Clinical data | |
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Trade names | Pamelor, Noritren, Nortrilen, others |
Other names | Desitriptyline; ELF-101; E.L.F. 101; N-7048 |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682620 |
License data | |
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Routes of administration | By mouth |
Drug class | Tricyclic antidepressant (TCA) |
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Pharmacokinetic data | |
Bioavailability | 32–79% [3] |
Protein binding | 92% [3] |
Metabolism | Liver |
Metabolites | 10-E-Hydroxynortriptyline |
Elimination half-life | 18–44 hours (mean 30 hours) [3] |
Excretion | Urine: 40% [3] Feces: minor [3] |
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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 |
3D model (JSmol) | |
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Nortriptyline, sold under the brand name Pamelor, among others, is a medication used to treat depression. This medicine is also sometimes used for neuropathic pain, attention deficit hyperactivity disorder (ADHD), smoking cessation and anxiety. [4] [5] As with many antidepressants, 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. [5] Nortriptyline is a less preferred treatment for ADHD and stopping smoking. [5] It is taken by mouth. [5]
Common side effects include dry mouth, constipation, blurry vision, sleepiness, low blood pressure with standing, and weakness. [5] Serious side effects may include seizures, an increased risk of suicide in those less than 25 years of age, urinary retention, glaucoma, mania, and a number of heart issues. [5] Nortriptyline may cause problems if taken during pregnancy. [5] Use during breastfeeding appears to be relatively safe. [4] It is a tricyclic antidepressant (TCA) and is believed to work by altering levels of serotonin and norepinephrine. [5] [lower-alpha 1]
Nortriptyline was approved for medical use in the United States in 1964. [5] It is available as a generic medication. [4] In 2021, it was the 139th most commonly prescribed medication in the United States, with more than 4 million prescriptions. [6] [7]
Nortriptyline is used to treat depression. [8] This medication is in capsule or liquid and is taken by the mouth one to four times a day, with or without food. [8] Usually people are started on a low dose and it is gradually increased. [8] A level between 50 and 150 ng/mL of nortriptyline in the blood generally corresponds with an antidepressant effect. [9]
In the United Kingdom, it may also be used for treating nocturnal enuresis, with courses of treatment lasting no more than three months. It is also used off-label for the treatment of panic disorder, irritable bowel syndrome, migraine prophylaxis and chronic pain or neuralgia modification, particularly temporomandibular joint disorder. [10]
Although not approved by the FDA for neuropathic pain, many randomized controlled trials have demonstrated the effectiveness of TCAs 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. [11] However, in a 2015 Cochrane systematic review the authors did not recommend nortriptyline as a first-line agent for neuropathic pain. [12]
Nortriptyline has also been used as an off-label treatment for irritable bowel syndrome (IBS). [13]
Nortriptyline should not be used in the acute recovery phase after myocardial infarction (viz, heart attack). [14] Use of tricyclic antidepressants along with a monoamine oxidase inhibitor (MAOI), linezolid, or IV methylene blue are contraindicated as it can cause an increased risk of developing serotonin syndrome. [15]
Closer monitoring is required for those with a history of cardiovascular disease, [16] stroke, glaucoma, or seizures, as well as in persons with hyperthyroidism or receiving thyroid hormones.
The most common side effects include dry mouth, sedation, constipation, increased appetite, blurred vision and tinnitus. [17] [18] An occasional side effect is a rapid or irregular heartbeat. Alcohol may exacerbate some of its side effects. [17]
The symptoms and the treatment of an overdose are generally the same as for the other TCAs, including anticholinergic effects, serotonin syndrome and adverse cardiac effects. TCAs, particularly nortriptyline, have a relatively narrow therapeutic 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, low body temperature, stiff muscles and vomiting. [8]
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 or suicidal ideation.
