Inflammatory Bowel Disease Pharmacology, Part 1
Aminosalicylates · Corticosteroids · Thiopurines · Methotrexate
Aminosalicylates (5-ASA Agents)
Sulfasalazine
Prodrug Cleaved by Colonic Bacteria
  • Azo bond links mesalamine + sulfapyridine carrier
  • Bacteria cleave azo bond → mesalamine released in colon
  • Sulfapyridine causes most adverse effects
  • Requires: folic acid 1 mg daily (folate absorption inhibited)
  • Requires: screen for glucose-6-phosphate dehydrogenase deficiency
Mesalamine Formulations
Site-Specific Delivery Without Sulfapyridine
  • pH-release coatings: dissolve at pH 6–7 → terminal ileum + colon
  • Multi-matrix (once daily): slow release throughout entire colon; best adherence
  • Rectal suppository: rectum and distal 15 cm
  • Enema: left colon to splenic flexure
  • Oral + rectal combination is superior to either alone in left-sided UC
Corticosteroids in IBD
Agent Bioavailability Best Use Key Limitation
Prednisone ~80–100% Moderate–severe UC and CD; disease beyond ileum Full systemic adverse effects; no maintenance role; steroid dependence = escalate
Budesonide (ileal-release) 10–15% (first-pass CYP3A4) Mild–moderate ileocaecal CD Not effective for colonic CD; CYP3A4 inhibitors increase systemic exposure
IV methylprednisolone Parenteral Severe acute UC Assess response at day 3; rescue if no response (infliximab or cyclosporine)
Thiopurines: Three Competing Pathways
Anabolic Pathway (Desired)
HGPRT → 6-TGN
  • 6-thioguanine nucleotides incorporated into lymphocyte DNA
  • Terminates lymphocyte proliferation
  • Therapeutic target: 6-TGN levels 235–450 pmol
  • Onset: 3–6 months
Catabolic Pathway
Xanthine Oxidase → Thiouric Acid
  • Inactive metabolite — eliminated renally
  • Allopurinol blocks this pathway
  • Blocking without dose reduction → fatal myelosuppression
Methylation Pathway
TPMT → 6-MMP
  • 6-methylmercaptopurine: inactive but hepatotoxic at high levels
  • Poor metabolizers (0.3%): no TPMT → all flux to 6-TGN → myelosuppression
  • Test TPMT and NUDT15 before starting
  • Poor metabolizers: reduce dose to ~10% or avoid
Methotrexate in IBD
Key Pharmacology
Folate Antagonist → Adenosine Release
  • Dihydrofolate reductase inhibition → polyglutamate accumulation
  • Adenosine release → suppresses T-cell proliferation and cytokines
  • Parenteral route preferred (variable oral absorption)
  • Folic acid 1 mg daily: reduces mucosal and marrow toxicity
  • Indicated: Crohn's disease (not ulcerative colitis)
Safety Rules
Monitoring and Contraindications
  • Teratogenic: absolute contraindication in pregnancy
  • Contraception mandatory; stop 3 months before conception
  • Hepatotoxicity: check liver function tests every 4–8 weeks
  • Myelosuppression: check complete blood count every 4–8 weeks
  • Contraindicated: glomerular filtration rate below 30 mL/min
Critical Rule — Allopurinol + Thiopurine

Allopurinol blocks xanthine oxidase, the catabolic thiopurine pathway. Co-prescribing at full doses causes fatal myelosuppression. Always check for thiopurine use before prescribing allopurinol. If intentional combination: reduce azathioprine to 25–33% immediately.