Azathioprine (AZA) is approved by the Food and Drug Administration (FDA) for symptomatic treatment of active rheumatoid arthritis. It also has approval as adjunctive therapy for the prevention of kidney transplant rejection.
AZA used off-label for the treatment of inflammatory bowel disease, Churg-Strauss syndrome, autoimmune hepatitis (for maintenance treatment along with steroids), chronic ITP (second line agent), lupus nephritis, connective tissue disease-associated ILD, multiple sclerosis, severe myasthenia gravis, recurrent pericarditis, psoriasis, non-infectious uveitis, relapsing polychondritis, dermatomyositis/polymyositis, erythema multiforme, severe and refractory atopic dermatitis, chronic actinic dermatitis, pyoderma gangrenosum, Behcet disease, cutaneous vasculitis, pityriasis rubra pilaris, lichen planus, bullous pemphigoid and pemphigus vulgaris. Of note, AZA or 6-MP are treatment options for Crohn disease in children as a maintenance treatment.
Azathioprine is a purine analog that converts to its active metabolites, mercaptopurine (6-MP) and thioguanine (6-TGN), by hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thiopurine methyltransferase (TPMT) enzymes, then inhibits purine synthesis. Its metabolites are incorporated into the replicating DNA and halt division. AZA metabolites may also mediate most of its immunosuppressive and toxic effects. AZA is absorbed rapidly through the GI system and does not penetrate the blood-brain barrier. It undergoes metabolism in the liver and excreted through the kidneys, which increases its toxicity in renal failure.
The starting dose for AZA is 2 to 2.5 mg/kg/day, except for patients with TPMT gene mutation, in which the starting dose is lower than normal. Dose adjustments are necessary in hepatic and kidney disease.
AZA tablets may be administered after meals to decrease adverse GI effects. Administration can be by IV push over 5 minutes, at a concentration not exceeding 5mg/ml. It can be further diluted with NS or DW and administered by intermittent infusion over 30 to 60 minutes. However, it may also be infused over 5 minutes up to over 8 hours.
Complications occur in 15 to 28% of patients.
Relative contraindications are:
Toxicity symptoms include gastrointestinal symptoms, bradycardia, hepatotoxicity, myelosuppression. Acute toxicity usually happens when more than 1.5 times of daily dose taken by the patient.
In the acute setting, activated charcoal may help with decreasing the symptoms within 2 hours of ingestion. No specific antidote is known for AZA. In severe cases of toxicity, dialysis is permissible as AZA is dialysable.
In cases of hepatic sinusoidal obstruction syndrome, it must discontinue permanently. If severely leukopenic, thrombocytopenic, or infected, treatment should stop.
Azathioprine is an immunomodulator which is associated with several serious adverse effects. Susceptibility to its toxicity varies with age, genetic differences, and medication dosage. Its adverse effects are a limiting factor in the patient's compliance. Therefore regular follow-up and frequent laboratory workup are key to avoiding its complications. Physicians and pharmacists should be aware of potential adverse effects with AZA, even in asymptomatic patients.
In summary, azathioprine therapy requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]
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