Hepatic reactions to drugs

Abstract

In this review article the drug metabolizing enzyme reactions of the liver and the pathomechanism of hepatotoxicity are discussed. Drugs rarely seem to cause damage by direct action on the liver cell, rather they act indirectly in two ways: by their metabolites which may turn out to be potent alkylating agents causing cell necerosis, and by development of an immunological reaction to the drug which, by binding to cell components, renders them antigenic. The metabolite-related damage is dose dependent and, is increased by pretreatment with inducers (which promote the production of toxic metabolites). Cellular glutathione plays a significant role in binding the toxic metabolites. For replenishment of the exhausted glutathione stores treatment with N-acetyl cysteine appears to be the method of choice. The hepatotoxic effects induced by the immunological mechanism are unrelated to dose. The drug acts as a hapten with cellular membrane antigens. Lymphocytes are sensitized and re-exposure to the drug induces delayed hypersensitivity reaction against cell components and necrosis ensues. Symptoms and histology resemble those of viral hepatitis. In the second part of the paper the clinical manifestations of hepatotoxic states caused by a great number of more commonly used drugs, including some prognostic and therapeutic guide lines, are described. In addition the cholestatic effects and the more recently recognized hepatic adenoma inducing effect of steroid hormones and contraceptives are discussed. There is a valuable list of 89 basic references.