Thiopurines (Azathioprine and Mercaptopurine)

Note: Mercaptopurine == 6-Mercaptopurine

Indications :

• FDA Indications:
  • Azathioprine: Rheumatoid arthritis and Renal Transplant
  • Mercaptopurine: ALL
• Lots of off-label indications:
  • Mercaptopurine (less commonly used it appears)
    • IBD
    • Autoimmune hepatitis
  • Azathioprine:
    • IBD/Autoimmune hepatitis
    • Polyarteritis Nodosa/Behçet syndrome/Lupus Nephritis/Sarcoidosis/Takayasu arteritis
    • Bullous pemphigoid/Pemphigus vulgaris
    • Dermatomyositis/Polymyositis
    • GPA/EGPA/MPA
    • Heart/Lung/Liver transplantation
    • Refractory ITP
    • ILD
• Drugs appear to be used interchangeably in IBD.
  • Lit search revealed a single post-hoc study in IBD showing more toxicity with Mercaptopurine 2/2 higher doses require to reach therapeutic effect as compared to Azathioprine

Contraindications:

Dosing :

MoA :

• Azathioprine is a prodrug of Mercaptopurine.
• Mercaptopurine is a purine antagonist which inhibits DNA and RNA synthesis; acts as false metabolite and is incorporated into DNA and RNA, eventually inhibiting their synthesis; specific for the S phase of the cell cycle
• Metabolites are incorporated into replicating DNA and halt replication; also block the pathway for purine synthesis (Taylor 2005). The 6-thioguanine nucleotide metabolites appear to mediate the majority of azathioprine's immunosuppressive and toxic effects.

Pharmacokinetics :

Toxicities/Monitoring :

• Myelosuppression: may manifest as anemia, thrombocytopenia, and neutropenia. Regular monitoring of blood counts is necessary.
  • Exacerbated in pts w/ decreased or absent thiopurine methyltransferase enzyme.
• Hepatotoxicity: Elevated liver enzymes. Regular monitoring of LFTs
• Gastrointestinal symptoms: Nausea, vomiting, and abdominal pain
• Pancreatitis: rare but potentially serious side effect.
• Malignancies: Chronic use can lead to a slightly increased risk of malignancies, particularly non-melanoma skin cancers and lymphoma.
  • Must inform patients of the risk of malignancy.
  • Per UTD, reports of malignancy include post-transplant lymphoma and hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease.
• Teratogenicity: Effective contraception is recommended for both males and females while on these medications.
• Because azathioprine is metabolized by xanthine oxidase, concomitant use with Xanthine oxidase inhibitors (Allopurinol, Febuxostat) is contraindicated.

References: