lower GI drugs pharmacology

Question 1

how do glucocorticoids work in inflammation

Answer 1

glucocorticoid receptor complex can inactivate pro-inflammatory transcription factors to prevent them from activating mediators (T cell activation inhibitors)

Question 2

MOA corticosteroids

Answer 2

1. 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

Question 3

how does azathioprine work

Answer 3

inhibits de novo synthesis - anti-proliferative - interferes with DNA/RNA/protein synthesis

Question 4

two inactivation pathways of azathioprine

Answer 4

1. thiopurine s methyltransferase - 6-TGN2. xanthine oxidase - 6-thiouric acid

Question 5

how does azathioprine cause T-cell apoptosis

Answer 5

1. 6-thio-gtp activates rac1 instead of GTP 2. rac1 target genes are suppressed by azathioprine leading to mitochondrial apoptosis

Question 6

how does mesalazine work

Answer 6

inhibits COX1/2, NFkB and PPARy to inhibit cell proliferation (reducing prostaglandin synthesis)

Question 7

how does mesalazine reduce reactive oxygen metabolites

Answer 7

scavenges free radicals during superoxide anion generation in neutrophils

Question 8

how does ciclosporin work

Answer 8

calcineurin inhibitor

Question 9

ciclosporin moa

Answer 9

1. 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

Question 10

how does methotrexate work

Answer 10

inhibits dihydrofolate reductase which stops the formation of tetrahydrofolate - stopping purine synthesis

Question 11

effects of methotrexate purine synthesis inhibition

Answer 11

• T cell proliferation inhibited - apoptosis by ROS- inhibits lymphocyte proliferation - suppresses production of inflammatory cytokines - blocks leukocyte-endothelial adhesion molecules

Question 12

3 examples of anti tnf agents

Answer 12

infliximab, golimumab and adalimumab

Question 13

why does anti-TNF therapy work in IBD

Answer 13

in IBD TNF is elevated and causes - macrophage activation - increased apoptosis of gut epithelial cells - T cell apoptosis regulation - necroptosis of paneth cells

Question 14

how does TNF signal

Answer 14

membrane bound via TNFR1/2soluble via TNFR1

Question 15

pathway of TNFR1

Answer 15

intracellular signalling cascade with pleiotropic effects - mainly apoptosis - or cytokine secretion (IL1/8)

Question 16

pathway of TNFR2

Answer 16

does not contain a death domain and can result in cell proliferation, migration and cytokine production (IL1/6)

Question 17

effects of blocking TNFa

Answer 17

• induces t cell apoptosis - reduce cytokine production - reduce paneth cell necroptosis - reduce epithelial cell apoptosis - elevate regulatory macrophages

Question 18

2 examples of t cell homing therapies

Answer 18

vedolizumab and ustekinumab

Question 19

why do t cell homing therapies work in IBD

Answer 19

T cell cells migrate to the gut tissues and accumulate - releasing inflammatory cytokines - chronic inflammation

Question 20

how does t cell homing happen

Answer 20

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

Question 21

how does vedolizumab work

Answer 21

Anti a4b7 antibody blocking homing of T cells to the inflamed gut

Question 22

how does ustekinumub work

Answer 22

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

Question 23

name 2 JAK inhibitors

Answer 23

tofacitinib and filgotinib

Question 24

how to JAK inhibitors work

Answer 24

By inhibiting JAKs it stops the signalling of chemokines and stops translation of pro-inflammatory mediators

Question 25

give two examples of future therapies in the treatment of IBD

Answer 25

Faecal Microbial Transfer (FMT) and probiotic transfer and Phosphatidylcholine

Question 26

what is the proposed MOA of Faecal Microbial Transfer (FMT) and probiotic transfer

Answer 26

dedifferentiation of cells into new healthy intestinal tissue that are resistant to adverse inflammatory events

Question 27

how would Phosphatidylcholine work in the treatment of IBD

Answer 27

essential protective component of colonic mucus - modified release helps build it back up in UC patients