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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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Chlorpromazine

Last Update: October 5, 2017.

OVERVIEW

Introduction

Chlorpromazine is a phenothiazine that was once the most commonly prescribed antipsychotic agent, but that is now rarely used. Chlorpromazine can cause mild and transient serum enzyme elevations and is also a well known cause of clinically apparent acute and chronic cholestatic liver injury.

Background

Chlorpromazine (klor proe' ma zeen) is a tricyclic aliphatic phenothiazine which acts by postsynaptic inhibition of dopamine receptors. Chlorpromazine has other peripheral and central nervous system effects, producing both alpha adrenergic stimulation and blocking histamine- and serotonin-mediated effects. Chlorpromazine is indicated for the therapy of acute and chronic psychosis and for nausea and intractable hiccups. Chlorpromazine was approved for use in the United States in 1957 and was formerly the most commonly prescribed antipsychotic medication, being the prototypic, standard neuroleptic agent against which other antipsychotic agents were tested. In recent years, chlorpromazine has been replaced in large part by the atypical antipsychotics, which have fewer extrapyramidal and hepatic side effects. Current indications include psychotic disorders, schizophrenia, nausea and vomiting, acute intermittent porphyria and intractable hiccups. Chlorpromazine is available in multiple generic forms as tablets of 10, 25, 50, 100 and 200 mg, as extended release capsules of 200 and 300 mg, and as syrup in various concentrations. Parenteral forms are also available. Chlorpromazine was formerly available under the brand names Thorazine and Largactil. The typical maintenance dose of chlorpromazine is 100 to 200 mg daily. Common side effects include drowsiness, dizziness, headache, blurred vision, dry mouth, constipation, tremor, restlessness, muscle spasms and weight gain.

Hepatotoxicity

Liver test abnormalities have been reported to occur in up to 40% of patients on long term therapy with chlorpromazine, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually self-limited and unaccompanied by symptoms, reversing even without discontinuation.

Chlorpromazine is also a well known cause of acute cholestatic liver injury. Numerous instances of clinically apparent acute liver injury due to chlorpromazine have been reported in the literature, which is estimated to occur in 1:500 persons exposed. Chlorpromazine was formerly the most common cause of drug induced liver injury in the United States, but with the decrease in its use, chlorpromazine associated jaundice is now rarely reported. The clinical presentation and course are well defined. The onset of jaundice is usually within 1 to 5 weeks, and the pattern of serum enzyme elevations is typically cholestatic or mixed (Case 1). Immunoallergic manifestations (fever, rash and eosinophilia) occur in some but not all cases, and these manifestations are usually mild and self-limited. Autoantibody formation is rare. Most importantly, chlorpromazine jaundice can be prolonged and associated with vanishing bile duct syndrome (Case 2).

Likelihood score: A (well known cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which chlorpromazine causes serum aminotransferase elevations is not known. The clinically apparent liver injury due to chlorpromazine is likely due to hypersensitivity, based upon the clinical features of a short latency period, fever, eosinophilia, and rapid recurrence upon reexposure. Chlorpromazine is extensively metabolized by the liver via sulfoxidation and oxidation, and some instances of serum aminotransferase elevations as well as more clinically apparent liver injury may be caused by production of a toxic intermediate of its metabolism. Chlorpromazine therapy can also cause weight gain, and some instances of liver test abnormalities during therapy may due to nonalcoholic fatty liver disease.

Outcome and Management

The serum aminotransferase elevations that occur on chlorpromazine therapy are usually self-limited and do not require dose modification or discontinuation of therapy. The acute cholestatic hepatitis caused by chlorpromazine is typically self-limited and benign, but should prompt immediate discontinuation. Up to 7% of cases of chlorpromazine induced cholestasis are followed by prolonged jaundice, and several instances of vanishing bile duct syndrome have been attributed to chlorpromazine. Many patients with chronic cholestasis eventually improve, but they often have persistent enzyme elevations and may develop biliary cirrhosis. Fatalities from chlorpromazine jaundice have been reported. Rechallenge with chlorpromazine usually causes a prompt recurrence of the liver injury and should be avoided. Patients with chlorpromazine induced liver injury may have cross sensitivity to other phenothiazines, but generally tolerate the atypical antipsychotics. Patients with symptomatic cholestasis may benefit from ursodiol therapy (12-15 mg/kg/day). Ursodiol is generally safe and well tolerated, but it has not been rigorously evaluated for efficacy in controlled trials in drug induced liver injury. Corticosteroids are often used in patients with severe cholestatic injury due to medications, particularly if there are accompanying signs of hypersensitivity, but their efficacy has never been shown and they rarely appear to have an effect on cholestasis.

