Aminosalicylates

Aminosalicylates are a class of anti-inflammatory drugs primarily used in the management of inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD). They are derivatives of 5-aminosalicylic acid (5-ASA, also known as mesalamine) and act locally within the intestinal mucosa to reduce inflammation. These agents represent the cornerstone of mild-to-moderate ulcerative colitis therapy and play a limited but important role in Crohn’s disease, especially when colonic involvement is present.

This professional overview will explore their mechanism of action, therapeutic uses, available agents with doses, adverse effects, contraindications, precautions, and drug interactions.

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Mechanism of Action

The exact mechanism is not fully understood, but multiple anti-inflammatory and immunomodulatory pathways have been identified:

• Inhibition of cyclooxygenase (COX) and lipoxygenase pathways, reducing the synthesis of prostaglandins and leukotrienes, which are major mediators of inflammation.

• Scavenging of reactive oxygen species (ROS), limiting oxidative stress in the colonic mucosa.

• Inhibition of nuclear factor kappa B (NF-κB) activation, suppressing pro-inflammatory cytokine production (e.g., TNF-α, IL-1, IL-6).

• Modulation of immune cell function, particularly reducing neutrophil chemotaxis and macrophage activation in the intestinal lining.

• Local (topical) action in the gut lumen, with minimal systemic absorption being sufficient for therapeutic effect.

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Clinical Uses

1. Ulcerative Colitis (UC)

• First-line therapy for mild to moderate UC, both for induction of remission and maintenance therapy.

• Rectal formulations (suppositories, enemas) are highly effective in distal UC and proctitis.

2. Crohn’s Disease (CD)

• Less effective than in UC but may be used for mild colonic disease.

• Not recommended for small bowel or severe Crohn’s disease due to limited efficacy.

3. Other Uses (less common)

• Prevention of post-operative pouchitis after ileal pouch-anal anastomosis.

• Some investigational use in colorectal cancer chemoprevention (due to anti-inflammatory and anti-oxidant properties).

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Major Aminosalicylate Agents and Dosing

1. Mesalamine (5-ASA)

• The active compound in all aminosalicylates.

• Available in various formulations designed to release the drug at specific sites in the gastrointestinal tract.

Oral Formulations (doses vary by product):

• Asacol HD: 1.6 g three times daily (induction), 1.6 g once or twice daily (maintenance).

• Lialda: 2.4–4.8 g once daily.

• Pentasa: 1 g four times daily (induction), 1 g twice daily (maintenance).

• Apriso: 1.5 g once daily (maintenance).

Rectal Formulations:

• Suppository (Canasa): 1 g once or twice daily.

• Enema: 4 g once nightly.

2. Sulfasalazine

• A prodrug consisting of 5-ASA linked to sulfapyridine via an azo bond. Colonic bacteria cleave the bond to release 5-ASA.

• Dose: 2–4 g daily in divided doses for induction; 1–2 g daily for maintenance.

• Particularly effective in UC but limited by sulfa-related side effects.

3. Olsalazine

• A dimer of two 5-ASA molecules linked by an azo bond; cleaved in the colon to release active 5-ASA.

• Dose: 500 mg twice daily, may increase to 1 g twice daily.

• Often associated with diarrhea as a side effect.

4. Balsalazide

• A prodrug consisting of 5-ASA linked to an inert carrier molecule, cleaved in the colon to release 5-ASA.

• Dose: 2.25 g three times daily for induction; 1.5–2.25 g twice daily for maintenance.

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Adverse Effects

Most aminosalicylates are well tolerated, particularly mesalamine. Side effects vary depending on the specific agent.

Common adverse effects:

• Headache, nausea, abdominal pain, flatulence.

• Diarrhea (especially with olsalazine).

• Fatigue.

Sulfasalazine-specific adverse effects:

• Hypersensitivity reactions (rash, fever).

• Hemolytic anemia in G6PD-deficient patients.

• Oligospermia (reversible).

• Folate deficiency (due to interference with absorption).

Serious but rare adverse effects:

• Nephrotoxicity (interstitial nephritis, renal impairment).

• Hepatotoxicity.

• Blood dyscrasias (agranulocytosis, aplastic anemia, thrombocytopenia).

• Pancreatitis.

• Pericarditis and myocarditis (rare hypersensitivity reactions).

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Contraindications

• Hypersensitivity to salicylates or sulfa drugs (for sulfasalazine).

• Severe renal or hepatic impairment.

• Known hypersensitivity to aspirin (cross-reactivity risk).

• Intestinal obstruction (due to local action and formulation issues).

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Precautions

• Renal function monitoring: Baseline and periodic monitoring of serum creatinine and urinalysis.

• Hepatic monitoring: Especially in patients with liver disease or those on hepatotoxic drugs.

• Blood counts: Recommended with sulfasalazine due to risk of hematologic toxicity.

• Folate supplementation: Advised in patients on sulfasalazine (1 mg/day folic acid).

• Pregnancy and breastfeeding:

  • Mesalamine is generally considered safe.

  • Sulfasalazine can be used but requires folate supplementation.

  • Excreted in breast milk; caution with nursing infants (especially risk of diarrhea).

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Drug Interactions

• Sulfasalazine: May reduce folic acid absorption; concurrent folate supplementation required.

• Mesalamine: Can increase nephrotoxic risk when combined with NSAIDs, cyclosporine, or tacrolimus.

• Sulfasalazine: Can displace warfarin, methotrexate, and sulfonylureas from protein-binding sites, enhancing their effects/toxicity.

• Thiopurines (azathioprine, 6-mercaptopurine): Co-administration with mesalamine can increase myelotoxicity risk by inhibiting thiopurine metabolism.

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Summary of Key Agents with Usual Doses

• Mesalamine: Oral (2.4–4.8 g daily), rectal suppository (1 g), enema (4 g).

• Sulfasalazine: 2–4 g daily (induction), 1–2 g daily (maintenance).

• Olsalazine: 500 mg–1 g twice daily.

• Balsalazide: 2.25 g three times daily (induction), 1.5–2.25 g twice daily (maintenance).