Pharmacodynamics +<unk>  and metabolite Site Species Ref (MK-801) 2,120–8,945 486–906 Rat σ1 142–652 118–481 Rat σ2 11,060–22,864 11,325–15,582 Rat 1,280 420>1,000 RatHuman 11,500 34,700 Rat 7,000 5,950 Rat 23–40 401–484 Rat ≥240 ≥340 Rat >1,000 >1,000 Rat 5-HT1A >1,000 >1,000 Rat 5-HT1B/1D 61% at 1 μM 54% at 1 μM Rat 5-HT2A >1,000 >1,000 Rat α1 >1,000 >1,000 Rat α2 60% at 1 μM >1,000 Rat β >1,000 35% at 1 μM Rat D2 >1,000 >1,000 Rat H1 >1,000 95% at 1 μM Rat >1,000 100% at 1 μM Rat 700–8,900(IC50) 1,300–29,600(IC50) Rat >50,000 (IC50) Rat Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.<unk>  has been found to possess the following actions (1 receptor agonist * Negative allosteric modulator of nicotinic acetylcholine receptors * Ligand of the serotonin 5-HT1B/1D, histamine H1, α2-adrenergic, and muscarinic acetylcholine receptors<unk>  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<unk>  itself. What role, if any, (+)-3-methoxymorphinan,<unk> 's other major metabolite, plays in its effects is not entirely clear. Pharmacokinetics Following oral administration,<unk>  is rapidly absorbed from the gastrointestinal tract, where it enters the bloodstream and crosses the blood–brain barrier. At therapeutic doses,<unk>  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.<unk>  is rapidly absorbed from the gastrointestinal tract and converted into the active metabolite dextrorphan in the liver by the cytochrome P450 enzyme<unk> . 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."<unk>  has an elimination half-life of approximately 4 hours in individuals with an extensive metabolizer phenotype; this is increased to approximately 13 hours when<unk>  is given in combination with quinidine. The duration of action after oral administration is about three to eight hours for<unk>  hydrobromide, and 10 to 12 hours for<unk>  polistirex. Around one in 10 of the Caucasian population has little or no<unk>  enzyme activity, leading to long-lived high drug levels. Metabolism Main metabolic pathways of<unk>  degradation, which are catalyzed by cytochrome P450 monooxygenases (CYP3A4 and<unk>  and UDP-glucuronosyl-transferase (UGT). The first pass through the hepatic portal vein results in some of the drug being metabolized by O-demethylation into an active metabolite of<unk>  called dextrorphan, the 3-hydroxy derivative of<unk> . The therapeutic activity of<unk>  is believed to be caused by both the drug and this metabolite.<unk>  also undergoes N-demethylation (to 3-methoxymorphinan or MEM), and partial conjugation with glucuronic acid and sulfate ions. Hours after<unk>  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<unk> . A significant portion of the population has a functional deficiency in this enzyme and are known as poor<unk>  metabolizers. O-demethylation of<unk>  to dextrorphan contributes to at least 80% of the dextrorphan formed during<unk>  metabolism. As<unk>  is a major metabolic pathway in the inactivation of<unk> , the duration of action and effects of<unk>  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<unk> . A number of alleles for<unk>  are known, including several completely inactive variants. The distribution of alleles is uneven amongst ethnic groups. A large number of medications are potent inhibitors of<unk> . Some types of medications known to inhibit<unk>  include certain SSRIs and tricyclic antidepressants, some antipsychotics, and the commonly available antihistamine diphenhydramine. Therefore, the potential of interactions exists between<unk>  and medications that inhibit this enzyme, particularly in slow metabolizers.<unk>  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<unk> . A number of other CYP enzymes are implicated as minor pathways of<unk>  metabolism.<unk>  is more effective than CYP3A4 at N-demethylation of<unk> , but since the average individual has a much lower<unk>  content in the liver compared to CYP3A4, most N-demethylation of<unk>  is catalyzed by CYP3A4.
Dextromethorphan
Nalorphine
Pethidine
Dextrorphan
Aceclidine
Betamethadol
Fentanyl
Procaine