Dextromethorphan

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Dextromethorphan
Dextromethorphan2DACS2.svg
Dextromethorphan-from-xtal-3D-balls-A.png
Systematic (IUPAC) name
(4bS,8aR,9S)-3-methoxy-11-methyl-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene
Clinical data
Trade names Robitussin, Delsym, DM, DexAlone, Duract
AHFS/Drugs.com monograph
MedlinePlus a682492
Pregnancy cat. A (AU) C (US)
Legal status Pharmacy Only (S2) (AU) OTC (CA) OTC (UK) OTC (US)
Dependence liability Low
Routes Oral
Pharmacokinetic data
Bioavailability 11%[1]
Metabolism Hepatic (liver) enzymes: major CYP2D6, minor CYP3A4, and minor CYP3A5
Half-life 2-4 hours (extensive metabolisers); 24 hours (poor metabolisers)[2]
Excretion Renal
Identifiers
CAS number 125-71-3 YesY
ATC code R05DA09
PubChem CID 15978238
DrugBank DB00514
ChemSpider 13109865 YesY
UNII 7355X3ROTS YesY
KEGG D03742 YesY
ChEMBL CHEMBL52440 YesY
Chemical data
Formula C18H25NO 
Mol. mass 271.40 g/mol
Physical data
Melt. point 111 °C (232 °F)
 YesY (what is this?)  (verify)

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, including generic labels and store brands, Benylin DM, Mucinex DM, Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, TheraFlu, and others. 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.[3]

DXM is also used recreationally. When exceeding label-specified maximum dosages, dextromethorphan acts as a dissociative hallucinogen. Its mechanism of action is via multiple effects, including actions as a nonselective serotonin reuptake inhibitor[4] and a sigma-1 receptor agonist.[5][6] The major metabolite of DXM, dextrorphan, also acts as an NMDA receptor antagonist. In high doses this produces effects similar to, yet distinct from, the dissociative states created by other dissociative anaesthetics such as ketamine and phencyclidine.[7] As well, the metabolite 3-methoxymorphinan of dextrorphan (thus a second-level metabolite of DXM) produces local anesthetic effects in rats with potency above dextrorphan, but below that of DXM.[8]

Medical use[edit]

Generic Dextromethorphan syrup.

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 particle irritants.[9]

A 2004 study showed that dextromethorphan was no more effective for children than a placebo.[10] Studies conducted by the American Academy of Pediatrics show that dextromethorphan is not superior to a placebo in providing nocturnal symptom relief for children with cough and sleep difficulty due to upper respiratory infections.[11]

A combination of dextromethorphan and quinidine, a CYP2D6 inhibitor, has been shown to alleviate symptoms of easy laughing and crying (pseudobulbar affect) in patients with amyotrophic lateral sclerosis and multiple sclerosis.[12] Dextromethorphan is also being investigated as a possible treatment for neuropathic pain and pain associated with fibromyalgia.[13] In 2010, the FDA approved the combination product dextromethorphan/quinidine (Nuedexta) for the treatment of pseudobulbar affect (PBA).

Dextromethorphan has been shown to be effective in treating opioid withdrawal. At doses of 2mg/kg in rats all signs of opioid withdrawal were eliminated.[14]

Recreational use[edit]

Dextromethorphan gel capsules

Over-the-counter preparations containing dextromethorphan have been used in manners inconsistent with their labeling, often as a recreational drug.[15] At doses much higher than medically recommended, dextromethorphan is classified as a dissociative hallucinogen, possessing certain effects that are somewhat similar to the dissociative agents ketamine and phencyclidine. It may produce distortions of the visual field - feelings of dissociation, distorted bodily perception, and excitement, as well as 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".[16][17][18]

Adverse effects[edit]

Side-effects of dextromethorphan use can include:[2][19][9]

At normal doses:

Rare side effects include respiratory depression.[9] It is considered less addictive than the other common weak opioid cough suppressant, codeine.[2]

At dosages 3 to 10 times the recommended therapeutic dose:[20]

  • Increased energy
  • Increased confidence
  • Slight Nauseousness
  • Restlessness
  • Insomnia
  • "speeding"/talking fast
  • Feelings of increased strength
  • Enlargened pupils/glazed eyes (but not red)

At dosages 15 to 75 times the recommended therapeutic dose:[20]


