19: Inflammatory Bowel Disease Flashcards
What are the two most common types of Inflammtory Bowel Disease? (IBD?)
What is their cause?
Both are Autoimmune-inflammtory diseases
- Ulcerative Colitis
- Crohn’s disease
–> can present very differently but in 10% conditions are indistiguishable, no clear diagnosis can be made
What are the main mediators in UC?
Th2 mediated via IL-13+5
What are important inflammatory mediators in Crohns diesease?
Th1 mediated via many factors including
- TNF-alpha
- IL-1ß
- IL-6
What are the pathological features of Ulcerative Colitis?
- Continous inflammation
- Starts at rectum and progresses proximally
- Mucosal layer is affected
- Normally not associalted with fissures/fistules/ abcesses
- Surgery is curative
What are the main pathological features of Crohn’s disease?
- Patchy inflammation
- In whole GI tract
- And all layers
- Commonly associated with absesses, fissures, fistules etc.
- Surgery is not always curative
What are the supportive therapies in IBD?
To treat acute attack
- Fluid/electrolyte replacement
- Blood transfustion (in bloodloss, mainly Crohns)
- Nutritional support (malnutrition common)
What kind of drugs can be used in an acute attack of UC or Crohn’s?
- Aminosalicylates eg Mesalazine
- Glucocorticoids eg Prednisolone
- Immunosuppressives eg Azathioprine
What is the MOA of Aminosalicylates?
It is an anti-inflammtory drug
It binds to receptor and alters transcripiton in nucleus
- downregulated pro-inflammtory mediators
- TFN-alpha
- IL-6, more IL
- Inhibits Cox2
- downregulation of pro-inflammtory prostaglandins
Compare two Aminosalicylated regarding their Pharmacokinetics and action
- Mesalazine or 5-aminosalicylic acid (5-ASA)
- absorbed in small bowel and colon
- Olsalazine (2 linked 5-ASA molecules)
- absorbed in colon
- needs to be metabolised by gut bacteria first–> in colon so more targeted treatment
What is the use of Aminosalicylates in Ulcerative colitis?
- First line of treatment
- good at inducing and maintaining remission
- better than many glococorticoids
- PO+ rectal (combined) administration
Explain the used of Aminosalicylates in the treatment of Crohns Disease
Ineffective in inducing remission of CD
- A very modest amount of evidence for effectiveness in maintenance
- However, other therapies!1 preferable for maintenance
What are the side-effects of Aminosalicylates?
Common: GI disturbance
Diarrhoea; gastrointestinal discomfort; gastrointestinal disorders; nausea;
skin reactions; vestibular syndrome; vomiting
Uncommon: Agranulocytosis
What is the MAO of Glucocorticoids?
Very powerful immunosupressant anti-inflammatory drug
- alters transcription of cells and pro-inflammatory mediators
Explain the use of Glucocorticodis in the treatment of Ulcerative colitis
- Inducing and Maintaining Remission:
- Might be Effective, but not recommended (Aminosalicylates more effective )
Explain the use of Glucocorticoids in the treamtent of Crohns Disease?
- Inducing Remission
- Effective, Choice of treatment (Budesonide preferred in mild cases)
- Maintaining Remission
- Avoid due to severe side effects
What are the side effects of the use of glucocorticoids?
Severe + Common
Cushing’s, electrolyte imbalance, osteoporosis, mood disturbance, hirsutism, HTN, etc. etc.
Which glucocorticoids could you use in the treatment of Cohn’s disease?
When would you use them? Why?
- Prednisolone
- in severe cases to induce remission
- Budesonide
- in less severe cases
- it is less effective but also has less side effects due to local administration (gets metablised and inactivated locally)
What is Azathioprine?
An immunosupressant drug used in treamtne of IBD (pruine antagonist)
Explain the MOA of Azathioprine
Purine antagonist: impairs
- cell- and antibody-mediated immune responses
- lymphocyte proliferation
- mononuclear cell infiltration
- synthesis of antibodies
•It enhances
- T cell apoptosis
What are the side effects of the use of Azathioprine?
- •Nearly 10% patients have to stop treatment because of side effects
- •Pancreatitis
- •Bone marrow suppression
- •Hepatotoxicity
- •Increased risk (~ 4 fold) of lymphoma and skin cancer
What is the use of Azathioprine in the treatment of Crohns disease?
- NOT: For active disease
- Azathioprine or other immunosuppressants recommended for maintaining remission
- Glucocorticoid-sparing
- Slow onset – 3 to 4 months treatment for clinical benefit
When does Azathiorine develops its effects?
After 3-4 Month of treament
What are the different techniques that can be used in the alteration of the Micorbiome in IBD?
- Exclusive enternal nutrition
- Probiotics
- Fecal Transplant
- ABX
What is the overall mechanism of biologial treamts in the treament of IBD?
They are: antibodies to important inflammatory mediators (e.g. anti- TNF-alpha)
What is Infliximab?
What is its MOA?
It is an anti-TNFalpha (antibody)
- Inhibits TNF-alpha and thereby
- neutralizing TNF-α–mediated proinflammatory cell signaling and inhibiting the expression of inflammatory genes
- Induces cytolysis of cells expressing TNFa
- Promotes apoptosis of activated T cells
Summarise the Pharmacokinetics and ROA of infliximab
- IV administration
- Long t1/2: 9.5 days –> adminsitration every 8 Weeks
Explain the use of anti-TNF-alpha in treatment of Crohns disease
- Potentially curative, but high risk of tolerance
- effective in induction and maintainance of mucosal healing in Crohns
- Successful for reduction and stabelization of fistules
- Preferable early use in combination with Azathioprine
What are the side effects of anti-TNF alpha treatments?
- 4x - 5x increase in incidence of tuberculosis
- Also risk of reactivating dormant TB
- Increased risk of septicaemia
- Worsening of heart failure
- Increased risk of demyelinating disease
- Increased risk of malignancy
- Can be immunogenic – azothiaprinereduces risk, but raises TB /maligancyrisk
What are the main problems of anti-TNF alpha drugs?
- High tolerance–> 50% loose response within 3 years
- •due to
- production of anti-drug antibodies
- and increased drug clearance.
What is the clinical presentation of IBD?
- Abdominal pain and crampitng
- Diarrhoea, bloody faeces
- Mouth ulcers
- Anaemia
- Fever
- Arthritic pain
- Skin rashes
- Uveitis
- Weight loss
How is azathioprine metabolised, and why is this clinically important in Crohn’s disease? (2 marks)
Prodrug activated by gut flora
Metabolised by xanthine oxidase. Coadministration with drugs that inhibit xanthine oxidase such as Allopurinol used to treat gout can cause build up of 6-mercaptopurine leading to blood disorders, hepatotoxicity.
