immunomodulator drug use for inflammatory bowel disease

1. practical management of inflammatory
bowel
disease patients taking
immunomodulators
1

2. Comprised of two major disorders:
Ulcerative Colitis (UC)
Crohn’s Disease (CD)
2

3. • Ulcerative colitis is a disease that causes ulcers in the lining of
the rectum and colon. It is one of a group of diseases called
inflammatory bowel disease. Ulcers form where inflammation
has killed the cells that usually line the colon.
• Ulcerative colitis can happen at any age, but it usually starts
between the ages of 15 and 30. It tends to run in families.
Ulcerative Colitis Symptoms :
• Bloody diarrhea
• Symptoms of rectal urgency and tenesmus
• Weight loss
• rectal pain
Some patients with Ulcerative Colitis also develop symptoms
outside of the gastrointestinal tract; these symptoms include:
• Osteoporosis
• Oral ulcerations
• Arthritis
3

4. • Crohn's disease causes inflammation of the
digestive system. It is one of a group of diseases
called inflammatory bowel disease. The disease
can affect any area from the mouth to the anus. It
often affects the lower part of the small intestine
called the ileum.
• Crohn's disease seems to run in some families. It
can occur in people of all age groups but is most
often diagnosed in young adults.
4

5. Common symptoms of Crohn's disease:
• abdominal pain
• diarrhoea
• weight loss
Less common symptoms include:
• poor appetite
• fever, night sweats
• rectal pain/rectal bleeding
Some patients with Crohn's disease also develop symptoms outside of the
gastrointestinal tract; these symptoms include:
• arthritis
• skin rash
• inflammation of the iris of the eye.
5

6. 1-Azathioprine and Mercptopurine
2-Ciclosporin
3-Methotrexate
4-Tacrolimus
6

7. Introduction :
•The purine analogues azathioprine and mercaptopurine are
effective in inducing and maintaining remission in patients with
ulcerative colitis and Crohn’s disease.
•Azathioprine is a prodrug which is converted to mercaptopurine
and then metabolised to the active metabolite 6-thioguanine.
thioguanine has been used for treatment of IBD, but caution is
appropriate because of potential hepatotoxicity.
•Thiopurine Methyl Transferase (TPMT) converts mercaptopurine to
6-methyl-mercaptopurine. When TPMT levels are low, higher levels
of 6-thioguanine are produced and this is associated with a greater
risk of myelosuppression.
•The onset of action of these drugs is very variable and in many
patients, the beneficial effects may not be seen for 3 – 4 months,
and in some cases even longer.
7

8. azthioprine given in doses between 2–2.5 mg/kg/day and 6-MP
of 1–1.5 mg/kg/day in both UC and CD.
Monitoring therapy
Measurement of full blood count and liver function tests are
advisable before and within 4 weeks of starting therapy, then
monthly.
Direct Toxicity :
Pancreatitis; bone marrow suppression; allergic reactions including
nausea, swinging fevers); drug induced hepatitis
Indirect toxicity :
Infections – bacterial and viral (including herpes zoster and
simplex, Epstein Barr virus (EBV); Cytomegalovirus (CMV).
8

9. • Nausea / vomiting and loss of appetite
• Abdominal pain – should this develop, the drug
should be stopped immediately
• Hair loss
• Adverse effects on the blood
• Fever, weakness and fatigue (rare)
• Unusual bleeding / bruising (rare)
• Jaundice (rare)
• Rashes (rare)
9

10. Introduction :
• The main role for ciclosporin is in the treatment of patients with severe steroid
refractory Ulcerative Colitis.
• Response rates are improved by the addition of azathioprine or
Mercaptopurine2,3, and ciclosporin can be used as a bridge for maintenance
therapy having a slow onset of action.
• Ciclosporin is of little benefit in Crohn’s disease and should be avoided
Mechanism of Action:
Ciclosporin (CsA) is an inhibitor of calcineurin, preventing clonal
expansion of T-cell subsets.
it has effective in the management of severe UC.
10

11. Ciclosporin may be given either intravenously (2mg/kg/day) or orally in
a microemusion formula (Neoral) in doses between 4.6 – 7.5 mg kg/day.
Cautions :
1.Uncontrolled hypertension
2.Use of potassium sparing diuretics
3.Pregnancy and lactation
4.Grape fruit juice – to be avoided within one hour of ingestion
5.Drug interactions
Agents likely to increase Ciclopsorin levels such as:
1-Calcium channel blockers(Diltiazem, Verapamil, -Nifedipine, Amlodipine)
2-Grapefruit juice
3-Tacrolimus
4-Oral contraceptives(Danazol)
11

12. 1.Uncontrolled hypertension
2.Renal and liver failure
3.Severe electrolyte disturbance i.e. hyperkalaemia
Side effect
Nephrotoxicity, hemolytic–uremic syndrome, hypertension,
neurotoxicity, gum hyperplasia, skin changes, hirsutism, post-
transplantation diabetes mellitus, hyperlipidemia; trough
monitoring or checking levels two hours after administration
required
12

13. Introduction :
Methotrexate is an immunomodulator used to induce
and maintain remission of Crohn’s disease and
Ulcerative colitis in patients who have steroid
dependent or refractory disease, or who have been
intolerant of either azathioprine or 6-Mercaptopurine.
Methotrexate inhibits the enzyme dihydrofolate
reductase, essential for the synthesis of purines and
pyrimidines. Although unlicensed to treat inflammatory
bowel disease, methotrexate is widely used in Crohn’s
disease (BNF section 1.5) and less commonly in
ulcerative colitis.
13

