Azathioprine

Azathioprine antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins. It may also interfere with cellular metabolism and inhibit mitosis. Its mechanism of action is likely due to incorporation of thiopurine analogues into the DNA structure, causing chain termination and cytotoxicity.

Renal Homotransplantation: The dose of Azathioprine required to prevent rejection and minimize toxicity will vary with individual patients; this necessitates careful management. The initial dose is usually 3 to 5 mg/kg daily, beginning at the time of transplant. Azathioprine is usually given as a single daily dose on the day of, and in a minority of cases 1 to 3 days before, transplantation. Dose reduction to maintenance levels of 1 to 3 mg/kg daily is usually possible. The dose of Azathioprine should not be increased to toxic levels because of threatened rejection. Discontinuation may be necessary for severe hematologic or other toxicity, even if rejection of the homograft may be a consequence of drug withdrawal.

Rheumatoid Arthritis: Azathioprine is usually given on a daily basis. The initial dose should be approximately 1.0 mg/kg (50 to 100 mg) given as a single dose or on a twice-daily schedule. The dose may be increased, beginning at 6 to 8 weeks and thereafter by steps at 4-week intervals, if there are no serious toxicities and if initial response is unsatisfactory. Dose increments should be 0.5 mg/kg daily, up to a maximum dose of 2.5 mg/kg per day. Therapeutic response occurs after several weeks of treatment, usually 6 to 8; an adequate trial should be a minimum of 12 weeks. Patients not improved after 12 weeks can be considered refractory. Azathioprine may be continued long-term in patients with clinical response, but patients should be monitored carefully, and gradual dosage reduction should be attempted to reduce risk of toxicities.

Maintenance therapy should be at the lowest effective dose, and the dose given can be lowered decrementally with changes of 0.5 mg/kg or approximately 25 mg daily every 4 weeks while other therapy is kept constant. The optimum duration of maintenance Azathioprine has not been determined. Azathioprine can be discontinued abruptly, but delayed effects are possible.

Metabolism inhibited by allopurinol. Reduces the neuromuscular blockade of curare, tubocurarine but potentiates that of succinylcholine.

Azathioprine should not be used for treating rheumatoid arthritis in pregnant women.Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan, or others) may have a prohibitive risk of malignancy if treated with Azathioprine

Opportunistic infections especially in transplant patients receiving concomitant other immunosuppressants. Bone marrow depression, leucopenia, thrombocytopenia, nausea. Uncommonly, anaemia, hypersensitivity reactions, cholestasis, pancreatitis.

Pregnancy Category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk

Monitor FBC wkly during 1st 8 wk of therapy especially with high dose or severe renal/hepatic impairment. Inherited deficiency of thiopurine methyltransferase enzyme. Avoid excessive sun/UV exposure.

Use In Renal Dysfunction: Relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of Azathioprine or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses. Procedures for proper handling and disposal of this immunosuppressive antimetabolite drug should be considered. Several guidelines on this subject have been published.25-31 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Cytotoxic immunosuppressants

Azathioprine should be stored at 15 to 25° C in a dry place and protected from light.