Inflammatory bowel disease: aminosalicylates Domina Petric, MD

Topical corticosteroids (proctitis) Surgery Natalizumab Cyclosporine TNF antagonists Iv. corticosteroids Oral corticosteroids Methotrexate Azathioprine 6-Mercaptopurine Budesonide (ileitis) Topical corticosteroids (proctitis) Antibiotics 5-Aminosalicylates Severe disease Refractory Moderate disease Mild disease Responsive

Aminosalicylates These drugs contain 5-aminosalicylic acid (5-ASA). 5-ASA differs from salicylic acid only by the addition of an amino group at the 5 (meta) position. Aminosalicylates work topically in areas of diseased gastrointestinal mucosa. A number of formulations have been designed to deliver 5-ASA to various distal segments of the small bowel or the colon. Sulfasalazine, olsalazine, balsalazide and various forms of mesalamine.

Azo-compounds Sulfasalazine, balsalazide and olsalazine contain 5-ASA bound by an azo (N=N) bond to an inert compound or to another 5-ASA molecule. Sulfasalazine: 5-ASA is bound to sulfapyridine. Balsalazide: 5-ASA is bound to 4-aminobenzoyl-β-alanine. Olsalazine: two 5-ASA molecules are bound together. The azo structure markedly reduces absorption of the parent drug from the small intestine.

Azo-compounds In the terminal ileum and colon, resident bacteria cleave the azo bond by means of an azoreductase enzyme, releasing the active 5-ASA. High concentrations of active drug are made available in the terminal ileum or colon.

Mesalamine compounds These compounds have been designed to package 5-ASA itself in various ways to deliver it to different segments of the small or large bowel. Pentasa is a mesalamine formulation that contains timed-release microgranules that release 5-ASA throughout the small intestine.

Mesalamine compounds Asacol and Apriso have 5-ASA coated in a pH-sensitive resin that dissolves at pH 6-7: distal ileum and proximal colon. Lialda uses a pH-dependent resin that encases a multimatrix core: slow release of mesalamine throughout the colon.

Mesalamine compounds Enema formulations (Rowasa) and suppositories (Canasa) are used to deliver 5-ASA in high concentrations to the rectum and sigmoid colon.

Lialda Lialda Pentasa Lialda Asacol, Apriso Rowasa Canasa http://humananatomylesson.com

Pharmacokinetics Unformulated 5-ASA is readily absorbed from the small intestine. Absorption of 5-ASA from the colon is extremely low. 20-30% of 5-ASA from current oral mesalamine formulations is systemically absorbed in the small intestine.

Pharmacokinetics Absorbed 5-ASA undergoes N-acetylation in the gut epithelium and liver to a metabolite that does not possess significant anti-inflammatory activity. The acetylated metabolite is excreted by the kidneys.

Pharmacokinetics The azo compounds, 10% of sulfasalazine and less than 1% of balsalazide are absorbed as native compounds. After azoreductase breakdown of sulfasalazine, over 85% of the carrier molecule sulfapyridine is absorbed from the colon.

Pharmacokinetics Sulfapyridine undergoes hepatic metabolism (including acetylation) followed by renal excretion. After azoreductase breakdown of balsalazide, over 70% of the carrier peptide is recovered intact in the feces. Only a small amount of systemic absorption occurs.

Pharmacodynamics The primary action of salicylate and other NSAIDs is due to blockade of prostaglandin synthesis by inhibition of cyclooxygenase. 5-ASA modulates inflammatory mediators derived from both the cyclooxygenase and lipooxygenase pathways.

Pharmacodynamics 5-ASA inhibits the activity of nuclear factor-κB (NF-κB): that is important transcription factor for proinflammatory cytokines. 5-ASA may inhibit cellular functions of natural killer cells, mucosal lymphocytes and macrophages. It may also scavenge reactive oxygen metabolites.

Clinical use 5-ASA drugs induce and maintain remission in ulcerative colitis: first-line agents for treatment of mild to moderate active UC. Efficacy in Crohn´s disease is unproven, but 5-ASA are used as first-line therapy for mild to moderate disease involving the colon or distal ileum.

Clinical use 5-ASA suppositories or enemas are useful in patients with ulcerative colitis or Crohn´s disease confined to the rectum (proctitis) or distal colon (proctosigmoiditis).

Clinical use In patients with UC or Crohn´s colitis that extends to the proximal colon, both the azo compounds and mesalamine formulations are useful. For the treatment of Crohn´s disease involving the small bowel: mesalamine compounds, which release 5-ASA in the small intestine.

Adverse effects Slow acetylators of sulfapyridine have more frequent and more severe adverse effects than fast acetylators. Up to 40% of patients can not tolerate therapeutic doses of sulfasalazine. Dose-related side effects: nausea, gastrointestinal upset, headaches, arthralgias, myalgias, bone marrow suppresion, malaise.

Adverse effects Hypersensitivity to sulfapyridine or, rarely, 5-ASA can result in fever, exfoliative dermatitis, pancreatitis, pneumonitis, hemolytic anemia, pericarditis or hepatitis. Sulfasalazine can cause oligospermia, which reverses upon discontinuation of the drug.

Adverse effects Sulfasalazine impairs folate absorption and processing: dietary supplementation with 1 mg/d folic acid is recommended. Olsalazine may stimulate a secretory diarrhea in 10% of patients. High doses of aminosalicylates may cause renal tubular damage.

Adverse effects Rare cases of interstitial nephritis are reported, particularly in association with high doses of mesalamine formulations. Sulfasalazine and other aminosalicylates rarely cause worsening of colitis.

Literature Katzung, Masters, Trevor. Basic and clinical pharmacology. http://humananatomylesson.com