Dextromethorphan can also cause other gastrointestinal disturbances. Dextromethorphan had been thought to cause Olney's Lesions when administered intravenously; however, this was later proven inconclusive, due to lack of research on humans. Tests were performed on rats, giving them 50 mg and up every day up to a month. Neurotoxic changes, including vacuolation, have been observed in posterior cingulate and retrosplenial cortices of rats administered other NMDA antagonists such as PCP, but not with dextromethorphan.[21][22] In many documented cases, dextromethorphan has produced psychological dependence in people who used it recreationally. However, it does not produce physical addiction, according to the WHO Committee on Drug Dependence.[23]

Contraindications[edit]

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 healthcare professional.[19]

Drug interactions[edit]

Dextromethorphan should not be taken with monoamine oxidase inhibitors (MAOIs)[19] due to the potential for serotonin syndrome, which is a potentially life-threatening condition that can occur rapidly, due to a buildup of an excessive amount of serotonin in the body. Dextromethorphan can also cause serotonin syndrome when used with SSRI medicines, an interaction which has been documented in clinical cases where dextromethorphan is taken at recreational doses. It has been suggested that the link between therapeutic dosages of dextromethorphan and serotonin syndrome is less conclusive.[24]

Food interactions[edit]

Caution should be exercised when taking dextromethorphan when drinking grapefruit juice or eating grapefruits, as compounds in grapefruit affect a number of drugs, including dextromethorphan, through the inhibition of the cytochrome p450 system in the liver and can lead to excessive accumulation and prolonged effects. It is generally recommended that grapefruits and grapefruit juices (especially white grapefruit juice, but also including other citrus fruits such as bergamot and lime, as well as a number of non-citrus fruits[25]) be avoided while using dextromethorphan and numerous other medications.

Lab testing[edit]

Testing for this drug is done either by blood or by urine. Blood can be either serum or plasma, serum in a plain red top 2mL preferred. Urine requires only 2mL minimum.

Chemistry[edit]

Dextromethorphan is the dextrorotatory enantiomer of levomethorphan, which is the methyl ether of levorphanol, both opioid analgesics. 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 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).[citation needed]

Pharmacology[edit]

Pharmacodynamics[edit]

Dextromethorphan has been shown to possess the following properties, mainly in binding assays to various receptors of animal tissues. Low Ki values mean strong binding or high affinity; high Ki values mean weak binding to the target or low affinity:

Its affinities for some of the sites listed are relatively very low and are probably insignificant, such as binding to NMDA receptors and opioid receptors, even at high recreational doses.[citation needed] Instead of acting as a direct antagonist of the NMDA receptor itself, it is likely that dextromethorphan functions as a prodrug to its nearly 10-fold more potent metabolite dextrorphan, and this is the true mediator of its dissociative effects.[26] It is not entirely clear what role, if any, (+)-3-methoxymorphinan, dextromethorphan's other major metabolite, plays in its effects.[38]

Pharmacokinetics[edit]

Following oral administration, dextromethorphan is rapidly absorbed from the gastrointestinal tract, where it enters the bloodstream and crosses the blood–brain barrier.[citation needed]

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 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 is 60 mg in the adult and repeat dosing should be infrequent rather than the qds recommended."[39]

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.[40]

Because administration of dextromethorphan can trigger a histamine release (an allergic reaction), its use in atopic children is very limited.[19]

Metabolism[edit]

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),[41] 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.[19]

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 100% of the DXO formed during DXM metabolism.[41] 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.[42] 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.[43] 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. There exists, therefore, the potential of interactions between dextromethorphan and medications that inhibit this enzyme, particularly in slow metabolizers.[citation needed] 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.[41]

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.[41]

History[edit]

Dextromethorphan was identified as one of three compounds tested as part of US Navy and CIA-funded research that sought a "nonaddictive substitute for codeine"; it is implied that the compound was first found to have clinical potential in this study.[44] It was first patented in 1949.[45] The U.S. Food and Drug Administration (FDA) approved dextromethorphan as a prescription antitussive drug on September 24, 1954, and subsequently as an over-the-counter cough suppressant in 1958. This filled the need for a cough suppressant lacking the sedative side-effects, stronger potential for misuse, and physically addictive properties of codeine phosphate, the most widely used cough medication at the time.[15]

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, and was replaced by cough syrup in an attempt to cut down on abuse[15] As of January 1, 2012, dextromethorphan is prohibited for sale to minors in the state of California, except with a doctor's prescription.[46]

See also[edit]

References[edit]

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  39. ^ Professor Alyn H Morice paper titled 'Cough' par. 'Dextromethorphan' http://www.issc.info/cough.html
  40. ^ Professor Alyn H Morice paper titled 'Cough' http://www.issc.info/cough.html
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  46. ^ http://www.leginfo.ca.gov/pub/11-12/bill/sen/sb_0501-0550/sb_514_bill_20110831_chaptered.pdf

External links[edit]