Trazodone hepatotoxicity

Nefazodone is chemically related to trazodone. Its primary metabolites, hydroxynefazodone and m-cpp are both inhibitors of the 5-HT2 receptor. Nefazodone received an FDA black box warning in 2001 implicating it in hepatotoxicity, including... 

SERT. However, trazodone has rarely been associated with inducing priapism. The effects of both nefazodone and trazodone since tx-blocking agents result in a dose-related orthostatic hypotension in some patients. Nefazodone has been associated with hepatotoxicity, including rare fatalities and cases of fulminant hepatic failure requiring transplantation. The rate of serious hepatoxicity with nefazodone has been estimated at 1 in 250,000 to 1 in 300,000 patient-years of nefazodone treatment. 

Hepatotoxicity, a known hazard of tricyclic compounds, has been reported with trazodone (22,23). 

Fernandes NE, Martin RR, Schenker S. Trazodone-induced hepatotoxicity A case report with comments on drug-induced hepatotoxicity. Am J Gastroenterol 2000 95 532-535. 

Trazodone therapy has been associated with several cases of idiosyncratic hepatotoxicity (see Chapter 10). Although the mechanism of hepatotoxicity remains unknown, the generation of an iminoquinone, an epoxide reactive metabolite or both may play a role in the initiation of trazodone-mediated hepatotoxicity (Fig. 

Nefazodone is a phenylpiperazine antidepressant structurally related to trazodone, but it differs pharmacologically from trazodone, the SSRIs, the MAOIs, and the TCAs (Fig. 21.22). When compared with trazodone, nefazodone displays approximately twice the affinity potency for SERT. Nefazodone therapy, however, was associated with life-threatening cases of idiosyncratic hepatotoxicity, and as a result, nefazodone was withdrawn from both the North American and European markets in 2003. The mechanism of hepatotoxicity remains unknown, but nefazodone, being structurally similar to trazodone (Fig. 21.23), is metabolized to p-hydroxynefazodone, m-CPP, and phenoxyethyltriazoledione. In turn, p-hydroxynefazodone is thought to be oxidized to an iminoquinone and/or an epoxide reactive metabolite, which may play a role in the initiation of nefazodone-mediated hepatotoxicity (76). 

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