Dextromethorphan

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Dextromethorphan ( DXM or DM ) is a morphine-type drug with sedative, dissociative, and stimulant properties (at higher doses). It is a cough suppressant in many over-the-counter cough and cold medicines including generic labels and store brands, Benylin DM, Mucinex DM, Camydex-20, Robitussin, (Robocough) NyQuil, Dimetapp, Vicks, Coricidin, Delsym, TheraFlu, Cheracol D , and others. Dextromethorphan has also found many other uses in medicine, ranging from pain relievers (either as primary analgesics, or opioid potentiators) to psychological applications for the treatment of addiction. It is sold in the form of syrups, tablets, sprays, and candies.

In its pure form, dextromethorphan occurs as a white powder.

DXM is also used recreationally. When the approved dose exceeds, dextromethorphan acts as a dissociative anesthetic. It has several mechanisms of action, including action as a non selective selective serotonin reuptake inhibitor and sigma-1 receptor agonist. DXM and its major metabolites, dextrorphan, also act as high-dose NMDA receptor antagonists, producing effects similar to, but different from, dissociative states created by other dissociative anesthetics such as ketamine and phencyclidine.

The metabolic pathway continues from dextrorphan to 3-methoxymorphinan to 3-hydroxymorphinan. The 3-methoxymorphinan metabolite produces local anesthetic effects in mice, with potential between dextrorphan and DXM.

Video Dextromethorphan

Medical use

Cough suppression

The main use of dextromethorphan is as a cough suppressant, to remove a temporary cough caused by mild and bronchial throat irritation (as usually accompanying flu and common cold), and resulting from irritation of the inhaled particles. However, controlled studies have found the symptomatic efficacy of dextromethorphan similar to placebo.

Neuropsychiatric disorders

In 2010, the FDA approved a combination of dextromethorphan/quinidine drugs for the treatment of pseudobulbar affects (emotional instability). Dextromethorphan is the actual therapeutic agent in combination; quinidine only serves to inhibit dextromethorphan enzymatic degradation and thereby increase concentrations circulating through inhibition of CYP2D6.

In 2016, ASA released promising studies with a combination of dextromethorphan with pregabalin, acetaminophen, and naproxen showing a decrease in the intensity of postoperative pain (preemptive analgesia).

Maps Dextromethorphan

Contraindications

Because dextromethorphan can trigger the release of histamine (an allergic reaction), atopic children, who are particularly susceptible to allergic reactions, should be given dextromethorphan only if absolutely necessary, and only under the watchful eye of health professionals.

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Adverse effects

Side effects of dextromethorphan at normal therapeutic doses may include:

Rare side effects are respiratory depression.

Neurotoxicity

Dextromethorphan has been thought to cause an Olney lesion when administered intravenously; However, this then proved inconclusive, due to lack of research on humans. Tests were performed on mice, giving them 50 mg and daily to one month. Neurotoxic changes, including vacuolation, have been observed in the posterior cingulate and retrosplenial cortex in mice given other NMDA receptor antagonists such as PCP, but not with dextromethorphan.

Dependence and tethering

In many documented cases, dextromethorphan has resulted in psychological dependence on people who use it on a recreational basis. However, it does not result in physical addiction, according to the WHO Committee on Drug Addiction. It is considered less addictive than other soft opiate cough suppressants, codeine. Because dextromethorphan also acts as a serotonin reuptake inhibitor, the user describes that regular recreational use over a long period of time can lead to withdrawal symptoms similar to the antidepressant termination syndrome. In addition, disorders have been reported in sleep, senses, movement, mood, and thinking.

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Overdose

Side effects of dextromethorphan in overdose at a dose of 3 to 10 times recommended therapeutic dose:

At a dose of 15 to 75 times the recommended therapeutic dose:

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Interactions

Dextromethorphan should not be taken with monoamine oxidase inhibitors (MAOIs) because of the potential of serotonin syndrome, which is a potentially life-threatening condition that can occur quickly, due to the buildup of large amounts of serotonin in the body.

Attention should be taken when taking dextromethorphan when drinking orange juice or eating grapefruits, as a compound in oranges affects a number of drugs, including dextromethorphan, through inhibition of the p450 cytochrome system in the liver, and can lead to excessive accumulation and prolonged effects. Grapefruit and grapefruit juice (especially white grapefruit juice, but also other citrus fruits such as bergamot and lemon, as well as a number of non-digested fruit) are generally advised to avoid using dextromethorphan and many other drugs.

