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| Clinical data | |
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| Trade names | Aventyl, others |
| Other names | Desitriptyline; ELF-101; E.L.F. 101; N-7048 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682620 |
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| Routes of administration | By mouth |
| Drug class | Tricyclic antidepressant (TCA) |
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| Pharmacokinetic data | |
| Bioavailability | 32–79%[6] |
| Protein binding | 92%[6] |
| Metabolism | Liver |
| Metabolites | 10-E-Hydroxynortriptyline |
| Eliminationhalf-life | 18–44 hours (mean 30 hours)[6] |
| Excretion | Urine: 40%[6] Feces: minor[6] |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.000.717 |
| Chemical and physical data | |
| Formula | C19H21N |
| Molar mass | 263.384 g·mol−1 |
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Nortriptyline, sold under the brand nameAventyl, among others, is atricyclic antidepressant. This medicine is also sometimes used forneuropathic pain,attention deficit hyperactivity disorder (ADHD),smoking cessation andanxiety.[7][8] Its use for young people with depression and other psychiatric disorders may be limited due to increased suicidality in the 18–24 population initiating treatment.[8] Nortriptyline is not a preferred treatment for attention deficit hyperactivity disorder or smoking cessation.[8] It is takenby mouth.[8]
Common side effects include dry mouth, constipation, blurry vision, sleepiness,low blood pressure with standing, and weakness.[8] Serious side effects may includeseizures, an increased risk ofsuicide in those less than 25 years of age,urinary retention,glaucoma,mania, and a number of heart issues.[8] Nortriptyline may cause problems if taken during pregnancy.[8] Use duringbreastfeeding appears to be relatively safe.[7] It is atricyclic antidepressant (TCA) and is believed to work by altering levels ofserotonin andnorepinephrine.[8]
Nortriptyline was approved for medical use in the United States in 1964.[8] It is available as ageneric medication.[7] In 2023, it was the 204th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[9][10]
Nortriptyline is used to treat depression.[11] A level between 50 and 150 ng/mL of nortriptyline in the blood generally corresponds with an antidepressant effect.[12]
It is also usedoff-label for the treatment ofpanic disorder, ADHD,irritable bowel syndrome, tobacco-cessation,migraine prophylaxis and chronic pain orneuralgia modification, particularlytemporomandibular joint disorder.[13][14][15][16]
Nortriptyline has also been used as an off-label treatment forirritable bowel syndrome (IBS).[17]
Nortriptyline should not be used in the acute recovery phase aftermyocardial infarction (heart attack).[5] Use of tricyclic antidepressants along with amonoamine oxidase inhibitor (MAOI),linezolid, or IVmethylene blue are contraindicated as it can cause an increased risk of developing serotonin syndrome.[18]
Closer monitoring is required for those with a history of cardiovascular disease,[19]stroke,glaucoma, orseizures, as well as in persons withhyperthyroidism or receiving thyroid hormones.
The most common side effects include dry mouth, sedation, constipation, increased appetite, blurred vision and tinnitus.[20][21] An occasional side effect is a rapid orirregular heartbeat.Alcohol may exacerbate some of its side effects.[20]
The symptoms and the treatment of an overdose are generally the same as for the other tricyclic antidepressants, includinganticholinergic effects,serotonin syndrome and adverse cardiac effects. TCAs, particularly nortriptyline, have a relatively narrowtherapeutic index, which increase the chance of an overdose (both accidental and intentional). Symptoms of overdose include:irregular heartbeat,seizures,coma,confusion,hallucination, widened pupils,drowsiness,agitation,fever, lowbody temperature,stiff muscles andvomiting.[11]
Excessive consumption of alcohol in combination with nortriptyline therapy may have a potentiating effect, which may lead to the danger of increased suicidal attempts or overdosage, especially in patients with histories of emotional disturbances orsuicidal ideation.
