Nortriptyline

Nortriptyline
Clinical data
Trade names Allegron, Aventyl, Noritren, Nortrilen, Pamelor, others
Synonyms Desitriptyline; ELF-101; E.L.F. 101; N-7048
AHFS/Drugs.com Monograph
MedlinePlus a682620
Pregnancy
category
  • AU: C
  • US: D (Evidence of risk)
    Routes of
    administration
    Oral
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability 32–79[1]
    Protein binding 92%[1]
    Metabolism Hepatic
    Metabolites 10-E-Hydroxynortriptyline
    Elimination half-life 18–44 hours (mean 30 hours)[1]
    Excretion Urine: 40%[1]
    Feces: minor[1]
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    ECHA InfoCard 100.000.717
    Chemical and physical data
    Formula C19H21N
    Molar mass 263.384 g/mol
    3D model (JSmol)
      (verify)

    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.[2] 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.[2]

    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.[3]

    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.[4]

    Contraindications

    Nortriptyline should not be used in the acute recovery phase after myocardial infarction (viz, heart attack). Unlike the TCAs clomipramine and imipramine, concurrent use of nortriptyline with monoamine oxidase inhibitors does not pose a risk of serotonin syndrome, although there is still a risk of hypertensive crisis.

    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.[2][5] An occasional side effect is a rapid or irregular heartbeat. Alcohol may exacerbate some of its side effects.[2]

    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.

    Pharmacology

    Pharmacodynamics

    Nortriptyline[6]
    SiteKi (nM)SpeciesRef
    SERT15–18Human[7][8]
    NET1.8–4.4Human[7][8]
    DAT1,140Human[7]
    5-HT1A294Human[9]
    5-HT2A5.0–41Human/rat[10][9]
    5-HT2C8.5Rat[10]
    5-HT31,400Rat[11]
    5-HT6148Rat[12]
    α155Human[9]
    α22,030Human[9]
    β>10,000Rat[13]
    D22,570Human[9]
    H13.0–15Human[14][9][15]
    H2646Human[14]
    H345,700Human[14]
    H46,920Human[14]
    mACh37Human[9]
      M140Human[16]
      M2110Human[16]
      M350Human[16]
      M484Human[16]
      M597Human[16]
    σ12,000Guinea pig[17]
    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. Its pharmacologic profile is as the table to the right shows (inhibition or antagonism of all sites).[6][18]

    These effects account for some therapeutic actions as well as for most side effects such as sedation, hypotension, anticholinergic effects, etc. Nortriptyline may also have a sleep-improving effect due to antagonism of the H1 and 5-HT2A receptors.[19] 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.[20] The authors of a review noted that the nortriptyline group had more episodes prior to treatment.[20]

    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).[7]

    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.[21] 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.[22][23][24]

    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,[24] 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.[22][23][24]

    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.[24] 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.[25]

    Chemistry

    Nortriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure.[26] Other dibenzocycloheptadiene TCAs include amitriptyline (N-methylnortriptyline), protriptyline, and butriptyline.[26][27] Nortriptyline is a secondary amine TCA, with its N-methylated parent amitriptyline being a tertiary amine.[28][29] Other secondary amine TCAs include desipramine and protriptyline.[30][31] 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.[32] The drug is used commercially mostly as the hydrochloride salt; the free base form is used rarely.[32][33] The CAS Registry Number of the free base is 72-69-5 and of the hydrochloride is 894-71-3.[32][33][34]

    History

    Nortriptyline was developed by Geigy.[35] It first appeared in the literature in 1962 and was patented the same year.[35] The drug was first introduced for the treatment of depression in 1963.[35][36]

    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.[32][33][37][38] Its generic name in Spanish and Italian and its DCIT are nortriptilina, in German is nortriptylin, and in Latin is nortriptylinum.[32][33][37][38]

    Brand names

    Brand names of nortriptyline include Allegron, Aventyl, Noritren, Norpress, Nortrilen, Norventyl, Norzepine, Pamelor, and Sensoval, among many others.[32][33][38]

    References

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