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Azathioprine

Azathioprine

Imuran Azasan Azahexal Azamun

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Updated: December 06, 2025

Overview

Azathioprine is an immunosuppressive medication primarily used to prevent organ transplant rejection and treat autoimmune diseases. It belongs to the class of purine analog antimetabolites and works by inhibiting DNA/RNA synthesis in rapidly dividing cells, particularly lymphocytes. As a prodrug, azathioprine is converted in the body to its active metabolite, mercaptopurine, which interferes with purine metabolism. This drug requires careful monitoring due to its narrow therapeutic index and potential for serious adverse effects, including bone marrow suppression and increased cancer risk.

Drug Class

Immunosuppressive agent Antimetabolite Thiopurine analog Disease-modifying antirheumatic drug (DMARD)

Mechanism of Action

Azathioprine is a purine analog that undergoes conversion to 6-mercaptopurine (6-MP) in vivo. The active metabolites (6-thioguanine nucleotides) incorporate into DNA/RNA and inhibit: • Purine synthesis via inhibition of amidophosphoribosyltransferase • Lymphocyte proliferation by interfering with DNA replication • T-cell function and antibody production • Inflammatory response through multiple immunomodulatory pathways

Pharmacokinetics

Absorption: Oral bioavailability is approximately 60%, with peak plasma concentrations in 1-2 hours Distribution: Widely distributed throughout body tissues, crosses placenta Metabolism: Extensive hepatic metabolism via xanthine oxidase and thiopurine methyltransferase (TPMT) Excretion: Primarily renal (50-60%), with some biliary excretion Half-life: 3-5 hours (parent drug), active metabolites have longer half-lives

Pharmacodynamics

• Suppresses cell-mediated immunity • Reduces antibody production • Decreases circulating lymphocytes • Anti-inflammatory effects • Delayed onset of action (3-12 weeks for clinical effect)

Indications

• Prevention of renal transplant rejection (combined with other immunosuppressants) • Severe rheumatoid arthritis (DMARD-unresponsive cases) • Systemic lupus erythematosus • Autoimmune hepatitis • Inflammatory bowel disease (Crohn's disease, ulcerative colitis) • Myasthenia gravis • Vasculitis syndromes

Contraindications

Absolute: • Hypersensitivity to azathioprine or mercaptopurine • Pregnancy (in rheumatoid arthritis patients) • Concurrent treatment with febuxostat Relative: • Severe bone marrow suppression • Active infection • TPMT deficiency • Hepatic dysfunction • Concurrent use with other myelosuppressive agents

Dosage & Administration

Organ transplantation: Initial 3-5 mg/kg/day, maintenance 1-3 mg/kg/day Rheumatoid arthritis: Start 1 mg/kg/day, may increase by 0.5 mg/kg every 4-6 weeks (max 2.5 mg/kg/day) Autoimmune hepatitis: 1-2 mg/kg/day Inflammatory bowel disease: 2-3 mg/kg/day Dose adjustments required for TPMT deficiency and drug interactions

Special Populations

Pediatric: Use with caution, similar mg/kg dosing as adults Geriatric: Increased susceptibility to myelotoxicity, use lower doses Renal impairment: Reduce dose by 30-50% if CrCl <50 mL/min Hepatic impairment: Reduce dose by 50-75%, monitor closely

Adverse Effects

Common (>10%): • Bone marrow suppression (leukopenia, anemia, thrombocytopenia) • Nausea/vomiting • Diarrhea • Mild liver enzyme elevations Serious (<1%): • Severe myelosuppression • Hepatotoxicity • Pancreatitis • Lymphoma/skin cancer • Serious infections • Hypersensitivity reactions

Drug Interactions

• Allopurinol/febuxostat: Increases toxicity (reduce azathioprine dose by 75%) • Warfarin: Decreased anticoagulant effect • ACE inhibitors: Increased risk of anemia • Live vaccines: Reduced efficacy, potential infection risk • Other myelosuppressants: Additive toxicity

Warnings & Precautions

• Black Box Warning: Chronic immunosuppression increases risk of malignancy • May cause severe bone marrow suppression • Test for TPMT deficiency before therapy • Monitor for infections (including opportunistic) • Hepatotoxicity may occur • Potential for drug-induced hypersensitivity syndrome

Pregnancy & Lactation

Pregnancy: FDA Category D (positive evidence of risk) • Teratogenic in animals • Use only if potential benefit justifies risk • Contraindicated in RA patients during pregnancy Lactation: Contraindicated • Excreted in breast milk • Potential for serious adverse reactions in infants

Monitoring Parameters

• Complete blood count (weekly initially, then monthly) • Liver function tests (regular monitoring) • TPMT enzyme activity (prior to initiation) • Signs of infection • Drug toxicity symptoms • Therapeutic drug monitoring in some cases

Patient Counseling

• Take with food to reduce GI upset • Report signs of infection (fever, sore throat) • Avoid crowds/people with infections • Use sun protection (increased skin cancer risk) • Do not receive live vaccines • Inform all providers about azathioprine use • Adhere to monitoring requirements

Storage & Stability

Store at 20-25°C (68-77°F) Protect from light and moisture Keep in original container Suspension stable for 28 days at room temperature

Clinical Pearls

• Check TPMT status before starting therapy • Dose reductions needed with allopurinol coadministration • Therapeutic effects may take 6-12 weeks in autoimmune diseases • Consider alternate therapies in patients with severe TPMT deficiency • Gradual dose escalation helps minimize GI side effects

References

• Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 14th ed • Lexicomp Drug Information: Azathioprine Monograph • American College of Rheumatology Guidelines for Rheumatoid Arthritis • UpToDate: Azathioprine drug information • FDA Prescribing Information for Imuran