Drugs for Inflammatory Bowel Disease (IBD)

Introduction / Overview

Inflammatory bowel disease (IBD) encompasses a heterogeneous group of chronic, relapsing disorders primarily represented by ulcerative colitis (UC) and Crohn’s disease (CD). These conditions involve dysregulated immune responses to intestinal microbiota in genetically susceptible individuals, leading to mucosal ulceration, ulcerative lesions, and systemic manifestations. The prevalence of IBD has risen globally, and it imposes significant morbidity, healthcare costs, and impairment of quality of life. Consequently, the development and refinement of pharmacotherapeutic strategies remain central to contemporary gastroenterology and pharmacy education.

Drug therapy for IBD aims to induce and maintain remission, prevent complications, and improve patient outcomes. The therapeutic arsenal has expanded from traditional aminosalicylates to biologic agents and small molecules that target specific inflammatory pathways. Understanding the pharmacology of these agents is essential for prescribing clinicians, pharmacists, and researchers, given the complexity of drug selection, dosing strategies, and safety monitoring.

Learning Objectives

• Identify the principal drug classes employed in IBD management and their chemical classifications.
• Describe the pharmacodynamic mechanisms, including receptor interactions and cellular pathways, underlying each drug class.
• Explain the pharmacokinetic profiles and dosing considerations of representative agents.
• Recognize the approved indications, off‑label uses, and therapeutic contexts for each drug group.
• Evaluate common adverse effects, serious risks, and key drug–drug interactions.
• Apply special considerations regarding pregnancy, lactation, pediatrics, geriatrics, and organ impairment to therapeutic decision‑making.

Classification

1. Aminosalicylates (5‑ASA)

Aminosalicylates constitute the first line of therapy for mild to moderate UC. They are structurally characterized by a sulfonic acid group linked to a substituted benzene ring. Representative agents include mesalamine, sulfasalazine, and olsalazine.

2. Corticosteroids

Systemic and topical corticosteroids are employed for moderate to severe flares. Steroid molecules such as prednisone and budesonide share a core glucocorticoid skeleton but differ in tissue permeability and metabolic pathways.

3. Immunomodulators

These agents modulate immune function through nucleoside analogues or thiopurines. Azathioprine, 6‑mercaptopurine, and methotrexate belong to this class. Their structures are derived from purine and folate analogues, respectively.

4. Biologic Therapies

Biologics are recombinant proteins or monoclonal antibodies targeting specific cytokines or cell surface molecules. Subgroups include anti‑tumor necrosis factor (TNF‑α) agents (infliximab, adalimumab, golimumab, certolizumab pegol), anti‑integrin agents (vedolizumab, natalizumab), and anti‑interleukin (IL) agents (ustekinumab).

5. Small‑Molecule Targeted Therapies

Orally administered small molecules inhibit intracellular signaling pathways. Janus kinase inhibitors (tofacitinib, upadacitinib) and sphingosine‑1‑phosphate receptor modulators are examples.

6. Other Agents

Supportive medications such as antidiarrheals, antibiotics, and probiotics are adjunctive but not core anti-inflammatory drugs.

Mechanism of Action

Aminosalicylates

5‑ASA derivatives are believed to exert anti-inflammatory effects through inhibition of cyclooxygenase and lipoxygenase pathways, thereby reducing prostaglandin and leukotriene synthesis. They also scavenge reactive oxygen species and inhibit the nuclear factor‑kappa B (NF‑κB) signaling cascade. The sulfonamide moiety of sulfasalazine is cleaved by colonic bacteria, releasing mesalamine and sulfapyridine; only mesalamine is considered active locally in the colon.

Corticosteroids

Corticosteroids bind intracellular glucocorticoid receptors, translocating to the nucleus and modulating gene transcription. Transrepression of pro‑inflammatory genes (e.g., IL‑1, IL‑6, TNF‑α) and induction of anti‑inflammatory proteins (e.g., lipocortin) are central. Budesonide, with high first‑pass hepatic metabolism, achieves localized activity in the ileum and ascending colon, thus limiting systemic exposure.

Immunomodulators

Azathioprine and 6‑mercaptopurine are converted to 6‑mercaptopurine ribonucleotides, which incorporate into DNA and RNA, inhibiting purine synthesis and lymphocyte proliferation. Methotrexate inhibits dihydrofolate reductase, reducing thymidylate and purine synthesis, and promotes adenosine release, which exerts anti‑inflammatory effects.

