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Nortriptyline, sold under the brand names Allegron, Aventyl, Noritren, Nortrilen, and Pamelor among others, is a tricyclic antidepressant (TCA) used to treat clinical depression. Another licensed use for it is in the treatment of childhood bedwetting. Off-label uses include chronic pain and migraine and labile affect in some neurological disorders. Chemically, it is a secondary amine dibenzocycloheptene and pharmacologically it is classed as a second-generation TCA.
Nortriptyline has less anticholinergic (like dry mouth, constipation, blurred vision, etc. ), antihistamine (like sedation and possibly weight gain ), antiadrenergic (like orthostatic hypotension ), and cardiotoxic (heart-toxic, namely the capacity of these drugs to interfere with normal heart rhythm) effects than the older first-generation TCAs.
Nortriptyline is the major active metabolite of amitriptyline, a first-generation TCA. It is the N -desmethyl metabolite of amitriptyline. Like amitriptyline it works by inhibiting the reuptake of serotonin and norepinephrine, thereby enhancing synaptic signalling via these neurotransmitters. It preferentially inhibits the reuptake of norepinephrine over serotonin, which is the opposite to amitriptyline.
Contents
1 Medical uses
1.1 Neuropathic pain
2 Contraindications
3 Side effects
4 Overdose
5 Interactions
6 Pharmacology
6.1 Pharmacodynamics
6.2 Pharmacokinetics
6.2.1 Pharmacogenetics
7 Chemistry
8 History
9 Society and culture
9.1 Generic names
9.2 Brand names
10 References
11 External links
Medical uses
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.
Neuropathic pain
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.
Contraindications
Nortriptyline should not be used in the acute recovery phase after myocardial infarction (viz, heart attack)
Closer monitoring is required for those with a history of cardiovascular disease, stroke, glaucoma, or seizures, as well as in persons with hyperthyroidism or receiving thyroid hormones.
Side effects
The most common side effects include dry mouth, sedation, constipation, increased appetite, blurred vision and tinnitus.
Overdose
Main article: Tricyclic antidepressant overdose
The symptoms and the treatment of an overdose are generally the same as for the other TCAs, including serotonin syndrome and adverse cardiac effects. Because TCAs have a relatively narrow therapeutic index, the likelihood of serious overdose (both accidental and intentional) is fairly high. A nortriptyline overdose is considered a medical emergency and frequently results in death.
Interactions
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:
heart rhythm medications such as flecainide (Tambocor), propafenone (Rhythmol), or quinidine (Cardioquin, Quinidex, Quinaglute)
cimetidine
guanethidine
reserpine
Pharmacology
Pharmacodynamics
See also: Pharmacology of antidepressants and Tricyclic antidepressant § Binding profiles
Nortriptyline
Site
K i (nM)
Species
Ref
SERT
15–18
Human
NET
1.8–4.4
Human
DAT
1,140
Human
5-HT 1A
294
Human
5-HT 2A
5.0–41
Human/rat
5-HT 2C
8.5
Rat
5-HT 3
1,400
Rat
5-HT 6
148
Rat
α 1
55
Human
α 2
2,030
Human
β
>10,000
Rat
D 2
2,570
Human
H 1
3.0–15
Human
H 2
646
Human
H 3
45,700
Human
H 4
6,920
Human
mACh
37
Human
   M 1
40
Human
   M 2
110
Human
   M 3
50
Human
   M 4
84
Human
   M 5
97
Human
σ 1
2,000
Guinea pig
Values are K i (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. Its pharmacologic profile is as the table to the right shows (inhibition or antagonism of all sites).
These effects account for some therapeutic actions as well as for most side effects such as sedation, hypotension, anticholinergic effects, etc. In the short term, however, nortriptyline may disturb sleep due to its activating effect.
Like other TCAs, nortriptyline also blocks sodium channels, possibly accounting in part for its analgesic action.
In one study of long-term efficacy, nortriptyline showed a higher relapse rate in comparison with phenelzine in individuals being treated for depression, possibly due to the toxic metabolite 10-hydroxynortriptyline being produced.
In one study, nortriptyline had the highest affinity for the dopamine transporter among the TCAs (K D = 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 (K D = 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.
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,
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.
Chemistry
Nortriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure.
History
Nortriptyline was developed by Geigy.
Society and culture
50mg (left) and 25mg generic Nortriptyline HCL capsules made by Teva Pharmaceutical Industries.
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.
Brand names
Brand names of nortriptyline include Allegron, Aventyl, Noritren, Norpress, Nortrilen, Norventyl, Norzepine, Pamelor, and Sensoval, among many others.

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