to a state of being on moderate amounts of alcohol and cannabis at the same time, featuring euphoria, sedation and minor hallucinations. The third plateau induces a significant dissociative state which can often cause anxiety in users. Reaching the fourth plateau is said to cause extreme sedation and a significant hallucinatory state as well as complete dissociation from reality. Teenagers tend to have a higher likelihood to use dextromethorphan-related drugs as they are easier to access, and an easier way to cope with psychiatric disorders.[53]
Research
The combination drug dextromethorphan/quinidine (AVP-923),[54][55] traditionally used to treat pseudobulbar affect, is under investigation for the treatment of a variety of other neurological and neuropsychiatric conditions including agitation associated with Alzheimer's disease, among others.[16][56] In 2013, a randomized clinical trial found that dextromethorphan may reduce the overall discomfort and duration of withdrawal symptoms associated with opioid use disorder. When combined with clonidine, dextromethorphan reduced the overall time needed for withdrawal symptoms to peak by 24 hours while reducing severity of symptoms compared to clonidine alone.[57]
References
- ^ "Dextromethorphan Monograph for Professionals". Drugs.com.
- S2CID 221798401.
- PMID 15500572.
- ^ a b c "Balminil DM, Benylin DM (dextromethorphan) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 15 April 2014.
- S2CID 252736111.
By sales, dextromethorphan is the most widely used OTC antitussive drug in the United States, and approximately 85% to 90% of OTC cough medicines contain dextromethorphan
- S2CID 232141396.
- PMID 27139517.
- ^ "Reference Tables: Description and Solubility - D". Archived from the original on 2017-07-04. Retrieved 2011-05-06.
- ^ S2CID 37817922.
- S2CID 43230896.
- PMID 15723099.
- ISBN 9783527607495.
- PMID 21724464.
- ^ ISBN 978-0-9805790-9-3.[page needed]
- ^ "Nuedexta- dextromethorphan hydrobromide and quinidine sulfate capsule, gelatin coated". DailyMed. 23 June 2019. Retrieved 23 October 2020.
- ^ PMID 26826604.
- ^ "Auvelity (dextromethorphan hydrobromide/bupropion hydrochloride)" (PDF). Axsome Therapeutics. Archived (PDF) from the original on 21 August 2022. Retrieved 19 August 2022.
- S2CID 253158902.
- ^ a b c d "Dextromethorphan". National Highway Traffic Safety Administration (NHTSA). Archived from the original on 2008-08-01.
- PMID 2660263.
- PMID 17573115.
- ^ a b "Teen Drug Abuse: Cough Medicine and DXM (Dextromethorphan)". webmd. Archived from the original on 2017-11-21.
- ^ PMID 28936010.
- PMID 28784915.
- ^ "Inhibitors of CYP3A4". ganfyd.org. Archived from the original on 2017-07-20. Retrieved 23 August 2013.
- ^ Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
- S2CID 38476281.
- ^ PMID 27139517.
- PMID 7815359.
- PMID 17346698.
- PMID 23139844.
- ^ PMID 24648790.
- S2CID 22762264.
- S2CID 5638973.
- ^ a b Morice AH. "Cough". International Society for the Study of Cough. Archived from the original on 2017-05-09.
- PMID 19445995.
- ^ PMID 11602530. Archived from the originalon 2020-03-12. Retrieved 2015-04-26.
- S2CID 10147669.
- S2CID 37950361.
- ^ "Dextromethorphan (PIM 179)". www.inchem.org. Archived from the original on 2017-03-10. Retrieved 2018-03-24.
- ISSN 0931-7597.
- ^ PMID 24678061.
- ^ "Memorandum for the Secretary of Defense" (PDF). Archived (PDF) from the original on 2017-09-16. Retrieved 2013-07-28.
- ^ a b c "Dextromethorphan (DXM)". Cesar.umd.edu. Archived from the original on 2018-01-06. Retrieved 2013-07-28.
- ^ Nordqvist C. FDA panel: cough meds should stay over the counter. Sept. 14, 2010. Medical News Today Website. http://www.medicalnewstoday.com/articles/201227.php. Accessed May 18, 2020.
- ^ "Senate Bill No. 514" (PDF). An act to add Sections 11110 and 11111 to the Health and Safety Code, relating to nonprescription drugs. State of California, Legislative Counsel. Archived (PDF) from the original on 2018-03-08.
- ^ "BPOM Tetap Batalkan Izin Edar Obat Dekstrometorfan" [BPOM Still Cancels Dextromethorphan Drug Distribution Permit]. VIVAnews (in Indonesian). 22 May 2014. Archived from the original on 2015-05-28.
- ^ "SINDOnews | Berita Daerah Dan Provinsi Di Indonesia". daerah.sindonews.com (in Indonesian). Retrieved 2017-12-10.[dead link]
- ^ "Pimpinan dan Apoteker Penanggung Jawab" (PDF). Archived from the original (PDF) on 2017-08-10.
- ^ "Badan Pengawas Obat dan Makanan - Republik Indonesia". www.pom.go.id. Archived from the original on 2017-02-03. Retrieved 2017-12-10.
- ^ "Dextromethorphan" (PDF). Drugs and Chemicals of Concern. Drug Enforcement Administration. August 2010. Archived from the original (PDF) on 2012-10-16.
- ISBN 1570660530.[page needed]
- S2CID 70666093.
- PMID 20373255.
- S2CID 231987025.
- S2CID 46777150.
- PMID 23864983.
External links
Media related to Dextromethorphan at Wikimedia Commons