This document discusses the pharmacology of glucocorticoids, purine analogs, and methotrexate for treatment of inflammatory bowel disease. It describes the mechanisms of action, pharmacokinetics, clinical uses, and adverse effects of these drugs. Glucocorticoids such as prednisone are commonly used orally or rectally to treat moderate to severe IBD. Purine analogs azathioprine and 6-mercaptopurine are used to induce and maintain remission. Methotrexate given weekly can also induce and maintain remission of Crohn's disease. Adverse effects include bone marrow suppression, liver toxicity, and opportunistic infections which require monitoring.

1. IBD: GC, purine analogs
and MTX
Domina
Petric, MD
Inflammatory
Bowel
Disease
Pharmacology

2. Glucocorticoids (GC)
In gastrointestinal practice,
prednisone and prednisolone are
the most commonly used oral GC.
These drugs have an intermediate
duration of biologic activity: once-
daily dosing.

3. Glucocorticoids (GC)
• Hydrocortisone enemas, foam and
suppositories are used to maximize
colonic tissue effects and minimize
systemic absorption via topical tratment
of active inflammatory bowel disease in
the rectum and sigmoid colon.
• Absorption of hydrocortisone is reduced
with rectal administration.
• 15-30% of the administered dosage is
still absorbed.

4. Budesonide
• It is potent synthetic analog of
prednisolone that has high affinity for
the glucocorticoid receptor.
• It is a subject to rapid first-pass
hepatic metabolism (in part by
CYP3A4).
• That results in low oral bioavailability.

5. Budesonide
• A controlled-release oral
formulation of budesonide
(Entocort) releases the drug in
the distal ileum and colon.
• The bioavailability of controlled-
release budesonide capsule is
approximately 10%.

6. Glucocorticoids:
• inhibit production of inflammatory
cytokines (TNF-α, IL-1) and
chemokines (IL-8)
• reduce expression of inflammatory
cell adhesion molecules
• inhibit gene transcription of nitric
oxide synthase, phospholipase A2,
cyclooxygenase-2 and NF-κB

7. Clinical uses
• GC are commonly used in the
treatment of patients with
moderate to severe active
inflammatory bowel disease.
• Active disease is treated with an
initial oral dosage of 40-60 mg/d
of prednisone or prednisolone.

8. Clinical uses
• Once a patient responds to initial
therapy (usually within 1-2 weeks),
the dosage is tapered to minimize
development of adverse effects.
• In severely ill patients, the drugs
are usually administered
intravenously.

9. Clinical uses
For IBD involving the rectum or
sigmoid colon, rectally
administered GC are preffered
(lower systemic absorption).
Oral controlled-release
budesonide 9 mg/d is used in the
treatment of mild to moderate
Crohn´s disease involving the
ileum and proximal colon.

10. Clinical uses
GC are not useful for
maintaining disease remission.
Aminosalicylates or
immunosupressive agents are
used for this purpose.

11. Most common side effects
• sodium and fluid retention in the body
• weight gain
• swelling of the legs (edema)
• high blood pressure
• loss of potassium
• headache
• muscle weakness

12. Most common side effects
• puffiness of the face (moon face)
• facial hair growth
• thinning and easy bruising of the skin
• slow wound healing
• glaucoma, cataract
• ulcers in the stomach and duodenum
• osteoporosis

13. Most common side effects
• loss of diabetes control
• menstrual irregularity
• buffalo hump (rounding of the upper
back)
• obesity, diabetes
• depression, euphoria, insomnia
• mood swings

14. PURINE ANALOGS:
AZATHIOPRINE,
6-MERCAPTOPURINE

15. Pharmacokinetics
• Azathioprine and 6-mercaptopurine
(6-MP) are purine antimetabolites
with immunosuppressive properties.
• The bioavailability of azathioprine
(80%) is superior to 6-MP (50%).
• After absorption azathioprine is
rapidly converted by a non-enzymatic
process to 6-MP.

16. Pharmacokinetics
• 6-MP undergoes a complex
biotransformation via competing
catabolic enzymes: xanthine oxidase,
thiopurine methyltransferase.
• These enzymes produce inactive
metabolites and anabolic pathways
that produce active thioguanine
nucleotides.