Drug Class: Gastrointestinal Agents; Antipsychotic Agents

Other Drugs in the Subclass, Antipsychotic Agents, Phenothiazines: Fluphenazine, Perphenazine, Prochlorperazine, Thioridazine, Trifluoperazine

CASE REPORTS

Case 1. Acute cholestatic hepatitis due to chlorpromazine.

[Modified from: Werther JL, Korelitz BI. Chlorpromazine jaundice: analysis of twenty-two cases. Am J Med 1957; 22: 351-66. PubMed Citation] [Case 4]

A 26 year old woman with depression was started on chlorpromazine (75 mg/day) and developed generalized pruritus one week later followed by fever, nausea and dark urine. After 21 days of therapy, she was seen by her physician and chlorpromazine was stopped. There was no history of liver disease or alcohol abuse. She was jaundiced but afebrile and without rash. The liver was enlarged but nontender. Serum bilirubin was 12.4 mg/dL and alkaline phosphatase 36.3 King-Armstrong units (normal <13) (Table). A total white blood cell count was normal and eosinophils were 4% (~330/µL). An oral cholecystogram was normal. A liver biopsy showed intrahepatic cholestasis and portal infiltrates populated by eosinophils. Over the next few weeks she began to improve and laboratory test results returned to normal within 10 weeks.

Key Points

Medication:Chlorpromazine (75 mg/day)
Pattern:Cholestatic
Severity:3+ (jaundice, hospitalization)
Latency:1-2 weeks
Recovery:6 weeks
Other medications:None mentioned

Laboratory Values

Time After StartingTime After StoppingAlk P
(K-A U/L)		Bilirubin (mg/dL)Other
PreChlorpromazine (75 mg/day) given for 21 days
3 weeks4 days36.312.4Eosinophils 4%
4 weeks11 days25.69.1Eosinophils 6%
5 weeks18 days30.46.1
6 weeks25 days19.43.8
13 weeks10 weeks7.70.7
Normal Values <13 <1.2

* Some values estimated from Figure 1 and bilirubin converted from μmol/L to mg/dL.

Comment

The typical cholestatic hepatitis caused by chlorpromazine (“Thorazine jaundice”) is marked by short incubation period (1-4 weeks), jaundice and pruritus (the itching can arise even before jaundice) and a benign, self-limited course. This case was published before general availability of serum aminotransferase measurements, and long before availability of commercial assays for hepatitis A (1982), B (1972) and C (1992). Chlorpromazine used to be the most common cause of drug induced liver injury in the United States and many western countries. Now, chlorpromazine is rarely used, and it no longer even appears in the lists of drugs implicated in case series of drug induced liver injury. Most of the other phenothiazines used in treatment of psychosis have also been implicated in cases of cholestatic jaundice with a similar clinical course, but at a lower frequency than with chlorpromazine.

Case 2. Acute cholestatic hepatitis evolving into chronic cholestatic syndrome with paucity of bile ducts and biliary fibrosis.

[Modified from: Moradpour D, Altorfer J, Flury R, Greminger P, Meyenberger C, Jost R, Schmid M. Chlorpromazine-induced vanishing bile duct syndrome leading to biliary cirrhosis. Hepatology 1994; 20: 1437-41. PubMed Citation]

A 34 year old pregnant woman was treated with chlorpromazine (25 mg twice daily) for hyperemesis gravidarum and developed fatigue and dark urine 2 weeks later followed by pruritus and jaundice. Chlorpromazine was stopped. Blood testing showed marked increases in serum bilirubin, ALT and alkaline phosphatase (Table). Tests for acute hepatitis A, B and C were negative as were autoantibodies including antinuclear, smooth muscle and mitochondrial antibodies. She had no previous history of liver disease, risk factors for viral hepatitis or alcohol abuse. She was approximately 2 months pregnant. She remained jaundiced throughout pregnancy that was terminated by Caesarian section at week 28. A concurrent liver biopsy showed severe intrahepatic cholestasis, portal inflammation and bile duct injury. After delivery of twin girls she remained jaundiced and had persistent and unrelenting pruritus. Various therapies including antihistamines, phenobarbital, cholestyramine, S-adenosylmethionine, prednisone, phototherapy and plasmapheresis were of minimal benefit. A repeat liver biopsy at 8 months after onset showed increased cholestasis and reduction in number of bile ducts, and a third liver biopsy after 14 months showed bridging fibrosis and paucity of bile ducts (ducts were detectable in only 3 of 16 portal tracts). She had enlargement of the liver and spleen, marked weight loss, steatorrhea, and symptoms of severe pruritus and fatigue. She was started on ursodiol (900 mg daily) and simultaneously began to improve clinically. Jaundice resolved 20 months after initial onset, after which serum alkaline phosphatase and ALT levels fell into the range of 1.5 to 3 fold elevated. Serum albumin and prothrombin time remained normal throughout the course. Ultrasound of the abdomen showed changes suggestive of cirrhosis and a fourth liver biopsy, 46 months after initial onset, showed biliary cirrhosis with minimal inflammation and focal areas of cholestasis and bile duct paucity (ducts detected in 5 of 12 portal tracts).