It may interact with the following drugs:[22]
Nortriptyline is a strongnorepinephrine reuptake inhibitor and a moderateserotonin reuptake inhibitor. Additionally, nortriptyline inhibits the activity of histamine and acetylcholine. Its pharmacologic profile is as the table shows with (inhibition or antagonism of all sites).[23][24]
| Site | Ki (nM) | Species | Ref |
|---|---|---|---|
| SERTTooltip Serotonin transporter | 15–18 | Human | [25][26] |
| NETTooltip Norepinephrine transporter | 1.8–4.4 | Human | [25][26] |
| DATTooltip Dopamine transporter | 1,140 | Human | [25] |
| 5-HT1A | 294 | Human | [27] |
| 5-HT2A | 5.0–41 | Human/rat | [28][27] |
| 5-HT2C | 8.5 | Rat | [28] |
| 5-HT3 | 1,400 | Rat | [29] |
| 5-HT6 | 148 | Rat | [30] |
| α1 | 55 | Human | [27] |
| α2 | 2,030 | Human | [27] |
| β | >10,000 | Rat | [31] |
| D2 | 2,570 | Human | [27] |
| H1 | 3.0–15 | Human | [32][27][33] |
| H2 | 646 | Human | [32] |
| H3 | 45,700 | Human | [32] |
| H4 | 6,920 | Human | [32] |
| mAChTooltip Muscarinic acetylcholine receptor | 37 | Human | [27] |
| M1 | 40 | Human | [34] |
| M2 | 110 | Human | [34] |
| M3 | 50 | Human | [34] |
| M4 | 84 | Human | [34] |
| M5 | 97 | Human | [34] |
| σ1 | 2,000 | Guinea pig | [35] |
| Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. | |||
Nortriptyline is an active metabolite ofamitriptyline by demethylation in the liver. Chemically, it is asecondary aminedibenzocycloheptene and pharmacologically it is classed as a first-generation antidepressant.[36]
Nortriptyline may also have a sleep-improving effect due to antagonism of the H1 and 5-HT2A receptors.[37] In the short term, however, nortriptyline may disturb sleep due to its activating effect.
In one study, nortriptyline had the highest affinity for thedopamine transporter among the tricyclic antidepressants (KD = 1,140 nM) besidesamineptine (anorepinephrine–dopamine reuptake inhibitor), although its affinity for this transporter was still 261- and 63-fold lower than for thenorepinephrine andserotonin transporters (KD = 4.37 and 18 nM, respectively).[25]
Nortriptyline is metabolized in the liver by the hepatic enzymeCYP2D6, 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.[38] Increased concentrations of nortriptyline may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy.[39][40][41]
Individuals can be categorized into different types ofCYP2D6 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,[41] 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.[39][40][41]
The Clinical Pharmacogenetics Implementation Consortium recommends avoiding nortriptyline in persons who areCYP2D6 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 areCYP2D6 intermediate metabolizers. If use of nortriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments.[41] The Dutch Pharmacogenetics Working Group recommends reducing the dose of nortriptyline inCYP2D6 poor or intermediate metabolizers, and selecting an alternative drug or increasing the dose in ultrarapid metabolizers.[42]
Nortriptyline is atricyclic compound, specifically adibenzocycloheptadiene, and possesses threerings fused together with aside chain attached in itschemical structure.[43] Other dibenzocycloheptadiene tricyclic antidepressants includeamitriptyline (N-methylnortriptyline),protriptyline, andbutriptyline.[43][44] Nortriptyline is asecondary amine tricyclic antidepressant, with itsN-methylatedparent amitriptyline being atertiary amine.[45][46] Other secondary amine tricyclic antidepressants includedesipramine andprotriptyline.[47][48] Thechemical name of nortriptyline is 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine and itsfree base form has achemical formula of C19H21N1 with amolecular weight of 263.384 g/mol.[49] The drug is used commercially mostly as thehydrochloridesalt; the free base form is used rarely.[49][50] TheCAS Registry Number of the free base is 72-69-5 and of the hydrochloride is 894-71-3.[49][50][51]
Nortriptyline was developed byGeigy.[52] It first appeared in the literature in 1962 and was patented the same year.[52] The drug was first introduced for the treatment of depression in 1963.[52][53]
Nortriptyline is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,BANTooltip British Approved Name, andDCFTooltip Dénomination Commune Française, while nortriptyline hydrochloride is itsUSANTooltip United States Adopted Name,USPTooltip United States Pharmacopeia,BANMTooltip British Approved Name, andJANTooltip Japanese Accepted Name.[49][50][54][55] Its generic name in Spanish and Italian and itsDCITTooltip Denominazione Comune Italiana are nortriptilina, in German is nortriptylin, and in Latin is nortriptylinum.[49][50][54][55]
Brand names of nortriptyline include Allegron, Aventyl, Noritren, Norpress, Nortrilen, Norventyl, Norzepine, Pamelor, and Sensival, among many others.[49][50][55]
Although not approved by the USFood and Drug Administration (FDA) forneuropathic pain, randomized controlled trials have demonstrated the effectiveness of tricyclic antidepressants for the treatment of this condition in both depressed and non-depressed individuals. In 2010, an evidence-based guideline sponsored by the International Association for the Study of Pain recommended nortriptyline as a first-line medication for neuropathic pain.[56] However, in a 2015Cochrane systematic review the authors did not recommend nortriptyline as a first-line agent for neuropathic pain.[57][58]
It may be effective in the treatment of tobacco-cessation.[59][60]
