Azathioprine pancreatitis with

Ghntborg B. Pancreatitis hos en patient med morbus Crohn behandlet med mesalazin og azathioprin. [Pancreatitis in a patient with Crohn disease treated with mesalazine and azathioprine.] Ugeskr Laeger 2000 162(34) 4553. ... 

Agents targeting the excessive immune response or cytokines involved in IBD are potential treatment options (Table 16-3). Azathioprine and its active metabolite 6-mercaptopurine (6-MP) are inhibitors of purine biosynthesis and reduce IBD-associated GI inflammation. They are most useful for maintaining remission of IBD or reducing the need for long-term use of corticosteroids. Use in active disease is limited by their slow onset of action, which may be as long as 3 to 12 months. Adverse effects associated with azathioprine and 6-MP include hypersensitivity reactions resulting in pancreatitis, fever, rash, hepatitis, and leukopenia.25,26... 

With azathioprine and 6-MP, monitor for hypersensitivity reactions, including severe skin rashes and pancreatitis. Educate the patient regarding signs and symptoms of pancreatitis (nausea, vomiting, and abdominal pain). 

Immunosuppressive agents such as azathioprine and mercaptopurine (a metabohte of azathioprine) are sometimes used for the treatment of IBD. These agents are generally reserved for cases that are refractory to steroids and may be associated with serious adverse effects such as lymphomas, pancreatitis, or nephrotoxicity. Cyclosporine has been of short-term benefit in acute, severe ulcerative colitis when used in a continuous infusion. 

Immunosuppressants such as azathioprine and mercaptopurine have a significant potential for adverse reactions, including bone marrow suppression, and have been associated with lymphomas (in renal transplant patients) and pancreatitis. Myelosuppression resulting in leukopenia is related to a deficiency in TPMT in some patients. 

Patients with frequent relapses despite apparently adequate prophylactic treatment should be reviewed carefully. Associated milk intolerance or coeliac disease need treatment on their merits. Colonoscopic evidence of dysplasia raises the question of undiagnosed malignancy. Occasionally the prophylactic agents themselves can cause watery diarrhoea (particularly olsalazine) or a hypersensitivity colitic disease. Prophylactic azathioprin should be considered in those in whom relapse is frequent despite use of aminosalicylates or if they are poorly tolerated. In the effective dose of 2 mg/kg adverse effects of bone marrow depression are uncommon, but still occur, and regular haematological review is essential (monthly or bi-monthly). Azathioprin-induced pancreatitis is an uncommon but well-recognised entity. 

Dose-related toxicities of azathioprine or 6-mercaptopurine include nausea, vomiting, bone marrow depression (leading to leukopenia, macrocytosis, anemia, or thrombocytopenia), and hepatic toxicity. Routine laboratory monitoring with complete blood count and liver function tests is required. Leukopenia or elevations in liver chemistries usually respond to medication dose reduction. Severe leukopenia may predispose to opportunistic infections leukopenia may respond to therapy with granulocyte stimulating factor. Hypersensitivity reactions to azathioprine or 6-mercaptopurine occur in 5% of patients. These include fever, rash, pancreatitis, diarrhea, and hepatitis. 

MERCAPTOPURINE ANTIGOUT DRUGS -ALLOPURINOL t mercaptopurine levels with risk of toxicity (e.g. myelosuppression, pancreatitis) Azathioprine is metabolized to mercaptopurine. Allopurinol inhibits hepatic metabolism of mercaptopurine 1 doses of azathioprine and mercaptopurine by up to three-quarters and monitor FBC, LFTs and amylase carefully... 

Pancreatitis due to azathioprine or mercaptopurine has usually been reported as part of the hypersensitivity syndrome (SEDA-16,520) (SEDA-20,341). It has mostly been observed in patients with inflammatory bowel disease, and required withdrawal of treatment in 1.3% of patients with Crohn s disease (3). Pancreatitis was not dose-related within the therapeutic range of doses and often recurred in patients who were rechallenged with either drug (SEDA-20, 341) (35). Fatal hemorrhagic pancreatitis occurred in one patient, but a role of concomitant drugs was also possible (SEDA-20, 341). Pancreatitis or hyperamylasemia were not significantly different in renal transplant patients randomly assigned to receive azathioprine or ciclosporin, and other causative factors were found in most patients with pancreatitis (36). 

