2. What is CD AND UC?????
CD is a condition of chronic inflammation
potentially involving any location of the GIT
from mouth to anus.
UC is an inflammatory disorder that affects the
rectum and extends proximally to affect variable
extent of the colon.
6. Therapy
Goals of therapy
– Induce and maintain remission.
– Ameliorate symptoms
– Improve patient’s quality of life
– Adequate nutrition
– Prevent complication of both the disease and medication
PRACTICAL CHALLENGES IN DRUG TREATMENT
•How sick is the patient?
•What is the disease distribution?
•Are there complications abscess, fistula, obstuction
•Has the patient had prior surgery for Crohn’s disease?
7.
8. 5-Aminosalicylates
What are the drugs?
• Sulfasalazine Tab 0.5-4g
• Mesalamine
– Pentasa 2 -4g QID
(mesalamine DR tab)
– Asacol 1.6-2.4g tid
(mesalamine DR tab)
– Rowasa – 4 g enema qd
(mesalmine rectal enema)
– Canasa – 1 gram supp QD
(mesalamine rectal supp)
– Lialda – 1.2 gram tablet QD
(Mesalamine DR tab)
• Balsalazide 6.75g Caps
• Osalazine 1g Caps
What are the issues?
• Differ in release characteristics
• Evidence based medicine
greater role in UC than CD
• Sulfasalazine have efficacy in
colonic CD
• Use in mild disease
• Adverse events: worsening of
disease activity, increased
serum creatinine, pancreatitis,
allergic reaction (rash).
9. Mechanism Of Action
Arachidonic Acid
5-Lipoxygenase
X
Cyclo-oxygenase
X
SULFASALAZI
NE
MESALAMINE
Leukotrienes
Prostaglandins
Inflammation
10. 5-amino salicylic acid(5-ASA)
The mainstay treatment of mild to moderately
active UC and CD (induction).
5-ASA may act by
blocking the production of prostaglandins and
leukotrienes,
inhibiting bacterial peptide–induced neutrophil
chemotaxis and adenosine-induced secretion,
scavenging reactive oxygen metabolites
11. 5-amino salicylic acid
For patients with distal colonic disease, a
suppository or enema form will be most
appropriate.
Maintenance treatment with a 5aminosalicylic acid can be effective for
sustaining remission in ulcerative colitis but is
of questionable value in Crohn's disease.
15. Blood disorders
• Agranulocytosis; aplastic anaemia; leucopenia;
neutropenia; thrombocytopenia;
methaemoglobinemia
• Patients should advised to report any unexplained
bleeding; bruising; purpura; sore throat; fever or
malaise
16. Contraindications
/cautions
• 5-ASA
- Salicylate hypersensitivity
• Sulfapyridine + 5-ASA = Sulfasalazine(cleaved in
colon by colonic bacteria)
- G6PD deficiency (haemolysis)
- Slow acetylator status (↑ risk of hepatic and blood
disorders)
17. Steroids
The National Cooperative Crohn’s Disease
Study and The European Co-operative Crohn’s
Disease Study demonstrated that steroids are
efficacious-inducing remission
ineffective- maintaining remission
DRUGS:
Prednisolone oral/ enema
Hydrocortisone iv
Budesonide (poorly absorbed – used for
iliocaecal CD/ UC)
18. Budesonide in Crohn’s Disease
Budesonide vs. Mesalamine
Patients in remission
Budesonide - Entocort
• 3 mg capsules P/O BD
• 9mg capsules P/O qd
• Ileal release based on pH
dependent mechanism
• Steroid with rapid 1st pass
metabolism less systemic
effects
Thomsen et al 339 (6): 370
19. • Indicated in mild to moderate ileal Crohn’s disease
• Prescribing information for 9 week course of
therapy – 3 weeks at each dose 9 mg, 6 mg, 3 mg
• Can be used as a long term drug therapy in some
patients
• bone density- needs a check!!
20. Steroids and IBD
•
•
•
•
•
Role
important role in the
management of acute disease
No maintenance role in either
UC or CD
Oral prednisone or prednisolone
is used for moderately severe
UC or CD, in doses ranging up to
60 mg per day.
For acute disease 40 mg/day x 3
weeks then start taper at 5 mg q
1-2 weeks
IV steroids for hospitalized,
severely ill patient.