Anti‑TNF‑α Agents

These monoclonal antibodies or ligand‑trapping molecules bind soluble and membrane‑bound TNF‑α, preventing interaction with TNF receptors on immune cells. This reduces cytokine signalling, neutrophil recruitment, and apoptosis of intestinal epithelial cells. The pegylated antibody certolizumab lacks an Fc region, altering effector functions.

Anti‑Integrin Agents

Vedolizumab targets α4β7 integrin expressed on gut‑homing T lymphocytes, inhibiting their adhesion to mucosal addressin cell adhesion molecule‑1 (MAdCAM‑1) and subsequent transmigration into intestinal tissue. Natalizumab binds α4 integrin subunits, blocking both α4β1 and α4β7 mediated migration, which accounts for its higher systemic immunosuppressive profile.

Anti‑IL Agents

Ustekinumab is a human IgG1κ monoclonal antibody that binds the p40 subunit common to IL‑12 and IL‑23, thereby inhibiting downstream signaling in Th1 and Th17 cells. This reduces granulocyte and macrophage activation in the gut mucosa.

Janus Kinase Inhibitors

Tofacitinib, a pan‑JAK inhibitor, blocks JAK1 and JAK3, interrupting cytokine receptor signalling for multiple interleukins (IL‑2, IL‑4, IL‑6, IL‑7, IL‑9, IL‑15, IL‑21). Upadacitinib preferentially inhibits JAK1, offering similar blockade with potentially reduced off‑target effects. This modulation dampens T cell activation and cytokine release.

Sphingosine‑1‑Phosphate Receptor Modulators

These agents bind S1P receptor 1 on lymphocytes, inducing sequestration in lymph nodes and preventing egress into systemic circulation. This reduces peripheral lymphocyte counts and dampens inflammatory responses in the gut.

Pharmacokinetics

Aminosalicylates

Mesalamine is absorbed primarily in the small intestine; its bioavailability ranges from 30–50 %. Metabolism occurs via glucuronidation and sulfation in the liver, followed by biliary excretion. The half‑life is approximately 1–3 h; dosing frequency reflects the absorption profile, with sustained‑release formulations prolonging colonic delivery. Sulfasalazine is poorly absorbed in the upper GI tract, with bacterial cleavage in the colon yielding active mesalamine.

Corticosteroids

Systemic steroids such as prednisone have high oral bioavailability (>90 %) and undergo hepatic metabolism (CYP3A4). The half‑life is 3–4 h for prednisone, but effects persist due to prolonged genomic actions. Budesonide, in contrast, has a bioavailability of <10 % owing to extensive first‑pass metabolism, leading to a half‑life of 2–4 h and localized action. Dosing schedules are tailored to disease severity and patient tolerance.

Immunomodulators

Azathioprine is rapidly hydrolyzed to 6‑mercaptopurine (MP), which is further metabolized by thiopurine methyltransferase (TPMT) to 6‑methyl‑mercaptopurine and by xanthine oxidase to 6‑thiouric acid. The active metabolite, 6‑mercaptopurine ribonucleotides, has a half‑life of 5–10 h. TPMT activity varies genetically, influencing drug clearance. Methotrexate is absorbed orally with variable bioavailability (30–60 %) and eliminated primarily via renal excretion; hepatic metabolism occurs for high‑dose regimens.

Biologic Therapies

Monoclonal antibodies are administered intravenously or subcutaneously and exhibit long half‑lives (15–20 days for infliximab; 22–26 days for adalimumab). They are predominantly distributed in the vascular and interstitial spaces. Clearance is mediated by target‑mediated drug disposition and proteolytic catabolism. Pegylation of certolizumab extends its half‑life to ~21 days. Dosing intervals are adjusted according to pharmacokinetic modeling and therapeutic drug monitoring.

Small‑Molecule Targeted Therapies

Tofacitinib is orally absorbed, with a peak plasma concentration within 1 h. It is metabolized mainly by CYP3A4 and CYP2C8, with a half‑life of 3–5 h. Upadacitinib follows similar pharmacokinetics but has a slightly longer half‑life (~7–8 h). S1P receptor modulators exhibit rapid absorption and are extensively metabolized by cytochrome P450 enzymes, with half‑lives ranging from 5–7 h. Renal excretion accounts for a minor portion of elimination, with hepatic metabolism being predominant.

