Azathioprine monitoring therapy with

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. 

AZATHIOPRINE LEFLUNOMIDE T risk of serious infections (sepsis) and of opportunistic infections (Pneumocystis jiroveci pneumonia, tuberculosis, aspergillosis) Additive immunosuppression Monitor platelets, white bloods cell, haemoglobin and haematocrit at baseline and regularly - weekly, during concomitant therapy. With evidence of bone marrow suppression, discontinue leflunomide and administer colestyramine or charcoal to T elimination of leflunomide - For signs and symptoms of immunosuppression, see Qinical Features of Some Adverse Drug Interactions, Immunosuppression and blood dyscrasias... 

The immunosuppressive agents (azathioprine and mercaptopurine) are generally limited to use in patients not achieving adequate response to standard medical therapy, or to reduce steroid doses when toxic doses are required. The usual dose of azathioprine is 2 to 3 mg/kg/day and 1 to 1.5 mg/kg/day for mercaptopurine. Up to 3 to 4 months may be required to observe a response. Starting doses are typically 50 mg/day and increased at 2-week intervals while monitoring complete blood count with differential. 

Fig. 13.2 Thiopurine methyl transferase (TPMT) methylator genotypes in Crohn s disease during azathioprine/6-mercaptopurine (AZA/6-MP) treatment influences the time in months to development of severe myelosuppression. However, only 27% of patients with Crohn s disease and myelo-suppression during AZA therapy had mutant alleles of the TPMT gene associated with enzyme deficiency. Myelosuppression is more often caused by other factors. Continued monitoring of blood cell counts remains mandatory in patients treated with AZA. (Reproduced from ref 35.)...

Psychiatric adverse effects have not previously been reported with azathioprine. Neither does the database of the WHO Uppsala Monitoring Centre mention obsessive-compulsive symptoms or panic attacks as a possible adverse effect of azathioprine. However, the time course in this case and the absence of symptoms before and after azathioprine therapy suggest a causal relation. It is possible that the combination of subtle cerebral dysfunction as a result of the vasculitis and the use of azathioprine may have caused the symptoms in this patient. 

Ciclosporin may induce remission in some patients with severe ulcerative colitis unresponsive to corticosteroid. The drug is given in a dose of 2-4 mg/kg i.v. until remission is attained. Renal function should be monitored closely as ciclosporin is nephrotoxic (see p. 620). For maintenance therapy azathioprine (see below) is often substituted. Ciclosporin use only delays surgery for many patients after 1 year 50% will have relapsed and undergone colectomy. 

Of the toxic side effects, a major concern among clinicians is for dose-dependent bone marrow suppression (myelotoxicity), which occurs in 2. 6% of patients and can be fatal if not addressed properly. Study data suggest that a high incidence of secondary acute myeloid leukemia or brain cancer is correlated with low TPMT activity and high 6-TGN levels in children under immunosuppressive therapy. TPMT activity is subject to wide interindividual and interethnic variability due to TPMT gene polymorphism. In the Caucasian population, 0.3% of all individuals have no TPMT activity and 11% have intermediate activity, leading some to advocate additional monitoring of this activity in patients to help prevent unnecessary bone marrow toxicity from azathioprine treatment. 

Gilissen LP, Derijks LJ, Bos LP, et al. Therapeutic dmg monitoring in patients with inflammatory bowel disease and established azathioprine therapy. Chn Dmg Investig 2004 24 479 86. 

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