Key Points

Medication:Chlorpromazine (50 mg daily for 20 days)
Pattern:Cholestatic (R=~0.1 at peak)
Severity:4+ (prolonged jaundice, cirrhosis)
Latency:2 weeks
Recovery:Incomplete after 4 years
Other medications:None mentioned

Laboratory Values

Time After StartingTime After StoppingALT* (U/L)Alk P* (U/L)Bilirubin* (mg/dL)Other
PreChlorpromazine (50 mg daily for 20 days) given for nausea
3 weeks0601007.02 Months pregnant
5 months4 months6051035.0Delivery: liver biopsy #1
6 months12040022.0
8 months184412832.7Liver biopsy #2
10 months140180019.0
12 months150210022.9
14 months11055020.5Liver biopsy #3
4 years1002801.5Liver biopsy #4
Normal Values <42 <90 <1.2

* Some values estimated from Figure 4 and bilirubin converted from μmol/L to mg/dL.

Comment

A typical cholestatic hepatitis from chlorpromazine was followed by persistent cholestasis with jaundice and pruritus. Her pregnancy was terminated early because of the jaundice, with a Caesarian section during which a liver biopsy was done that showed severe cholestatic hepatitis with bile duct injury. Follow up liver biopsies at 8, 12 and 46 months after onset showed loss of bile ducts, but eventually a gradual improvement in cholestasis. Nevertheless, the patient developed cirrhosis and the long term prognosis remains uncertain. This is a dramatic and well documented example of vanishing bile duct syndrome developing after an acute cholestatic hepatitis due to chlorpromazine. Ursodiol therapy appeared to improve both symptoms and laboratory test results, but some degree of clinical improvement had started before therapy was initiated. Many instances of vanishing bile duct syndrome due to chlorpromazine have been published. Ursodiol is often used, but its efficacy in ameliorating or shortening the course of illness is not clear. It is appropriate to use, particularly if there is symptomatic improvement.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Chlorpromazine – Generic, Largactil®, Thorazine®

DRUG CLASS

Gastrointestinal Agents; Antipsychotic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Chlorpromazine 50-53-3 C17-H19-Cl-N2-S
Chlorpromazine Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 05 October 2017

