cough syrup

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
Y(what is this?)  (verify)

Dextromethorphan (DXM or DM) is an antitussive drug. It is one of the active ingredients used to prevent coughs in many over-the-counter cold and cough medicines. 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 manufactured under several different brand names and generic labels. In its pure form, dextromethorphan occurs as a white powder.

Dextromethorphan may be modestly effective in decreasing cough associated with an upper respiratory tract infection in adults. In children however it has not been found to be effective.^[2]

When exceeding label-specified maximum dosages, dextromethorphan acts as a dissociative psychedelic drug. Its mechanism of action is as an NMDA receptor antagonist, producing effects similar to those of the controlled substances ketamine and phencyclidine (PCP).^[3]

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.^[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 rules for sale of pseudoephedrine. As with most cough suppressants, studies show that dextromethorphan's effectiveness is highly debatable,^[5] especially in children.^[6]

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.

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).

Indications

The primary use of dextromethorphan is as a cough suppressant, for the temporary relief of cough caused by minor throat and bronchial irritation (as commonly accompanies the 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.^[7] Dextromethorphan is also being investigated as a possible treatment for neuropathic pain and pain associated with fibromyalgia.^[8]

Pharmacokinetics

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."^{[citation needed]}

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.^[9]

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

Side-effects

Side-effects of dextromethorphan use can include:^[10]

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.^[11][12] In some rare documented cases, dextromethorphan has produced psychological dependence in people that abused it. However, it does not produce physical addiction, according to the WHO Committee on Drug Dependence.^[13]

Drug interactions

Dextromethorphan should not be taken with either of the following:

• monoamine oxidase inhibitors (MAOIs)^[10]
• selective serotonin reuptake inhibitors (SSRIs)^[10]

CNS depressant drugs and substances, including some psychotropics such as alcohol, will have a cumulative CNS depressant effect if taken with dextromethorphan.^[10]

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.^[10]

Clinical pharmacology

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

Nervous system activity

• NMDA receptor antagonist
• σ₁ and σ₂ sigma receptor agonist.^[14]
• α3β4 nicotinic receptor antagonist^[15]
• 5-HT (serotonin) reuptake inhibition^[16]
• Dopamine reuptake inhibitor (disputed)^[10][17]
• NADPH oxidase inhibitor^[18]

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),^[19] 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.^[10]

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.^[19] 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.^[20] 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.^[21] 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.^[19]

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.^[19]

Alternatives

A single dose of buckwheat honey has been found to offer similar statistical results for the relief of coughs in children with upper respiratory tract infections.^[22]

Recreational use

Since their introduction, over-the-counter preparations containing dextromethorphan have been used in a manner 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.^[23][24]

See also

Wikimedia Commons has media related to: Dextromethorphan

• Hallucinogen

• Morphinan
  • Dextrorphan
  • Levomethorphan
  • Methorphan

• Psychedelic

• Psychedelic drug
  • Dissociatives
    • Ketamine
    • Nitrous Oxide
    • Phencyclidine
• Recreational use of dextromethorphan

References

v • d • e Recreational drug use Major Recreational Drugs Cannabinoids THC (Cannabis) (Hashish) (Hash oil) Depressants Barbiturates · Benzodiazepines · Ethanol (Alcohol) · GHB · Nonbenzodiazepines Entactogens MDMA (Ecstasy) Hallucinogens Psychedelics DMT (Ayahuasca) · LSD · Mescaline (Peyote, San Pedro) · Psilocybin (Magic Mushrooms) Dissociatives DXM · Inhalants · Ketamine · Nitrous Oxide · PCP · Salvinorin A (Salvia) Deliriants Datura · Deadly Nightshade · Henbane · Mandrake Opioids Codeine · Heroin · Hydrocodone · Morphine (Opium) · Oxycodone Stimulants Amphetamine · Arecoline (Areca) · Betel · Caffeine (Coffee, Tea) · Cathinone (Khat) · Cocaine (Coca) · Ephedrine (Ephedra) · Methamphetamine · Methylphenidate · Nicotine (Tobacco) · Theobromine (Cocoa) Culture and Related Topics Cannabis 420 · Stoner Film · Spiritual Use of Cannabis · Medical Cannabis · Cannabis Cultivation · Cannabis smoking Psychedelic Art · Drug · Experience · Literature · Music Other Counterculture of the 1960s · Club Drug · Dance Party · Drug Tourism · Drug Paraphernalia · Hippie · Party and Play · Poly Drug Use · Rave · Sex and Drugs Spiritual use of drugs Problems With Drug Use Abuse · Addiction (Prevention · Rehabilitation · Responsible Use) · Illegal Trade · Overdose Legality of Drug Use International 1961 Narcotic Drugs · 1971 Psychotropic Substances · 1988 Drug Trafficking State Level Drug Policy (Prohibition · Decriminalization) · Policy Reform (Liberization · Harm Reduction · Demand Reduction) Other Drug Possession · Drug Test · Hard and Soft Drugs · Narc · War on Drugs Lists of Countries By... Alcohol Consumed · Cannabis Legality (Annual Use · Lifetime Use) · Cocaine Use · Opiate Use · Tobacco Smoked