drug management of inflammatory bowel disease

Question 1

similarities in pathogenesis of CD and UC

Answer 1

inappropriate inflammatory responses to environmental and/or self targets
true aetiology unknown however likely response to environmental triggers in genetically susceptible individuals

Question 2

clinical similarities between UC and CD

Answer 2

chronics, potential for acute exacerbations over time

Question 3

differences in pathology between UC and CD

Answer 3

UC is a mucosal inflammation while Chron’s is transmural
responses to drug therapy are slightly different
UC higher risk of colorectal cancer
strictures, fistulae occur in chrons
UC starts in distal large bowel
chrons has skip lesions, can affect any part of the bowel with predilection for terminal ileum

Question 4

non-pharmacological considerations for IBD

Answer 4

• stop smoking, reduces recurrence risk in churns
• dietary and drug management of diarrhoea
• psychological support
• surgery for localised complications - chrons mainly
• probiotics, faecal microbiota transplantation

Question 5

salicylates

Answer 5

based on salicylic acid

eg. aspirin, sulphasalazine, mesalazine

Question 6

aminosalicylates

Answer 6

main role is for maintaining remission in UC (can also be used for mild flares)
limited use in chrons
sulfalazine, mesalazine
exact mechanism of action unknown
available in PO and PR (enemas and suppositories)

Question 7

adverse effects of aminosalicylates

Answer 7

common - headache, nausea, diarrhoea, epigastric pain

for sulfasalazine - serious (rare and idiosyncratic): SJS (Stephen-johnson’s Syndrome), pancreatitis, agranulocytosis

Question 8

corticosteroids

Answer 8

potent anti-inflammatory agents
used for moderate-severe relapses of both UC and chrons - short term therapy with gradual weaning dose
IV hydrocortisone,
PO prednisolone/budenoside,
PR (foam/enemas) hydrocortisone/budesonide

Question 9

adverse effects of corticosteroids

Answer 9

short term - increased blood sugar, hunger, increased blood pressure, neuropsychiatric irritability, psychosis
long term - osteoporosis, steroid induced diabetes mellitus, proximal myopathy, thin skin

Question 10

thiopurines

Answer 10

results in immunomodulation via induction of T cell apoptosis by modulating cell (rac-1) signalling
azathioprine and 6-mecaptopurine
- AZA is a prodrug for 6-MP
oral agents

Question 11

adverse effects of thiopurines

Answer 11

antiproliferative actions - bone marrow failure

• hapetotoxicity
• allergic skin rash
• teratogenicity risk

Question 12

azathioprine is a pro-drug for

Answer 12

6-marcaptopurine

Question 13

TPMT enzyme

Answer 13

transforms 6-marcaptopurine into hepatotoxic forms

Question 14

measuring activity of TPMT

Answer 14

low activity means more drug is metabolised into the hepatotoxic pathway leading to increased concentrations of 6-TGN and increased risk of myelosuppression

Question 15

if TPMT enzyme activity is low

Answer 15

depending on extent of reduction eitherr reduce doses or avoid thiopurines

Question 16

measuring metabolite levels of metabolism of thiopurine

Answer 16

undetectable 6-TGN and 6-MMP = non-compliance
both are low = under dosing
low 6-TGN, high 6-MMP = high TPMT activity
high both = thiiopurine refractory or overdosing
high 6-TGN and low 6-MMP = overdosing with risk of myelotoxicity

Question 17

co-adminitration of allopurinol and thiopurines

Answer 17

increases 6-TGN and decreases 6-MMP

Question 18

anti-TNF-alpha agents

Answer 18

regulates immune cells, produced mainly by macrophages
efficacy proven for both UC and chrons
intravenous (infliximab), subcutaneous (infliximab, adalimumab, etercept etc.)

Question 19

adverse effects of anti-TNF-alpha agents

Answer 19

immune suppression - infections from opportunistic organisms esp. TB
increased rate of malignancies - lymphoma
drug induced lupus

Question 20

anti-TNF alpha agents are made in

Answer 20

in-vitro cell culture

Question 21

anti-integrin antibody

Answer 21

integrin-mediated adhesion allows leukocytes to attach to capillaries and enter into tissues
vedolizumab (humanised, monoclonal antibody
IV infusion

Question 22

anti-integrin antibody targets

Answer 22

a4B7 intern, specific to leukocytes that can enter the gut tissues

Question 23

adverse effects of anti-integrin antibody

Answer 23

nasopharyngitis, arthralgia, fever, upper respiratory tract infection

Question 24

anti-IL-12/23

Answer 24

involved in the recruitment of lymphocytes and enhance the cytotoxicity of NK and T cells
IL-12 promotes Th1 response (intracellular killing)
IL-23 - promotes Th17 response (produce IL-17, a highly inflammatory cytokine)

Question 25

Ustekinumab

Answer 25

humanised monoclonal antibody targeting the common p40 subunit

Question 26

JAK inhibitors

Answer 26

janus kinase (JAK1, JAK2, JAK3, and Tyk2) are associated with cytokine receptors which are involved in signalling of inflammatory cells
Tofacitinib has evidence for UC but not CD
oral

Question 27

adverse effects of JAK inhibitors

Answer 27

ifenction - herpes zoster, anal abscess, cellulitis, C defficile infection, pneumonia
venous thromboembolism
increased malignancy risk