Mesalazine and Sulfasalazine

Mechanism

💊 Mesalazine

• Composition: Free 5-aminosalicylic acid (5-ASA) in delayed release formulations (pH dependent or osmotic).
• RAM profile: Excellent general clinical tolerance.
• Does not contain sulfamide transporters, eliminating class toxicity and hypersensitivity reactions.

🧪 Sulfasalazine

• Composition: A 5-ASA molecule covalently linked via an azo bond to sulfapyridine.
• Activation: Requires the azoreductases of the colonic bacterial microbiota to cleave the azo bond to release the substances.
• Associated with severe ADRs mediated by sulfapyridine absorption.

Mechanism of action

The mechanism of action of 5-ASA is predominantly topical on the inflamed intestinal epithelium:

• Inhibition of the Arachidonic Acid Cascade: Selectively inhibits mucosal cyclooxygenase (COX) and lipoxygenase (5-LOX), decreasing the production of inflammatory prostaglandins and potent leukotrienes (especially leukotriene LTB₄, a neutrophil chemotactic agent).
• Modulation of NF-κB Signaling: By acting as an agonist ligand of the peroxisome proliferator-type nuclear receptor gamma (PPAR-γ), it inhibits the nuclear translocation of the proinflammatory transcription factor NF-κB, drastically reducing the synthesis of proinflammatory cytokines such as TNF-α, IL-1 and IL-6.
• Free Radical Purification: Blocks the formation of reactive oxygen and nitrogen species in the inflamed intestinal lamina propria.

Mechanism of the Formulation and Release of Mesalazine

Free 5-ASA administered by the conventional oral route is almost completely absorbed in the duodenum and proximal jejunum, not reaching therapeutic concentrations in the terminal ileum or colon. To avoid this, modern formulations employ specialized coatings:

• Eudragit-S coating: Acrylic polymer that dissolves only at pH 7.0 (typical of the terminal ileum and right colon).
• Multi-matrix systems (MMX): They delay physical dissolution uniformly along the entire gastric colonic path.
• Enemas and Suppositories: Deliver high concentrations directly to the rectum and descending colon, effectively bypassing upper tract absorption.

Pharmacokinetics

Pharmacokinetics

• Absorption: Mesalazine released in the colon is ≈ 20% - 30% absorbed systemically; the rest acts locally and is eliminated. The sulfapyridine released from sulfasalazine is almost completely absorbed systemically (90%).
• Metabolism: Absorbed mesalazine is rapidly acetylated in the liver and colonic mucosal wall to its inactive metabolite N-acetyl-5-ASA by the enzyme cellular acetyltransferase.
• Excretion: Renal for the absorbed acetylated fraction. Fecal for free and unabsorbed polymerized 5-ASA.

Indicators and dose

Approved indications

• Ulcerative Colitis (UC): Treatment of choice for the induction of clinical remission in outbreaks of mild to moderate intensity, and maintenance of long-term remission.
• Crohn's disease (CD): Limited usefulness, mainly confined to mild colonic or ileocolonic involvement.

Dosage and Clinical Adjustment

Ulcerative Colitis (Adults):

• Active outbreak (Induction): 2.4 g to 4.8 g orally of mesalazine per day in a single or divided dose.
• Maintenance of remission: 1.6 g to 2.4 g orally of mesalazine daily continuously indefinitely.
• Treatment of active left proctitis and colitis: 1 g of mesalazine per day in suppositories rectally (at night) or 1 g to 4 g in enemas.

Adjustment in Renal Failure: Contraindicated in GFR < 30 mL/min. In moderate renal failure (eGFR 30 - 59 mL/min), closely monitor urinary glomerular function and reduce the daily dose to the minimum effective.

Breastfeeding and Folic Acid

Use in Pregnancy: Safe and widely controlled clinical use. The use of sulfasalazine interferes with the intestinal absorption of dietary folic acid by inhibiting its transporters. For this reason, maternal supplementation with folic acid (5 mg per day) is mandatory to prevent neural tube defects.

Breastfeeding: Compatible with monitoring. The acetylated metabolite is excreted in milk in minimal proportions. The infant should be monitored for the appearance of watery diarrhea.

Security

Contraindications

• Absolute: Known hypersensitivity to salicylates (acetylsalicylic acid) or mesalazine. Additionally, for sulfasalazine, demonstrated severe hypersensitivity to sulfas or sulfonamides. Coexistence of severe hemorrhagic diathesis or severe renal dysfunction (eGFR < 30 mL/min).

Adverse effects (ADRs)

Drug interactions

• Purine Analogs (Azathioprine, 6-MP): Mesalazine inhibits the liver enzyme thiopurine methyltransferase (TPMT) in the mucosa. Inhibition of TPMT reduces the metabolism of azathioprine, dramatically increasing the risk of severe myelosuppression with fatal pancytopenia. Mandatory surveillance: Monitor leukocyte count if they are associated.
• Oral Anticoagulants (Warfarin): It can enhance the anticoagulant effect with unexpected elevation of the INR.