Transcript DRUG TREATMENT OF INFLAMMATORY BOWEL DISEASE

DRUG TREATMENT OF
INFLAMMATORY BOWEL
DISEASE
Objectives

Describe the mechanism of action,
pharmacokinetics and adverse effects
of drugs in IBD
INFLAMMATORY BOWEL DISEASE

Ulcerative Colitis

Crohn’s disease
Inflammatory bowel disease

Inappropriate inflammatory response to
intestinal microbes in a genetically
susceptible host
Ulcerative colitis
- diffuse mucosal
inflammation
- limited to colon
- defined by location
(eg
proctitis;pancolitis)
Crohn’s disease
- patchy transmural
inflammation
- fistulae, strictures
- any part of GI tract
AIMS OF THERAPY

Suppress inflammatory response

Suppress the immune reaction


Aminosalicylates
Acute
maintenance
corticosteroids
acute
Aminosalicylates
•
precise MOA unknown
•
act on epithelial cells
•
anti-inflammatory
•
modulate release of cytokines and reactive
oxygen species
Aminosalicylates

Local effect on mucosa in reducing inflammation
Aminosalicylates
Sulfasalazine
Mesalamine
Olsalazine
Aminosalicylates
Sulfasalazine
Mesalamine
Olsalazine
Sulphasalazine

Broken down by gut bacterial azoreductase to 5aminosalicylate & sulphapyridine
SULFASALAZINE
Bacterial Flora Bacterial azoreductase
(Colon)
Sulfapyridine
Absorbed
Systemic Adverse Effect
5-aminosalicylic Acid
Acts through the lumen
Anti-inflammatory Effect
Aminosalicylates

5-ASA absorbed in small intestine

Acetylated by N- acetyltransferase-1

Excreted in urine
Indications

Maintaining remission in UC
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Reduce risk of colorectal cancer by 75%
(long term Rx for extensive disease)

Less effective for maintenance in CD

Inducing remission in mild UC/CD (higher
doses)
Contraindications
/cautions


5-ASA
- Salicylate hypersensitivity
Sulfapyridine
- G6PD deficiency (haemolysis)
- Slow acetylator status ( risk of
hepatic and blood disorders)
Adverse effects

Dose-related

Idiosyncratic (rare)
- blood disorders
- skin reactions – lupus like syndrome;
Stevens-Johnson syndrome; alopecia
Blood disorders

Agranulocytosis; aplastic anaemia;
leucopenia; neutropenia;
thrombocytopenia; methaemoglobinemia

Patients should advised to report any
unexplained bleeding; bruising; purpura;
sore throat; fever or malaise
Steven’s Johnson syndrome



immune-complex–
mediated
hypersensitivity
erythema
multiforme
target lesions,
mucosal
involvement
Newer formulations
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Mesalazine (5-ASA)
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Balsalazide (a prodrug of 5-ASA)
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Olsalazine (5-ASA dimer)
Mesalazine
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Available as



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Enteric-coated tablets (for ileal Crohn’s disease)
Slow release tablets (for proximal bowel Crohn’s)
Enemas, suppositories (for distal colonic disease)
Used when sulphasalazine can not be
tolerated
Aminosalicylates
Sulfasalazine
 Oral use
Mesalamine (5-aminosalicylic acid).


Oral delayed release capsules
Enema
Olsalazine.

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5-ASA-n=n-5-ASA
Bacterial flora breaks it into 5-ASA
Anti-inflammatory &
Immunosuppressive Drugs
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Corticosteroids
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Prednisolone

Hydrocortisone
Corticosteroids
USES

Remission Induction

Route of Administration
Oral
Intravenous
Topical (Enema)
Indications
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Moderate to severe relapse UC & CD
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No role in maintenance therapy
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Combination oral and rectal
Immunomodulators
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Azathioprine
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Cyclosporine
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Infliximab (Anti-TNF-)
Thiopurines
Azathioprine

MOA: inhibit ribonucleotide synthesis;
induce T cell apoptosis by modulating
cell (Rac1) signalling
Indications
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Steroid sparing agents
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Active disease CD/UC
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Maintenance of remission CD/UC
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Generally continue treatment x 3-4years
Ciclosporin

MOA:inhibitor of calcineurin
preventing clonal expansion of T
cells
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Indicated in Severe UC
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No value in CD
Methotrexate

MOA: inhibitor of dihyrofolate reductase;
anti-inflammatory

Inducing remission/preventing relapse
in CD
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Refractory to or intolerant of
Azathioprine
Infliximab

Indicated active and fistulating CD
- in severe CD refractory or intolerant
of steroids & immunosupressants
- for whom surgery is inappropriate

MOA: anti-TNF monoclonal antibody
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Potent anti-inflammatory
Antibiotics
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Metronidazole
Ciprofloxacin
Clarithromycin
“Probiotics” (administration of “healthy”
bacteria)
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Summary
Drugs for IBD
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Aminosalicylates
Glucocorticoids
Immunosuppressives
Cytokine modulators
Antibiotics
Management of UC
to induce remission
1.
2.
3.
4.
oral +- topical 5-ASA
+- oral corticosteroids
Azathioprine
iv steroids/Colectomy/ ciclosporin
(severe)
Maintaining remission
1.
oral +- topical 5-ASA
2.
+- Azathioprine (frequent relapses)
Management of CD
to induce remission
1.
oral high dose of 5-ASA
1.
+- oral corticosteroids reducing over 8/52
2.
Azathioprine
3.
iv steroids/ metronidazole/elemental
diet/surgery/infliximab
Maintaining remission
+- Azathioprine (frequent relapses)
Methotrexate (intolerant of
azathioprine)
Infliximab infusions (8 weekly)