**9. Drugs for gastrointestinal diseases and their implication in adverse reactions**

Most of adverse reactions with drugs used for treating gastrointestinal diseases are proton pump inhibitors. New antiTNF drugs, steroids and immunosuppressant in general used for

RUCAM algorithm (Roussel Uclaf Causality Assessment Method) was the first algorithm developed specifically for DILI. After the meeting sponsored by the CIOMS (Paris, 1989), with the support of Russel Uclaf pharmaceutical company, the terminology and diagnosis criteria for causality assessment was proposed. The algorithm was validated using external cases with positive rechallenge (49 cases) and 28 controls (patients with acute liver damage not related to drugs) with available information before occurrence of re-exposure, with results of high sensitivity (86%), specificity (89%), positive predictive value (93%) and negative predictive

International DILI Expert Working Group of clinicians and scientists reviewed current DILI terminology and diagnostic criteria so as to develop more uniform criteria that could be define and characterize the spectrum of clinician syndromes that constitute DILI. In Appendix 2 of supplementary information you will find threshold criteria for definition of a case as being DILI (Box 1), the pattern of liver injury (Box 2), severity (Box 3), causality assessment (Box 4), and chronicity (Box 5). Consensus was also reached on approaches to characterizing DILI in the setting of chronic liver diseases (Box 6), including autoimmune

A very large number of different drugs have been associated with liver injury. There is a clear difference in the documentation or the evidence for hepatotoxicity associated with these drugs. Isoniazid, phenytoin, disulfiram, amoxicillin/clavulanate, halothane and chlopromazine are drugs with well characterized hepatotoxicity. More recently antibiotics (amoxicillin/clavunalate, erytromicin, flucloxacillin, trimethoprim-sulpha, nitrofurantoin, isoniazid and rifampicin), analgesics and NSAIDs (diclofenac, dextropropoxyphene, paracetamol, ibuprofen) probably the most common type of drugs associated with DILI. In hospitalized patients, antineoplasic agents seem to commonly lead to DILI and are probably underreported. In a Spanish pharmacovigilance prospective program based on laboratory signals at hospital all patients with liver test abnormalities ( x 3 upper limits of normal) were evaluated being antibiotics (19.5%), hormonal contraceptives (14.6%) and anticancer agents (10%) were the most frequent drug-groups associated to liver injury. In out-patients, the single most common drug implicated in ine series was diclofenac. Among patients with acute liver failure resulting from drugs in the US who underwent liver transplantation, paracetamol (acetaminophen) was the most common causative drug, followed by isoniazid, propylthiouracil, phenytoin and valproate.. Herbal and dietary supplements are implicated in approximately 11% of patients who developed acute serious liver disease of unknown

The expectrum of DILI is varied, acute liver injury with or without jaundice, chronic hepatitis, although rare, liver cirrhosis has been reported to occur with long-standing drug treatment suspected to have caused DILI, and approximately 25-30% of DILI present with symptom of immunoallergic drug reactions. Table 2 showed the most common types of liver

Most of adverse reactions with drugs used for treating gastrointestinal diseases are proton pump inhibitors. New antiTNF drugs, steroids and immunosuppressant in general used for

**9. Drugs for gastrointestinal diseases and their implication in adverse** 

value (78%) [Algorithm RUCAM are showed in Table 1 and 2 of Appendix 2].

hepatitis (Box 7).

cause in Spain.

**reactions** 

injury that have been identified with drugs.


Table 2. Types of DILI (adapted from Björnsson )

inflammatory bowel disease cause also adverse drug reactions but the extended use of IBP makes them responsible of most of the adverse reactions with gastrointestinal drugs: hypergastrinemia, hypomagnesemia, tumors and, recently, enteric infections, pneumonia and osteoporosis (Maffei, 2007). There is a controversy about the probability of some of theses adverse drug reactions with IBPs. In the recent review by Thomson (2010) they failed to found risk of carcinoid tumors, cancer or nosocomial pneumoniae. There still controversy about the risk of osteoporosis with the long term use of IBPs.