Side effects
• Osteoporosis
• Cataracts
• Poor tissue healing
• Increased complications
• Infections
21.
22. IMMUNOSUPPRESSIVES
• These agents are generally appropriate for patients in whom
the dose of corticosteroids cannot be tapered or
discontinued.
• Azathioprine & 6-MP
– The most extensively used immunosuppressive agents.
– The mechanisms of action unknown but may include
• suppressing the generation of a specific subgroup of T
cells.
– The onset of benefit takes several weeks up to six months.
– Dose-related BM suppression is uniformly observed
23. CONTD..
• Methotrexate
– Effective in steroid-dependent active CD and in
maintaining remission.
• Cyclosporine
– Severe UC not responding to IV steroid &need
urgent proctocolectomy.
– 50% of the responders will need surgery within a
year.
24. Azathioprine/6MP in IBD
Efficacy/Issues
• Effective in 50 – 70% of
patients with IBD
• 30% failure due to
intolerance (15%) or no
response (15%)
• Metabolism issues TPMT
• Uses
– Steroid sparing
– Post operative
prophylaxis
Intolerance/Risks
• Bone marrow suppression
• Pancreatitis
• Hepatotoxicity
• Nausea
• Myalgias – flu like
symptoms
• Other Risks
– Lymphoma – 4 fold
– Infection
27. Ciclosporin
• Indicated in Severe UC
• No value in CD
• MOA:inhibitor of calcineurin preventing clonal
expansion of T cells
• S/E dose dependent
nephrotoxicityhepatotoxicity;hypertension;
hypertrichosis; gingival hypertrophy etc.
• Need to monitor BP; FBC/ RF and levels
28. Methotrexate
• Inducing remission/preventing relapse in CD
(Unlicensed indication)
• Refractory to or intolerant of Azathioprine
• MOA: inhibitor of dihyrofolate reductase; antiinflammatory
• S/E: myelosupression*;mucositis;GI; hepatotoxicity;
pneumonitis
• Co-administration of folinic acid reduces
myelosupression;mucositis
29. Methotrexate
• Immunomodulatory vs. Immunosuppressant
• Active both in induction and maintenance of remission
• 25 mg sc/week x 16 weeks then dosage reduce to 15 mg
sc/week
• Refractory to or intolerant of Azathioprine
• MOA: inhibitor of dihyrofolate reductase; antiinflammatory
• S/E: myelosupression*;mucositis;hepatotoxicity;
pneumonitis
• Co-administration of folinic acid reduces
myelosupression;mucositis
• Monitor LFTs, CBC
30. Metronidazole -Spectrum of activity
E. histolytica
Trichomonas vaginalis
Giardia lambia
Anaerobes : Gm+ve & Gm-ve
Bacteroides fragilis, other species
Clostridium
Fusobacterium
Peptococcus
Peptostreptococcus
Eubacterium
Helicobacter
31. Metronidazole - Mechanism of action
I t is a prodrug activated by the
susceptible microorganisms to a highly
reactive nitro radical anion that target
the DNA and other molecules.
Development of resistance limited.
32.
33. Adverse effects of Methotrexate
Serious Adverse Events
• Hepatotoxicity
• Hypersensitivity
pneumonitis
• Myelosuppression
• Birth defects in offspring
Common Adverse Events
• Nausea and vomiting
(42%)
• Diarrhea(7%)
• Headache
(17%)
• Abdominal pain
(18%)
• Joint pain
(16%)
• Elevated AST, ALT
• Stomatitis
36. How do they differ?
• Route of administration
– Infliximab IV
– Certilizumab and Adalimumab: SC
– Natalizumab iv infusions
• Amount of Mouse protein
37. INFLIXIMAB
• Potent anti-inflammatory
• Indicated active and fistulating CD
- in severe CD refractory or intolerant
of steroids & immunosupressants
- for whom surgery is inappropriate
• MOA: anti-TNF monoclonal antibody
• S/E: infusion reactions/anaphylaxis- COMMON
• infection (TB reactivation; overwhelming sepsis) ????
malignancy
38. Anti-TNF therapy
• Infliximab (infusion)
▫ Induction
▫ Maintenance
5mg/kg IV at weeks 0, 2 and 6
5mg/k IV at 8 weeks
• Cetolizumab pegol ( SC , nurse administered)
▫ Loading dose
▫ Maintenance
400 mg sc at weeks 0, 2 and 4
400 mg sc at 4 weeks
• Adalimumab ( SC, prefilled syringe)
▫ Loading dose
▫ Maintenance
160 mg at week 0, 80 mg at week 2
40 mg sc EOW or weekly
39. According to AAFP Guidelines:
• patients with Crohn's disease need vitamin and mineral
supplementation.
