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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Amitriptyline

Last Update: March 1, 2016.

OVERVIEW

Introduction

Amitriptyline is a tricyclic antidepressant that is widely used in the therapy of depression. Amitriptyline can cause mild and transient serum enzyme elevations and is rare cause of clinically apparent acute cholestatic liver injury.

Background

Amitriptyline (am" i trip' ti leen) is a tricyclic antidepressant which is believed to act by inhibition of serotonin and norepinephrine reuptake within synaptic clefts in the central nervous system, thus increasing brain levels of these neurotransmitters. Amitriptyline is indicated for therapy of depression and was approved for this indication in the United States in 1961, and is still widely used, with more than 10 million prescriptions for amitriptyline being filled yearly. Amitriptyline is also used for anorexia and bulimia and for adjunctive treatment of neurogenic pain. Amitriptyline is available in generic forms and under the brand name of Elavil in 10, 25, 50, 75, 100 and 150 mg tablets. The typical recommended dose for depression in adults is 75 to 100 mg daily in divided doses, increasing gradually to a maximum of 300 mg daily. Amitriptyline can also be given as a single nighttime dose of 50 to 150 mg. Common side effects include dizziness, headache, drowsiness, restlessness, confusion, gastrointestinal upset, increased appetite, weight gain, blurred vision, dry mouth and urinary retention.

Hepatotoxicity

Liver test abnormalities have been reported to occur in 10% to 12% of patients on amitriptyline, 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 in patients on amitriptyline. The latency to onset is quite variable, ranging from 1 to 14 months of starting the medication. The reported pattern of serum enzyme elevations has varied from hepatocellular to cholestatic. An acute hepatitis-like syndrome with acute liver failure has been reported, as well as acute cholestatic hepatitis and prolonged jaundice compatible with vanishing bile duct syndrome. Signs or symptoms of hypersensitivity (rash, fever and eosinophilia) are frequent, but are usually mild and transient. Autoantibody formation is rare.

Likelihood score: B (highly likely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which amitriptyline causes serum aminotransferase elevation is not known. It undergoes extensive hepatic metabolism and a possible cause of liver injury is production of a toxic intermediate of metabolism. Many cases have features of hypersensitivity and more rapid recurrence with reexposure and it has been associated with a specific HLA haplotype (A11).

Outcome and Management

The serum aminotransferase elevations that occur on amitriptyline therapy are usually self-limited and do not require dose modification or discontinuation of therapy. The acute liver injury caused by amitriptyline is typically self-limited, but progressive and fatal instances of acute hepatitis and prolonged cholestasis with vanishing bile duct syndrome have been reported. Rechallenge with amitriptyline usually causes a prompt recurrence of the liver injury which can be fatal and should be avoided. Cross reactivity of hepatic injury with other tricyclic antidepressants has been described, but is not invariable. Thus, switching from one to another tricyclic antidepressant after clinically apparent liver injury should be avoided or done with caution. 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: Amoxapine, Clomipramine, Desipramine, Doxepin, Imipramine, Nortriptyline, Protriptyline, Trimipramine

CASE REPORTS

Case 1. Acute liver failure due to amitriptyline.

[Modified from: Danan G, Bernuau J, Moullot X, Degott C, Pessayre D. Amitriptyline-induced fulminant hepatitis. Digestion 1984; 30: 179-84. PubMed Citation]

A 51 year old woman developed fever and arthralgias followed 2 days later by jaundice, approximately 14 months after starting amitriptyline (30 mg daily) and perphenazine (12 mg daily). She was icteric and febrile but without rash or pruritus. Serum bilirubin levels were elevated (Table) and ALT levels were 27 times the upper limit of the normal range. She tested negative for hepatitis B surface antigen and an ultrasound showed no evidence of biliary obstruction. The symptoms and jaundice resolved with stopping the medication and all tests were normal 2 months later. Soon thereafter, however, amitriptyline and perphenazine were restarted. Within 12 days, she redeveloped jaundice and fever that progressed to hepatic failure marked by confusion, asterixis and ascites. There was no eosinophilia or autoantibodies. A transjugular liver biopsy showed massive necrosis. Serum bilirubin levels peaked a week after stopping therapy and then improved. She again had a slow clinical recovery, and four months later all liver tests were normal.

