Page 1123 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 62 Drugs Used in the Treatment of Gastrointestinal Diseases 1109

attributable to the higher serum 5-ASA levels attained with these Adverse Effects
drugs. Sulfasalazine and other aminosalicylates rarely cause worsen-
ing of colitis, which may be misinterpreted as refractory colitis. Oral controlled-release budesonide formulations are metabolized
extensively in the liver by CYP3A4. Potent inhibitors of CYP3A4
can increase budesonide plasma levels several-fold, increasing the
GLUCOCORTICOIDS likelihood of adverse effects. General adverse effects of glucocorti-
coids are reviewed in Chapter 39.
Pharmacokinetics & Pharmacodynamics
In gastrointestinal practice, prednisone and prednisolone are PURINE ANALOGS: AZATHIOPRINE &
the most commonly used oral glucocorticoids. These drugs have 6-MERCAPTOPURINE
an intermediate duration of biologic activity allowing once-daily
dosing. Pharmacokinetics & Pharmacodynamics
Hydrocortisone enemas, foam, or suppositories are used to
maximize colonic tissue effects and minimize systemic absorp- Azathioprine and 6-mercaptopurine (6-MP) are purine antime-
tabolites that have immunosuppressive properties (see Chapters 54
tion via topical treatment of active IBD in the rectum and sig- and 55).
moid colon. Absorption of hydrocortisone is reduced with rectal The bioavailability of azathioprine (80%) is superior to 6-MP
administration, although 15–30% of the administered dosage is (50%). After absorption, azathioprine is rapidly converted by a
still absorbed. nonenzymatic process to 6-MP. 6-Mercaptopurine subsequently
Budesonide is a potent synthetic analog of prednisolone that
has high affinity for the glucocorticoid receptor but is subject to undergoes a complex biotransformation via competing catabolic
enzymes (xanthine oxidase and thiopurine methyltransferase)
rapid first-pass hepatic metabolism (in part by CYP3A4), result- that produce inactive metabolites and anabolic pathways that
ing in low oral bioavailability. Two pH-controlled delayed-release produce active thioguanine nucleotides. Azathioprine and 6-MP
oral formulations of budesonide are available that release the drug have a serum half-life of less than 2 hours; however, the active
either in the distal ileum and colon (pH > 5.5, Entocort) or in the 6-thioguanine nucleotides are concentrated in cells resulting
colon (pH > 7, Uceris), where it is absorbed. The bioavailability in a prolonged half-life of days. The prolonged kinetics of
of controlled-release budesonide capsules is approximately 10%. 6-thioguanine nucleotide results in a median delay of 17 weeks
As in other tissues, glucocorticoids inhibit production of
inflammatory cytokines (tumor necrosis factor [TNF]-α, interleu- before onset of therapeutic benefit from oral azathioprine or
6-MP is observed in patients with IBD.
kin [IL]-1) and chemokines (IL-8); reduce expression of inflam-
matory cell adhesion molecules; and inhibit gene transcription of Clinical Uses
nitric oxide synthase, phospholipase A , cyclooxygenase-2, and
2
NF-κB. Azathioprine and 6-MP are important agents in the induction
and maintenance of remission of ulcerative colitis and Crohn’s
Clinical Uses disease. Although the optimal dose is uncertain, most patients
with normal thiopurine-S-methyltransferase (TPMT) activity (see
Glucocorticoids are commonly used in the treatment of patients below) are treated with 6-MP, 1–1.5 mg/kg/d, or azathioprine,
with moderate to severe active IBD. Active disease is commonly 2–2.5 mg/kg/d. After 3–6 months of treatment, 50–60% of
treated with an initial oral dosage of 40–60 mg/d of prednisone patients with active disease achieve remission. These agents help
or prednisolone. Higher doses have not been shown to be more maintain remission in up to 80% of patients. Among patients
efficacious but have significantly greater adverse effects. Once a who depend on long-term glucocorticoid therapy to control active
patient responds to initial therapy (usually within 1–2 weeks), disease, purine analogs allow dose reduction or elimination of
the dosage is tapered to minimize development of adverse steroids in the majority.
effects. In severely ill patients, the drugs are usually administered
intravenously. Adverse Effects
For the treatment of IBD involving the rectum or sigmoid
colon, rectally administered glucocorticoids are preferred because Dose-related toxicities of azathioprine or 6-MP include nausea,
of their lower systemic absorption. vomiting, bone marrow depression (leading to leukopenia, mac-
The oral controlled-release budesonide (9 mg/d) formulations rocytosis, anemia, or thrombocytopenia), and hepatic toxicity.
described above are used in the treatment of mild to moderate Routine laboratory monitoring with complete blood count and
Crohn’s disease involving the ileum and proximal colon (Ento- liver function tests is required in all patients. Leukopenia or
cort) and ulcerative colitis (Uceris). They are slightly less effective elevations in liver chemistries usually respond to medication dose
than prednisolone in achieving clinical remission but have signifi- reduction. Severe leukopenia may predispose to opportunistic
cantly less adverse systemic effects. infections; leukopenia may respond to therapy with granulocyte
Corticosteroids are not useful for maintaining disease remis- stimulating factor. Catabolism of 6-MP by TPMT is low in 11%
sion. Other medications such as aminosalicylates or immunosup- and absent in 0.3% of the population, leading to increased pro-
pressive agents should be used for this purpose. duction of active 6-thioguanine metabolites and increased risk of