Azathioprine
**Azathioprine** is a potent purine antagonist immunosuppressive agent widely used in veterinary medicine, primarily in dogs, to treat a variety of immune-mediated and autoimmune diseases (e.g., immune-mediated hemolytic anemia [IMHA], inflammatory bowel disease [IBD], myasthenia gravis, and pemphigus). **Key Clinical Pearls:** * **Steroid-Sparing Effect:** It is frequently co-administered with corticosteroids (like prednisone or prednisolone). This combination allows for a gradual reduction in the corticosteroid dose, minimizing long-term steroid adverse effects while maintaining disease remission. * **Delayed Onset:** Azathioprine is not fast-acting. It typically requires **2 to 6 weeks** to achieve full immunosuppressive clinical efficacy. Therefore, it is not suitable as a sole agent for acute, life-threatening autoimmune crises. * **Species Sensitivity:** **Cats are exquisitely sensitive** to azathioprine-induced bone marrow suppression due to naturally low levels of the enzyme thiopurine methyltransferase (TPMT). Its use in felines is highly controversial and generally avoided. * **Toxicity Risks:** The most significant adverse effect is **myelosuppression** (leukopenia, anemia, thrombocytopenia). Hepatotoxicity and acute pancreatitis are also notable risks in dogs.
กลไกการออกฤทธิ์: Azathioprine is a **prodrug** that must be metabolized to exert its effects. * **Pathway:** Azathioprine is rapidly converted in the body (primarily in erythrocytes and the liver) to **6-mercaptopurine (6-MP)**. * 6-MP is further metabolized into active thioguanine nucleotides (TGNs). * **Mechanism:** These active metabolites act as **purine antagonists**. They are falsely incorporated into cellular DNA and RNA, which **inhibits purine metabolism, RNA/DNA synthesis, and cellular mitosis**. * **Immunological Effect:** Because lymphocytes (T-cells and B-cells) lack a salvage pathway for purine synthesis and rely heavily on *de novo* synthesis, they are profoundly affected. This leads to a marked suppression of **delayed hypersensitivity** and **cellular immunity**, with a lesser effect on humoral antibody responses.
ขนาดยาตามชนิดสัตว์
- Inflammatory bowel disease · Initially 2 mg/kg PO once daily for 2 weeks, then tapered to 2 mg/kg PO every other day for 2-4 weeks, then 1 mg/kg PO every other day. · PO · q24h then tapered · Long-term · May take 2-6 weeks before beneficial effects are seen.
- Immune-mediated anemia, colitis, immune-mediated skin disease, and acquired myasthenia gravis · 2 mg/kg PO once daily (q24h); long-term therapy 0.5-1 mg/kg PO every other day · PO · q24h then q48h · Long-term · With prednisolone administered on the alternate days.
- Adjunctive therapy in myasthenia gravis in non-responsive patients · Initially, 1 mg/kg PO once daily. If neutrophil and platelet counts are normal after 2 weeks, dose is increased to 2 mg/kg PO once daily. · PO · q24h · Until clinical remission · Taper to every other day when clinical remission occurs. Discontinue if WBC <4,000 cells/mcL or neutrophils <1,000 cells/mcL.
- Lymphoplasmacytic enteritis (if poor response to prednisolone) · 2 mg/kg PO once daily for 5 days, then on alternate days to prednisolone · PO · q24h then q48h · Long-term
- Severe cases of immune-mediated hemolytic anemia (IMHA) · 2.2 mg/kg PO once daily (q24h) · PO · q24h · Long-term · In addition to prednisone. Tapered gradually.
- Acute immune-mediated hemolytic anemia (IMHA) with glucocorticoids · 1-2 mg/kg PO once daily · PO · q24h · Long-term maintenance · Used for long-term maintenance as steroid side effects become intolerable.
- Severe and refractory inflammatory bowel disease · 2.2 mg/kg PO once daily · PO · q24h · Long-term · A lag time of 3-5 weeks is expected before clinical improvement is noted.
- Adjunctive treatment of ocular fibrous histiocytomas · 2 mg/kg PO daily for 2 weeks, reevaluate, and reduce to 1 mg/kg every other day for 2 weeks, then 1 mg/kg once weekly for 1 month · PO · Tapering schedule · 10 weeks
วิธีการให้ยา
ข้อห้ามใช้
- Known hypersensitivity to azathioprine
- Cats (generally contraindicated due to severe, potentially fatal myelotoxicity)
อาการไม่พึงประสงค์
- Bone marrow suppression (leukopenia, anemia, thrombocytopenia)
- Gastrointestinal distress (vomiting, diarrhea, anorexia)
- Acute pancreatitis
- Hepatotoxicity
- Poor hair growth
- Increased susceptibility to secondary infections
- Increased risk of neoplastic illnesses with long-term use
อันตรกิริยาระหว่างยา
- ACE Inhibitors (e.g., benazepril, enalapril) · Increased potential for hematologic toxicity
- Allopurinol · Decreases hepatic metabolism of azathioprine; significantly increases toxicity risk. Dose of azathioprine must be reduced to 1/4 to 1/3 of the usual dose if used concurrently. · major
- Aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine) · Increased risk for azathioprine toxicity
- Non-depolarizing muscle relaxants (e.g., pancuronium, tubocurarine) · Neuromuscular blocking activity may be inhibited or reversed by azathioprine
- Corticosteroids · Often used together intentionally, but carries a greater potential risk for overall toxicity development · moderate
- Drugs affecting myelopoiesis (e.g., trimethoprim/sulfa, cyclophosphamide) · Increased potential for hematologic toxicity (additive bone marrow suppression)
- Warfarin · Potential for reduced anticoagulant effect
- Aminosalicylates · Increased risk of azathioprine toxicity. · moderate
- ACE inhibitors · May increase the potential for haematological adverse events (e.g., severe anaemia or leucopenia). · major
การติดตาม
- Hemograms (CBC including platelets): Monitor closely; initially every 1-2 weeks, then every 1-2 months on maintenance therapy. Reduce dose by 25% if WBC drops to 5,000-7,000 cells/mcL. Discontinue if WBC < 5,000 cells/mcL until resolved.
- Liver function tests (ALT, AST, ALP, Bilirubin)
- Serum amylase/lipase (if pancreatitis is suspected)
- Clinical efficacy and signs of secondary infection
การได้รับยาเกินขนาด
There is limited specific information regarding acute overdose of azathioprine in veterinary patients. * **Decontamination:** If ingestion was recent, use standard protocols to empty the GI tract (emesis induction, activated charcoal). * **Treatment:** Provide aggressive supportive care. Monitor hematologic parameters closely for delayed bone marrow suppression. * **Consultation:** Contact an animal poison control center for the most up-to-date guidance.
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