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Pharmacology > Inflammatory bowel disease > Flashcards

Inflammatory bowel disease Flashcards

1
Q

What are the 2 main forms of IBD?

A
  • Ulcerative colitis

- Crohn’s disease

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2
Q

How does the incidence of CD and UC differ in Western Europe compared to the rest of the world and why?

A

The incidence of both UC and CD are twice as high in the Western Europe compared to the Eastern

This may be to do with diet and other lifestyle factors

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3
Q

Who does IBD affect?

A

IBD can affect people of any age: children, adolescents and adults

It most commonly occurs and presents first in late adolescents and young adults

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4
Q

What are the genetic risk factors for IBD?

A
  • The causes are incompletely understood
  • There is genetic predisposition to Crohn’s: 201 loci have been identified and people of White European origin are most susceptible
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5
Q

What are the 3 most important environmental risk factors for IBD?

A

smoking, diet and microbiome

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6
Q

What kind of conditions are IBD?

A

autoimmune

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7
Q

Compare Crohn’s and Ulcerative Colitis on the following points:

  • what mediates the disease?
  • which gut layers are affected?
  • which regions of the gut are affected?
  • inflamed areas are?
  • are abscesses/fissures/fistulae common?
  • can surgery cure?
A

Crohn’s

  • Th1-mediated e.g. IFN-gamma, TNF-alpha, IL-17, IL-23, florid T cell expansion, defective T cell apoptosis
  • All layers
  • Any part of GI tract
  • Patchy
  • Common
  • Not always curative

UC:

  • Th2- mediated .g. IL-5, IL-13, limited clonal expansion, normal T cell apoptosis
  • Mucosa and submuscoa
  • Rectum
  • Continuous
  • Not common
  • Curative
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8
Q

Layers of gut revise

A

…

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9
Q

What are the symptoms of UC and CD?

A
  • ulcers
  • diarrhoea
  • abdominal pain
  • fevers
  • sweating
  • anaemia
  • arthritis
  • weight loss
  • skin rashes
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10
Q

What are the supportive treatments available?

A
  • Fluid/electrolyte replacement
  • Blood transfusion/oral iron if necessary
  • Nutritional support (malnutrition common in IBD patients)
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11
Q

What are some symptomatic treatments (for active disease and preventing relapse)?

A

Aminosalicylates e.g. mesalazine, olsalazine

Glucocorticoids e.g. Prednisolone

Immunosuppressive agents e.g. Azathioprine

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12
Q

Aminosalicylclates - what is the active component?

A

Mesalazine or 5-aminosalicylic acid (5-ASA, olsalazine (2 of the 5-ASAs joined)

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13
Q

Pharmacokinetics of aminosalicyclates - mesalazine and olsalazine

A

Mesalazine –does not need to be metabolised and is absorbed by small bowel and colon. Good at maintaining remission in UC. Topical 5-ASA is better than topical steroids at inducing UC remission. Combined topical 5-ASA and oral steroids better at inducing remission than oral 5-ASA alone

Olsalazine –metabolised by gut flora and absorbed by the colon. So olsalazine only works in the colon

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14
Q

Which 2 pathways regulated inflammation?

A

NF-KB/MAPK: down-regulate pro-inflammatory cytokines – TNF-alpha, IL-1B and IL-6

COX-2: down-regulates prostaglandins – PGE2 and PGF2

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15
Q

Aminosalicyclates for UC and CD

A

Ulcerative Colitis

  • First line for both inducing and maintaining remission
  • Good evidence base for this

Crohn’s Disease

  • Literature is unclear
  • It is ineffective in inducing remission in Crohn’s
  • Less clear cut than utility in UC
  • Glucocorticoids are probably better in Crohn’s
  • It may be effective in a subgroup of patients
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16
Q

Glucocorticoids: examples and what do they do

A
  • Examples: Prednisolone, Fluticasone, Budesonide
  • These are powerful anti-inflammatory and immunosuppressive drugs
  • They are derived from the hormone cortisol – so they have lots of side effects
  • They activate intracellular Glucocorticoid Receptors which can then act as positive or negative TFs
17
Q

How do glucorticoids work in IBD?

A
  • Glucocorticoids act at multiple points in the inflammation seen in bowel disease
  • They can inhibit the production of IL-1 and TNF-alpha by dendritic cells
  • Dendritic cells are thought to have an important role in IBD
  • They have very potent anti-inflammatory and immunosuppressive actions of GCs
  • When given systemically, chronic glucocorticoid administration causes many unwanted effects
18
Q

How do aminosalicyclates work?

A
  • Inhibitionof IL-1, TNF-a and PAF(Platelet Activating Factor)
  • Decrease antibody secretion
  • Non-specific cytokine inhibition
  • Reduce cell migration –macrophages
  • Localised inhibition of immune responses
19
Q

How can glucocorticoids be used whilst minimising SE?

A

-Glucocorticoids have many long-term use side effects -> methods for reducing SEs:

  • Administer topically
  • Use a low-dose in combination with another drug (steroid-sparing agent)
  • Use an oral/topical drug with high first-pass metabolism (e.g. Budesonide), so little escapes systemically
20
Q

Pros and cons of budenoside

A
  • Has fewer SE than prednisolone
  • Glucocorticoids have many long-term use side effects -
  • Oral GCs are better than Budesonide at inducing remission in active Crohn’s disease
  • Budesonide is a better than placebo at preventing CD relapse
21
Q

Glucocorticoids in UC and CD

A

Ulcerative colitis

  • Use of glucocorticoids is in decline, due to evidence that aminosalicylates are superior
  • Glucocorticoids are best avoided due to their side effects

Crohn’s Disease

  • Glucocorticoids remain the drugs of choice for inducing remission in Crohn’s
  • Budesonide is preferred if the disease is mild
  • Patients are likely to get side effects if GCs are used to maintain remission (long-term use)
22
Q

What is azathioprine?