Therapeutic Uses / Clinical Applications

Aminosalicylates

They are indicated for induction and maintenance of remission in mild to moderate UC. Off‑label use includes mild CD confined to the colon, although efficacy is less robust. Sulfasalazine may be used for mild arthritis in IBD patients.

Corticosteroids

Systemic steroids are reserved for moderate to severe flares unresponsive to aminosalicylates or biologics. Topical budesonide is employed for distal colitis and left‑sided UC. In CD, steroids can induce remission in acute exacerbations but are not suitable for long‑term maintenance.

Immunomodulators

Azathioprine and 6‑mercaptopurine serve as steroid‑sparing agents and maintenance therapy in both UC and CD. They are also used in combination with biologics to reduce immunogenicity. Methotrexate is primarily utilized for CD refractory to other agents, especially in patients with extra‑intestinal manifestations such as arthritis.

Biologic Therapies

Anti‑TNF‑α agents are first‑line biologics for moderate to severe UC and CD, including patients with fistulizing or stricturing disease. Vedolizumab is preferred in patients at high risk for systemic immunosuppression or those with prior TNF‑α inhibitor failure. Ustekinumab is indicated for moderate to severe CD, particularly post‑TNF‑α inhibitor failure. Natalizumab is reserved for highly refractory CD but is limited by the risk of progressive multifocal leukoencephalopathy (PML).

Small‑Molecule Targeted Therapies

Tofacitinib is approved for moderate to severe UC in adults, with data supporting maintenance therapy. Upadacitinib is in late‑stage development for UC and CD. S1P receptor modulators are investigational for IBD, primarily in early-phase trials. These agents provide oral alternatives to biologics.

Other Agents

Antibiotics such as metronidazole and ciprofloxacin are used for perianal disease, fistulas, or bacterial overgrowth. Probiotics may be considered adjunctively, though evidence is variable. Antidiarrheal agents (loperamide) and fiber supplements are supportive but not disease‑modifying.

Adverse Effects

Aminosalicylates

Common side effects include nausea, abdominal discomfort, headache, and mild hypersensitivity reactions. Rarely, mesalamine may induce nephrotoxicity, hepatotoxicity, or leukopenia. Sulfasalazine carries the risk of sulfa hypersensitivity, anemia, and teratogenicity. Black‑box warnings are absent.

Corticosteroids

Systemic steroids can cause hyperglycemia, hypertension, osteoporosis, mood disturbances, and increased susceptibility to infection. Long‑term use may precipitate adrenal suppression. Budesonide’s local activity reduces systemic exposure but may still cause mild hyperglycemia or adrenal suppression in high doses.

Immunomodulators

Azathioprine and 6‑mercaptopurine are associated with myelosuppression, hepatotoxicity, pancreatitis, and increased risk of lymphoma and non‑melanoma skin cancers. TPMT deficiency predisposes to severe myelosuppression. Methotrexate can cause hepatotoxicity, mucositis, pulmonary fibrosis, and cytopenias. Black‑box warnings exist for azathioprine regarding lymphoma risk.

Biologic Therapies

Anti‑TNF‑α agents increase the risk of serious infections, including tuberculosis and opportunistic infections. Infusion reactions and hypersensitivity are possible. Natalizumab carries a risk of PML, requiring monitoring of JC virus serostatus. Vedolizumab has a lower systemic infection risk but may still cause mild infusion reactions. Ustekinumab can lead to infections and, rarely, inflammatory bowel disease flare. Black‑box warnings are present for anti‑TNF‑α agents regarding serious infections and malignancy risk.

Small‑Molecule Targeted Therapies

Tofacitinib is associated with increased risk of herpes zoster, venous thromboembolism, and elevated lipid levels. Lab monitoring is required. Upadacitinib shares similar safety concerns. S1P receptor modulators may cause bradycardia, conduction abnormalities, and macular edema. Black‑box warnings are included for JAK inhibitors regarding thromboembolic events and malignancy.

Drug Interactions

Aminosalicylates

Mesalamine may reduce absorption of oral contraceptives and levothyroxine. Sulfasalazine can inhibit the metabolism of drugs metabolized by CYP450, notably phenytoin and carbamazepine. Co‑administration with NSAIDs may increase GI ulceration risk.

