Azathioprine
Azathioprine
Generic Name
Azathioprine
Mechanism
Azathioprine is a pro‑drug that is converted to 6‑mercaptopurine (6-MP). 6‑MP interferes with purine synthesis, inhibiting DNA and RNA synthesis in rapidly dividing immune cells.
• Conversion pathway: *Azathioprine → 6-MP* → *active metabolites* 6‑thioinosine monophosphate (6-TIMP) and 6‑thio-ATP.
• Immunosuppression: Blocks T‑cell proliferation and attenuates B‑cell‑mediated antibody production.
• Enzyme regulation: Thiopurine methyltransferase (TPMT) activity determines the balance between therapeutic efficacy and hepatotoxicity.
Pharmacokinetics
- Absorption: ~85 % oral bioavailability; peak plasma concentration 2–3 h post‑dose.
- Distribution: Widely distributed; protein binding ≤ 5 %.
- Metabolism: Heterolytic conversion → 6‑MP → first‑pass hepatic metabolism:
- *Xanthine oxidase* → inactive 6‑thiouric acid.
- *TPMT* → 6‑MeMP (inactive, hepatotoxic).
- *NUDT* → 6‑TIMP (active).
- Elimination: Primarily renal excretion (~60 % unchanged drug).
- Half‑life: 1–2 h for 6‑MP; overall drug effect lasts 4–54 days due to metabolite persistence.
Indications
- Autoimmune disorders:
- Systemic lupus erythematosus (SLE)
- Rheumatoid arthritis (RA)
- Organ transplantation:
- Solid‑organ (kidney, heart, liver) & bone marrow transplant rejection prophylaxis.
- Inflammatory bowel disease:
- Crohn’s disease, ulcerative colitis (maintenance therapy).
- Pediatric indications:
- Severe aplastic anemia, idiopathic thrombocytopenic purpura.
Contraindications
- Absolute contraindications:
- Active, untreated infection.
- Severe, uncontrolled myelosuppression.
- Known hypersensitivity to thiopurines.
- Severe hepatic impairment (ALT > 3× ULN).
- Precautions:
- Pregnancy: Category D; teratogenic → avoid.
- TPMT deficiency: ↑ risk of hepatotoxicity & leukopenia.
- Concurrent myelosuppressants: e.g., cyclosphamide; additive bone‑marrow toxicity.
- Black‑box: rare risk of drug‑induced lymphomas and solid‑organ cancers with prolonged use.
Dosing
| Condition | Typical Starting Dose |
| Transplant rejection prophylaxis | 1–2 mg/kg/day (split BID) |
| SLE / RA | 1–1.5 mg/kg/day (cap ≤ 3 mg/kg) |
| IBD maintenance | 1.5 mg/kg/day (max 150 mg) |
| Pediatric (<12 y) | 2–3 mg/kg/day |
• Titration: Increase by 0.5–1 mg/kg every 4–6 weeks based on response & labs.
• Maintenance: Often lower dose (0.5–1 mg/kg) after remission.
• Administration: Oral liquid or capsule; can be taken with or without food.
Monitoring
| Parameter | Frequency | Goal/Alert |
| CBC with diff | At baseline, 2–3 weeks post‑initiation, then monthly (or as clinically indicated). | Neutrophils 3× ULN → hold. |
| TPMT activity (if available) | Prior to initiation. | Low/absent TPMT → dose 1/10 or consider alternative. |
| Total IgE (in IBD) | Optional for monitoring response. | Elevated IgE → disease activity. |
| Drug levels (6-TGN/6-MMP) | At 3–6 months if refractory or toxicity suspected. | 6-TGN 230–430 pmol/8 × 10⁸ RBC. |
Clinical Pearls
- TPMT genotyping – the single most predictive tool for adverse events; a practical approach is dose reduction to 0.1–0.3 mg/kg/day in TPMT‑deficient patients.
- Drug interactions:
- Azathioprine + 6‑mercaptopurine (another thiopurine) = additive toxicity.
- Azathioprine + 5‑ASA (mesalamine) may increase hepatotoxicity.
- Azathioprine + ciprofloxacin → ↑ neutropenia risk.
- Stopping rules: Stop if neutrophils ≤ 1 × 10⁹/L, platelets ≤ 50 × 10⁹/L, or hepatic enzymes > 3× ULN.
- Patient education: Advise strict avoidance of live vaccines and discuss risk of fungal infections; use antifungal prophylaxis in high‑risk transplant recipients.
- Drug compatibility: Azathioprine can be safely combined with mycophenolate mofetil (MMF) in transplant regimens, but monitor for overlapping myelosuppression.
- Re‑treatment: If azathioprine is held for > 24 h, restart with *max 75 % of prior dose* and titrate cautiously.
--
• *Meta‑data suggestions for SEO*: Azathioprine drug facts, immunosuppressant mechanism, dosing for transplant, TPMT testing.