Azathioprine toxic effects

Azathioprine is a cytotoxic inhibitor of purine synthesis effective for the control of tissue rejection in organ transplantation. It is also used in the treatment of autoimmune diseases. Its biologically active metabolite, mercaptopurine, is an inhibitor of DNA synthesis. Mercaptopurine undergoes further metabolism to the active antitumour and immunosuppressive thioinosinic acid. This inhibits the conversion of purines to the corresponding phosphoribosyl-5 phosphates and hypoxanthine to inosinic acid, leading to inhibition of cell division and this is the mechanism of the immunosuppression by azathioprine and mercaptopurine. Humans are more sensitive than other species to the toxic effects of the thiopurines, in particular those involving the haematopoietic system. The major limiting toxicity of the thiopurines is bone marrow suppression, with leucopenia and thrombocytopenia. Liver toxicity is another common toxic effect. 

The chief toxic effect of azathioprine and mercaptopurine is bone marrow suppression, usually manifested as leukopenia, although anemia and thrombocytopenia may occur. Skin rashes, fever, nausea and vomiting, and sometimes diarrhea occur, with the gastrointestinal symptoms seen mainly at higher dosages. Flepatic dysfunction, manifested by very high serum alkaline phosphatase levels and mild jaundice, occurs occasionally, particularly in patients with preexisting hepatic dysfunction. 

AZATHIOPRINE VACCINES i effectiveness of vaccines, t risk of adverse/toxic effects of live vaccines (e.g. measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, TY21a typhoid), e.g. vaccinal infections Disseminated infection due to enhanced replication of vaccine virus in the presence of diminished immunocompetence Do not vaccinate when patients are on immunosuppressants. Vaccination should be deferred for at least 3 months after discontinuing immunosuppressants/myelosuppres-sants. If an individual has been recently vaccinated, do not initiate therapy for at least 2 weeks after vaccination... 

Additive renal toxic effects may occur with immunosuppressants (e.g. azathioprine, ciclosporin, tacrolimus), ACE inhibitors, penicillamine, irinotecan and aminoglycoside antibiotics. A deterioration of renal function may even occur after the topical use of NSAIDs. Guidelines are variable for the use of NSAIDs with differing degrees of renal function, as assessed by creatinine clearance measurements. 

A feature of the pharmacologic action of azathioprine is its delayed onset, which may take 8-12 weeks to become apparent, possibly due to the slow accumulation of 6-TGN within the cells. The same is not necessarily true for the toxic effects of azathioprine, some of which may occur at any time during treatment (e.g., bone marrow suppression). Azathioprine appears to be a more potent immunosuppressive agent than does 6-MP itself, which may reflect differences in the pharmacodynamics and pharmacokinetics of the two compounds, as well as the relative abundance of different metabolites which are formed after their administration. Studies with hepatocytes have found that azathioprine toxicity involves depletion of reduced glutathione leading to mitochondrial injury with profound depletion of ATP and cell death by necrosis. Cell death was... 

There is no antidote for azathioprine toxicity. Treatment for an overdose entails ipecac within 30 min or lavage within 1 h, followed by activated charcoal. Side effects may be minimized with adequate monitoring of peripheral blood count and liver enzymes. Asymptomatic leucopenia, as well as most other side effects, may be treated with dose reduction or drug cessation (and changing to 6-MP) however, a life-threatening leucopenic episode may require administration of granulocyte colony-stimulating factor as well as other supportive care. 

Toxicity The major toxic effect is bone marrow suppression, but gastrointestinal irritation, skin rashes, and liver dysfunction also occur. The use of azathioprine is associated with an increased incidence of cancer. The active metabolite of azathioprine, mercaptopurine, is metabolized by xanthine oxida.se, and toxic effects may be increased by allopuri-nol given for byperuricemia. 

Azathioprine is firstly metabolised in the liver to mercaptopurine and then enzymatically oxidised in the liver and intestinal wall by xanthine oxidase to an inactive compound (6-thiouric acid), which is excreted. Allopurinol inhibits first-pass metabolism by xanthine oxidase so that mercaptopurine accumulates, blood levels rise and its toxic effects develop (leucopenia, thrombocytopenia, etc.). 

