Pharmacology
Pharmacodynamics
Dextromethorphan has been found to possess the following actions (<1 μM) using rat tissues:
Uncompetitive antagonist of the NMDA receptor via the MK-801/PCP site
SERT and NET blocker (cf. serotonin–norepinephrine reuptake inhibitor)
Sigma σ1 receptor agonist
Negative allosteric modulator of nicotinic acetylcholine receptors
Ligand of the serotonin 5-HT1B/1D, histamine H1, α2-adrenergic, and muscarinic acetylcholine receptorsDextromethorphan is a prodrug of dextrorphan, which is the actual mediator of most of its dissociative effects through acting as a more potent NMDA receptor antagonist than dextromethorphan itself. What role, if any, (+)-3-methoxymorphinan, dextromethorphans other major metabolite, plays in its effects is not entirely clear. 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 dose necessary for effective antitussive therapy is between 10 and 45 mg, depending on the individual. The International Society for the Study of Cough recommends "an adequate first dose of medication is 60 mg in the adult and repeat dosing should be infrequent rather than qds recommended. "Dextromethorphan has an elimination half-life of approximately 4 hours in individuals with an extensive metabolizer phenotype; this is increased to approximately 13 hours when dextromethorphan 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 polistirex. Around one in 10 of the Caucasian population has little or no CYP2D6 enzyme activity, leading to long-lived high drug levels. Metabolism
The first pass through the hepatic portal vein results in some of the drug being metabolized by O-demethylation into an active metabolite of dextromethorphan called 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 also undergoes N-demethylation (to 3-methoxymorphinan or MEM), 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.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 dextromethorphan to dextrorphan contributes to at least 80% of the dextrorphan formed during dextromethorphan metabolism. 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. 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 dextromethorphan. A number of alleles for CYP2D6 are known, including several completely inactive variants.