Azathioprine administration

Muszkat M, Pappo O, Caraco Y, Haviv YS. Hepatocanalicular cholestasis after 24 years of azathioprine administration for myasthenia gravis. Clin Drug Invest 2000 19 75-8. 

Azathioprine is effective in preventing relapse of ulcerative colitis for periods exceeding 4 years. However, 3 to 6 months may be required for beneficial effect. For patients who initially respond to infliximab, continued administration of 5 mg/kg every 8 weeks as maintenance therapy is an alternative for steroid dependent patients. 

Pharmacokinetics Azathioprine is well absorbed following oral administration. Blood levels are of little value for therapy because the magnitude and duration of clinical effects correlate with thiopurine nucleotide levels in tissues rather than with plasma drug levels. 

Concurrent immunosuppressants Sirolimus has been administered concurrently with cyclosporine and corticosteroids. The efficacy and safety of the use of sirolimus in combination with other immunosuppressive agents have not been determined. Renai function impairment Mean serum creatinine was increased and mean glomerular filtration rate was decreased in patients treated with sirolimus and cyclosporine compared with those treated with cyclosporine and placebo or azathioprine controls. Monitor renal function during the administration of maintenance immunosuppression regimens including sirolimus in combination with cyclosporine, and consider appropriate adjustment of the immunosuppression... 

Azathioprine is well absorbed following oral administration, with peak blood levels occurring within 1 to 2 hours. It is rapidly and extensively metabolized to 6-mercaptopurine, which is further converted in the liver and erythrocytes to a variety of metabolites, including 6-thiouric acid. Metabolites are excreted in the urine. The half-life of azathioprine and its metabolites in the blood is about 5 hours. 

The therapeutic use of azathioprine has been limited by the number and severity of adverse effects associated with its administration. Bone marrow suppression resulting in leukopenia, thrombocytopenia, or both may... 

Cholinesterase inhibitors—but not direct-acting acetylcholine receptor agonists—are extremely valuable as therapy for myasthenia. Patients with ocular myasthenia may be treated with cholinesterase inhibitors alone (Figure 7-4B). Patients having more widespread muscle weakness are also treated with immunosuppressant drugs (steroids, cyclosporine, and azathioprine). In some patients, the thymus gland is removed very severely affected patients may benefit from administration of immunoglobulins and from plasmapheresis. 

Azathioprine is well absorbed from the gastrointestinal tract and is metabolized primarily to mercaptopurine. Xanthine oxidase splits much of the active material to 6-thiouric acid prior to excretion in the urine. After administration of azathioprine, small amounts of unchanged drug and mercaptopurine are also excreted by the kidney, and as much as a twofold increase in toxicity may occur in anephric or anuric patients. Since much of the drug s inactivation depends on xanthine oxidase, patients who are also receiving allopurinol (see Chapters 36 and 54) for control of hyperuricemia should have the dose of azathioprine reduced to one-fourth to one-third the usual amount to prevent excessive toxicity. 

Combined administration of azathioprine and allopurinol may result in severe pancytopenia. The dose of Azathioprine should be reduced by two-thirds when given with allopurinol. Azathioprine rarely causes liver dysfunction, frequently manifested by an isolated rise in ALT and bilirubin. With the introduction of mycophenolate mofetil, azathioprine may be relegated to a second-line anti metabolite for the prevention of graft rejection. 

A 33-year-old woman took immunosuppressive therapy after renal transplantation ciclosporin (dosage adjusted to achieve blood concentrations of 120-160 ng/ml), azathioprine 1 mg/kg (frequency of administration not stated), and methylprednisolone 40 mg/ day from day 1 after transplantation, tapered weekly by 4—8 mg/day. Because of rejection symptoms at weeks 1, 4, and 7, she received three cycles of intravenous methylprednisolone 250 mg/day, each cycle lasting 5-7 days she also received a bolus dose of methylprednisolone 500 mg on day 0. Pregnancy was diagnosed on day 12 after transplantation (9 weeks after conception). At week 6 after transplantation she had a missed abortion. Curettage was performed and a partial hydatidiform mole was detected. She was discharged at week 10 and immunosuppressive therapy was tapered. 

The second approach to prolonged therapeutic action is based on the controlled rate of conversion of the promoiety into the active compound in vivo. This approach requires particularly detailed study of the kinetics of prodrug-drug conversion. A classic example is bioconversion of azathioprine to 6-mercaptopurine. Azathioprine is used commonly in kidney transplantation, rheumatoid arthritis, and the treatment of various skin disorders. After administration, azathioprine undergoes slow... 

Steroids do not have a role in the maintenance of remission with ulcerative cohtis because they are ineffective. Steroids should he gradually withdrawn after remission is induced (over 3 to 4 weeks). If they are continued, the patient will he exposed to steroid side effects without likelihood of benefits. Azathioprine is effective in preventing relapse of ulcerative colitis for periods exceeding 4 years. However, 3 to 6 months may be required for beneficial effect. For patients who initially respond to infliximab, continued administration of 5 mg/kg every 8 weeks as maintenance therapy is an alternative for steroid dependent patients. 

CHLORAMBUCIL AZATHIOPRINE t risk of myelosuppression and immunosuppression. Deaths have occurred following profound myelosuppression and severe sepsis Additive myelotoxic effects Azathioprine is metabolized to 6-mercatopurine in vivo, which results in additive myelosuppression, immunosuppression and hepatotoxicity Avoid co-administration... 

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