Relative Frequencies Of Drugs Implicated

Advances in drug development have allowed the replacement of many potentially toxic drugs with ''safer'' alternatives. For example, oxyphenisatin has been withdrawn as a laxative in most countries, alpha-methyldopa is now rarely used as an antihypertensive agent, and perhexilene has been replaced by alternative, safer agents. As might be expected, this has led to a change in the pattern of implicated drugs causing hepatotoxicity over the last few decades. In the 1960s chlorpro-mazine was most commonly associated with hepatotoxicity (Cook and Sherlock, 1965) and in the 1970s halothane was responsible for 25% of hepatotoxic drug reactions reported (Dossing and Andreasen, 1982). Even though this has led to a significant reduction in use in the United Kingdom, halothane continues to account for significant numbers of hepatotoxic adverse reactions in Europe and New Zealand (Friis and Andreasen, 1992; Pillans, 1996). Similarly, liver injury secondary to antitubercular drugs such as isoniazid continues to be reported worldwide (Acharya et

Table 37.1. Drugs causing adverse hepatic reactions.

Acute hepatocellular and mixed pattern of liver injury (or acute hepatitis)

NSAIDs: diclofenac, ibuprofen, naproxen, nimesulide, piroxicam, sulindac

Anaesthetics: enflurane, halothane, isoflurane

Antimicrobials: ketoconozole, ofloxacin, sulphamides, sulphones, terbinafine, tetracyclines; antimycobacterials such as isoniazid, pyrazinamide, rifampicin; anti-HIV agents such as didanosine, indinavir, zidovudine

Neuropsychotropics: tricyclics (most), fluoxetine, paroxitine, pemoline, sertraline, tacrine, riluzole; illegal compounds such as cocaine and Ecstasy

Antiepileptics: carbamazapine, phenytoin, valproate

Cardiovascular drugs: bezafibrate, captopril, diltiazem, enalapril, lisinopril, lovastatin, simvastatin, ticlopidine

Antineoplastic and immunomodulatory agents: cyclophosphamide, cis-platinum, doxorubcine, granulocyte colony stimulating factor, interleukin (IL)-2, lL-12, tamoxifen

Others: etretinate, glipizide, herbal remedies, ranitidine

Acute cholestatic pattern of liver injury and cholestatic hepatitis

Hormonal preparations: androgens, oral contraceptives, tamoxifen

Antimicrobials: clindamycin, co-amoxiclav, co-trimoxazole, erythromycin, flucloxacillin, troleandomycin

Analgesic/anti-inflammatory drugs: gold salts, propoxyphene, sulindac

Neuropsychiatric drugs: carbamazapine, chlorpromazine, tricyclic antidepressants

Antineoplastic and immunomodulatory agents: asparaginase, azathioprine, cyclosporin

Cardiovascular drugs: ajmaline, captopril, propafenone, ticlopidine

Others: allopurinol, chlorpropamide

Chronic hepatitis and/or cirrhosis

Aspirin, diclofenac, halothane, herbal medicine (germander), isoniazide, methotrexate, methyldopa, nitrofurantoin, papaverine, vitamin A

Chronic cholestasis and ductopenia

Ajmaline, carbamazepine, chlorpromazine, co-amoxiclav, co-trimoxazole, erythromycin, flucloxacillin, methyltestosterone, phenytoin

Granulomatous hepatitis

Allopurinol, carbamazapine, cephalexin, dapsone, diltiazem, gold salts, hydralazine, isoniazid, methyldopa, nitrofurantoin, penicillin, penicillamine, phenytoin, procainamide, quinidine, sulphonamides, sulphfonylureas

Macro and microvesicular steatosis

Amiodarone, asparaginase, buprenorphine, corticosteroids, flutamide, female sex hormone, methotrexate, perhexiline, salicylate, tacrine, tetracycline, valproate, zidovudine

Hepatic vascular lesions

Hepatic vein thrombosis/veno-occlusve disease: azathioprine, dacarbazine, combination chemotherapy (carmustine, cytarabine, mitomycin, thioguanine, urethane), oral contraceptives

Sinusoidal dilation/peliosis: anabolic steroids, azathioprine, hydroxyurea, oral contraceptives

Perisinusidal fibrosis: azathioprine, methotrexate, vitamin A

Tumors

Androgens, oral contraceptives

For more comprehensive lists see Farrell (1994), Pillans (1996), Desmet (1997), Erlinger (1997), Larrey (2000), Krahenbuhl (2001), and Lucena et al. (2001).

al, 1996; Ostapowicz et al, 1999; Lucena et al, 2001). As the relatively "high-risk" agents have been replaced, relatively rare reactions to commonly prescribed "low-risk" agents have become the most important cause of hepatotoxicity. In the last few years, non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac and sulindac, antimicrobials such as co-amoxiclav, flucloxacillin and erythromycin, and H2 antagonists have become important causes of hepatotoxicity (Pil-lans, 1996; Lucena et al., 2001). In addition, hepatotoxicity due to substances that were previously thought to have little toxicity, such as "Ecstasy" (recreational amphetamine) and herbal remedies, are being increasingly recognised (Lar-rey, 1997; Andreu et al., 1998). A brief list of the drugs which are important causes of hepatotoxi-city and the pattern of the liver injury are shown in Table 37.1.

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