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    (35 year old woman developed neutropenia 2 months after starting chlorpromazine with oral ulcers, fever and agranulocytosis with recovery within a few weeks; high Alk P [normal ALT and bilirubin] led to liver and bone marrow biopsy which showed granulomas).
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    (Among 1100 cases of drug induced liver injury reported between 1978 and 1987 in Denmark, 24 were due to chlorpromazine with 1 fatality).
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    (Analysis of databases of clinical information from clinicians in the UK; among 10,502 persons given chlorpromazine, 14 developed possible liver injury, for a population based rate of 1.3/1000 users; risk factors were first prescription and age [12-fold increased risk for >70 vs <50 years], but not sex).
  • Moradpour D, Altorfer J, Flury R, Greminger P, Meyenberger C, Jost R, Schmid M. Chlorpromazine-induced vanishing bile duct syndrome leading to biliary cirrhosis. Hepatology 1994; 20: 1437-41. [PubMed: 7982642]
    (33 year old pregnant woman had onset of jaundice 2 weeks after starting chlorpromazine, jaundice lasting 22 months with pruritus and high Alk P; ultimately resolving jaundice, but with biliary cirrhosis and absence of bile ducts: Case 2).
  • Wang CK, Liu JD, Lin SY, Liao LY, Cheng NY, Wang CS, Siauw CP, et al. Drug-induced liver disease--a review of 14 cases. Gaoxiong Yi Xue Ke Xue Za Zhi 1995; 11: 213-9. [PubMed: 7602656]
    (Among 14 cases of drug induced liver disease seen between 1986-1991 at one hospital in Taiwan, 2 were due to isoniazid/rifampin, 2 oral contraceptives, 1 each for aspirin, chlorpromazine, mefenamic acid, acetaminophen, ketoconazole, paraquat, trimethoprim-sulfamethoxazole, chenodeoxycholate, "cold" pill and herbals).
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    (Between 1974 and 1995, New Zealand registry received 943 reports of liver injury involving 205 drugs; chlorpromazine was listed in the top 20 drugs implicated, but proportions fell over the 21 year period from 4.2% to 2.9% to 1.5% of cases, one fatality).
  • Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156: 1686-96. [PubMed: 10553730]
    (Systematic review of 81 articles on weight change with antipsychotics; using change after 10 weeks to compare agents: clozapine +5.7, olanzapine +4.2, chlorpromazine +4.2, risperidone +1.7, loxapine +0.6, haloperidol +0.5, ziprasidone +0.3, molindone -0.1, and pimozide -2.7 kg).
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  • De Valle MB, Av Klinteberg V, Alem N, Olsson R, Bjöson E. Drug-induced liver injury in a Swedish University hospital out-patient hepatology clinic. Aliment Pharmacol Ther 2006; 24: 1187-95. [PubMed: 17014577]
    (Among 77 cases of drug induced liver injury seen between 1995 and 2005 at a single Swedish hospital, none were due to phenothiazines).
  • Minondo Amuchasteguia L, Egiguren Urrosolo L, Zapata Morcillo E, Castiella Eguzkiza A. [Chlorpromazine-induced cholestatic hepatitis in intractable hiccups]. Gastroenterol Hepatol 2007; 30: 103. Spanish. [PubMed: 17335721]
    (78 year old man developed weakness and dark urine during 12 day course of chlorpromazine for hiccups [bilirubin 2.8 mg/dL, ALT 222 U/L, Alk P 291 U/L] without fever or eosinophilia; resolving within 2 months of stopping).
  • Sabaté, Ibánez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, et al. Risk of acute liver injury associated with the use of drugs: a multicentre population survey. Aliment Pharmacol Ther 2007; 25: 1401-9. [PubMed: 17539979]
    (Among 126 cases of drug induced liver injury seen in Spain between 1993 and 2000, 3 were due to chlorpromazine with relative risk of 613: frequency of 261 per 100,000 person year exposures).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, none were attributed to phenothiazines).
  • Flanagan RJ. Fatal toxicity of drugs used in psychiatry. Hum Psychopharmacol 2008; 23 Suppl 1: 43-51. [PubMed: 18098225]
    (Deaths from fatal poisonings decreased in England and Wales between 1993-2004, antipsychotic overdose fatalities higher for phenothiazines than atypicals; deaths/million prescriptions being 29 for chlorpromazine, 15.5 thioridazine, 3.9 trifluoperazine, 13.3 olanzapine, 21 clozapine and 31.3 quetiapine; deaths were due to respiratory depression and not acute liver failure).
  • Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]
    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, including 4 due to psychotropic agents; one each for quetiapine, nefazodone, fluoxetine and venlafaxine, but none for phenothiazines).
  • Molleston JP, Fontana RJ, Lopez MJ, Kleiner DE, Gu J, Chalasani N; Drug-induced Liver Injury Network. Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN prospective study. J Pediatr Gastroenterol Nutr 2011; 53: 182-9. [PMC free article: PMC3634369] [PubMed: 21788760]
    (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 perphenazine).
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    (Systematic review of the literature found rates of any serum enzyme elevation during antipsychotic therapy to range from 5% to 78% and "clinically significant' elevations in 0% to 15%, highest rates being reported with haloperidol, olanzapine, risperidone, clozapine, perphenazine and perazine; chlorpromazine is reported to cause severe injury and several fatal cases have been published).
  • Jaiprakash H, Narayana S, Mohanraj J. Drug-induced hepatotoxicity in a tertiary care hospital in rural South India. N Am J Med Sci 2012; 4: 90-3. [PMC free article: PMC3296326] [PubMed: 22408755]
    (During a one year period, 65 cases of drug induced liver injury were seen in a rural hospital in South India, the most common causes being antituberculosis medications and cholesterol lowering drugs; chlorpromazine accounted for ~2 cases).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period including one non-fatal but icteric case due to chlorpromazine).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America: an analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (Among 176 reports of drug induced liver injury from Latin America published between 1996 and 2012, one non-fatal, but icteric case [from 2003] was attributed to chlorpromazine).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 5 [0.4%] were attributed to antipsychotic agents, including 3 to quetiapine and 2 olanzapine, but none chlorpromazine.

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