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 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 That may lead to severe leukopenia.
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 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.