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

1356 rapid acetylators have lower systemic levels of the drug and fewer
adverse effects. By contrast, only 25% of mesalamine is absorbed
from the colon, and most of the drug is excreted in the stool. The
small amount that is absorbed is acetylated in the intestinal mucosal
wall and the liver and then excreted in the urine. Intraluminal concentrations
of mesalamine therefore are very high (~1500 μg/mL or
10 mM in patients taking a typical dose of 3 g/day).
The pH-sensitive coatings (methyl-methacrylate methacrylic
acid copolymer) of ASACOL (EUDAGRIT) and LIALDA/MEZAVANT limit
gastric and small intestinal absorption of 5-ASA, as assessed by urinary,
ileostomal, and fecal measurements of the various metabolites.
The pharmacokinetics of PENTASA differ somewhat. The
ethylcellulose- coated micro- granules are released in the upper GI tract
as discrete prolonged- release units of mesalamine. Acetylated
mesalamine can be detected in the circulation within an hour after
ingestion, indicating some rapid absorption, but some intact microgranules
also can be detected in the colon. Because it is released in
the small bowel, a greater fraction of PENTASA is absorbed systemically
compared with the other 5-ASA preparations.
SECTION VI
DRUGS AFFECTING GASTROINTESTINAL FUNCTION
Adverse Effects. Side effects of sulfasalazine occur in 10-45% of
patients with ulcerative colitis and are related primarily to the sulfa
moiety. Some are dose related, including headache, nausea, and
fatigue. These reactions can be minimized by giving the medication
with meals or by decreasing the dose. Allergic reactions include rash,
fever, Stevens- Johnson syndrome, hepatitis, pneumonitis, hemolytic
anemia, and bone marrow suppression. Sulfasalazine reversibly
decreases the number and motility of sperm but does not impair
female fertility. Sulfasalazine inhibits intestinal folate absorption and
is usually administered with folate.
The newer mesalamine formulations generally are well tolerated,
and side effects are relatively infrequent and minor. Headache,
dyspepsia, and skin rash are the most common. Diarrhea appears to
be particularly common with olsalazine (occurring in 10-20% of
patients); this may be related to its ability to stimulate chloride and
fluid secretion in the small bowel. Nephrotoxicity, although rare, is
a more serious concern. Mesalamine has been associated with interstitial
nephritis; although its pathogenic role is controversial, renal
function should be monitored in all patients receiving these drugs.
Both sulfasalazine and its metabolites cross the placenta but have
not been shown to harm the fetus. Although less well studied, the
newer formulations appear to be safe in pregnancy. The risks to the
fetus from the consequences of uncontrolled IBD in pregnant women
are believed to outweigh the risks associated with the therapeutic
use of these agents.
GLUCOCORTICOIDS
The effects of glucocorticoids on the inflammatory
response are numerous and well documented (Chapters 38
and 42). Although glucocorticoids are universally recognized
as effective in acute exacerbations, their use in
either ulcerative colitis or Crohn’s disease involves considerable
challenges and pitfalls, and they are indicated
only for moderate to severe IBD.
The response to glucocorticoids in individual
patients with IBD divides them into three general classes:
responsive, dependent, and unresponsive. Glucocorticoidresponsive
patients improve clinically, generally within
1-2 weeks and remain in remission as the steroids
are tapered and then discontinued. Glucocorticoiddependent
patients also respond to glucocorticoids but
then experience a relapse of symptoms as the steroid
dose is tapered. Glucocorticoid- unresponsive patients do
not improve even with prolonged high- dose steroids.
Approximately 40% of patients are glucocorticoid
responsive, 30-40% have only a partial response or
become glucocorticoid dependent, and 15-20% of
patients do not respond to glucocorticoid therapy.
Glucocorticoids sometimes are used for prolonged
periods to control symptoms in corticosteroid- dependent
patients. However, the failure to respond to steroids with
prolonged remission (i.e., a disease relapse) should
prompt consideration of alternative therapies, including
immunosuppressive agents and anti- TNFα therapies.
Glucocorticoid are not effective in maintaining remission
in either ulcerative colitis or Crohn’s disease
(Steinhart et al., 2003); their significant side effects have
led to increased emphasis on limiting the duration and
cumulative dose of corticosteroids in IBD.
The approach to glucocorticoid therapy in IBD differs somewhat
from that in diseases such as asthma or rheumatoid arthritis.
Initial doses are 40-60 mg of prednisone or equivalent per day; higher
doses generally are no more effective. The glucocorticoid dose in IBD
is tapered over weeks to months. Even with these slow tapers, however,
efforts should be made to minimize the duration of therapy.
Glucocorticoids induce remission in most patients with either ulcerative
colitis or Crohn’s disease (Faubion et al., 2001). Oral prednisone
is the preferred agent for moderate to severe disease, and the typical
dose is 40-60 mg once a day. Most patients improve substantially
within 5 days of initiating treatment; others require treatment for several
weeks before remission occurs. For more severe cases, glucocorticoids
are given intravenously. Generally, methylprednisolone or
hydrocortisone is used for intravenous therapy, although some experts
believe that corticotropin (ACTH) is more effective in patients who
have not previously received any steroids.
Topically acting agents (i.e., given by enema) have fewer adverse
effects than systemic steroids but are also less effective in reducing
remission. Glucocorticoid enemas are useful mainly in patients whose
disease is limited to the rectum and left colon. Hydrocortisone is available
as a retention enema (100 mg/60 mL), and the usual dose is one
60-mL enema per night for 2 or 3 weeks. When administered optimally,
the drug can reach up to or beyond the descending colon. Patients with
distal disease usually respond within 3-7 days. Absorption, although
less than with oral preparations, is still substantial (up to 50-75%).
Hydrocortisone also can be given once or twice daily as a 10% foam suspension
(CORTIFOAM) that delivers 80 mg hydrocortisone per application;
this formulation can be useful in patients with very short areas of
distal proctitis and difficulty retaining fluid.
Budesonide (ENTOCORT ER) is an enteric- release form of a
synthetic steroid that is used for ileocecal Crohn’s disease