title: Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use.
abstract: Dextromethorphan (DM) has been used for more than 50years as an over-the-counter antitussive. Studies have revealed a complex pharmacology of DM with mechanisms beyond blockade of N-methyl-d-aspartate (NMDA) receptors and inhibition of glutamate excitotoxicity, likely contributing to its pharmacological activity and clinical potential. DM is rapidly metabolized to dextrorphan, which has hampered the exploration of DM therapy separate from its metabolites. Coadministration of DM with a low dose of quinidine inhibits DM metabolism, yields greater bioavailability and enables more specific testing of the therapeutic properties of DM apart from its metabolites. The development of the drug combination DM hydrobromide and quinidine sulfate (DM/Q), with subsequent approval by the US Food and Drug Administration for pseudobulbar affect, led to renewed interest in understanding DM pharmacology. This review summarizes the interactions of DM with brain receptors and transporters and also considers its metabolic and pharmacokinetic properties. To assess the potential clinical relevance of these interactions, we provide an analysis comparing DM activity from in vitro functional assays with the estimated free drug DM concentrations in the brain following oral DM/Q administration. The findings suggest that DM/Q likely inhibits serotonin and norepinephrine reuptake and also blocks NMDA receptors with rapid kinetics. Use of DM/Q may also antagonize nicotinic acetylcholine receptors, particularly those composed of α3β4 subunits, and cause agonist activity at sigma-1 receptors.
authors.affiliation: CpTaylor Consulting, Chelsea, MI, USA. Electronic address: taylor.charles54@gmail.com.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Taylor
authors.affiliation: Dept. of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
authors.affiliation: Avanir Pharmaceuticals, Inc., Aliso Viejo, CA, USA.
authors.forename: Joao
authors.initials: J
authors.lastname: Siffert
authors.affiliation: Avanir Pharmaceuticals, Inc., Aliso Viejo, CA, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Pope
authors.affiliation: College of Pharmacy, Touro University California, Vallejo, CA, USA.
authors.forename: Rae R
authors.initials: RR
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D003915:Dextromethorphan / Q000493:pharmacokinetics / Q000494:pharmacology*; D004338:Drug Combinations; D004357:Drug Synergism; D006801:Humans; D009638:Norepinephrine / Q000378:metabolism; D011802:Quinidine / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D017480:Receptors, sigma / Q000819:agonists / Q000187:drug effects; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D003915:Dextromethorphan; D004338:Drug Combinations; D009638:Norepinephrine; D011802:Quinidine; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D017480:Receptors, sigma; D050486:Serotonin Plasma Membrane Transport Proteins; D000097605:Sigma-1 Receptor
keywords: NMDA receptors; Nicotinic receptor; Pharmacokinetics; Pseudobulbar affect; Serotonin transporter; Sigma receptor