IBD Flashcards
What do corticosteroids do for IBD
Inactivate proinflammatory transcription factors:
eg, NFkB and AP1
prevents activation of inflammatory mediators= IL-6 and leukotrienes
Also inhibit T cell activation
How do glucocorticoids work?
Passively go into cells and bind to glucocorticoid receptor (GR). The GR is bound to the heat shock protein complex which contains chaperone molecules.
Glucocorticoids bind to GR and become activated inhibiting promotor regions = no transcription of proinflammatory cytokines
How does azathioprine work?
Inhibits new purine synthesis and is antiproliferative
Azathioprone-> 6MP -> TIMP -> incorporation into DNA or inhibits purine synthesis
How does azathioprine control Tcell Apoptosis?
Modulates Rac1
6-thio-GTP from azathioprine binds instead of GTP
Supresses Rac1 target genes = apoptosis
How do Aminosalicylates work?
Mesalazine, sulphasalazine etc
Affects prostaglandin synthesis and the cyclooxygenase pathway and suppresses pro-inflammatory cytokines
Action via COX Inhibition
Suppresses cytokines via inhibiting PPARgamma NFkB etc
Can also scavange reactive oxygen metabolites during superoxide anion production in neutrophils, inhibiting ROM generation so inhibits oxidative DNA damage
What is the arachidonic acid pathway?
Phospholipids-> arachidonic acid and cyclooxygenase = PGG2-> PGH2->other prostaglandins causes increased cell growth and survival
Or phospholipids -> arachidonic acid and lipoxygenase -> HPETE -> leukotrienes
How does ciclosporin work
Binds to cyclophilin, CsA specific competitive inhibition of calcineurin Ca2+ and calmodulin dependant phosphates
Cytokine gene expression blocked
How does methotrexate work
Dihydrofolate reductase inhibitor
Prevents new thymidylate and purine synthesis therefore less DNA production
Blocks survival of Tcells
Supresses proinflammatory cytokines IL-6, IL-13 , TNFa and IFN-y
What does TNFa do in IBD
TNF elevated
Activates macrophages to produce proinflammatory cytokines incr. apoptosis of gut epithelial cells
What is Tcell homing?
T cells migrate to gut tissues where secrete cytokines and cause chronic inflammation
Tcells express molecule for emigration-> defects occur in IBD
What is Tcell retention?
Tcells retained in gut tissue as bind alpha4B7 integrin to E cadherin on epithelial cells
What drugs block Tcell homing and retention for IBD?
Velolizumab- antia4b7 antibody blocking homing of Tcells
Sphingosine 1-phosphate- S1P receptor controls egression of immune cells from lymph nodes.
S1PR1 agonists causes a decrease in lymphocytes
How does ustekinumab work
Targets 1l12 and il23
Supresses Th1 and Th17 -? decreases cytokines
How does JAK inhibitors work
tofacitinib and filgotinib
INHIBITS—|Causes STAT to form a dimer and be phosphorylated causing a proinflammatory effect
What is the treatment guide for proctitis UC
Topical aminosalicylate (supp)
Add oral if remission not in 4 weeks
Further treatment needed = topical/ oral corticosteroid
What is the treatment guide for Proctosigmoiditis and left sided colitis UC
Topical aminosalicylate (enema)
if remission not in 4 weeks consider high dose oral aminosalicylate
or switch to high dose oral AS and topical corticosteroid
What is the treatment guide for Extensive UC
Topical aminosalicylate and high dose ORAL aminosalicylate
No remission in 4 weeks-> stop topical and offer TL oral corticosteroids
How do you induce remission for UC?
Oral corticosteroid or JAKs or biologics
ow do you induce remission for UC in hospital?
IV corticosteroids (and IV ciclosporin if after 72hrs no response)
What is the maintenance therapy for mild to moderate UC?
Proctitis and proctosigmoiditis
*Topical aminosalicylate
*oral aminoS and topical
*Oral aminoS
Left-sided and extensive
*Low dose of oral aminoS
What would you give a patient who isn’t on aminosalicylates or has had 2 or more inflammatory exacerbations in 12 months?
Mecaptopurine or azathioprine
How do you induce remission in crohns
Prednisolone, hydrocortisone (IV)
Budesonide of CI^ - not for severe
Add on therapy: azathioprine or mecaptopurine
Methotrexate if cant tolerate azath or mecap.
If no response- infliximab or adalimumab
How do you maintain remission in crohns
Azathioprine or mecaptopurine
Consider methotrexate if previously used
Or no treatment but follow up
If surgery - consider these treatments
What can prolonged use of corticosteroids do for IBD?
Increase infection risk, osteoporosis, adrenal suppression, weight gain, diabetes, CV disease
