Dextromethorphan

Dextromethorphan

Systematic (IUPAC) name
(+)-3-methoxy-17-methyl-(9α,13α,14α)-morphinan
Identifiers
CAS number	125-71-3
ATC code	R05DA09
PubChem	CID 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]

History

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^[3]. It 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.^[4] 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 modern rules for sale of pseudoephedrine.

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.^[4]

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.

As with most cough suppressants, studies show that dextromethorphan's effectiveness is unproven,^[5] especially in children.^[6] 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.^[7]

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.^[8] Dextromethorphan is also being investigated as a possible treatment for neuropathic pain and pain associated with fibromyalgia.^[9]

Recreational use

Dextromethorphan gel capsules

Since their introduction, over-the-counter preparations containing dextromethorphan have been used in manners inconsistent with their labeling, often as a recreational drug.^[4] 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.^[10][11]

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

• Uncompetitive NMDA receptor (PCP site) antagonist (K_i = 7,253 nM).^{[12][13][14][15]}
• σ₁ and σ₂ sigma receptor agonist (K_i = 205 nM and 11,060 nM, respectively). In a comparative investigation of dimemorfan, dextromethorphan and dextrorphan in mouse cells, dextromethorpan binds with relatively high affinity to Sigma-1 receptors and with very low affinity to Sigma-2 receptors.^[12]
• α₃β₄-, α₄β₂-, and α₇-nACh receptor (K_i = in the μM range) antagonist. Dextromethorphan binds to nicotinic receptors in frog eggs (Xenopus oocytes), human embryonic kidney cells and mouse tissue. It inhibits the antinociceptive (pain killing) action of nicotine in the tail-flick test in mice, where mouse tails are exposed to heat, which makes the mouse flick its tail if it feels pain.^[16][17][18]
• μ-, δ-, and κ-opioid receptor agonist (K_i = 1,280 nM, 11,500 nM, and 7,000 nM, respectively).^[19]
• SERT and NET blocker (K_i = 23 nM and 240 nM, respectively).^{[19][20][21][22]}
• NADPH oxidase inhibitor.^[23]

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. 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.^[12] It is not entirely clear what role, if any, (+)-3-methoxymorphinan, dextromethorphan's other major metabolite, plays in its effects.^[24]

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 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."^[25]

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.^[26]

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),^[27] 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.^[28]

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.^[27] 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.^[29] 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.^[30] 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.^[27]

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.^[27]

Side effects

Side-effects of dextromethorphan use can include:^[28]

• Note: In the article cited, those marked with asterisks are listed not as side effects per se, but , rather as overdose symptoms, occurring at dosages 12.5 to 75 times the recommended therapeutic dose.

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 50mg and up every day up to a month. Small lesions were believed to be found during the autopsy on the brain. However the only side effect the rats showed was a change in personality.^[32][33] 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.^[34]

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.^[28]

Drug interactions

Dextromethorphan should not be taken with any of the following:

• Monoamine oxidase inhibitors (MAOIs)^[28]
• Serotonin reuptake inhibitors (like SSRIs, SNRis, TCAs, etc.)^[28]
• Opiates
• CNS depressant drugs and substances, including some psychotropics such as alcohol, will have a cumulative CNS depressant effect if taken with dextromethorphan.^[28]

See also

References

External links

• U.S. National Library of Medicine: Drug Information Portal - Dextromethorphan

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