17. Pharmacokinetics
• Azathioprine and 6-MP have a serum half-
life of less than 2 hours.
• The active 6-thioguanine nucleotides are
concentrated in cells resulting in a
prolonged half-life of days.
• The prolonged kinetics of 6-thioguanine
nucleotide results in a median delay of 17
weeks before onset of therapeutic benefit
from orally administered purine analogs.

18. Clinical uses
Purine analogs are important agents in
the induction and maintenance of
remission of IBD.
Most patients with normal thiopurine-S-
methyltransferase (TPMT) activity are
treated with 1-1,5 mg/kg/d of 6-MP and
2-2,5 mg/kg/day of azathioprine.

19. Clinical uses
• After 3-6 months of treatment, 50-
60% of patients with active disease
achieve remission.
• These agents help maintain
remission in up to 80% of patients.
• Purine analogs allow dose reduction
or elimination of GC in most of the
patients.

20. Adverse effects
• Dose-related toxicities of purine
analogs are nausea, vomiting,
bone marrow depression and
hepatic toxicity.
• Bone marrow depression leads
to leukopenia, macrocytosis,
anemia and thrombocytopenia.

21. Adverse effects
• Routine laboratory monitoring of
complete blood count and liver
function tests is required in all
patients.
• Leukopenia and elevations in
liver chemistries usually respond
to medication dose reduction.

22. Adverse effects
Severe leukopenia may
predispose to opportunistic
infections.
Leukopenia may respond to
therapy with granulocyte
stimulating factor.

23. Adverse effects
• Catabolism of 6-MP by TPMT is
low in 11% and absent in 0,3% of
the population.
• In those patients there is increased
production of active 6-thioguanine
metabolites and increased risk of
bone marrow depression.

24. Adverse effects
• TPMT levels can be measured
before initiating therapy.
• These drugs should not be
administered to patients with no
TPMT activity.
• For the patients with intermediate
activity lower doses are needed.

25. Adverse effects
Hypersensitivity reactions to purine
analogs occur in 5% of patients:
• fever
• rash
• pancreatitis
• diarrhea
• hepatitis

26. Adverse effects
• There may be increased risk of
lymphoma in patients taking
purine analogs.
• Although these drugs cross the
placenta, risk of teratogenicity
appears to be small.

27. Drug interactions
Allopurinol markedly reduces xanthine oxide
catabolism of the purine analogs, potentially
increasing active 6-thioguanine nucleotides.
That may lead to severe leukopenia.
Allopurinol should be avoided in patients taking
purine analogs, except in carefully monitored
situations and if necessary.

28. METHOTREXATE (MTX)

29. Pharmacokinetics
• MTX is antimetabolite used in IBD.
• It may be given orally,
subcutaneously or intramuscularly.
• Reported oral bioavailability is 50-
90% at doses used in chronic
inflammatory diseases.

30. Pharmacodynamics
• The principal mechanism of action is
inhibition of dihydrofolate reductase,
an enzyme important in the
production of thymidine and purines.
• At the high doses used for
chemotherapy, MTX inhibits cellular
proliferation.

31. Pharmacodynamics
At low doses used in the treatment of
IBD (12-25 mg/weak), the
antiproliferative effects may not be
evident.
MTX may interfere with the
inflammatory actions of IL-1.

32. Pharmacodynamics
• It may also stimulate increased
release of adenosine, an
endogenous anti-inflammatory
autacoid.
• MTX may also stimulate
apoptosis and death of activated
T lymphocytes.

33. Clinical uses
• MTX is used to induce and
maintain remission in patients
with Crohn´s disease.
• Its efficacy in ulcerative colitis is
uncertain.
• To induce remission, MTX is
given once weekly 15-25 mg sc.

34. Clinical uses
If a satisfactory response
is achieved within 8-12
weeks, the dose is
reduced to 15 mg/wk.

35. Adverse effects
• At higher dosage, MTX may cause
bone marrow depression,
megaloblastic anemia, alopecia and
mucositis.
• At lower doses used in IBD these
side effects are less common.
• Folate supplementation is
recommended.

36. Adverse effects
• In patients with psoriasis treated with
MTX, hepatic damage is common.
• Among patients with IBD and
rheumatoid arthritis, the risk is
significantly lower.
• Renal insufficiency may increase risk
of hepatic accumulation and toxicity.

37. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.
• www.medicinenet.com