DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1354 mediated inflammatory processes. In contrast, the
inflammatory response in ulcerative colitis resembles
aspects of that mediated by the T H
2 pathway. Recently,
this relatively simplistic classification has been revised
in the light of the description of regulatory T cells and
pro-inflammatory T H
17 cells, a novel T- cell population
that expresses IL-23 receptor as a surface marker
and produces, among others, the pro-inflammatory
cytokines IL-17, IL-21, IL-22, and IL-26. Several studies
have demonstrated an important role of T H
17 cells
in intestinal inflammation, particularly in Crohn’s disease
(Cho, 2008; Strober et al., 2007).
SECTION VI
DRUGS AFFECTING GASTROINTESTINAL FUNCTION
Important insights into pathogenesis have emerged from
genetic analyses of Crohn’s disease. Mutations in the gene NOD2
(nucleotide-binding oligomerization domain-2; also called CARD15)
are associated with both familial and sporadic Crohn’s disease in
whites (Hugot et al., 2001; Ogura et al., 2001). NOD2 is expressed
in monocytes, granulocytes, dendritic cells, Paneth cells, and epithelial
cells. It is proposed to function as an intracellular sensor for bacterial
infection by recognizing peptidoglycans, thereby playing an
important role in the natural immunity to bacterial pathogens.
Consistent with this model, other studies have identified bacterial
antigens, including pseudomonal protein I2 (Dalwadi et al., 2001)
and a flagellin protein (Lodes et al., 2004), as dominant superantigens
that induce the T H
1 response in Crohn’s disease (shown as bacterial
products in Figure 47–1). More recently, genome- wide studies
have revealed other genes associated with IBD, whose identification
may lead to the development of novel therapeutics (Cho, 2008)
Thus, these converging experimental approaches are generating
novel insights into the pathogenesis of Crohn’s disease that soon
may translate into novel therapeutic approaches to IBD. The major
therapeutic agents available for IBD are described next.
MESALAMINE (5-ASA)-BASED THERAPY
Chemistry, Mechanism of Action, and Pharmacological
Properties. First- line therapy for mild to moderate
ulcerative colitis generally involves mesalamine (5-
aminosalicylic acid, or 5-ASA). The archetype for this
class of medications is sulfasalazine (AZULFIDINE),
which consists of 5-ASA linked to sulfapyridine by an
azo bond (Figure 47–2). Although this drug was developed
originally as therapy for rheumatoid arthritis, clinical
trials serendipitously demonstrated a beneficial
effect on the GI symptoms of subjects with concomitant
ulcerative colitis. Sulfasalazine is a prime example of
an oral drug that is delivered effectively to the distal GI
tract. Given individually, either 5-ASA or sulfapyridine
is absorbed in the upper GI tract; the azo linkage in sulfasalazine
prevents absorption in the stomach and small
intestine, and the individual components are not liberated
for absorption until colonic bacteria cleave the
HO
HOOC
HO
HOOC
5-ASA
Mesalamine
NaOOC
HO
N
NH 2
NaOOCCH 2 CH 2 NH
Sulfasalazine
N
H 2 N
Olsalazine
Balsalazide
O
C
N
SO 2
SO 2
Sulfapyridine
COONa
COONa
bond. 5-ASA is now regarded as the therapeutic moiety,
with little, if any, contribution by sulfapyridine.
Mesalamine is a salicylate, but its therapeutic effect
does not appear to relate to cyclooxygenase inhibition;
indeed, traditional nonsteroidal anti- inflammatory drugs
and selective inhibitors of cyclooxygenase-2 (“coxibs”)
may exacerbate IBD. Many potential sites of action have
been demonstrated in vitro for either sulfasalazine or
mesalamine: inhibition of the production of IL-1 and
TNFα, inhibition of the lipoxygenase pathway, scavenging
of free radicals and oxidants, and inhibition of NFκB,
a transcription factor pivotal to production of
inflammatory mediators. Specific mechanisms of action
of these drugs have not been identified.
Although not active therapeutically, sulfapyridine
causes many of the adverse effects observed in patients
taking sulfasalazine. To preserve the therapeutic effect
of 5-ASA without the adverse effects of sulfapyridine,
several second- generation 5-ASA compounds have
been developed (Figures 47–2, 47–3, and 47–4). They
are divided into two groups: prodrugs and coated drugs.
Prodrugs contain the same azo bond as sulfasalazine
but replace the linked sulfapyridine with either another
5-ASA (olsalazine, DIPENTUM) or an inert compound
N
N
N
H
N
H
N
OH
N
N
OH
Figure 47–2. Structures of sulfasalazine and related agents. The
red N atoms indicate the diazo linkage that is cleaved to generate
the active moiety.