Dextromethorphan

Absorption

A 30mg oral dose of dextromethorphan reaches a Cmax of 2.9 ng/mL, with a Tmax of 2.86 h, and an AUC of 17.8 ng*h/mL.

Toxicity

A dextromethorphan overdose may present as nausea, vomiting, stupor, coma, respiratory depression, seizures, tachycardia, hyperexcitability, toxic psychosis, ataxia, nystagmus, dystonia, blurred vision, changes in muscle reflexes, and serotonin syndrome. Overdose should be managed through symptomatic and supportive measures.

Description

Dextromethorphan is an over-the-counter drug that is sold alone and in combination with other products as a cough suppressant for children and adults. We have previously recommended dextromethorphan as a safe and effective cough suppressant for both children and adults. However, the weight of the evidence now suggests that dextromethorphan is no more effective than an inactive placebo syrup in suppressing a nighttime cough in children. It is the disomer of the potent opiate analgesic 3-methoxyN-methylmorphine (levorphanol). Although dextromethorphan is structurally related to opioids, it is devoid of analgesic or sedative effects at therapeutic doses. Dextromethorphan is metabolized by CYP2D6 to a more potent metabolite, dextrorphan. Dextrorphan is a stronger noncompetitive antagonist than dextromethorphan for the N-methyl-D-aspartate (NMDA) glutamate receptor.These properties promote its use in treatment of neuropathic and postoperative pain management.

Description

Dextromethorphan is a commonly used cough suppressant. It is the dextrorotatory form of the racemic racemethorphan, which was patented by Hoffmann-La Roche in 1954. O. H?fliger and co-workers prepared the chiral form in 1956. Dextromethorphan is an over-the-counter drug formulated most often as the hydrobromide monohydrate.
At high doses, dextromethorphan is a dissociative hallucinogen. Its effects are similar to those of phencyclidine (“angel dust”).
Recently, the combination of dextromethorphan and quinidine was shown to alleviate the symptoms of pseudobulbar affect: laughing and crying in patients with multiple sclerosis, amyotrophic lateral sclerosis, and other neurologic diseases. The combination drug was approved for this use by the US Food and Drug Administration in 2010. It is marketed by Avanir under the trade name Nuedexta.

Chemical properties

Dextromethorphan is a white to slightly yellow, odorless, crystalline powder. The hydrobromide salt of dextromethorphan occurs as white crystals or a white crystalline powder, soluble in water, alcohol, and chloroform. It acts upon the central nervous system to suppress the cough reflex.

The Uses of Dextromethorphan

Dextromethorphan is used therapeutically as an over-thecounter cough suppressant and antitussive. It is also commonly abused particularly by adolescents because of its relative ease of availability.

Indications

Dextromethorphan is indicated in combination with brompheniramine and pseudoephedrine in the treatment of coughs and upper respiratory symptoms associated with allergies or the common cold. Dextromethorphan is also used in combination with guaifenesin as an over-the-counter product to relieve a cough. Dextromethorphan in combination with quinidine is indicated in the treatment of pseudobulbar affect.

Background

Dextromethorphan is a levorphanol derivative and codeine analog commonly used as a cough suppressant and also a drug of abuse. Although similar in structure to other opioids, it has minimal interaction with opioid receptors.
Dextromethorphan was granted FDA approval before 3 December 1957.

Definition

ChEBI: Dextromethorphan is a 6-methoxy-11-methyl-1,3,4,9,10,10a-hexahydro-2H-10,4a-(epiminoethano)phenanthrene in which the sterocenters at positions 4a, 10 and 10a have S-configuration. It is a prodrug of dextrorphan and used as an antitussive drug for suppressing cough. It has a role as a NMDA receptor antagonist, a neurotoxin, a xenobiotic, an environmental contaminant, an antitussive, a prodrug and a oneirogen. It is functionally related to a dextrorphan. It is an enantiomer of a levomethorphan.

Indications

Dextromethorphan is used in treating nonproductive cough. It is available widely in a variety of nonprescription forms, such as capsules, lozenges, syrups, extended-release oral suspension, and chewable tablets. This drug possesses a pronounced anticough effect and minimal action on the CNS. It is not addictive.

brand name

Benylin DM (Parke-Davis); Dextromethorphan Hydrobromide OROS Tablets (Ciba-Geigy); Drixoral Cough (Schering-Plough HealthCare); PediaCare 1 (McNeil Consumer); Romilar (Hoffmann-LaRoche-International); St. Joseph Cough Syrup (Schering-Plough HealthCare);Agrippol;Dextophan;Dextrophen.

Biological Functions

Dextromethorphan hydrobromide is the D-isomer of levorphanol. It lacks CNS activity but acts at the cough center in the medulla to produce an antitussive effect. It is half as potent as codeine as an antitussive. Anecdotal reports of abuse exist, but studies of abuse potential are lacking. It has few side effects but does potentiate the activity of monoamine oxidase inhibitors, leading to hypotension and infrequently coma. Dextromethorphan is often combined in lozenges with the local anesthetic benzocaine, which blocks pain from throat irritation due to coughing.

