Mercaptopurine adverse effects

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... 

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. 

Mercaptopurine is generally well tolerated. Adverse effects include bone marrow depression, anorexia, nausea, vomiting and sometimes jaundice associated with hepatic toxicity. 

Azathioprine can be administered both orally and intravenously. It is well absorbed orally and after its rapid conversion to 6-mercaptopurine it is inactivated by xanthine oxidase which converts 6-mercaptopurine to 6-thiouric acid. This final metabolite is then excreted in the urine. In combination with the xanthine oxidase inhibitor allopurinol dose adjustments of azathioprine are needed. Renal disease also raises 6-mercaptopurine concentrations and can make dose adjustments necessary. Azathioprine is still used in organ transplantation programs and for the management of several autoimmune diseases. Its adverse effects include nausea, vomiting, diarrhea and, more seriously, bone marrow suppression and hepatotoxicity. Azathioprine is not thought to cause fetal malformation. 

Myelosuppression, with leukopenia and thrombocytopenia appearing 7 to 10 days after treatment, and mild nausea are the most common adverse effects. Liver toxicity with jaundice has been reported in some patients but appears to be less common than with mercaptopurine. 

Therapeutic pyramid approach to inflammatory bowel diseases. Treatment choice is predicated on both the severity of the illness and the responsiveness to therapy. Agents at the bottom of the pyramid are less efficacious but carry a lower risk of serious adverse effects. Drugs may be used alone or in various combinations. Patients with mild disease may be treated with 5-aminosalicylates (with ulcerative colitis or Crohn s colitis), topical corticosteroids (ulcerative colitis), antibiotics (Crohn s colitis or Crohn s perianal disease), or budesonide (Crohn s ileitis). Patients with moderate disease or patients who fail initial therapy for mild disease may be treated with oral corticosteroids to promote disease remission immunomodulators (azathioprine, mercaptopurine, methotrexate) to promote or maintain disease remission or anti-TNF antibodies. Patients with moderate disease who fail other therapies or patients with severe disease may require intravenous corticosteroids, anti-TNF antibodies, or surgery. Natalizumab is reserved for patients with severe Crohn s disease who have failed immunomodulators and TNF antagonists. Cyclosporine is used primarily for patients with severe ulcerative colitis who have failed a course of intravenous corticosteroids. TNF, tumor necrosis factor. 

The special risk is observed in patients with hepatic or renal impairment. It is not advised to use allopurinol in acute attacks of gout, but it is useful in chronic gout. Excretion of allopurinol and its active metabolite oxypurinol is primarily via the kidneys and therefore the dosage should be reduced if renal function is impaired. The adverse effects have been reported in patients receiving allopurinol with thiazide diuretics, particularly in patients with impaired renal function. The metabolism of azathioprine and mercaptopurine is inhibited by allopurinol and their doses should be reduced to one-quarter to one-third of the usual dose when either of them is given with allopurinol to avoid potentially life-threatening toxicity.27-29... 

Azathioprine [a zah THIO preen] has been the cornerstone of immunosuppressive therapy over the last several decades. It has a nitroimidazoloyl side chain attached to the sulfur of 6-mercap-topurine, which is removed by non-enzymatic reduction in the body by glutathione to yield 6-mercaptopurine (6-MP). The latter is then converted to the corresponding nucleotide, thioinosinic acid (TIMP), by the salvage pathway enzyme, hypoxanthine-gua-nine phosphoribosyl transferase. The immunosuppressant effects of azathioprine are due to this fraudulent nucleotide. (See pp. 380-381 for a discussion of 6-MP s mechanism of action, resistance, pharmacokinetics, and adverse effects.) Because of their rapid proliferation in the immune response, and their dependence on de novo synthesis of purines required for cell division, lymphocytes are predominantly affected by the cytotoxic effects of azathioprine. The drug has little effect on suppressing a secondary immune response. 

Most patients who receive asparaginase develop hver function abnormalities, which can be fatal (12). This adverse effect is of major concern in patients who are also taking other hepatotoxic drugs, such as methotrexate and mercaptopurine. Jaundice and increased serum bihr-ubin and transaminases occur often, and hepatomegaly and fatty deposits occur occasionally. 

A 50-year-old woman with Crohn s disease and active disease throughout the colon was given prednisolone, mesalazine, and azathioprine 50 mg/day. After 3 weeks, the dose of azathioprine was increased to 100 mg/day, but she developed nausea, severe diarrhea, and abdominal tenderness. The symptoms subsided after azathioprine was withdrawn. She was then given mercaptopurine, without significant adverse effects. 

The chemical structure of 6-thioguanine, which results from the metabolism of azathioprine/mercaptopurine, is very similar to that of mercaptopurine. Therefore, a history of previous adverse effects with mercaptopurine should be anticipated in patients considered for 6-thioguanine treatment. 

Drug intolerance often limits the usefulness of agents used to treat IBD. Many patients receiving sulfasalazine, mesalamine, corticosteroids, metronidazole, azathioprine, mercaptopurine, or infliximab experience some undesired effects. In some cases, these adverse effects can be significant and require discontinuation of the therapy. Knowledge of the common or important adverse reactions will assist in avoiding or minimizing their effects. 

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. 

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