GI Pharmacology · Module 3 of 8

Inflammatory Bowel Disease Pharmacology, Part 1

Aminosalicylates · Corticosteroids · Thiopurines · Methotrexate

Aminosalicylates: sulfasalazine is a prodrug linking mesalamine to sulfapyridine via an azo bond cleaved by colonic bacteria; the therapeutic activity is entirely in mesalamine; sulfapyridine causes most adverse effects (nausea, hemolytic anemia in G6PD deficiency, oligospermia, folate malabsorption); two pre-treatment checks: G6PD screen + start folic acid 1 mg daily; mesalamine formulations (pH-release, multi-matrix, rectal) bypass sulfapyridine; oral + rectal combination is first-line for mild-moderate active UC.
Corticosteroids are effective inducers of remission in UC and Crohn's but have no maintenance role; steroid dependence (inability to taper without relapse, or need >1 course/year) is an indication to escalate — not to continue steroids; budesonide (10–15% bioavailability via CYP3A4 first-pass) is preferred for mild-moderate ileocaecal/right-sided Crohn's; prednisone 40–60 mg for moderate-severe disease or beyond the ileum; IV methylprednisolone for severe acute UC — assess response at day 3; rescue with IV cyclosporine or infliximab if no response.
Thiopurine metabolic cascade: azathioprine → 6-MP → three competing pathways: anabolic (HGPRT → 6-TGN, active, target 235–450 pmol), catabolic (xanthine oxidase → thiouric acid, inactive), methylation (TPMT → 6-MMP, inactive but hepatotoxic at high levels); onset 3–6 months — not induction agents; mandatory pre-treatment: TPMT + NUDT15 genotyping/phenotyping; TPMT poor metabolizers (0.3%) accumulate fatal 6-TGN at standard doses — reduce to ~10% or avoid.
Allopurinol + thiopurine is one of the most dangerous interactions in gastroenterology: allopurinol blocks xanthine oxidase → 6-MP cannot be catabolized → massive 6-TGN accumulation → fatal myelosuppression; always check for thiopurine use before prescribing allopurinol; if intentional combination used (as rescue strategy for high 6-MMP levels), immediately reduce azathioprine to 25–33% and intensify blood count monitoring.
Methotrexate for Crohn's disease (not UC — weak evidence): mechanism at IBD doses is adenosine release (not direct antifolate cytotoxicity); parenteral route preferred (variable oral absorption, especially >15 mg); folic acid 1 mg daily required; absolute contraindication in pregnancy — teratogenic and abortifacient; contraception mandatory, stop 3 months before conception (both sexes); monitor LFTs and CBC every 4–8 weeks; contraindicated if eGFR <30 mL/min.

5-ASA = 5-aminosalicylic acid (mesalamine) · 6-MMP = 6-methylmercaptopurine · 6-MP = 6-mercaptopurine · 6-TGN = 6-thioguanine nucleotides · CBC = complete blood count · CD = Crohn’s disease · CYP3A4 = cytochrome P450 3A4 · eGFR = estimated glomerular filtration rate · G6PD = glucose-6-phosphate dehydrogenase · HGPRT = hypoxanthine-guanine phosphoribosyltransferase · HPA = hypothalamic-pituitary-adrenal · LFT = liver function test · TPMT = thiopurine methyltransferase · UC = ulcerative colitis

Aminosalicylates (5-ASA Agents)

Sulfasalazine

Prodrug Cleaved by Colonic Bacteria

Azo bond links mesalamine (active) + sulfapyridine (carrier); colonic bacteria cleave azo bond → mesalamine released at site of inflammation
Therapeutic activity entirely in mesalamine; sulfapyridine responsible for most adverse effects: nausea, headache, reversible oligospermia, hemolytic anemia (G6PD deficiency), folate malabsorption
Screen for G6PD deficiency before starting
Start folic acid 1 mg daily simultaneously — sulfapyridine inhibits intestinal folate absorption; essential in women of childbearing potential
Neither check required for sulfapyridine-free mesalamine formulations

Mesalamine Formulations

Site-Specific Delivery Without Sulfapyridine

pH-release coatings: dissolve at pH 6–7 → drug released in terminal ileum + colon
Multi-matrix (MMX, once daily): slow release throughout entire colon → best adherence
Rectal suppository: rectum and distal 15 cm → proctitis
Enema: left colon to splenic flexure → left-sided disease
Oral + rectal combination produces higher mucosal concentrations and better remission rates than either route alone in left-sided UC — first-line for mild-moderate active UC
Limited role in Crohn's disease; not effective for post-operative recurrence prevention

Corticosteroids in IBD

Agent	Bioavailability	Best Use	Key Limitation
Prednisone	~80–100%	Moderate–severe UC and CD; disease beyond ileum and right colon; taper over 8–16 weeks	Full systemic adverse effects; no maintenance role; steroid dependence = escalate to immunomodulator or biologic
Budesonide (ileal-release)	10–15% (extensive first-pass CYP3A4 metabolism)	Mild–moderate ileocaecal or right-sided CD; MMX formulation for mild-moderate UC	Not effective for colonic CD (drug absorbed before reaching colon); CYP3A4 inhibitors markedly increase systemic exposure; HPA suppression not absent with prolonged use
IV methylprednisolone	Parenteral	Severe acute UC (40–60 mg/day); IV hydrocortisone 300 mg/day also used	Assess response formally at day 3; if no response, rescue immediately with IV cyclosporine or infliximab — do not continue steroids beyond 5–7 days; 30–40% of admissions will require colectomy

