Azathioprine

Immunosuppressive Agent Purine Analog / Antimetabolite

Dosage & Administration Guidelines

Species Route Dose Frequency Duration & Clinical Notes
Dog PO 2 mg/kg q24h Duration: Initially 2-4 weeks; then taper to every other day or as needed for maintenance.
Notes: May be given with food to reduce GI upset. Monitor CBC and liver enzymes regularly.
Cat PO 0.3-0.5 mg/kg (or 1.25-2.5 mg/cat) q48h or 3 times weekly Duration: Long-term; adjust based on response and toxicity.
Notes: Cats are more sensitive to myelosuppression; use lower doses and monitor closely.
Horse PO 1-3 mg/kg q24h Duration: Long-term; adjust based on response.
Notes: Use with caution; monitor for bone marrow suppression.
Cattle PO 2 mg/kg q24h Duration: Short-term; not commonly used.
Notes: Extra-label use; observe withdrawal times.
Small Ruminants PO 2 mg/kg q24h Duration: Short-term; not commonly used.
Notes: Extra-label use; observe withdrawal times.
Rabbit PO 1-2 mg/kg q24h Duration: Not well established; use with caution.
Notes: Limited data; monitor for GI and bone marrow toxicity.
Bird/Poultry PO Not established Not established Duration: Not established
Notes: Not recommended due to lack of safety and efficacy data.
Exotic/Other PO Not established Not established Duration: Not established
Notes: Use only with extreme caution and based on extrapolation from other species.

Clinical Indications & Species Uses

General Indications
  • Immunosuppressive therapy for various immune-mediated diseases, often as a steroid-sparing agent.
Dog (Canine)
  • Immunosuppressive therapy for immune-mediated diseases (e.g., immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, polyarthritis, inflammatory bowel disease, lupus erythematosus, pemphigus complex, myasthenia gravis, chronic active hepatitis)
Cat (Feline)
  • Immunosuppressive therapy for immune-mediated diseases (e.g., inflammatory bowel disease, eosinophilic granuloma complex, pemphigus foliaceus, immune-mediated hemolytic anemia, chronic stomatitis)
Horse (Equine)
  • Immunosuppressive therapy for immune-mediated diseases (e.g., immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, pemphigus foliaceus, recurrent uveitis, chronic obstructive pulmonary disease (heaves) - as a steroid-sparing agent)

Pharmacology & Mechanism of Action

Drug Class: Immunosuppressive Agent | Pharmacological Group: Purine Analog / Antimetabolite

Mechanism of Action: Azathioprine is a prodrug of 6-mercaptopurine (6-MP). After absorption, it is converted to 6-MP via a non-enzymatic nucleophilic attack by glutathione. 6-MP is then metabolized to active thiopurine nucleotides (e.g., 6-thioguanine nucleotides) that are incorporated into DNA and RNA, inhibiting purine synthesis and cell division. It also suppresses T-cell and B-cell function, reduces natural killer cell activity, and inhibits primary antibody responses. The drug is most effective in suppressing cell-mediated immunity.

Pharmacodynamics: Azathioprine suppresses both humoral and cell-mediated immunity. It inhibits DNA synthesis, thereby reducing proliferation of lymphocytes and other rapidly dividing cells. It also has anti-inflammatory effects by decreasing the production of reactive oxygen species and reducing the migration of neutrophils and monocytes to sites of inflammation. Clinical effects may take several weeks to become apparent.

⚑ Pharmacokinetics Summary

Absorption: Azathioprine is well absorbed after oral administration in most species. In dogs, oral bioavailability is approximately 60-80%. Food may reduce the rate of absorption but not the extent.
Distribution: Azathioprine is widely distributed throughout the body. It crosses the placenta and is distributed into milk. Protein binding is approximately 30%.
Metabolism: Azathioprine is rapidly metabolized to 6-mercaptopurine (6-MP) in the liver and red blood cells. 6-MP is further metabolized by three competing pathways: xanthine oxidase to thiouric acid (inactive), thiopurine methyltransferase (TPMT) to 6-methylmercaptopurine, and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) to active 6-thioguanine nucleotides. Genetic variations in TPMT activity can affect drug efficacy and toxicity.
Excretion: The metabolites are excreted primarily in the urine. A small amount is excreted in feces. In dogs, the elimination half-life of azathioprine is approximately 3-5 hours, but the active metabolites have a longer half-life.
Half-Life: Dogs: ~3-5 hours (parent drug); Cats: ~2-4 hours; Horses: ~2-3 hours; Cattle: ~2-4 hours (estimated).
Bioavailability: Oral: Dogs ~60-80%; Cats ~50-70% (estimated); Horses ~40-60% (estimated).
Protein Binding: Approximately 30% (primarily to albumin).