The daily dose of allopurinol is 300-600 mg. In combination with benzbromarone, the daily allopurinol dose is reduced to 100 mg. In general, allopurinol is well tolerated. The incidence of side effects is 2-3%. Exanthems, pruritus, gastrointestinal problems, and dty mouth have been observed. In rare cases, hair loss, fever, leukopenia, toxic epidermolysis (Lyell syndrome), and hqDatic dysfunction have been reported. Allopurinol inhibits the metabolic inactivation of the cytostatic dtugs azathioprine and 6-mercaptopurine. Accordingly, the administered doses of azathioprine and 6-mercaptopurine must be reduced if allopurinol is given simultaneously. 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

When immunosuppressive therapy is administered for long periods, the patient must be monitored closely for chronic toxicity. Blood counts should be monitored routinely in patients on azathioprine because hematologic toxicity resulting in infection and bleeding may occur. Cushingoid effects, aseptic... 

When azathioprine is administered concomitantly with allopurinol, there is a risk of enhanced effects and increased toxicity of azathioprine. Doses of azathioprine should be reduced to one quarter of the usual dose. Both allopurinol and azathioprine may cause hypersensitivity reactions. 

Several types of immunosuppression have also been tried. Azathioprine alone was found to have no effect on PBC [82], but additional benificial effects were found in combination with ursodeoxychohc add and corticosteroids [78]. Cyclosporin showed some success, espe-dally in corticosteroid-resistant autoimmune hepatitis [83], but its use is generally considerably hmited by severe side-effects. Corticosteroids were effective in the management of several types of autoimmune chronic active hepatitis [84,85] and in the management of acute al-cohohc hepatitis [86]. Their use, however, has to be brief hi order to minimize side-effects. In the treatment of PBC, corticosteroids alone were found to be toxic and had only limited efficacy [77]. 

Hematoiogic effects Severe leukopenia or thrombocytopenia, macrocytic anemia, severe bone marrow depression, and selective erythrocyte aplasia may occur in patients on azathioprine. Hematologic toxicities are dose-related, may occur late in the... 

For immunosuppressive effects methotrexate is most frequently used in RA but also azathioprine and cyclosporin are employed. Methotrexate doses for this indication can be lower than those used for cancer chemotherapy but significant toxicity such as nausea, cytopenias and mucosal lesions, and with longterm therapy slowly progressive hepatotoxicity may still be seen. 

Sulfasalazine (Azulfidine) is approved for the treatment of rheumatoid arthritis and ulcerative colitis. It is also used to treat ankylosing spondylitis and Crohn s disease. Comparisons of sulfasalazine with other DMARDs suggest that it is more effective than hydroxychloroquine, azathioprine, and oral gold compounds. It is at least as effective as intramuscular gold and penicillamine. It has a greater degree of toxicity than hydroxychloroquine but less than gold compounds and penicillamine. After 5 years, approximately 75% of patients have discontinued sulfasalazine therapy, primarily because of a lack of efficacy as opposed to intolerable side effects. 

Adverse Side Effects. Azathioprine is relatively toxic, with more frequent and more severe side effects than other DMARDs.97 The primary side effects include fever, chills, sore throat, fatigue, loss of appetite, and nausea or vomiting these effects often limit the use of this drug. 

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... 

The risk of bone marrow depression by cytostatic drugs is potentiated by allopurinol, which also appears to potentiate the therapeutic effect of purine cytostatic drugs, since it competitively inhibits their metabolic breakdown. Studies in animals suggest that this reaction occurs only with oral mercaptopurine (28), although there is older evidence that the toxicity of cyclophosphamide and other cytostatic drugs can be increased by allopurinol (SED-9, 156). The danger of combining allopurinol with azathioprine has been confirmed by cases of bone marrow suppression, particularly in patients with impaired renal function (SEDA-16,114). 

Hematological toxicity is the most commonly reported severe adverse effect of azathioprine, and is marked by predominant leukopenia, thrombocytopenia, and pancytopenia (SED-13, 1120). In a 27-year survey of 739 patients treated with azathioprine 2 mg/kg for inflammatory bowel disease, dosage reduction or withdrawal of the drug because of bone marrow toxicity was necessary in 37 patients (5%) (11). There was moderate or severe leukopenia in 3.8% of patients in three patients pancytopenia resulted in severe sepsis or death. 

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