IBD Flashcards
What are the major forms of IBD?
Ulcerative Colitis
Crohn’s Disease
Indeterminate colitis - incomplete distinction between the two
How do CD and UC differ in terms of pathology?
CD:
- Th1-mediated
- All gut layers
- Any part of GIT
- Patchy inflamed areas
- Abcesses/fissures/fistulae common
UC:
- Th2-mediated
- Mucosa/submucosa
- rectum, spreads proximally
- Continuous inflamed areas
- Abcesses/fissures/fistulae uncommon
What are the major classes of drugs used to reduce inflammation and maintain remission IBD?
- Glucocorticoids - prednisolone
- Aminosalicylates - mesalazine
Immunosuppressives - azathioprine
How do aminosalicylates work to treat IBD?
- Inhibition of IL-1, TNFa, PAF (reduce inflamm mediators)
- Decreased antibody secretion
- Non-specific cytokine inhibition
- Reduced macrophage migration
- Localised inhibition of IR
How do CD and UC differ in terms of responsiveness to surgery?
CD: surgery not always curative
UC: surgery is curative
Are aminosalicylates more effective in UC or CD? Why is this unexpected?
- More effective in UC
- Odd because seem to target Th1 mechanisms (e.g. TNFa) but UC is mainly governed by Th2 system
How do CD and UC differ in terms of responsiveness to treatment?
UC - aminosalicylates 1st line induce + maintain remission
CD: glucocorticoids induce + maintain remission but SEs, aminosalicylates may help maintain surgically-induced remission
What are the 3 main categories of treatment for IBD?
- Supportive therapies
- Treatments to reduce inflammation and maintain remission
- Biologic therapies
What are the side effects of glucocorticoids?
- Osteoporosis
- Increased risk of gastric ulceration
- Suppression of HPA axis
- Type II diabetes
- Hypertension
- Susceptibility to infection
- Skin thinning, bruising and slow wound healing
- Muscle wasting and buffalo hump
How do glucocorticoids help treat IBD?
- Anti-inflammatory drugs
- Activate intracellular GC receptors
- Activated receptors act as positive TFs –> increase expression of anti-inflammatory genes
- Or, more frequently, negative TFs –> reduce expression of pro-inflammatory genes
- Act on many cell types and have powerful anti-inflammatory actions: reduce influx and activation of pro-inflammatory cells; reduce production of mediators which cause vasodilation, fluid exudation (swelling), further inflammatory cell recruitment and tissue degradation
- ALSO potent immunosuppressive drugs –> reduce antigen presentation, cell proliferation and clonal expansion
Why are aminosalicylates safer to use chronically for maintenance of remission?
- Have fewer anti-inflammatory actions than GCs
- No immunosuppressive effects
What modifications can be made to mesalazine (5-aminosalicylic acid) to target the drugs to different parts of the GIT?
- Olsalazine = 2 linked 5-ASA moieties
- Activated by gut flora in colon
- Tf only works in colon - highest conc here
- If disease is worst in colon, use olsalazine
How can immunosuppressive agents be used to treat IBD?
E.g. Azathioprine
- Mainly to maintain remission in CD
- Pro-drug activated by gut flora to its active component 6-mercaptopurine
- Purine analogue that interferes w/purine biosynthesis and hence w/DNA synthesis
- Impairs cell- and antibody-mediated IRs, mononuclear cell infiltration, lymphocyte proliferation and antibody synthesis, whilst enhancing T cell apoptosis
What are the side effects of azathioprine?
10% have to stop treatment bc of SEs:
- Pancreatitis
- Bone marrow suppression
- Hepatotoxicity
- Increased risk of lymphoma and skin cancer
Why should azathioprine not be co-administered w/allopurinol?
- Azathioprine is metabolised by enzyme xanthine oxidase
- Allopurinol is used for treatment of gout, which works by inhibiting this enzyme
- Tf azathioprine would be shunted through other metabolic pathways that produce hepatotoxic metabolites or metabolites that cause myelosuppression