Synthesis Reference(s)

The Journal of Organic Chemistry, 30, p. 1769, 1965 DOI: 10.1021/jo01017a014

General Description

Dextromethorphan is the dextrorotatory form of levorphanolwith a methoxy group on the 3-position. It is availablein more than 140 over-the-counter (OTC) cough and coldformulations. Evidence-based reviews have been unable toconclude that it is more effective than placebo in reducingcough. Like (+) and (-) levorphanol, (+) dextromethorphanis a potent NMDA antagonist and, in higher than recommendeddoses, has the potential for causing dissociativeanesthetic effects similar to ketamine or phencyclidine (PCP).The OTC status and availability of pure dextromethorphanpowder online has contributed greatly to its abuse in recentyears. DAWN reports that in 2004, there were approximately12,500 emergency room visits involving dextromethorphanwith 44% of those involving abuse of the drug. The 2006National Survey on Drug Abuse report shows that nearly 1million persons aged 12 to 25 years (1.7%) misused OTCcough and cold medications in the past year.
Dextromethorphan’s ability to antagonize the NMDA receptorhas led to its use to treat phantom pain, diabetic neuropathy,and postoperative acute pain.

Pharmacokinetics

Dextromethorphan is an opioid-like molecule indicated in combination with other medication in the treatment of coughs and pseudobulbar affect. It has a moderate therapeutic window, as intoxication can occur at higher doses. Dextromethorphan has a moderate duration of action. Patients should be counselled regarding the risk of intoxication.

Pharmacokinetics

Dextromethorphan is absorbed rapidly from the GI tract, with antitussive activity occurring within 15 to 30 minutes. It undergoes extensive hepatic metabolism. Excretion is mainly renal, with some drug eliminated unchanged but most eliminated as metabolites. Dextromethorphan is related chemically to the opiate agonists and can suppress coughing as effectively as narcotics. Cough suppression occurs by several mechanisms, but mainly the drug directly affects the cough center in the medulla. Therapeutic doses do not affect ciliary activity.

Side Effects

Although adverse effects are generally rare, dextromethorphan toxicity can occur and is characterized by nausea and vomiting, drowsiness, dizziness, irritability, and restlessness. In excessive doses, dextromethorphan poisoning may occur and induce symptoms similar to those associated with phencyclidine.

Safety

Despite the safety of dextromethorphan when used at the recommended dosage (<120 mg/day), higher doses can result in nausea, vomiting, seizure, loss of consciousness, irregular heartbeat, and death. Serotonin syndrome may develop in patients on other serotonergic drugs, due to additive inhibition of serotonin reuptake by dextromethorphan. Patients with genetic variations in CYP2D6, causing rapid metabolism of dextromethorphan, may present with greater clinical effects.

Synthesis

Dextromethorphan, (9|á,13|á,14|á)-3-methoxy-17-methylmorphinane (23.2.1), is synthesized from (
)-3-hydroxy-N-methylmorphinane by methylating the phenol hydroxyl group using phenyltrimethylammonium chloride and sodium methoxide in methanol. The resulting racemic product (
)-3-methoxy-N-methylmorphinane is separated into isomers using D-tartaric acid, which produces dextromethor-phan.

Environmental Fate

Dextromethorphan is the D-isomer of the codeine analog, methorphan. Unlike the L-isomer, it has no analgesic or addictive properties and does not act through the opioid receptors. The exact mechanism for the antitussive effect by dextromethorphan remains unclear and is likely multifactorial. Dextromethorphan is known to be an N-methyl-D-aspartate (NMDA) receptor antagonist; however, dextromethorphan binding sites are not limited to the known distribution of NMDA receptors.
Dextromethorphan’s main metabolite, dextrorphan, has NMDA receptor antagonist properties similar to ketamine and phencyclidine. This NMDA receptor antagonism is believed to result in a decreased reuptake of catecholamines. Dextromethorphan also inhibits the reuptake of serotonin. These properties make dextromethorphan have a high abuse and misuse potential.
Dextromethorphan is a common ingredient in over-thecounter cough and cold preparations, and is often combined with other agents including concurrent antihistamines, decongestants, analgesics, and ethanol. Patients may exhibit toxicity due to these coingestants.

Metabolism

Dextromethorphan can be N-demethylated to 3-methoxymorphinan by CYP3A4, CYP2D6, and CYP2C9 or O-demethylated to dextrorphan by CYP2D6 and CYP2C9. Dextrorphan is N-demethylated by CYP3A4 and CYP2D6, while 3-methoxymorphinan is O-demethylated by CYP2D6. Both are metabolized to form 3-hydroxymorphinan. Dextrorphan and 3-hydroxymorphinan are both O-glucuronidated or O-sulfated.