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Pharmacology and Therapeutics > 19. Inflammatory bowel disease > Flashcards

19. Inflammatory bowel disease Flashcards

1
Q

What are the 2 main forms of IBD?

A

Ulcerative colitis and Crohn’s disease

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2
Q

How does the incidence of UC and CD compare in Western Europe to Eastern Europe?

A

Twice as high in Western Europe (diet and lifestyle)

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3
Q

In what age group does IBD most present in?

A

Late adolescents and young adults

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4
Q

What percentage of patients is the distinction between UC and CD incomplete?

A

10% (indeterminate colitis)

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5
Q

Is there a genetic risk factor to IBD?

A

• Crohn’s more extensively studied than UC
• Genetic predisposition to CD
- 201 loci identified
- White Europeans most susceptible

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6
Q

What are the 3 most important environmental in IBD?

A
  • Smoking
  • Diet
  • Microbiome
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7
Q

How can IBD caused by an autoimmune condition?

A
  • Begins as infection in the gut
  • Defective interaction between mucosal immune system and gut flora
  • Leads to pro-inflammatory compensatory responses
  • Results in physical damage and chronic inflammation
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8
Q 
How do the following compare in CD and UC:
• Cell mediation
• Gut layers affected
• Regions of gut affected
• Continuous/patchy
• Abscesses/fissures present?
• Surgery curative
A

Crohn’s | Ulcerative colitis
• Cell: Th1 mediated e.g. TNF-alpha | Th2 mediated e.g. IL-13
• Layers: all | (sub+)mucosa
• Abscess: common | not common
• Surgery: not always curative | curative

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9
Q

What are the systemic effects of IBD (that don’t directly affect the gut)?

A
  • Fevers
  • Sweating
  • Anaemia
  • Arthritis
  • Weight loss
  • Skin rashes
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10
Q

What do supportive therapies for acutely sick patients involve?

A
  • Fluid/electrolyte replacement
  • Blood transfusion/oral iron
  • Nutritional support
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11
Q

What are the classic symptomatic treatments?

A
  • Aminosalicylates
  • Glucocorticoids
  • Immunosuppressive agents
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12
Q

What is the active component of aminosalicylates and what do they do?

A
  • 5-aminosalicylic acid (5-ASA) - mesalazine
  • Olsalazine is 2 of these molecules linked
  • Both have anti-inflammatory actions
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13
Q

When is it better to give mesalazine and olsalazine?

A
  • Olsalazine (linked form) is metabolised by colonic flora
  • Only works in the colon - better to use this if this is where inflammation is most serious
  • Mesalazine is absorbed all the way through the gut
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14
Q

Which 2 pathways regulate inflammation in IBD, and how does targeting these pathways with 5-ASA affect them?

A
  • NF-KB/MAPK: down-regulation pro-inflammatory cytokines

* COX-2: down-regulation of prostaglandins

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15
Q

Is it better to use topical 5-ASA or topical steroids to induce UC remission?

A
  • Topic 5-ASA is better

* But both used together is even better

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16
Q

How effective are aminosalicylates in UC?

A
  • Effective first line for inducing and maintaining remission
  • Combine oral and rectal administration is more effective (rectal better for localised disease)
  • Better than glucocorticoids
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17
Q

How effective are aminosalicylates in CD?

A
  • Literature is unclear
  • Ineffective in inducing remission
  • May be better in a subgroup of patients
  • Glucocorticoids are probably better
18
Q

What do glucocorticoids do in IBD and how?

A
  • Powerful anti-inflammatory and immunosuppressive drugs
  • Activate intracellular glucocorticoid receptors => can act as +ve or -ve TFs
  • Inhibit dendritic cells from producing IL-1 and TNF-alpha
  • Down-regulate macrophages and T cells
  • Related to cortisol - many unwanted effects if given systemically (chronically)
19
Q

How can the unwanted effects of glucocorticoids be minimised?

A
  • Topical administration (fluid, foam enemas, oral preparations)
  • Lower dose and combine with other drugs
  • Use a different drug with high hepatic first pass metabolism
20
Q

How effective are glucocorticoids in treating UC?

A

Work, but evidence suggests that aminosalicylates are superior

21
Q

How effective are glucocorticoids in treating CD?

A
  • Drug of choice for inducing remission in Crohn’s

* Budesonide is preferred if disease is mild (less side effects)

22
Q

What is azathioprine?

A
  • Pro-drug
  • Activated by gut flora to 6-mercaptopurine (can just give this directly too)
  • Purine antagonist - immunosuppressive
23
Q

How does azathioprine work?