Corticosteroids

Systemic steroids induce CYP3A4, potentially reducing the efficacy of drugs such as ketoconazole, antifungals, and certain antihypertensives. Steroids can potentiate the effects of anticoagulants and antiplatelet agents, increasing bleeding risk.

Immunomodulators

Azathioprine and 6‑mercaptopurine interact with allopurinol, leading to myelosuppression. They inhibit TPMT, thereby affecting the metabolism of other drugs requiring this enzyme. Methotrexate should not be combined with NSAIDs or other hepatotoxic agents due to additive liver injury.

Biologic Therapies

Anti‑TNF‑α agents interfere with vaccine efficacy, particularly live vaccines. Concomitant use with other immunosuppressants increases infection risk. Vedolizumab may increase the risk of opportunistic infections when combined with systemic steroids.

Small‑Molecule Targeted Therapies

Tofacitinib is metabolized by CYP3A4; inhibitors such as ketoconazole can raise plasma concentrations, while inducers like rifampicin may reduce efficacy. P-glycoprotein inhibitors can also affect drug levels. Concomitant use of anticoagulants is cautioned due to thromboembolic risk.

Special Considerations

Pregnancy and Lactation

Aminosalicylates are generally considered safe in pregnancy; mesalamine crosses the placenta but has no teratogenic evidence. Steroids are used for severe disease flares; budesonide is preferred due to low systemic exposure. Azathioprine and 6‑mercaptopurine are category D; methotrexate is contraindicated due to teratogenicity. Anti‑TNF‑α agents can cross the placenta, especially in the third trimester, potentially causing neonatal immunosuppression; timing of last dose should be considered. Vedolizumab is not recommended in pregnancy due to limited data, while ustekinumab has insufficient safety data. Small‑molecule inhibitors are contraindicated in pregnancy and lactation due to insufficient evidence.

Pediatric Considerations

Mesalamine and steroids are approved for pediatric UC. Azathioprine and 6‑mercaptopurine are used with TPMT testing. Anti‑TNF‑α agents are indicated for moderate to severe CD and UC, with dosing adjusted for body weight. Vedolizumab and ustekinumab have emerging pediatric indications. JAK inhibitors are not yet approved for children. Dose adjustments for renal or hepatic impairment are necessary. Growth monitoring and bone health are critical due to steroid exposure.

Geriatric Considerations

Older adults have increased susceptibility to infections and adverse drug reactions. Polypharmacy necessitates close monitoring for drug interactions. Steroid‑induced osteoporosis is a significant concern; bisphosphonate prophylaxis may be considered. Immunomodulators and biologics require vigilance for malignancy risks. Dose adjustments for renal and hepatic function are essential.

Renal and Hepatic Impairment

Mesalamine is renally excreted; dose reduction is advised in severe renal impairment. Sulfasalazine is metabolized hepatically; caution is advised in hepatic disease. Steroids are metabolized by the liver; hepatic impairment may prolong effects. Azathioprine and 6‑mercaptopurine clearance is primarily renal; dose adjustment is necessary. Methotrexate requires careful monitoring of hepatic function and dose reduction in hepatic or renal insufficiency. Biologics are not substantially affected by organ impairment but require monitoring for infections. JAK inhibitors require dose adjustment in hepatic impairment and caution in renal impairment.

Summary / Key Points

• Aminosalicylates remain first‑line for mild to moderate UC, with limited efficacy in CD.
• Corticosteroids provide rapid symptom control but are unsuitable for maintenance due to adverse effect profile.
• Immunomodulators serve as steroid sparing and maintenance agents, with TPMT testing to mitigate myelosuppression risk.
• Biologic therapies target specific cytokines or cell adhesion molecules, offering disease‑modifying effects; anti‑TNF‑α agents are first‑line for severe disease.
• Small‑molecule inhibitors provide oral alternatives with distinct safety considerations (e.g., thromboembolism, infection).
• Drug interactions are frequent; therapeutic drug monitoring and careful medication reconciliation are vital.
• Special populations (pregnancy, pediatrics, geriatrics) require individualized dosing and safety strategies.

In summary, the pharmacologic management of IBD necessitates a multifaceted approach that integrates disease severity, patient comorbidities, and safety considerations. Ongoing research continues to refine therapeutic strategies, emphasizing the importance of staying current with evolving evidence.

References

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