A
  • immunosupressive agent
  • pro-drug that is activated by gut flora to form 6-mercaptopurine
  • purine antagonist
23
Q

How does azathioprine work?

A
  • Interferes with cell replication and DNA synthesis
24
Q

Azathioprine activation, roles of different products formed

A
  • Azathioprine can be activated to become 6-mercaptopurine
  • This can be metabolised by multiple routes
  • When it is metabolised to 6-TMP, it is further metabolised to produce the active drug gents
  • 6-MeMPN inhibits de novo purine synthesis
  • 6-TGN acts like a false purine molecule and gets incorporated into DNA
25
Q

What are the effects of azathioprine on the immune system - what does it impair and enhance?

A

Azathioprine impairs:

  • Cell-mediated and antibody-mediated immune responses
  • Lymphocyte proliferation
  • Mononuclear cell infiltration
  • Synthesis of antibodies

Azathioprine enhances:
- T cell apoptosis

26
Q

Azathioprine and UC and CD

A

Ulcerative Colitis

  • Some success in Ulcerative Colitis
  • But there is no real reason to use it if the response is good with 5-ASA

Crohn’s Disease

  • Azathioprine has no benefit at all in active disease
  • It is mainly used to maintain remission
  • Recent Cochrane review shows it be glucocorticoid-sparing
  • Azathioprine has a slow onset – 3 to 4 months treatment for clinical benefit to be observed

Azathioprine is effective in maintaining remission over long-term use.

27
Q

What are the unwanted effects of azathioprine?

A

Nearly 10% patients have to stop treatment because of the side effects – these are not trivial

  • Pancreatitis
  • Bone marrow suppression
  • Hepatotoxicity
  • Increased risk (around 4 fold) of lymphoma and skin cancers

6-MeMPN is hepatotoxic, despite being an inactive by-product of metabolism (in terms of protection). 6-TU is also inactive, but becomes toxic if taken with allopurinol (a drug taken for gout), because allopurinol inhibits xanthine oxidase. Gout is not uncommon.

6-TGN is beneficial in terms of immunosuppression, but also causes the myelosuppression associated with azathioprine

28
Q

What are some potentially curative therapies?

A

Curative options include manipulation of the microbiome and biologic therapies

  • Anti-TNF alpha e.g. Infliximab (monoclonal antibody to TNF-alpha)
29
Q

How can the microbiome be manipulated?

A
  1. Nutrition-based therapies
    - There is no evidence for probiotics in food stuffs have any impact at all in Crohn’s disease
    - There is some evidence for probiotics for maintenance of remission in Ulcerative Colitis
  2. Faecal microbiota replacement (FMT) therapies
    - Re-populating a patient’s bowel with healthy gut flora may solve the problem
    - There is insufficient evidence for FMT. More studies are needed
  3. Antibiotic Treatment with RIFAXIMIN
    - This interferes with bacterial transcription by binding to RNA polymerase
    - It induces and sustains remission in moderate Crohn’s disease
    - This may be beneficial in ulcerative colitis too
    - Microbiome modulator – rifaximin reduces inflammatory mediator mRNA in experimental colitis
30
Q

Anti-TNFa alpha antibodies - how does it work?

A
  • Infliximab
  • Antibodies will mop up any soluble TNF-alpha before it can bind and activate receptors. TNF-alpha is an upstream, pro-inflammatory mediator.
  • Anti-TNF alpha reduces activation of TNF a receptors in the gut
  • Reduces downstream inflammatory events
  • Also binds to membrane associated TNF alpha -> induces cytolysis of cells expressing TNF alpha
  • Promotes apoptosis of activated T cells
31
Q

How is infliximab administered, how often is it administered?

A

Intravenously and has a very long half-life (9.5 days)

Most patients relapse after 8–12 weeks, therefore the infusion needs to be repeated every 8 weeks

32
Q

Results from anti-TNF alpha antibodies

A
  • It has been used successfully in the treatment of Crohn’s disease
  • Only 60% of patients respond within 6 weeks – we haven’t understood the underlying pathology
  • Potentially curative, but many patients relapse with this treatment
  • Successful in some patients with refractory disease and fistulae (great for maintaining fistula closure)
33
Q

What are the problems with anti-TNF alpha antibodies?

A
  • Emerging evidence that up to 50% responders lose response within 3 years time
  • This is due to production of anti-drug antibodies and increased drug clearance
34
Q

What are some adverse effects associated with anti-TNF alpha antibodies?

A
  • 4x to 5x increase in incidence of tuberculosis
  • Also a risk of reactivating dormant TB
  • Increased risk of septicaemia
  • Worsening of heart failure
  • Increased risk of demyelinating disease (e.g. multiple sclerosis)
  • Increased risk of malignancy
35
Q

Infliximab..

A
  • Early use is better than using it as a last resort

- Combined infliximab and azathioprine therapy may be more effective than the antibody alone

36
Q

What are some new targets for IBD?

A

Integrins (needed for cells to migrate)

Interleukins (IL12; IL17;IL23)

Interleukin receptors

Janus kinase (JAK) cytoplasmic cell signalling

Pharmacology (26 decks)

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