Mechanism of Action of Leflunomide

Introduction

Leflunomide is an immunomodulatory and disease-modifying antirheumatic drug (DMARD) used primarily in the treatment of rheumatoid arthritis and psoriatic arthritis. It suppresses immune cell proliferation and reduces inflammation, thereby slowing disease progression and joint damage.

Mechanism of Action (Step-wise)

1. Prodrug Conversion
   Leflunomide is converted in the body to its active metabolite, teriflunomide (A77 1726).
2. Inhibition of Dihydroorotate Dehydrogenase (DHODH)
   Teriflunomide inhibits DHODH, a key mitochondrial enzyme involved in de novo pyrimidine synthesis.
3. Reduction in Pyrimidine Nucleotide Production
   Inhibition of DHODH decreases the synthesis of uridine monophosphate (UMP), leading to reduced DNA and RNA synthesis.
4. Inhibition of Lymphocyte Proliferation
   Activated T and B lymphocytes rely heavily on de novo pyrimidine synthesis; their proliferation is selectively inhibited.
5. Suppression of Autoimmune Response
   Reduced lymphocyte activity decreases the autoimmune response seen in rheumatoid arthritis.
6. Anti-inflammatory Effects
   Leflunomide reduces production of pro-inflammatory cytokines and mediators.

Pharmacokinetics

• Administration: Oral
• Absorption: Well absorbed
• Conversion: Rapid conversion to active metabolite
• Protein Binding: High
• Half-life: Long (~2 weeks)
• Excretion: Biliary and renal

Clinical Uses

• Rheumatoid arthritis
• Psoriatic arthritis
• Autoimmune disorders (off-label)

Adverse Effects

• Hepatotoxicity
• Diarrhea
• Hypertension
• Teratogenicity
• Bone marrow suppression
• Alopecia

Comparative Analysis

Leflunomide selectively inhibits lymphocyte proliferation by targeting pyrimidine synthesis, whereas methotrexate acts as a folate antagonist. It is often used as an alternative or adjunct in rheumatoid arthritis management.

MCQs

1. Leflunomide inhibits which enzyme?
   a) DNA polymerase
   b) DHODH
   c) Topoisomerase
   d) Cyclooxygenase
   Answer: b) DHODH
2. Active metabolite of leflunomide:
   a) Methotrexate
   b) Teriflunomide
   c) Azathioprine
   d) Cyclophosphamide
   Answer: b) Teriflunomide
3. Mechanism involves inhibition of:
   a) Purine synthesis
   b) Pyrimidine synthesis
   c) Protein synthesis
   d) Lipid synthesis
   Answer: b) Pyrimidine synthesis
4. Main effect on immune cells:
   a) Activation
   b) Proliferation inhibition
   c) Differentiation
   d) Apoptosis only
   Answer: b) Proliferation inhibition
5. Leflunomide is used in:
   a) Diabetes
   b) Hypertension
   c) Rheumatoid arthritis
   d) Asthma
   Answer: c) Rheumatoid arthritis
6. Major toxicity:
   a) Nephrotoxicity
   b) Hepatotoxicity
   c) Ototoxicity
   d) Cardiotoxicity
   Answer: b) Hepatotoxicity
7. Half-life of active metabolite:
   a) Short
   b) Moderate
   c) Long
   d) Very short
   Answer: c) Long
8. Teratogenic effect requires:
   a) Dose reduction
   b) Immediate discontinuation
   c) Monitoring only
   d) No action
   Answer: b) Immediate discontinuation
9. Leflunomide affects:
   a) RBCs only
   b) T and B lymphocytes
   c) Platelets only
   d) Neurons only
   Answer: b) T and B lymphocytes
10. It belongs to:
    a) NSAIDs
    b) DMARDs
    c) Antibiotics
    d) Antivirals
    Answer: b) DMARDs

FAQs

1. What is the mechanism of action of leflunomide?
   It inhibits DHODH, reducing pyrimidine synthesis and lymphocyte proliferation.
2. Why is leflunomide effective in rheumatoid arthritis?
   It suppresses immune-mediated inflammation by inhibiting lymphocyte activity.
3. What is teriflunomide?
   The active metabolite responsible for pharmacological effects.
4. Why is leflunomide teratogenic?
   It interferes with DNA synthesis and cell proliferation.
5. Does leflunomide affect purine synthesis?
   No, it mainly affects pyrimidine synthesis.
6. What is a major concern during therapy?
   Hepatotoxicity and monitoring liver function.

References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics – Immunosuppressive Agents
• Katzung: Basic and Clinical Pharmacology – Immunosuppressants
• Tripathi: Essentials of Medical Pharmacology
• Harrison’s Principles of Internal Medicine – Rheumatoid Arthritis

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