<unk>  is a strong norepinephrine reuptake inhibitor and a moderate serotonin reuptake inhibitor. Its pharmacologic profile is as the table shows with (inhibition or antagonism of all sites). Pharmacodynamics +<unk>  Site Ki (nM) Species Ref 15–18 Human 1.8–4.4 Human 1,140 Human 5-HT1A 294 Human 5-HT2A 5.0–41 Human/rat 5-HT2C 8.5 Rat 5-HT3 1,400 Rat 5-HT6 148 Rat α1 55 Human α2 2,030 Human β >10,000 Rat D2 2,570 Human H1 3.0–15 Human H2 646 Human H3 45,700 Human H4 6,920 Human 37 Human M1 40 Human M2 110 Human M3 50 Human M4 84 Human M5 97 Human σ1 2,000 Guinea pig Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.<unk>  is an active metabolite of amitriptyline by demethylation in the liver. Chemically, it is a secondary amine dibenzocycloheptene and pharmacologically it is classed as a first-generation antidepressant.<unk>  may also have a sleep-improving effect due to antagonism of the H1 and 5-HT2A receptors. In the short term, however,<unk>  may disturb sleep due to its activating effect. In one study,<unk>  had the highest affinity for the dopamine transporter among the TCAs (KD = 1,140 nM) besides amineptine (a norepinephrine–dopamine reuptake inhibitor), although its affinity for this transporter was still 261- and 63-fold lower than for the norepinephrine and serotonin transporters (KD = 4.37 and 18 nM, respectively). Pharmacokinetics Pharmacogenetics<unk>  is metabolized in the liver by the hepatic enzyme CYP2D6, and genetic variations within the gene coding for this enzyme can affect its metabolism, leading to changes in the concentrations of the drug in the body. Increased concentrations of<unk>  may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy. Individuals can be categorized into different types of CYP2D6 metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers. Most individuals (about 77–92%) are extensive metabolizers, and have "normal" metabolism of<unk> . Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers use<unk>  much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure. The Clinical Pharmacogenetics Implementation Consortium recommends avoiding<unk>  in persons who are CYP2D6 ultrarapid or poor metabolizers, due to the risk of a lack of efficacy and side effects, respectively. A reduction in starting dose is recommended for patients who are CYP2D6 intermediate metabolizers. If use of<unk>  is warranted, therapeutic drug monitoring is recommended to guide dose adjustments. The Dutch Pharmacogenetics Working Group recommends reducing the dose of<unk>  in CYP2D6 poor or intermediate metabolizers, and selecting an alternative drug or increasing the dose in ultrarapid metabolizers.
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