Dextromethorphan

Dextromethorphan (DM or DXM) is an antitussive drug that is found in many over-the-counter cold and cough preparations, usually in the form of dextromethorphan hydrobromide. It is also used as a recreational drug.

Chemistry

Dextromethorphan is a salt of the methyl ether dextrorotatory isomer of levorphanol, a narcotic (opioid) analgesic (and DXM itself is an enantiomeric isomer, that is, a mirror image in the 3D space, of levomethorphan, a substance considered an opioid). It is chemically named as 3-methoxy-17-methyl-9(alpha), 13(alpha), 14(alpha)-morphinan hydrobromide monohydrate. DXM occurs as white crystals, is sparingly soluble in water, and freely soluble in alcohol. The drug is dextrorotatory in water (at 20 degrees Celsius, Sodium D-line) with a specific rotation of +27.6 degrees.

Indications

The FDA approved dextromethorphan for over-the-counter sale as a cough suppressant in 1958. This filled the need for a cough suppressant lacking the abuse liability and addictive properties of codeine phosphate, the most widely used cough medication at the time. The advantage of dextromethorphan preparations over those containing codeine (now prescription only in the United States) was the lack of physical addiction potential and sedative side-effects, although as with most cough supressants, studies show that its effectiveness is highly debatable.

Pharmacodynamics

At therapeutic doses, the drug acts centrally to elevate the threshold for coughing, without inhibiting ciliary activity. Dextromethorphan is rapidly absorbed from the gastrointestinal tract, and exerts its activity within 15 to 60 minutes of ingestion. The duration of action after oral administration is approximately three to eight hours. Because administration of DXM can be accompanied by histamine release, its use in atopic children is very limited.

The average dosage necessary for effective antitussive therapy is between 10mg and 30mg every four to six hours.

According to the WHO committee on Drug Dependence, dextromethorphan, when used recreationally (see non-medical use of dextromethorphan), does not produce physical addiction but can generate slight psychological dependence in some users.

Clinical pharmacology

Following oral administration, dextromethorphan is rapidly absorbed from the gastrointestinal tract, where it enters the bloodstream and crosses the blood-brain barrier. The first-pass through the hepatic portal vein results in some of the drug being metabolized into an active metabolite of dextromethorphan, dextrorphan, the 3-hydroxy derivative of dextromethorphan. The therapeutic activity of dextromethorphan is believed to be caused by both the drug and this metabolite. Dextromethorphan is metabolized by various liver enzymes and subsequently undergoes O-demethylation (producing dextrorphan), N-demethylation, 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.

One well known metabolic catalyst involved is a specific 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). As CYP2D6 is the primary metabolic pathway in the inactivation of dextromethorphan, the duration of action and effects of dextromethorphan are significantly increased in such poor metabolizers. Deaths and hospitalizations have been reported in recreational use by poor CYP2D6 metabolizers.[verification needed]

A large number of medications (including antidepressants) are potent inhibitors of CYP2D6 (see CYP2D6 article). There exists, therefore, the potential of drug-drug interactions between dextromethorphan and concomitant medications. There have been reports of fatal consequences arising from such interactions.

Dextromethorphan crosses the blood-brain barrier, and the following pharmacological actions have been reported:

  • NMDA glutamatergic receptor antagonist
  • Dopamine reuptake inhibitor
  • σ1 and σ2 receptor agonist (Zhou & Musacchio, 1991)
  • α3β4 nicotinic receptor antagonist
  • Serotonin reuptake inhibitor

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