It may interact with the following drugs: [19]
Nortriptyline 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). [20] [21]
Site | Ki (nM) | Species | Ref |
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SERT | 15–18 | Human | [22] [23] |
NET | 1.8–4.4 | Human | [22] [23] |
DAT | 1,140 | Human | [22] |
5-HT1A | 294 | Human | [24] |
5-HT2A | 5.0–41 | Human/rat | [25] [24] |
5-HT2C | 8.5 | Rat | [25] |
5-HT3 | 1,400 | Rat | [26] |
5-HT6 | 148 | Rat | [27] |
α1 | 55 | Human | [24] |
α2 | 2,030 | Human | [24] |
β | >10,000 | Rat | [28] |
D2 | 2,570 | Human | [24] |
H1 | 3.0–15 | Human | [29] [24] [30] |
H2 | 646 | Human | [29] |
H3 | 45,700 | Human | [29] |
H4 | 6,920 | Human | [29] |
mACh | 37 | Human | [24] |
M1 | 40 | Human | [31] |
M2 | 110 | Human | [31] |
M3 | 50 | Human | [31] |
M4 | 84 | Human | [31] |
M5 | 97 | Human | [31] |
σ1 | 2,000 | Guinea pig | [32] |
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. |
Nortriptyline 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. [33]
Nortriptyline may also have a sleep-improving effect due to antagonism of the H1 and 5-HT2A receptors. [34] In the short term, however, nortriptyline may disturb sleep due to its activating effect.
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). [22]
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. [35] 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. [36] [37] [38]
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, [38] 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. [36] [37] [38]
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. [38] 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. [39]
Nortriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure. [40] Other dibenzocycloheptadiene TCAs include amitriptyline (N-methylnortriptyline), protriptyline, and butriptyline. [40] [41] Nortriptyline is a secondary amine TCA, with its N-methylated parent amitriptyline being a tertiary amine. [42] [43] Other secondary amine TCAs include desipramine and protriptyline. [44] [45] 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. [46] The drug is used commercially mostly as the hydrochloride salt; the free base form is used rarely. [46] [47] The CAS Registry Number of the free base is 72-69-5 and of the hydrochloride is 894-71-3. [46] [47] [48]
Nortriptyline was developed by Geigy. [49] It first appeared in the literature in 1962 and was patented the same year. [49] The drug was first introduced for the treatment of depression in 1963. [49] [50]
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 . [46] [47] [51] [52] Its generic name in Spanish and Italian and its DCIT are nortriptilina, in German is nortriptylin, and in Latin is nortriptylinum. [46] [47] [51] [52]
Brand names of nortriptyline include Allegron, Aventyl, Noritren, Norpress, Nortrilen, Norventyl, Norzepine, Pamelor, and Sensoval, among many others. [46] [47] [52]
Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.
Maprotiline, sold under the brand name Ludiomil among others, is a tetracyclic antidepressant (TeCA) that is used in the treatment of depression. It may alternatively be classified as a tricyclic antidepressant (TCA), specifically a secondary amine. In terms of its chemistry and pharmacology, maprotiline is closely related to such-other secondary-amine TCAs as nortriptyline and protriptyline and has similar effects to them, albeit with more distinct anxiolytic effects. Additionally, whereas protriptyline tends to be somewhat more stimulating and in any case is distinctly more-or-less non-sedating, mild degrees of sedation may be experienced with maprotiline.
Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat major depressive disorder, a variety of pain syndromes such as neuropathic pain, fibromyalgia, migraine and tension headaches. Due to the frequency and prominence of side effects, amitriptyline is generally considered a second-line therapy for these indications.
Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, social phobia, chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. Off-label uses include treatments for attention-deficit hyperactivity disorder (ADHD), obsessive–compulsive disorder (OCD), and migraine prevention. SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs), which act upon single neurotransmitters.
Atomoxetine, sold under the brand name Strattera, is a medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndrome. It may be used alone or along with psychostimulants. It is also used as a cognitive and executive functioning enhancer to improve self-motivation, persistence, attention, inhibition, and working memory. Use of atomoxetine is only recommended for those who are at least six years old. It is taken orally. Atomoxetine is a selective norepinephrine reuptake inhibitor and is believed to work by increasing norepinephrine and dopamine levels in the brain. The effectiveness of atomoxetine is comparable to the commonly prescribed stimulant medication methylphenidate.
Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. Imipramine is taken by mouth.
Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression. It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activities such as weak serotonin reuptake inhibitory, α1-blocking, antihistamine, and anticholinergic effects. The drug is not considered a first-line treatment for depression since the introduction of selective serotonin reuptake inhibitor (SSRI) antidepressants, which have fewer side effects and are safer in overdose.
Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA). It is used in the treatment of various conditions, most-notably obsessive–compulsive disorder but also many other disorders, including panic disorder, major depressive disorder, trichotilomania, body dysmorphic disorder and chronic pain. It has also been notably used to treat premature ejaculation and the cataplexy associated with narcolepsy.
