This document summarizes aminosalicylates, a class of drugs used to treat inflammatory bowel disease. It describes how various formulations like sulfasalazine, olsalazine, and mesalamine compounds deliver the active drug 5-aminosalicylic acid to different parts of the gastrointestinal tract. It also discusses the pharmacokinetics, pharmacodynamics, clinical uses, and potential adverse effects of aminosalicylates.
2. Surgery
Natalizumab
Cyclosporine
TNF antagonists
Iv. corticosteroids
TNF antagonists
Oral corticosteroids
Methotrexate
Azathioprine
6-Mercaptopurine
Budesonide (ileitis)
Topical corticosteroids (proctitis)
Antibiotics
5-Aminosalicylates
Severe disease
Moderate disease
Mild disease
Refractory
Responsive
3. • 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.
Aminosalicylates
4. 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.
5. 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.
6. 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.
7. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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).
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.