drug management of inflammatory bowel disease Flashcards
similarities in pathogenesis of CD and UC
inappropriate inflammatory responses to environmental and/or self targets
true aetiology unknown however likely response to environmental triggers in genetically susceptible individuals
clinical similarities between UC and CD
chronics, potential for acute exacerbations over time
differences in pathology between UC and CD
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
non-pharmacological considerations for IBD
- 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
salicylates
based on salicylic acid
eg. aspirin, sulphasalazine, mesalazine
aminosalicylates
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)
adverse effects of aminosalicylates
common - headache, nausea, diarrhoea, epigastric pain
for sulfasalazine - serious (rare and idiosyncratic): SJS (Stephen-johnson’s Syndrome), pancreatitis, agranulocytosis
corticosteroids
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
adverse effects of corticosteroids
short term - increased blood sugar, hunger, increased blood pressure, neuropsychiatric irritability, psychosis
long term - osteoporosis, steroid induced diabetes mellitus, proximal myopathy, thin skin
thiopurines
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
adverse effects of thiopurines
antiproliferative actions - bone marrow failure
- hapetotoxicity
- allergic skin rash
- teratogenicity risk
azathioprine is a pro-drug for
6-marcaptopurine
TPMT enzyme
transforms 6-marcaptopurine into hepatotoxic forms
measuring activity of TPMT
low activity means more drug is metabolised into the hepatotoxic pathway leading to increased concentrations of 6-TGN and increased risk of myelosuppression
if TPMT enzyme activity is low
depending on extent of reduction eitherr reduce doses or avoid thiopurines
measuring metabolite levels of metabolism of thiopurine
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
co-adminitration of allopurinol and thiopurines
increases 6-TGN and decreases 6-MMP
anti-TNF-alpha agents
regulates immune cells, produced mainly by macrophages
efficacy proven for both UC and chrons
intravenous (infliximab), subcutaneous (infliximab, adalimumab, etercept etc.)
adverse effects of anti-TNF-alpha agents
immune suppression - infections from opportunistic organisms esp. TB
increased rate of malignancies - lymphoma
drug induced lupus
anti-TNF alpha agents are made in
in-vitro cell culture
anti-integrin antibody
integrin-mediated adhesion allows leukocytes to attach to capillaries and enter into tissues
vedolizumab (humanised, monoclonal antibody
IV infusion
anti-integrin antibody targets
a4B7 intern, specific to leukocytes that can enter the gut tissues
adverse effects of anti-integrin antibody
nasopharyngitis, arthralgia, fever, upper respiratory tract infection
anti-IL-12/23
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)
Ustekinumab
humanised monoclonal antibody targeting the common p40 subunit
JAK inhibitors
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
adverse effects of JAK inhibitors
ifenction - herpes zoster, anal abscess, cellulitis, C defficile infection, pneumonia
venous thromboembolism
increased malignancy risk