Doxepin is a medication belonging to the tricyclic antidepressant (TCA) class of drugs used to treat major depressive disorder, anxiety disorders, chronic hives, and insomnia. For hives it is a less preferred alternative to antihistamines. It has a mild to moderate benefit for sleeping problems. It is used as a cream for itchiness due to atopic dermatitis or lichen simplex chronicus.
Viloxazine, sold under the brand name Qelbree and formerly as Vivalan among others, is a selective norepinephrine reuptake inhibitor medication which is used in the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults. It was marketed for almost 30 years as an antidepressant for the treatment of depression before being discontinued and subsequently repurposed as a treatment for ADHD. Viloxazine is taken orally. It was used as an antidepressant in an immediate-release form and is used in ADHD in an extended-release form.
Trimipramine, sold under the brand name Surmontil among others, is a tricyclic antidepressant (TCA) which is used to treat depression. It has also been used for its sedative, anxiolytic, and weak antipsychotic effects in the treatment of insomnia, anxiety disorders, and psychosis, respectively. The drug is described as an atypical or "second-generation" TCA because, unlike other TCAs, it seems to be a fairly weak monoamine reuptake inhibitor. Similarly to other TCAs, however, trimipramine does have antihistamine, antiserotonergic, antiadrenergic, antidopaminergic, and anticholinergic activities.
Trazodone, sold under many brand names, is an antidepressant medication. It is used to treat major depressive disorder, anxiety disorders, and insomnia. The medication is taken orally.
Dosulepin, also known as dothiepin and sold under the brand name Prothiaden among others, is a tricyclic antidepressant (TCA) which is used in the treatment of depression. Dosulepin was once the most frequently prescribed antidepressant in the United Kingdom, but it is no longer widely used due to its relatively high toxicity in overdose without therapeutic advantages over other TCAs. It acts as a serotonin–norepinephrine reuptake inhibitor (SNRI) and also has other activities including antihistamine, antiadrenergic, antiserotonergic, anticholinergic, and sodium channel-blocking effects.
Butriptyline, sold under the brand name Evadyne among others, is a tricyclic antidepressant (TCA) that has been used in the United Kingdom and several other European countries for the treatment of depression but appears to no longer be marketed. Along with trimipramine, iprindole, and amoxapine, it has been described as an "atypical" or "second-generation" TCA due to its relatively late introduction and atypical pharmacology. It was very little-used compared to other TCAs, with the number of prescriptions dispensed only in the thousands.
Lofepramine, sold under the brand names Gamanil, Lomont, and Tymelyt among others, is a tricyclic antidepressant (TCA) which is used to treat depression. The TCAs are so named as they share the common property of having three rings in their chemical structure. Like most TCAs lofepramine is believed to work in relieving depression by increasing concentrations of the neurotransmitters norepinephrine and serotonin in the synapse, by inhibiting their reuptake. It is usually considered a third-generation TCA, as unlike the first- and second-generation TCAs it is relatively safe in overdose and has milder and less frequent side effects.
Protriptyline, sold under the brand name Vivactil among others, is a tricyclic antidepressant (TCA), specifically a secondary amine, indicated for the treatment of depression and attention-deficit hyperactivity disorder (ADHD). Uniquely among most of the TCAs, protriptyline tends to be energizing instead of sedating, and is sometimes used for narcolepsy to achieve a wakefulness-promoting effect.
Desmetramadol, also known as O-desmethyltramadol (O-DSMT), is an opioid analgesic and the main active metabolite of tramadol. Tramadol is demethylated by the liver enzyme CYP2D6 to desmetramadol in the same way as codeine, and so similarly to the variation in effects seen with codeine, individuals who have a less active form of CYP2D6 will tend to have reduced analgesic effects from tramadol. Because desmetramadol itself does not need to be metabolized to induce an analgesic effect, it can be used in individuals with low CYP2D6 activity unlike tramadol.
Vortioxetine, sold under the brand names Trintellix and Brintellix among others, is a medication used to treat major depressive disorder. Its effectiveness is viewed as similar to that of other antidepressants. It is taken by mouth.
A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.
Nordoxepin, also known as N-desmethyldoxepin, is an organic compound. A colorless solid, it attracted attention as the major active metabolite of the tricyclic antidepressant (TCA) doxepin (Sinequan). It has been found to play a significant role in the antidepressant effects of doxepin.