Perphenazine is a phenothiazine and antipsychotic agent, now rarely used in clinical practice. Perphenazine can cause mild and transient serum enzyme elevations and is a rare cause of clinically apparent acute and chronic cholestatic liver injury.
Perphenazine (per fen' a zeen) is a piperazine phenothiazine derivative which acts by postsynaptic inhibition of dopamine receptors. Perphenazine has other peripheral and central nervous system effects, producing both alpha adrenergic stimulation and blocking histamine- and serotonin-mediated effects. Perphenazine is indicated for the therapy of acute and psychosis and is also used for management of nausea and vomiting. Perphenazine was approved for use in the United States in 1957 and was formerly a commonly prescribed antipsychotic, but in recent years, has been replaced in large part by the atypical antipsychotics, which have fewer extrapyramidal side effects. Perphenazine is available in generic forms as tablets of 2, 4, 8 and 16 mg and previously under the brand name of Trilafon. Oral solutions are also available. Typical doses used to treat schizopheria are 4 to 16 mg two to four times daily, attempting to reduce the dose as soon as possible to a minimum. Common side effects include drowsiness, dizziness, headache, blurred vision, dry mouth, constipation, tremor, restlessness, muscle spasms and weight gain.
Transient liver test abnormalities occur in a proportion of patients on long term therapy with perphenazine and other phenothiazines, but the elevations are usually mild, asymptomatic and reverse even with continuation of medication. Chlorpromazine, the prototype phenothiazine, is a well known cause clinically apparent acute liver injury which occurs in approximately 1% of treated patients. It is unclear whether perphenazine causes a similar syndrome, but if so, it is rare and far less common than with chlorpromazine. Case series of drug induced liver injury have occasionally listed perphenazine as a cause, but the clinical characteristics of the injury have not been described. Typical phenothiazine induced liver injury usually presents within 1 to 4 weeks of starting therapy, with a cholestatic or mixed pattern of serum enzyme elevations. Immunoallergic manifestations (fever and eosinophilia) are common but usually not prominent, and autoantibodies are rare. Phenothiazine induced jaundice can be severe and prolonged and result in vanishing bile duct syndrome, but is rarely fatal.
Mechanism of Injury
The mechanism by which perphenazine causes serum aminotransferase elevations is not known. The clinically apparent, cholestatic liver injury that occurs with many phenothiazines is likely to be due to hypersensitivity, being often accompanied by fever and eosinophilia and occurring with a shorted latency upon rechallenge. Perphenazine 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.
Outcome and Management
The serum aminotransferase elevations that occur on perphenazine therapy are usually self-limited and do not require dose modification or discontinuation of therapy. The acute cholestatic hepatitis caused by phenothiazines is typically self-limited and benign, but should lead to prompt discontinuation. A proportion of cases are followed by prolonged jaundice and cholestasis, and many instances of vanishing bile duct syndrome have been attributed to chlorpromazine and prochlorperazine. Many patients with chronic cholestasis eventually improve, but they often have persistent enzyme elevations and biliary cirrhosis. Rechallenge usually causes a prompt recurrence of the liver injury and should be avoided. Patients with perphenazine induced liver injury may have cross sensitivity to other phenothiazines, but should tolerate the atypical antipsychotics without increased risk of liver injury.
REPRESENTATIVE TRADE NAMES
Perphenazine – Generic, Trilafon®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 16 January 2014
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perphenazine. J Clin Psychiatry 2007; 68: 213-23. PubMed Citation (Controlled trial of aripiprazole vs perphenazine in 416 adults with treatment resistant schizophrenia; the "incidence of potentially clinically significant laboratory abnormalities during the study was low" and there was no mention of ALT elevations or hepatoxicity).
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. PubMed Citation (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, none were due to phenothiazines).
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. PubMed Citation (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. PubMed Citation (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).
Drugs for psychiatric disorders. Treat Guidel Med Lett 2013; 11 (130): 53-64. PubMed Citation (Concise review and recommendations on use of antidepressants and antipsychotic medications including phenphenazine; no discussion of hepatotoxicity).
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