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Pharmacology

Pharmacodynamics

Dextromethorphan has been found to have the following action (& lt; 1Ã,? M) using mouse tissue:

• An uncompetitive antagonist of the NMDA receptor through the PCK
• Sigma? ₁ receptor agonist
• ? - opioid receptor agonists
• SERT and NET blocker
• The negative allosteric modulator of the nicotinic acetylcholine receptor
• Ligand serotonin 5-HT _{1B / 1D} , histamine H ₁ ,? ₂ -adrenergic, and acetylcholine muscarinic receptor

Rather than acting as a direct NMDA receptor antagonist itself, dextromethorphan acts as a much more potent dextrorphan de metabolite prodrug, and this is the true mediator of its dissociative effect. What role, if any, () - 3-methoxymorphinan, another major metabolite of dextromethorphan, plays in its effect is not entirely clear.

Pharmacokinetics

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

In therapeutic doses, dextromethorphan acts centrally (meaning acting on the brain) as a local opponent (on the respiratory tract). This raises the threshold for coughing, without inhibiting ciliary activity. Dextromethorphan is rapidly absorbed from the gastrointestinal tract and converted to dextrorphan active metabolite in the liver by cytochrome P450 CYP2D6 enzyme. The average dose required for effective antitussive therapy is between 10 and 45 mg, depending on the individual. The International Society for the Study of Cough recommends "the first dose of the right drug is 60 mg in adults and recurrent doses should be rarer than the recommended qds."

DXM has a 4-hour elimination half-life in individuals with extensive metabolizer phenotypes; this increases to about 13 hours when DXM is given in combination with quinidine. The duration of action after oral administration is about three to eight hours for dextromethorphan hydrobromide, and 10 to 12 hours for dextromethorphan polystyrex. About one in 10 Caucasian populations have little or no CYP2D6 enzyme activity, leading to high long-lived drug levels.

Metabolism

The first path through the hepatic portal vein produces several drugs metabolized by O-demethylation to a dextromethorphan active metabolite called dextrorphan (DXO). DXO is a 3-hydroxy dextromethorphan derivative. The therapeutic activity of dextromethorphan is believed to be caused by these drugs and metabolites. Dextromethorphan also undergoes N-demethylation (to 3-methoxymorphinan or MEM), and partial conjugation with glucuronic acid and sulfate ions. Hours after dextromethorphan therapy, (in humans) metabolites () - 3-hydroxy-N-methylmorphinan, () -3-morphinan, and unchanged drug traces detected in the urine.

The major metabolic catalyst involved is a cytochrome P450 enzyme known as 2D6, or CYP2D6. Most populations have functional deficiencies in this enzyme and are known as poor CYP2D6 metabolites. O-demethylation DXM to DXO contributes at least 80% of the DXO formed during DXM metabolism. Because CYP2D6 is the main metabolic pathway in dextromethorphan inactivation, the duration of action and dextromethorphan effect can be increased three times in poor metabolism. In one study of 252 Americans, 84.3% were found to be "fast" (extensive) metabolites, 6.8% to "intermediate" metabolites, and 8.8% were "slow" metabolisms of DXM. A number of alleles for CYP2D6 are known, including some completely inactive variants. The distribution of alleles is uneven among ethnic groups.

A large number of drugs are potent CYP2D6 inhibitors. Several types of drugs known to inhibit CYP2D6 include certain SSRIs and tricyclic antidepressants, some commonly available anthypycarmy and antihistamine diphenhydramine. Therefore, the potential for interaction exists between dextromethorphan and the drugs that inhibit this enzyme, especially in slow metabolism.

DXM is also metabolized by CYP3A4. N-demethylation is mainly achieved by CYP3A4, contributing at least 90% of MEM formed as the main metabolite of DXM.

A number of other CYP enzymes are involved as a small path of DXM metabolism. CYP2B6 is actually more effective than CYP3A4 on 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 DXM is catalyzed by CYP3A4.

