MOA of leflunomide – 4 Important aspects of mechanism of action

MOA of leflunomide

Leflunomide is an immunosuppressive medication used primarily in the treatment of rheumatoid arthritis.

Its mechanism of action involves several processes:

  1. Inhibition of pyrimidine synthesis: Leflunomide blocks the enzyme dihydroorotate dehydrogenase (DHODH), which is involved in the de novo synthesis of pyrimidines, essential components of DNA and RNA. By inhibiting DHODH, leflunomide reduces the production of pyrimidines, leading to decreased proliferation of immune cells, such as T cells and B cells, that are involved in the inflammatory response.
  2. Suppression of immune response: Leflunomide inhibits the activation and proliferation of immune cells by affecting their metabolic pathways. The reduction in pyrimidine synthesis deprives immune cells of the necessary building blocks for DNA and RNA synthesis, thereby interfering with their replication and function.
  3. Anti-inflammatory effects: Leflunomide has anti-inflammatory properties that contribute to its therapeutic effects. It modulates the production and activity of various pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6). By reducing the levels of these inflammatory mediators, leflunomide helps to suppress the inflammatory response associated with conditions like rheumatoid arthritis.
  4. Antiproliferative effects: Leflunomide inhibits the proliferation of fibroblasts, which are involved in the formation of excessive connective tissue in conditions like rheumatoid arthritis. By reducing fibroblast proliferation, leflunomide helps to prevent joint damage and the progression of the disease.
  • It’s important to note that the active metabolite of leflunomide, known as A771726, is responsible for most of its therapeutic effects.
  • A771726 has a long half-life, which allows for once-daily dosing of leflunomide.
  • As with any medication, leflunomide may have side effects and requires monitoring during treatment.
  • It is essential to consult with a healthcare professional for proper evaluation, monitoring, and guidance regarding the use of leflunomide or any other medication.
  • Leflunomide is metabolized by the liver to its active metabolite, teriflunomide (A771726), which inhibits dihydroorotate dehydrogenase leading to a decrease in de novo synthesis of uridine, resulting in a decrease in the synthesis of pyrimidines.
  • Activated but not resting lymphocytes (B cells > T cells) have low pools of pyrimidine nucleotides, making them sensitive to this drug.
  • When uridine is lowered below a critical level, the tumor suppressor p53 is activated, arresting lymphocyte cell division in the G1 stage of the cell cycle.

Sign up to receive the trending updates and tons of Health Tips

Join SeekhealthZ and never miss the latest health information