In a review of definite or probable drug-associated pancreatitis spontaneously reported to the Dutch adverse drug reactions system during 1977-98, azathioprine was the suspected drug in four of 34 patients, two of whom had positive rechallenge (37). Although most of the carefully described reports of azathioprine-induced pancreatitis were found in patients with inflammatory bowel disease, transplant recipients can also suffer this complication. 

Several agents have been associated with producing acute pancreatitis or inflammation of the pancreas. The main causes are alcohol and a disturbance of the bile duct, which account for 50% of cases. Drugs with a clear association include sulfonamides, thiazide diuretics, tetracycline, azathioprine, estrogens, and valproic acid. The mechanism for the underlying injury is not well understood. Possible associations have been reported with other medications including methyldopa, procainamide, and 1-asparaginase. A relationship between cortico-steriods has not been established. 

Immunosuppressants such as azathioprine and mercaptopurine have a significant potential for adverse reactions. Azathioprine causes bone marrow suppression and has been associated with lymphomas (in renal transplant patients), skin cancer, and pancreatitis (about 3% of patients). Some investigators believe that induction of leukopenia may be necessary for therapeutic effect. Mercaptopurine causes adverse reactions similarly to azathioprine however, there are fewer reports of lymphomas with this agent. In one cohort of IBD patients, adverse effects from mercaptopurine were as follows pancreatitis, 1.2% allergic reactions, 3.9%, significant leukopenia, 11.5% and infectious complications, 14%. Ten percent of patients who received azathioprine or mercaptopurine required discontinuation of treatment because of adverse effects. Allopurinol inhibits the metabolism of mercaptopurine, and a dosage reduction of the latter is required when the two are used in combination. 

Dose-limiting adverse effects of azathioprine are often hematologic (see Table 87-4). Leukopenia, anemia, and thrombocytopenia can occur within the first few weeks of therapy and can be managed by dose reduction or discontinuation of azathioprine. Other common adverse effects include nausea and vomiting, which can be minimized by taking azathioprine with food. Alopecia, hepatotoxicity and pancreatitis are less common adverse effects of azathioprine they generally are reversible on dose reduction or discontinuation. ... 

A single case report describes a 51-year-old woman with a kidney transplant who developed pancreatitis after starting lamivudine. Azathioprine had been discontinued only 3 days before and it is possible (although the evidence is weak) that the residual serum azathioprine had interacted with lamivudine to cause the pancreatitis. ... 

Hypersensitivity reactions In 21 patients with inflammatory bowel disease who had hypersensitivity reactions to azathioprine or mercaptopurine within 6 weeks, thioguanine 10-40 mg/day elicited hypersensitivity reactions in only four, after a median of 9 days pancreatitis did not recur [1185]. 

Pancreas During 82 episodes of acute pancreatitis, most cases were attributed to drug exposure azathioprine/mercapto-purine (n = 46) and mesalazine (n = 6) [121 ]. In those with acute pancreatitis due to thiopurines, female sex (OR = 3.4 95% Cl = 1.3, 9.3) and Crohn s disease (OR = 5.8 95% Cl = 1.6,21) were susceptibility factors. 

Bermejo F, Lopez-Sanroman A, Taxonera C, Gisbert JP, P6rez-Calle JL, Vera I, Menchdn L, Martfn-Arranz MD, Opio V, Carneros JA, Van-Domselaar M, Mendoza JL, Luna M, L6pez P, Calvo M, Algaba A. Acute pancreatitis in inflammatory bowel disease, with special reference to azathioprine-induced pancreatitis. Aliment Pharmacol Ther 2008 28(5) 623-8. 

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