lower GI drugs pharmacology Flashcards
how do glucocorticoids work in inflammation
glucocorticoid receptor complex can inactivate pro-inflammatory transcription factors to prevent them from activating mediators (T cell activation inhibitors)
MOA corticosteroids
- passively enter cell and bind to receptor 2. receptor usually sequestered in cytoplasm by heat shock proteins 70/90 and immunophilin 3. binding forms homodimer of 2 active receptors 4. transported to nucleus and inhibits translation of genes
how does azathioprine work
inhibits de novo synthesis - anti-proliferative - interferes with DNA/RNA/protein synthesis
two inactivation pathways of azathioprine
- thiopurine s methyltransferase - 6-TGN2. xanthine oxidase - 6-thiouric acid
how does azathioprine cause T-cell apoptosis
- 6-thio-gtp activates rac1 instead of GTP 2. rac1 target genes are suppressed by azathioprine leading to mitochondrial apoptosis
how does mesalazine work
inhibits COX1/2, NFkB and PPARy to inhibit cell proliferation (reducing prostaglandin synthesis)
how does mesalazine reduce reactive oxygen metabolites
scavenges free radicals during superoxide anion generation in neutrophils
how does ciclosporin work
calcineurin inhibitor
ciclosporin moa
- antigen interacts with TH cell causing Ca2+ influx 2. Ca2+ activates calcineurin - ciclosporin binds to cyclophilin 3. calcineurin normally activates transcription factors to cause IL2 expression but cyclophilin inhibits translocation of NF-AT transcription factors and reduces transcription of cytokines
how does methotrexate work
inhibits dihydrofolate reductase which stops the formation of tetrahydrofolate - stopping purine synthesis
effects of methotrexate purine synthesis inhibition
- T cell proliferation inhibited - apoptosis by ROS- inhibits lymphocyte proliferation - suppresses production of inflammatory cytokines - blocks leukocyte-endothelial adhesion molecules
3 examples of anti tnf agents
infliximab, golimumab and adalimumab
why does anti-TNF therapy work in IBD
in IBD TNF is elevated and causes - macrophage activation - increased apoptosis of gut epithelial cells - T cell apoptosis regulation - necroptosis of paneth cells
how does TNF signal
membrane bound via TNFR1/2soluble via TNFR1
pathway of TNFR1
intracellular signalling cascade with pleiotropic effects - mainly apoptosis - or cytokine secretion (IL1/8)
pathway of TNFR2
does not contain a death domain and can result in cell proliferation, migration and cytokine production (IL1/6)
effects of blocking TNFa
- induces t cell apoptosis - reduce cytokine production - reduce paneth cell necroptosis - reduce epithelial cell apoptosis - elevate regulatory macrophages
2 examples of t cell homing therapies
vedolizumab and ustekinumab
why do t cell homing therapies work in IBD
T cell cells migrate to the gut tissues and accumulate - releasing inflammatory cytokines - chronic inflammation
how does t cell homing happen
TH1/TH2/TH17 cells have the necessary proteins on their surface to emigrate into gut tissue - a4b7 interacts with MAdCAM1 to migrate into gut tissue, once in laminar propria they are retained there by binding to E Cadherin
how does vedolizumab work
Anti a4b7 antibody blocking homing of T cells to the inflamed gut
how does ustekinumub work
targeting the p40 subunit of IL-12 and IL-23. IL-12 and IL-23 involved in activating a cascade of inflammatory mediators responsible for the pathogenesis IBD
name 2 JAK inhibitors
tofacitinib and filgotinib
how to JAK inhibitors work
By inhibiting JAKs it stops the signalling of chemokines and stops translation of pro-inflammatory mediators
give two examples of future therapies in the treatment of IBD
Faecal Microbial Transfer (FMT) and probiotic transfer and Phosphatidylcholine
what is the proposed MOA of Faecal Microbial Transfer (FMT) and probiotic transfer
dedifferentiation of cells into new healthy intestinal tissue that are resistant to adverse inflammatory events
how would Phosphatidylcholine work in the treatment of IBD
essential protective component of colonic mucus - modified release helps build it back up in UC patients