A
  • Activated to 6-MP
  • Metabolised to TIMP
  • Further metabolised to 6-MeMPN and 6-TGN
  • 6-MeMPN inhibits to de novo purine synthesis
  • 6-TGN is incorporated into DNA and disrupts synthesis
  • Leads to unwanted side effects too
24
Q

Which parts of the immune response does azathioprine ‘impair’ and ‘enhance’?

A 
Impairs
• cell-mediated + antibody-mediated responses
• lymphocyte proliferation
• mononuclear cell infiltration
• synthesis of antibodies

Enhances
• T cell apoptosis

25
Q

How effective is azathioprine in treating UC?

A
  • Some success

* No reason to use if response is good with 5-ASA

26
Q

How effective is azathioprine in treating CD?

A
  • No benefit in active disease
  • Can help induce remission in combination with steroid (glucocorticoid-sparing - can reduce dose of GCs to lessen side effects)
  • Mainly used to maintain remission
  • Slow onset (3-4 months for clinical benefit)
27
Q

What are the unwanted effects of azathioprine?

A
  • Pancreatitis
  • Bone marrow suppression (myelosuppression)
  • Hepatotoxicity
  • Increased risk of lymphoma and skin cancers
28
Q

Which inactive component of 6-MP metabolism is specifically hepatotoxic?

A
  • 6-MeMP

* Not beneficial and is an inactive by-product, but is still toxic

29
Q

Why is it toxic to take azathioprine with allopurinol (gout treatment)

A
  • Primary metabolism of azathioprine produces 6-TU (xanthine oxidase pathway)
  • Allopurinol inhibits xanthine oxidase
  • Metabolism forced to go through other pathways, producing toxic metabolites
30
Q

What are the different strategies for targeted drug delivery?

A
  • Prodrugs - metabolised before an effect
  • Polymer coating - dissolves at specific pH or after a specific amount of time
  • Osmosis - more flows into the capsule in the small intestine, forcing the drug out
31
Q

What is the problem with using time and pH as targeted drug delivery and how could this be overcome?

A
  • Time - could be released too early if taken on a full stomach (slower gastric emptying)
  • pH - small intestine has similar pH to colon, so drug could be released here (unwanted)
  • Combine pH and time - greater chance of drug being released into colon
32
Q

What are potential curative therapies for IBD?

A

Manipulation of the microbiome and biological therapies
• Anti-TNF alpha e.g. infliximab (monoclonal antibody)
• Other antibodies are effective, but some have more side-effects
• New humanised antibodies coming

New targets:
• Integrins
• Interleukins
• Interleukin receptors
• Janus kinase (JAK) cytoplasmic cell signalling
33
Q

What are 3 ways the microbiome can currently be manipulated to treat IBD?

A
  • Nutrition-based therapies
  • Faecal microbiota replacement (FMT) therapies
  • Antibiotic treatment with rifaximin
34
Q

What do nutrition-based therapies involve?

A
  • No evidence for probiotics to have an impact on CD

* Some evidence for probiotics inducing and sustaining remission in UC (as effectively as 5-ASA)

35
Q

How effective are faecal microbiota replacement therapies in treating IBD?

A
  • Insufficient evidence, but 2/3 studies showed benefit in UC
  • More studies needed
36
Q

How effective is rifaximin in treating IBD?

A
  • Interferes with bacterial transcription - binds to RNA polymerase
  • Induces and sustains remission in moderate CD
  • May be beneficial in UC too
  • Also reduces inflammatory mediator mRNA in experimental colitis
37
Q

How do anti-TNF alpha antibodies (infliximab) work?

A
  • Mops up any soluble TNF-alpha
  • Reduces activation of TNF-alpha receptors in the gut
  • Reduces downstream inflammatory events
  • Also binds to membrane-associated TNF-alpha => induces cytolysis of these cells
  • Promotes apoptosis of activated T cells
38
Q

How is infliximab administered, what is its half life and how often is it administered?

A
  • IV
  • Half-life - 9.5 days
  • Most patients relapse after 8-12 weeks - so infusion repeated every 8 weeks
39
Q

How useful is anti-tumour necrosis factor alpha in IBD?

A
  • It has been successful in treating CD
  • Underlying pathology not well understood
  • Potentially curative, but many patients relapse
  • Successful in some patients with refractory (‘stubborn’) disease and fistulae
40
Q

What is the problem with response to anti-TNF alpha antibodies over time?

A
  • 50% of patients lose response within 3 years

* Due to anti-drug antibodies and increased drug clearance

41
Q

What are the adverse effects associated with anti-TNF alpha?

A
  • 4-5x increase in TB
  • 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 (produce immune response)

Therefore it’s used as a last resort

Pharmacology and Therapeutics (33 decks)

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