Available Formulations & Strengths

Oral Tablet 50 mg, 75 mg, 100 mg (PO)
Injectable Solution (as sodium salt) 100 mg/20 mL (5 mg/mL) (IV (not commonly used in veterinary practice))

Contraindications & Clinical Warnings

Contraindications:
  • Known hypersensitivity to azathioprine or 6-mercaptopurine
  • Severe bone marrow suppression (e.g., leukopenia, thrombocytopenia, anemia)
  • Active severe infections (due to immunosuppressive effects)
  • Pregnancy (teratogenic; avoid unless benefits outweigh risks)
  • Lactation (drug is excreted in milk; use with caution)
Warnings & Clinical Precautions:
  • Monitor complete blood count (CBC) and platelet count regularly (e.g., every 2-4 weeks initially, then less frequently) to detect myelosuppression.
  • Monitor liver enzymes (ALT, AST, ALP) and renal function periodically.
  • Use with caution in patients with hepatic or renal impairment.
  • May increase risk of infections; avoid live vaccines during therapy.
  • Cats are particularly sensitive to azathioprine-induced bone marrow suppression; use lower doses and monitor closely.
  • May cause gastrointestinal upset; administer with food to reduce nausea.
  • Discontinue if severe leukopenia, thrombocytopenia, or signs of infection occur.
  • Use with caution in animals with TPMT deficiency (rare).
  • May be carcinogenic with long-term use (theoretical risk).

Adverse Effects & Reactions

Common:

  • Vomiting
  • Diarrhea
  • Anorexia
  • Lethargy
  • Mild leukopenia
  • Thrombocytopenia

Serious / Severe:

  • Severe bone marrow suppression (pancytopenia)
  • Hepatotoxicity (elevated liver enzymes, jaundice)
  • Pancreatitis (especially in dogs)
  • Increased susceptibility to infections
  • Gastrointestinal ulceration

Rare:

  • Hypersensitivity reactions (rash, fever)
  • Pulmonary toxicity
  • Teratogenic effects
  • Carcinogenesis (long-term use)

Key Drug Interactions

Interacting Drug / Class Clinical Effect & Mechanism Severity
Allopurinol Allopurinol inhibits xanthine oxidase, reducing metabolism of azathioprine to inactive metabolites, increasing risk of toxicity. Reduce azathioprine dose by 75% if used concurrently. High
Corticosteroids (e.g., prednisone) Additive immunosuppressive effects; may increase risk of infections. Monitor closely. Moderate
ACE inhibitors (e.g., enalapril) May increase risk of anemia and leukopenia. Moderate
Warfarin and other anticoagulants Azathioprine may reduce the anticoagulant effect by inhibiting the metabolism of warfarin or by other mechanisms. Monitor coagulation parameters. Moderate
Myelosuppressive agents (e.g., cyclophosphamide, chloramphenicol) Additive bone marrow suppression. High
Live vaccines Immunosuppression may reduce vaccine efficacy and increase risk of vaccine-induced disease. High

Overdose & Toxicity Management

Signs of Toxicity:

  • Severe bone marrow suppression (leukopenia, thrombocytopenia, anemia)
  • Gastrointestinal signs (vomiting, diarrhea)
  • Hepatotoxicity
  • Pancreatitis
  • Infections

Emergency Treatment Protocol: There is no specific antidote. Treatment is symptomatic and supportive. Discontinue the drug immediately. Provide supportive care including IV fluids, antiemetics, and gastrointestinal protectants. Monitor CBC and serum chemistry closely. In severe cases, consider bone marrow stimulants (e.g., granulocyte colony-stimulating factor) and antibiotics for infections. Hemodialysis may be considered in severe cases, but efficacy is limited.

Food Animal Withdrawal Times

πŸ₯© Meat: 30 daysπŸ₯› Milk: 7 days

Withdrawal times are not officially established for azathioprine in food animals. The values provided are conservative estimates based on the drug's half-life and potential for residues. Consult regulatory authorities for specific guidance.

Storage, Handling & Regulatory Information

Storage Temperature: Store at room temperature (20-25Β°C, 68-77Β°F). Protect from moisture.

Handling & Special Conditions: Keep in a tightly closed container. Do not store in damp or humid conditions.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: Not FDA-approved for veterinary use; approved for human use.

Extra-Label (Off-Label) Use: Azathioprine is not FDA-approved for use in animals. Its use in veterinary medicine is extra-label (off-label) under the Animal Medicinal Drug Use Clarification Act (AMDUCA). Extra-label use is permitted by or on the order of a licensed veterinarian within a valid veterinarian-client-patient relationship, provided that appropriate withdrawal times are observed for food animals.

Clinical Pearls & Practice Notes

πŸ’‘ Clinical Insights: Azathioprine is a potent immunosuppressive agent used primarily as a steroid-sparing drug in the management of immune-mediated diseases in dogs and cats. It is not a first-line therapy due to its delayed onset of action (2-4 weeks) and potential for serious adverse effects. Therapy should be initiated at the lowest effective dose and adjusted based on clinical response and hematologic monitoring. Complete blood counts should be monitored every 2 weeks initially, then monthly, and then every 3-6 months during long-term therapy. Liver enzymes should be monitored periodically. Cats are particularly sensitive to myelosuppression; therefore, lower doses are recommended. Azathioprine should be used with caution in animals with pre-existing bone marrow suppression, hepatic disease, or infections. It is contraindicated in pregnant animals. Due to the risk of severe immunosuppression, concurrent use of live vaccines should be avoided. In food animals, extra-label use requires careful attention to withdrawal times to prevent drug residues in edible tissues. Overall, azathioprine is a valuable therapeutic option for refractory immune-mediated diseases when used judiciously and with appropriate monitoring.

References & Literature

  • πŸ“š Plumb's Veterinary Drug Handbook
  • πŸ“š Papich Veterinary Pharmacology and Therapeutics
  • πŸ“š Compendium of Veterinary Products (CVP)