• vitamin B12, folic acid, fat soluable vitamins, and calcium
should be considered, and periodic checks may be
necessary.
• Osteopenia and osteoporosis are potential complications of
Crohn's disease, often aggravated by chronic steroid use.
• Despite expanding evidence of the carcinogenic potential
of longstanding Crohn's disease. Colonoscopic monitoring
10 years after the onset of disease is recommended, the
frequency of which depends on the extent of colonic
disease.
• Research suggests that supplemental folate may have a
protective effect against colon cancer.
43. Treatment of UC
CHALLENGES!!
•Induction vs. Maintenance
•Left-sided vs. pan-colonic
•Fulminate disease
•Steroid dependent disease
•Chemoprevention of colon cancer
44. What do we know?
•
•
•
•
•
•
•
5-Aminosalicylates
Steroids
Immunomodulators
Anti-TNF
Antibiotics
Probiotics
Nicotine
45.
46.
47. Surgical Therapy
There are four surgical
options in patients with
UC:
1)Total proctocolectomy
and ileostomy
2) total procto-colectomy
with continent ileostomy
(Koch pouch)
3) total procto-colectomy
with ileal pouch-anal
anastomosis (IPAA)
4) colectomy with
ileorectal anastomosis
THE SOCIETY FOR SURGERY OF ALIMENTARYT TRACT
48. REFERENCES
•
•
•
•
•
•
•
•
•
•
•
http://www.gastro.theclinics.com/article/S0889-8553(12)00005-2/pdf
Management of Crohn’s disease-A practical Approach; American Family
Physician; volume 68; Number 4; August 15,2003
Ulcerative Colitis- Diagnosis and Treatment; AAFP 2007 Annual Clinical
Focus On Management Of Chronic illness; pg 1331
British Society Of Paediatric and Gastroenterology and Hepatology And
Nutrition
GUT, 2002 october, 51(4):616
Journal Of Clinical Gastroenterology ,August 22,2012
En.wikipedia/wiki/crohns disease.html
En.wikipedia/wiki/ulcerative colitis.html
Gastroenterology clinics, elsevier
Disease Of Colon And Rectum; Wolter & Kluwers
CMDT; 2010
Editor's Notes
As mentioned earlier, the majority of 6-MP is lost to first pass metabolism, largely via xanthine oxidase, producing 6-thiouric acid (6-TU), an inactive metabolite. The 6-MP that escapes this pathway crosses cell membranes, and the remainder of its metabolism then takes place intracellularly.
Once intracellular, there are two competing routes of metabolism that reveal the reasons for therapeutic successes as well as failures.
One route of metabolism is via HPRT (hypoxanthine phosphoribosyl transferase), considered an anabolic enzyme. This metabolic route eventually produces 6-thioguanine nucleotides (6-TG). These 6-TG nucleotides are incorporated into the DNA of cells and interfere with cell replication and production of messenger RNA and DNA. This results in interference with cell proliferation and the ability of the cells to have normal metabolic function, including cytokine production.
The competing route is via TPMT (thiopurine methytransferase) enzyme (shown on bottom). This enzyme produces 6-methylmercaptopurine ribonucleotides (6-MMP). This is a catabolic pathway that results in an end product that has much less impact on the response to therapeutic use of AZA or 6-MP. However, 6-MMP can interfere with purine synthesis.
Methotrexate has a number of disadvantages in the treatment of CD. Of particular concern are the risks of hepatic and pulmonary toxicity, myelosuppression, and birth defects in offspring.66 Common AEs associated with methotrexate therapy are seen frequently during induction therapy. The significance of sustained elevated aminotransferases and their contribution to liver disease is not known. Myelosuppression should be monitored with periodic blood counts.
