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Azathioprine is an immunosuppressant used in the prevention of organ transplant rejection and the treatment of autoimmune diseases, including rheumatoid arthritis, inflammatory bowel disease, and autoimmune hepatitis.  It functions via inhibition of purine synthesis pathways.  Following ingestion, azathioprine is converted to 6-mercaptopurine, which is then converted to 6-thioguanine metabolites; these metabolites are pharmacologically active and mediate both the therapeutic and adverse effects of azathioprine.

The 6-thioguanine metabolites reduce cellular proliferation via 2 methods of purine synthesis inhibition:

• The metabolites inhibit phosphoribosylpyrophosphate (PRPP) amidotransferase, an enzyme that catalyzes an early step in de novo purine synthesis.
   
• The metabolites act as false nucleotides, incorporating into actively replicating DNA and RNA and rendering the growing nucleic acid strand nonfunctional.

These effects are exerted preferentially on rapidly dividing cells (eg, activated lymphocytes in the setting of organ transplant or autoimmune disease) but are otherwise nonspecific and disrupt other hematologic cell lines, including neutrophils, erythrocytes, and platelets.  Therefore, pancytopenia (ie, leukopenia, anemia, and thrombocytopenia) is a common adverse effect that must be monitored with periodic complete blood count testing.

(Choices B and C)  Unlike glucocorticoids, azathioprine has no adverse effects on glucose or lipid metabolism, an advantage of this medication over chronic glucocorticoid therapy.

(Choice D)  Azathioprine has no known effect on lung function.  The chemotherapeutic agent bleomycin may cause pulmonary fibrosis and therefore requires periodic monitoring of pulmonary function.

(Choice E)  The anemia caused by azathioprine and other antimetabolite drugs (eg, methotrexate) is typically macrocytic (due to impaired DNA synthesis), but this macrocytic effect is independent of vitamin B₁₂ levels.  Proton pump inhibitors and histamine 2 blockers can disrupt absorption of vitamin B₁₂ and may cause or contribute to its deficiency.

Educational objective:
Azathioprine is an immunosuppressant that functions via inhibition of purine synthesis by its pharmacologically active 6-thioguanine metabolites.  In addition to the desired effect of reduced lymphocyte proliferation, the proliferation of other hematologic cell lines (eg, neutrophils, erythrocytes, platelets) is reduced, leading to a common adverse effect of pancytopenia.