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.

1. Inflammatory bowel disease:
aminosalicylates
Domina Petric, MD

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.

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

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

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.

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