Thiopurines: Three Competing Pathways

Anabolic Pathway (Desired)

HGPRT → 6-TGN

6-thioguanine nucleotides incorporated into lymphocyte DNA → terminate proliferation and induce apoptosis
Therapeutic target: 6-TGN levels 235–450 pmol/8×10⁸ RBCs
Onset 3–6 months — thiopurines are maintenance, not induction agents
Combining azathioprine + anti-TNF biologic reduces anti-drug antibody formation; superior to either alone in CD

Catabolic Pathway

Xanthine Oxidase → Thiouric Acid

6-MP → inactive thiouric acid → renally excreted
Allopurinol and febuxostat block this pathway
Blocking at full thiopurine dose → massive 6-TGN accumulation → fatal myelosuppression
Intentional allopurinol co-administration is a rescue strategy for high 6-MMP — requires immediate 75% dose reduction

Methylation Pathway

TPMT → 6-MMP

6-methylmercaptopurine: inactive but hepatotoxic at high concentrations
TPMT poor metabolizers (0.3%): no TPMT activity → all flux to 6-TGN → fatal myelosuppression at standard doses; reduce to ~10% of standard dose or avoid
Intermediate metabolizers (6–11%): reduce dose 30–50%
NUDT15 R139C: independent myelotoxicity predictor; allele frequency ~10% in East Asian populations; test before starting
Test both TPMT and NUDT15 (CPIC guidelines) before initiating any thiopurine

Methotrexate in IBD

Key Pharmacology

Adenosine-Mediated Anti-Inflammatory Mechanism

Inhibits DHFR → methotrexate polyglutamate accumulation → inhibits AICAR transformylase in purine synthesis → adenosine release
Adenosine suppresses T-cell proliferation, cytokine production, neutrophil function — mechanism at low IBD doses (15–25 mg weekly), not direct cytotoxicity
Parenteral IM or SC preferred: oral bioavailability highly variable (25–100%), decreases at doses >15 mg (saturates intestinal folate transporters)
Folic acid 1 mg daily required: reduces non-immune tissue AEs (mucositis, nausea, alopecia, cytopenias) without reducing anti-inflammatory efficacy
Indicated: steroid-sparing maintenance in CD; evidence weak for UC — thiopurines preferred for UC

Safety Rules

Monitoring and Contraindications

Absolute contraindication in pregnancy: teratogenic and abortifacient (inhibits trophoblast proliferation and fetal folate metabolism → spontaneous abortion, major congenital malformations)
Reliable contraception mandatory; women: stop ≥3 months before planned conception; men: stop ≥3 months before partner attempts conception
Monitor LFTs every 4–8 weeks; persistent elevation >2× ULN → dose reduction; persistent elevation → discontinue
Monitor CBC every 4–8 weeks (myelosuppression, especially with renal impairment)
Contraindicated: eGFR <30 mL/min (methotrexate predominantly renally excreted)
Counsel and document teratogenicity risk at initiation and every prescription renewal

Critical Rule — Allopurinol + Thiopurine: A Potentially Fatal Interaction

Allopurinol (and febuxostat) inhibit xanthine oxidase, the catabolic enzyme that converts 6-mercaptopurine to inactive thiouric acid. Co-prescribing at full thiopurine doses eliminates the catabolic pathway, causing massive 6-TGN accumulation and potentially fatal myelosuppression. Always check for thiopurine use before prescribing allopurinol for gout or any other indication — this is one of the most dangerous drug interactions in gastroenterology. If the combination must be used (as an intentional rescue strategy for patients with high 6-MMP and low 6-TGN), immediately reduce azathioprine to 25–33% of the original dose and intensify complete blood count monitoring.

Suggested References

Author / Source	Title	Publication
Katzung BG, ed.	Basic and Clinical Pharmacology, 15th ed. — Chapter on Gastrointestinal Pharmacology	McGraw-Hill; 2021
Brunton L, Knollmann B, Hilal-Dandan R, eds.	Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th ed.	McGraw-Hill; 2023
Rubin DT et al.	ACG clinical guideline: ulcerative colitis in adults	Am J Gastroenterol. 2019;114(3):384–413
Lichtenstein GR et al.	ACG clinical guideline: management of Crohn’s disease in adults	Am J Gastroenterol. 2018;113(4):481–517
Lennard L	The clinical pharmacology of 6-mercaptopurine	Eur J Clin Pharmacol. 1992;43(4):329–339
Yang SK et al.	A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia	Nat Genet. 2014;46(9):1017–1020
Sparrow MP et al.	Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine	Aliment Pharmacol Ther. 2005;22(5):441–446
Feagan BG et al.	Methotrexate for the treatment of Crohn’s disease	N Engl J Med. 1995;332(5):292–297
Greenberg GR et al.	Oral budesonide for active Crohn’s disease	N Engl J Med. 1994;331(13):836–841
Turner D et al.	Response to corticosteroids in severe ulcerative colitis: a systematic review	Clin Gastroenterol Hepatol. 2007;5(1):103–110