Imuran
Mechanism of Action
Generic Name
Mechanism of Action
Mechanism
- Imuran (azathioprine) is a *purine analog* prodrug that is intracellularly converted to 6‑mercaptopurine (6‑MP).
- 6‑MP competes with adenosine and guanine nucleotides for incorporation into DNA and RNA, leading to inhibition of DNA synthesis.
- It also generates inactive cytotoxic metabolites that interfere with T‑cell cloning and B‑cell antibody production, resulting in cell‑cycle arrest in G1→S transition.
- Overall, the drug produces a dose‑dependent suppression of cellular proliferation, especially affecting rapidly dividing lymphocytes.
Pharmacokinetics
| Parameter | Details |
| Absorption | Rapid and nearly complete oral absorption; peak serum concentrations within 24 h. |
| Bioavailability | 45–55 % after oral dosing; hepatic metabolism predominates. |
| Metabolism | Thiopurine methyltransferase (TPMT) and xanthine oxidase convert 6‑MP to inactive metabolites (6‑MP‑N‑methyl‑4‑N‑phosphoribosyl‑pyrimidine and 6‑MP‑hydroximic acid).
TPMT activity varies 2,000‑fold, influencing drug response and toxicity. |
| Half‑life | Variable; 6‑MP ≈ 4–14 h, depending on TPMT genotype. |
| Elimination | Renal (≈ 30 %) and biliary excretion of 6‑MP metabolites. |
| Drug Interactions | 6‑MP is potentiated by *ketoconazole* (xanthine oxidase inhibition) and *cimetidine* (increased absorption). It is also an inhibitor of CYP450 isoforms, modestly affecting other drugs. |
Indications
- Organ transplantation: maintenance therapy in kidney, heart, and liver grafts.
- Autoimmune / inflammatory diseases: Crohn’s disease, ulcerative colitis, systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis.
- Other: autoimmune hemolytic anemia (rare), idiopathic inflammatory myopathies, graft‑vs‑host disease prophylaxis.
Contraindications
- Absolute Contraindications: marked bone marrow suppression, hypersensitivity to azathioprine or 6‑mercaptopurine, severe hepatic failure, active malignant neoplasms (except certain lymphomas), known pregnancy or lactation.
- Warnings:
- Myelosuppression—requires careful dose titration.
- Increased infection risk (both bacterial and opportunistic).
- Neoplastic potential—long‑term use may elevate lymphoma, skin cancers.
- Hepatotoxicity—risk of cholestatic and inflammatory liver injury.
- Hypersensitivity—rash, fever, or Stevens–Johnson syndrome can occur.
Dosing
| Condition | Initial Dose | Titration | Maintenance | Notes |
| Adults (transplant, RA, IBD) | 1–2 mg/kg body weight/day (often given as half‑daily dosing) | Increase by 2.5–5 mg/kg/day every 1–2 weeks until clinical response or ANC > 1500/µL; max 100 mg/day in adults (200 mg/day in pediatrics) | Adjust based on TPMT activity, CBC, LFTs | Start with low dose and titrate slowly, especially when co‑administered with mycophenolate or calcineurin inhibitors. |
| Pediatrics | 2 mg/kg/day (max 100 mg/day) | Increase in increments of 0.5–1 mg/kg/day | Maintain at lowest effective dose | Use *Body Surface Area* if dosing in mg/m²; children > 120 kg may require more than 100 mg/day. |
| Pregnancy (Category D) | Avoid in first trimester; use if benefits outweigh risks. | Not routinely recommended. | None | Discontinue if pregnancy confirmed; transfer to safer alternatives like methotrexate‑free regimens. |
> Important: Perform TPMT activity or genotype testing before initiating therapy. Dosing should be reduced (or withheld) in patients with low TPMT activity to avoid severe myelosuppression.
Adverse Effects
| Adverse Effect | Incidence | Management |
| Bone marrow suppression (neutropenia, thrombocytopenia) | 5–20 % | CBC monitoring; dose reduction or hold if ANC < 1500/µL or platelets 10× ULN. |
| Increased infection risk (bacterial, viral, fungal) | 10–20 % | Prophylactic antimicrobials as indicated; treat promptly. |
| Risk of malignancy (lymphoma, skin cancers) | Variable with long‑term exposure | Baseline skin exam; annual dermatologic surveillance; consider risk–benefit analysis after > 5 years. |
| Allergic reactions (rash, fever) | < 5 % | Discontinue; treat with antihistamine or steroids if severe. |
| Myopathy (rare) | < 1 % | Monitor CK; discontinue if symptomatic. |
Monitoring
- Baseline: CBC with differential, comprehensive metabolic panel (CMP), LFTs, TPMT activity, serum 6‑MP/6‑MMP levels (optional).
- During therapy:
- CBC and CMP every 2–4 weeks for the first 3–6 months, then every 2–3 months.
- LFTs at 4 weeks, 3 months, and then annually.
- TPMT genotype re‑assessment if dose escalation > 50 mg/day.
- Other: Regular skin checks, infection surveillance, and drug interactions review.
Clinical Pearls
1. TPMT Testing Is a Game‑Changer – A single pre‑starting TPMT activity level predicts 1/3 of patients who will develop severe myelosuppression. Never initiate Imuran without confirming TPMT status; dose can be safely increased in those with normal/high activity.
2. Body Surface Area (BSA) vs. Body Weight – For pediatric patients, BSA dosing (mg/m²) often yields more accurate and less toxic exposure, especially when extrapolating to adolescents.
3. Co‑therapy Considerations – Azathioprine’s immunosuppressive potency is amplified by calcineurin inhibitors (tacrolimus) and mycophenolate mofetil. When combined, lower starting doses (≈ 30 % reduction) mitigate bone marrow toxicity.
4. Avoid Polypharmacy with Inhibitors – Take *ketoconazole* and *cimetidine* cautiously; their inhibition of xanthine oxidase markedly raises 6‑MP concentrations, increasing adverse events.
5. Pregnancy Counseling – Although contraindicated in the first trimester, many clinicians switch to azathioprine for disease control during the second and third trimesters, monitoring weekly CBCs.
6. Hepatic Metabolism Matters – In patients with significant hepatic dysfunction, consider alternative agents (e.g., mycophenolate) because azathioprine’s metabolites are predominantly hepatically cleared.
7. Early Detection Saves Lives – The patient’s first sign of neutropenia is often a subtle fever or sore throat. Prompt CBC evaluation should precede infection treatment and drug dose adjustment.
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• Key Takeaway – Imuran (azathioprine) is a cornerstone immunosuppressant that requires meticulous TPMT screening, slow titration, and stringent monitoring to balance efficacy against its well‑documented marrow and hepatic toxicities.