IBD Flashcards
What are the 2 major forms of IDB?
Ulcerative colitis
Crohns disease
sometimes hard to distinguish
much higher in the west
Are there genetic factors to IBD? envirnemental?
Not fully understood
but LOT of genetic loci that predisposes (like 200)
causes by so many cells together
environemental-strong links to diet, medication and smoking
Microbiome unsure-but could be the effector of the rest (which came first)
Describe the mechanism of IBD?
AID-Defective interaction between mucosal immune system and gut flora interaction
10x gut microbiome than host cell normally-harmonious
Disrupted innate immunity and clearance-> pro-inflammatory rrsponse-> physical damage and chornic inflammation
less mucus, higher pathogens in the gut, less anti-inflammaotory bacteria
How do UC and Crohns differ in term of autoimmune disorder and what it affects
Crohns-Th1 mediated, TNFa-florid T cell expansion and T cell apoptosis reduced
Causes more damage-can affect all layers of gut (not just mucosae)-
Can affect every part of the gut-and can be patchy-one part healthy, one part not-cant always be cured by surgery
UC-Th2 mediated, IL13-normal T cells-affects mucosa
Usually rectum and spreads proximally (spreads up), and continuous-surgery curative
What are the clinical features of IBD?
Abdopain, cramping,
Diarrhoae, bloody faeces, mouth ulcers
systemic-aneamia, fever, arthiritic pain, skin rashes, uveititis, weight loss –more features of Crohns
What are the 4 groups of therapies for IBD?
Supportive-fluids,
Symtpomatic in active
Symptomatic prevent remission
Potentially curative
What are the supportive therapies for IBD?
For severe acute patients-if large diarrhoae-need support: fluid, electrolytes, even blood if aneamia
What are the symptomatic drugs available in active IBD?
Aminosalycytlates-mesalazine
Glucocorticosteroids-prednisoline
Immunosuppresives-azathioprine
Describe strucrure, action and role of Aminosalicylates
Mesalazine or 5ASA (active part)–anti inflammatory
Olsalazine 25ASA together-metablosed into 5ASA in colon by gut flora-reach target
Binds to PPAR receptors and downregulates pro-inflammatory molecule-like TNFa, IL6 (from NFKB). also down regulates COX2-down pro-inflam prostaglandins
Very good in induction and maintainance remission in UC
Pretty safe
If confined to rectum-rectal delivery
Probably better than steroids
BUT not very effective in inducing remission of Crohns, and midly okay for maintaining remission
What are the role of glucocortticoids in IBD?
Prednisoline, fluticasone (not absorbed and stayed in gut), budosenide-topical
Powerful anti-inflam+anti immune system
Bind steroid receptor in cell and modulate transcription-downregulate TNFa/IL1B
also down regulate actions of macriphages and T cells
SYstemically-will cause many side effects-like osteoporosis, upsetting electrolyte balance,etc
budosenide safer than prednistolone, but predni better at inducing remission
UC-aminosalycytates are better
Crohns-Drug of choice to induce remission-but avoid as maintainance therapy
Describe strucrure, action and role of Immunosuppresives-azathioprine
prodrug-activated by gut flora to 6mercatopurine
act as purine like -interferes with DNA synthesis and cell replication
Impairs cell and AB mediated response, down proliferation
also upregulates T cell apoptosis
only used for Crohns really-also bad for inducing remission (needs several month for effects)-much better at maintaining remission
Slow onset
at that point kinda last option before biological evidence
side effects-pancreatitis, bone marrow supression, hepatotoxicity, increased cancer risk–some of the metabolites cause the effects (want 6MeMPN, can be 6TGN-myelosupression)
also cant be used wih allopurinol because it inhbits inactivation
How can we reduce side effects of any of the IDB drugs?
Administer topically-fluid/foam enemas or suppositories
Lower dose with combination of other drug
Oral drug with high hepatic first passs metabolism-not escaping to system-burosemide
target better-with packaging ususally-pH dependent package (doesnt dregrade in stomach), time dependent , omsotic (has a push filling-as reach more aqueus intestine, water moves in and push drug out), and prodrugs
=> can be combines too-combine time and polymer
What are the potentially currative therapies for IDB?
Either-manipulation of microbiome
Or biolical therapies-anti TNFa, and other
What are the 4 manipulation of the microbiome therapies to treat IBD?
Several option
1)-eclusive enteral nutrition-liquid diet-allows resting of mucosa and recovery of the flora
But unpalatable and hard to maintiain
Good way to induce remission if steroids not usable
2) Probiotic thearpies-no evidence really (tiny in UC)-but unlikely to do harm :) -mainly because so many organism hard to find the right one
3) -feacal microbiota replacement/transplant-put poo in people by putting healthy stuff- trials have shown positive action-but unsure still
4) antibiotic treatment-Rifaximin-interferes with bacteria RNA poymerase
strong Experimental benefit in IDB-
not absorbed by gut-maybe microbiome modulator
weak clinical evidence-only use if specifically infection+IBD
What are the biological therapies to treat IBD?
Mainly; Anti TNFa -infliximab-only used in Crohns
other effective AB-all vary bweteen side effect/effectivness
Acts on TNFa in solute or on cell membrane-stops binding to receptor-break cascade
Reduce inflam, induce cytolosis that express lot of TNFa
Promotes apoptosis of T cells
Downside: has to be given IV
Long half life but most patient relapse after 8-12 months-not long term
Only 60% respond in a week-not magic bullet-and start forming AB vs anti-TNFa AB
can be curative but can relapse
Very good for patients with other features (like fistulae)-
increase indicence of TB, reactivation of TB
Increase risk of spectecemia, heart failure, demylinating disease, malignancy
early use better than last resport but in combination with azothiarpine
