Page 1122 - Basic _ Clinical Pharmacology ( PDFDrive )

1108 SECTION X Special Topics

Stomach Small Intestine Colon
Jejunum Ileum Proximal Distal Rectum
5-ASA delayed-release capsules (Pentasa)
5-ASA pH-dependent release (Asacol, Lialda)
Sulfasalazine

Balsalazide
5-ASA enema (Rowasa)

5-ASA suppository (Canasa)

FIGURE 62–9 Sites of 5-aminosalicylic acid (5-ASA) release from different formulations in the small and large intestines.

the colon. 5-ASA also may be delivered in high concentrations to disease is unproven, although many clinicians use 5-ASA agents as
the rectum and sigmoid colon by means of enema formulations first-line therapy for mild to moderate disease involving the colon
(Rowasa) or suppositories (Canasa). or distal ileum.
The effectiveness of 5-ASA therapy depends in part on achiev-
Pharmacokinetics & Pharmacodynamics ing high drug concentration at the site of active disease. Thus,
5-ASA suppositories or enemas are useful in patients with ulcer-
Although unformulated 5-ASA is readily absorbed from the small ative colitis or Crohn’s disease confined to the rectum (proctitis)
intestine, absorption of 5-ASA from the colon is extremely low. or distal colon (proctosigmoiditis). In patients with ulcerative
In contrast, approximately 20–30% of 5-ASA from current oral colitis or Crohn’s colitis that extends to the proximal colon, both
mesalamine formulations is systemically absorbed in the small the azo compounds and mesalamine formulations are useful. For
intestine. Absorbed 5-ASA undergoes N-acetylation in the gut epi- the treatment of Crohn’s disease involving the small bowel, mesa-
thelium and liver to a metabolite that does not possess significant lamine compounds, which release 5-ASA in the small intestine,
anti-inflammatory activity. The acetylated metabolite is excreted have a theoretic advantage over the azo compounds.
by the kidneys.
Of the azo compounds, 10% of sulfasalazine and less than Adverse Effects
1% of balsalazide are absorbed as native compounds. After azo-
reductase breakdown of sulfasalazine, over 85% of the carrier Sulfasalazine has a high incidence of adverse effects, most of
molecule sulfapyridine is absorbed from the colon. Sulfapyridine which are attributable to systemic effects of the sulfapyridine
undergoes hepatic metabolism (including acetylation) followed molecule. Slow acetylators of sulfapyridine have more frequent
by renal excretion. By contrast, after azoreductase breakdown of and more severe adverse effects than fast acetylators. Up to 40%
balsalazide, over 70% of the carrier peptide is recovered intact in of patients cannot tolerate therapeutic doses of sulfasalazine. The
the feces and only a small amount of systemic absorption occurs. most common problems are dose-related and include nausea, gas-
The mechanism of action of 5-ASA is not certain. The pri- trointestinal upset, headaches, arthralgias, myalgias, bone marrow
mary action of salicylate and other NSAIDs is due to blockade of suppression, and malaise. Hypersensitivity to sulfapyridine (or,
prostaglandin synthesis by inhibition of cyclooxygenase. However, rarely, 5-ASA) can result in fever, exfoliative dermatitis, pancre-
the aminosalicylates have variable effects on prostaglandin produc- atitis, pneumonitis, hemolytic anemia, pericarditis, or hepatitis.
tion. It is thought that 5-ASA modulates inflammatory mediators Sulfasalazine has also been associated with oligospermia, which
derived from both the cyclooxygenase and lipoxygenase pathways. reverses upon discontinuation of the drug. Sulfasalazine impairs
Other potential mechanisms of action of the 5-ASA drugs relate folate absorption and processing; hence, dietary supplementation
to their ability to interfere with the production of inflamma- with 1 mg/d folic acid is recommended.
tory cytokines. 5-ASA inhibits the activity of nuclear factor-κB In contrast to sulfasalazine, other aminosalicylate formula-
(NF-κB), an important transcription factor for proinflammatory tions are well tolerated. In most clinical trials, the frequency of
cytokines. 5-ASA may also inhibit cellular functions of natural drug adverse events is similar to that in patients treated with
killer cells, mucosal lymphocytes, and macrophages, and it may placebo. For unclear reasons, olsalazine may stimulate a secretory
scavenge reactive oxygen metabolites. diarrhea—which should not be confused with active IBD—in
10% of patients. Rare hypersensitivity reactions may occur with all
Clinical Uses aminosalicylates but are much less common than with sulfasalazine.
Careful studies have documented subtle changes indicative of renal
5-ASA drugs induce and maintain remission in ulcerative colitis tubular damage in patients receiving high doses of aminosalicylates.
and are considered to be the first-line agents for treatment of mild Rare cases of interstitial nephritis are reported, particularly in asso-
to moderate active ulcerative colitis. Their efficacy in Crohn’s ciation with high doses of mesalamine formulations; this may be