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Chemistry

Dextromethorphan is the dextrorotatory enonomer of levomethorphan, which is methyl ether levorphanol, both opioid analgesics. Named in accordance with IUPAC rules as () - 3-methoxy-17-methyl-9 ?, 13 ?, 14? -morphinan. As a pure form, dextromethorphan occurs as a white powder that is odorless and endless. It is freely soluble in chloroform and insoluble in water; water-soluble hydrobromide salts up to 1.5 g/100 mL at 25 ° C. Dextromethorphan is generally available as a hydrobromide monohydration salt, but some newer extended release formulations contain dextromethorphan bonded to ion-exchange resins based on polystyrene sulfonic acid. The specific rotation of Dextromethorphan in water is 27.6 Â ° (20 Â ° C, Sodium D-line).

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History

Racemorphan racem parent racemorphan was first described in the Swiss and US patent applications of Hoffmann-La Roche in 1946 and 1947, respectively; patents granted in 1950. A resolution of two racemorphan isomers with tartaric acid was published in 1952, and DXM was successfully tested in 1954 as part of the US Navy and CIA-funded research on a nonaddictive substitute for codeine. DXM was approved by the FDA in 1958 as an over-the-counter antitussive. As originally expected, DXM is the solution to some of the problems associated with the use of codeine phosphate as a cough suppressant, such as sedation and opiate dependence, but like dissociative anesthesia phencyclidine and ketamine, DXM is then associated with nonmedical use..

During the 1960s and 1970s, dextromethorphan became available in the form of over-the-counter tablets under the Romilar brand name. In 1973, Romilar was removed from the shelves after a sale spike due to frequent misuse, and was replaced by cough syrup in an attempt to reduce abuse. The emergence of widespread internet access in the 1990s enabled users to quickly disseminate information about DXM, and online discussion groups established around drug use and acquisition. In early 1996, DXM HBr powder can be purchased en masse from online retailers, allowing users to avoid consuming DXM in syrup preparations. Since January 1, 2012, dextromethorphan is prohibited from being sold to minors in the state of California, unless prescribed by a doctor.

In Indonesia, the National Agency for Drug and Food Control (BPOM-RI) prohibits the sale of single-component drugs of dextromethorphan with or without a prescription. Indonesia is the only country in the world that makes dextromethorphan an illegal component even with recipes and offenders can be prosecuted by law. The National Narcotics Agency (BNN) even threatened to revoke pharmacy and drugstore licenses if they still have dextromethorphan stock, and will notify the police for criminal prosecution. As a result of this regulation, 130 drugs have been withdrawn from the market, but drugs containing multicomponent dextromethorphan can be sold on the table. In its official press release, BPOM-RI also stated that dextromethorphan is often used as a substitute for marijuana, amphetamines, and heroin by drug users, and its use as an antitusive is less useful today.

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Society and culture

Use of recreation

Non-prescription preparations containing dextromethorphan have been used in behavior inconsistent with their labeling, often as recreational drugs. At much higher doses than is medically recommended, DXM and its major metabolites, dextrorphan, act as NMDA receptor antagonists, resulting in a dissociative hallucinogenic state somewhat similar to ketamine and phencyclidine. Together with other drugs such as ketamine or phencyclidine, also known as PCP, there is a path name for the dextromethorphan-infused substance also known as "Angel". This can produce visual field distortions - dissociation, distorted body perception, excitement, and loss of sense of time. Some users report such euphoria-stimulants, particularly in response to music. Dextromethorphan usually gives its recreational effect in a non-linear fashion, so that they experience in varying stages. These stages are usually referred to as "plateau". The plateau is labeled between one and four, the lowest one and so on. Each plateau is said to come with many different effects and experiences. Adolescents tend to have a higher likelihood of using dextromethorphan-related drugs because they are easier to access, and an easier way to deal with psychiatric disorders.

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Research

Dextromethorphan/quinidine is also being investigated for the treatment of various neurological and neuropsychiatric conditions other than the influence of pseudobulbar, such as agitation associated with Alzheimer's disease and major depressive disorder.

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See also

• List of antidepressants studied
• List of studied antipsychotics

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References

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External links

• US. National Library of Medicine: Drug Information Portal - Dextromethorphan
• Nuedexta (dextromethorphan hydrobromide and quinidine sulfate): Prescribing Information (Original FDA Approval Date: 29 October 2010)

Source of the article : Wikipedia