Nortriptyline

Publication Details

OVERVIEW

Introduction

Nortriptyline is a tricyclic antidepressant that is also used in smoking cessation. Nortriptyline can cause mild and transient serum enzyme elevations and is rare cause of clinically apparent acute and chronic cholestatic liver injury.

Background

Nortriptyline (nor trip' ti leen) is a tricyclic antidepressant which acts by inhibition of reuptake of serotonin and norepinephrine in synaptic clefts, thus increasing brain levels of these neurotransmitters. Nortriptyline was approved for use in the United States in 1964 for the treatment of depression. It is also used for smoking cessation and is commonly used in the United States, with more than 3 million prescriptions being filled yearly. Nortriptyline is available in generic forms and under the brand names of Aventyl and Pamelor in 10, 25, 50 and 75 mg tablets. An oral solution is also available. The typical recommended dose for depression is 25 mg three or four times daily, increasing based upon effect and tolerance to as much as 150 mg daily. The typical dose for smoking cessation is 25 mg daily, gradually increasing to a maximum of 100 mg daily. Common side effects include drowsiness, dizziness, restlessness, headache, blurred vision, dry mouth, constipation, and urinary retention.

Hepatotoxicity

Liver test abnormalities have been reported to occur in up to 16% of patients being treated with tricyclic antidepressants, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Rare instances of clinically apparent acute liver injury have been reported due to nortriptyline. The onset of jaundice is usually within 2 to 3 months of starting nortriptyline and the predominant enzyme pattern has been hepatocellular. Several acute instances of nortriptyline hepatotoxicity with marked elevations in serum aminotransferase levels and acute liver failure have been described. Signs and symptoms of hypersensitivity and autoimmunity are usually not present.

Likelihood score: C (probable rare cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which nortriptyline causes serum aminotransferase elevations and acute liver injury is not known. It undergoes extensive hepatic metabolism and a possible cause of liver injury is production of a toxic intermediate of metabolism.

Outcome and Management

The serum aminotransferase elevations that occur on nortriptyline therapy are usually self-limited and do not require dose modification or discontinuation of therapy. The acute hepatitis caused by nortriptyline can be severe and lead to acute liver failure. No cases of chronic liver injury or vanishing bile duct syndrome have been reported with nortriptyline therapy. While cross reactivity of hepatic injury with other tricyclic antidepressants has rarely been described, amitriptyline is metabolized to nortriptyline which is its active form. Thus, switching to amitriptyline after nortriptyline toxicity should be avoided. Switching to other forms of antidepressants such as the selective serotonin reuptake inhibitors is likely to be safe.

Drug Class: Antidepressant Agents

Other Drugs in the Subclass, Tricyclics: Amitriptyline, Amoxapine, Clomipramine, Desipramine, Doxepin, Imipramine, Protriptyline, Trimipramine

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Nortriptyline – Aventyl®, Pamelor®

DRUG CLASS

Antidepressant Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 05 April 2020

Abbreviations: MAO inhibitor, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor.

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    (65 year old woman developed fatigue and serum enzyme elevations [ALT ~1300 U/L; Alk P ~380 U/L] 1 month after starting trimipramine; 3 years later she developed nausea and ALT elevations 10 days after starting desipramine [ALT ~250 U/L], and 2 years later developed abdominal pain and fever and enzyme elevations [ALT ~1100 U/L, Alk P ~ 510 U/L] 8 days after starting cyamemazine; each time with rapid recovery and no jaundice).
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    (52 year old woman developed jaundice 3 months after starting nortriptyline [bilirubin 5.0 mg/dL, ALT 9,590 U/L, Alk P 343 U/L, prothrombin activity 18%], testing revealed high nortriptyline levels and no acetaminophen; rapid spontaneous recovery).
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    (Among 30 children with suspected drug induced liver injury, half [n=15] were due to antimicrobials [minocycline 4, INH 3, azithromycin 3] and the rest largely due to CNS agents and anticonvulsants; one case was attributed to amitriptyline, but no other tricyclic antidepressant was listed).
  • Park SH, Ishino R. Liver injury associated with antidepressants. Curr Drug Saf. 2013;8:207–23. [PubMed: 23914755]
    (Review of drug induced liver injury due to antidepressants; nortriptyline is not mentioned).
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    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, none of which were attributed to amitriptyline or other tricyclic antidepressant).
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    (Review of the frequency and clinical features of drug induced liver injury due to antidepressants; imipramine, desipramine, amitriptyline and clomipramine are discussed, but not nortriptyline).
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    (Among 184,234 psychiatric inpatients from 80 hospitals, 149 cases [0.08%] of drug induced liver injury were reported including 71 of 50,201 patients treated with tricyclics, 18 of 11,876 receiving trimipramine and 2 of 2,016 receiving nortriptyline).
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    (Among 5 million persons identified in a national French health insurance database who started an antidepressant between 2010 and 2015, 382 developed serious liver injury resulting in hospitalization, rates per 100,0000 persons-years being 19 for SSRIs, 22 venlafaxine, 13 duloxetine, and 33 mirtazapine; conventional tricyclics and MAO inhibitors not discussed).
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    (Analysis of data sources from 4 European countries identified 3.2 million persons initiating antidepressant therapy among whom there was no increased risk for acute liver injury for agomelatine compared to citalopram, an SSRI with a low rate of hepatotoxicity).
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