DRUG TREATMENT OF INFLAMMATORY BOWEL DISEASE
Dec 23, 2015
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 corticosteroids
Acute maintenance 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
Sulfasalazine Mesalamine
Olsalazine
Aminosalicylates
Sulfasalazine Mesalamine
Olsalazine
Aminosalicylates
Sulphasalazine Broken down by gut bacterial azoreductase to 5-
aminosalicylate & sulphapyridine
SULFASALAZINE
Bacterial Flora (Colon)
Bacterial azoreductase
Sulfapyridine 5-aminosalicylic Acid
Absorbed Acts through the lumen
Systemic Adverse Effect Anti-inflammatory Effect
Aminosalicylates
5-ASA absorbed in small intestine
Acetylated by N- acetyltransferase-1
Excreted in urine
Indications Maintaining remission in UC
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 Mesalazine (5-ASA)
Balsalazide (a prodrug of 5-ASA)
Olsalazine (5-ASA dimer)
Mesalazine Available as
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
Sulfasalazine Oral use
Mesalamine (5-aminosalicylic acid). Oral delayed release capsules Enema
Olsalazine. 5-ASA-n=n-5-ASA Bacterial flora breaks it into 5-ASA
Aminosalicylates
Anti-inflammatory &Immunosuppressive Drugs
Corticosteroids
Prednisolone
Hydrocortisone
Corticosteroids
USES Remission Induction
Route of Administration
Oral
Intravenous
Topical (Enema)
Indications Moderate to severe relapse UC & CD
No role in maintenance therapy
Combination oral and rectal
Indications
Immunomodulators
Azathioprine
Cyclosporine
Infliximab (Anti-TNF-)
Thiopurines
Azathioprine
MOA: inhibit ribonucleotide synthesis; induce T cell apoptosis by modulating cell (Rac1) signalling
Indications Steroid sparing agents
Active disease CD/UC
Maintenance of remission CD/UC
Generally continue treatment x 3-4years
Ciclosporin MOA:inhibitor of calcineurin
preventing clonal expansion of T cells
Indicated in Severe UC
No value in CD
Methotrexate MOA: inhibitor of dihyrofolate reductase;
anti-inflammatory
Inducing remission/preventing relapse in CD
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
Potent anti-inflammatory
Antibiotics Metronidazole Ciprofloxacin Clarithromycin
“Probiotics” (administration of “healthy” bacteria)
Summary
Drugs for IBD Aminosalicylates Glucocorticoids Immunosuppressives Cytokine modulators Antibiotics
Management of UC
to induce remission
1. oral +- topical 5-ASA
2. +- oral corticosteroids
3. Azathioprine
4. 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)