14. • Much of the evidence for the beneficial effects for
methotrexate has been with the intramuscular route of
administration. The evidence for the efficacy and
bioavailability of oral methotrexate is limited in Crohn’s
disease.
• Intramuscular route : 25mg once per week for up to 16
weeks, then reduced to 15mg once a week.
• Oral route : Intially 15mg once per week as a single dose,
increasing to 20mg once per week after 2 weeks and up to
a maximum of 25mg once a week after a further 2 weeks
as tolerated and according to response.
Cautions :
•Patients with clinically significant renal impairament from any cause
•Localised or systemic infection including hepatitis B & C and past history
of TB
•Unexplained anaemia or cytopenia associated with bone marrow failure
14

15. • Phenytoin, Co-trimoxazole, Trimethoprim – the antifolate effect of
methotrexate is increased
• Probenacid, Penicillin, Azapropazone, NSAID’s – Methotrexate
excretion is reduced (but a clinically significant interaction between
methotrexate and NSAID’s is rare
• Tolbutamide – serum concentrations of methotrexate may be
increased
Side effects:
1. Early toxicity from methotrexate is primarily gastrointestinal
(nausea, vomiting, diarrhoea, and stomatitis)
2. Other rare side effects include : headache; acne; skin irritation;
dry cough and / or shortness of breath.
Folic acid treatment :
Folic acid reduces the toxicity of methotrexate treatment and improves
continuation of therapy and compliance. Folic acid should be taken
ONCE weekly, but SHOULD NOT be taken on the same day as the
methotrexate.
15

16. Introduction :
Tacrolimus has been used to suppress the inflammation associated with
ulcerative colitis, Tacrolimus has shown to be significantly effective in the
suppression of outbreaks of UC.
Tacrolimus has similar actions to those of cyclosporine,but Tacrolimus is more
potent than cyclosporine.
Mechanism of Action:
*Tacrolimus binds to FK-binding protein,inhibiting cacineurin, a cytoplasmic
phosphatase.
*Calineurin regulates the ability of the nuclear factor of activated T cells to
translocate the nucleus and increase the production of cytokines.
*by this way,tacrolimus in hibit the synthesis of cytokines that
Normaly occur in response to T cell activation
16

17. *administrated orally or intravenously.Dosing should be 0.1-
0.2mg/kg/day if given orally or 0.01-0.02 mg/kg/day if given IV.
*oral absorption is in complete
*absorption is decrease if drug is taken with high fat or high
carbohydrate meals.
*highly bound to serum protein.
*metabolized in the liver by CYTP3A4.
*most of the drug and its metabolites are found in the feces
renal excretion is very low.
Drug-Drug Ineraction:
*anti-bacterial drugs.e.g.erythromycin
*anti-viral drugs
*calcium channels blockers.e.g.nifedipine
*danazole
*all these drugs increase the level of tacrolimus
17

18.  Nephrotoxicity
 Neurotoxicity-Tremor, headache, motor disturbances,
seizures
 Hypertension
 Hyperglycemia
 Risk of tumors, infections
 itching, insomnia, confusion, loss of appetite, weakness,
depression and cramps
18

19.  6-mercaptopurine and azathioprine are cornerstones in the
long-term management of Crohn’s disease and ulcerative
colitis. Methotrexate is an effective 2nd lineagent in Crohn’s
disease. Trends in early aggressivemanagement and “top-
down” therapy are bringing these medications to patients at an
earlier point in their disease. Safe and effective use of
immunomodulators is imperative to optimize the risk/benefit
profile.
 one third of patients treated with long term tacrolimus required
surgery. Although a proportion responded to tacrolimus therapy,
the majority of patients ultimately required alternative
therapies.
 Cyclosporin is a narrow therapeutic index drug whose high
pharmacokinetic variability markedly influences clinical
outcomes The first 4 hours post-dose are the period of highest
inter-subject pharmacokinetic variability and greatest
pharmacodynamic effects
19

20. 20

21. 1- Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002; 347: 417-29.
2-Siegel CA, Sands BE. Review article : practical management of inflammatory bowel disease
patients taking immunomodulators. Aliment. Pharmacol. Ther. 2005; 22 : 1-16
3-Pearson DC, May GR. Fick OH. Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn's
disease. A meta-analysis. Ann Intern Med 1995; 123: 132-42.
4-de Jong DJ, Goullet M, Naber TH. Side effects of azathioprine in patients with Crohn's
disease. Eur J Gastroenterot Hepatol 2004: 16: 207-12.
5-Dubinsky MC. Azathioprine, 6-mercaptopurine in inflammatory bowel disease:
pharmacology, efficacy, and safety. Clin Gastroenterol Hepatol 2004;2:731.
6-Hawthorne AB. Ciclosporin and refractory colitis. Eur J Gastroenterol Hepatol 2003;15:239–
44.
7-Nathan DM, Iser JH, Gibson PR. A single center experience of methotrexate in the treatment
of Crohn’s disease and ulcerative colitis: A case for subcutaneous administration. J
Gastroenterol Hepatol 2007 Jun 7 [epub ahead of print].
8-Sternthal M, George J, Kornbluth A, et al. Toxicity associated with the use of cyclosporin in
patients with inflammatory bowel disease (IBD). Gastroenterology 1996;110:A1019.
9-Sandborn WJ, Present DH, Isaacs KL, et al. Tacrolimus for the treatment of fistulas in
patients with Crohn’s disease: a randomized, placebo-controlled trial. Gastroenterology
2003;125:380.
21