In one study, nortriptyline 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
Nortriptyline 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 nortriptyline may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drugs 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 nortriptyline. 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 nortriptyline 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 nortriptyline 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 nortriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments. The Dutch Pharmacogenetics Working Group recommends reducing the dose of nortriptyline in CYP2D6 poor or intermediate metabolizers, and selecting an alternative drug or increasing the dose in ultrarapid metabolizers. Chemistry
Nortriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzocycloheptadiene TCAs include amitriptyline (N-methylnortriptyline), protriptyline, and butriptyline. Nortriptyline is a secondary amine TCA, with its N-methylated parent amitriptyline being a tertiary amine. Other secondary amine TCAs include desipramine and protriptyline. The chemical name of nortriptyline is 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine and its free base form has a chemical formula of C19H21N1 with a molecular weight of 263.384 g/mol. The drug is used commercially mostly as the hydrochloride salt; the free base form is used rarely. The CAS Registry Number of the free base is 72-69-5 and of the hydrochloride is 894-71-3. History
Nortriptyline was developed by Geigy. It first appeared in the literature in 1962 and was patented the same year. The drug was first introduced for the treatment of depression in 1963. Society and culture
Generic names
Nortriptyline is the English and French generic name of the drug and its INN, BAN, and DCF, while nortriptyline hydrochloride is its USAN, USP, BANM, and JAN. Its generic name in Spanish and Italian and its DCIT are nortriptilina, in German is nortriptylin, and in Latin is nortriptylinum.