Key Points

Medication:Amitriptyline
Pattern:Hepatocellular (R=22)
Severity:4+ (prolonged jaundice, liver failure)
Latency:Initially 14 months, 12 days on rechallenge
Recovery:Four months
Other medications:Perphenazine, sulpiride

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
Amitriptyline and perphenazine given for ~14 months
14 months0920Normal4.4Fever and jaundice
1 week10809.4
2 weeks560
4 weeks802.9
8 weeks401.2
Amitriptyline and perphenazine restarted for 12 days
12 days09606.4Asterixis and ascites
4 days104014.6
1 week136015.2
2 weeks84016.4
3 weeks20023.4Liver biopsy
4 weeks16016.4
5 weeks1408.8
6 weeks805.8
4 monthsNormalNormalNormal
Normal Values <42 <1.2

* Values estimated from Figure 2 and converted from x ULN to U/L and μmol/L to mg/dL.

Comment

The latency to onset was unusually long for tricyclic induced liver injury, but the rapid recurrence with rechallenge provided convincing evidence for a link between either amitriptyline or perphenazine and this acute hepatitis like reaction. Attribution of the injury to amitriptyline rather than perphenazine (a phenothiazine that has not been clearly linked to drug induced liver injury) rests largely on previous case reports and the hepatocellular pattern of injury, which is more typical of tricyclic than phenothiazine induced injury. The severity of the response to rechallenge argues against this practice particularly when dealing with hepatocellular injury.

Case 2. Cholestatic hepatitis due to amitriptyline.

[Modified from: Anderson BN, Henrikson IR. Jaundice and eosinophilia associated with amitriptyline. J Clin Psychiatry 1978; 39: 730-1. PubMed Citation]

A 55 year old woman developed pruritus 4 weeks after starting amitriptyline therapy for depression. She stopped taking the medication, but then noticed the onset of jaundice several days later. She had no previous history of liver disease or exposures to hepatitis and drank no alcohol. Her only other medication was flurazepam. On examination, she was jaundiced but had no fever or rash. Total bilirubin was 8.0 mg/dL and serum alkaline phosphatase and AST levels were elevated (Table). These tests had been normal shortly before she started taking amitripyline. Tests for hepatitis B and autoantibodies were negative and a liver scan was normal. She had eosinophilia which had been documented on routine blood counts taken 2 and 3 weeks after starting amitriptyline. Her jaundice and abnormal liver tests resolved over the following six weeks and her depression was managed using electrotherapy.

Key Points

Medication:Amitriptyline
Pattern:Cholestatic (R=0.8)
Severity:3+ (jaundice, hospitalization)
Latency:4 weeks
Recovery:6 weeks
Other medications:Flurazepam

Laboratory Values

Time After StartingTime After StoppingAST (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
PrePre10350.5Eosinophils 2%
2 weeksEosinophils 33%
3 weeksEosinophils 16%
Amitriptyline stopped because of pruritus
5 weeks0441708.0Eosinophils 10%
6 weeks1 week1101508.1Eosinophils 7%
6.5 weeks1.5 weeks581406.0
7 weeks2 weeks5.0
11 weeks6 weeks531.3
7 months6 months451.0
Normal Value <40 <85 <1.2

Comment

The latency of 3 to 4 weeks and cholestatic features are typical of tricyclic induced liver injury. The detection of marked eosinophilia during the first few weeks of therapy suggests a hypersensitivity reaction, but there was no rash or fever. Resolution of cholestatic hepatitis is usually slower than that of acute hepatocellular injury of similar severity.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Amitriptyline – Elavil®

DRUG CLASS

Antidepressant Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Amitriptyline 50-48-6 C20-H23-N
Image of Amitriptyline Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 01 March 2016

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