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Year 2 Pharma > Inflammatory Bowel Disease > Flashcards

Inflammatory Bowel Disease Flashcards

1
Q

What are the two major forms of IBD? What is a problem with the distinction

A

Ulterative colitis
Crohn’s disease - most studied of the two
The distinction is incomplete in ~10% of the patients (intermediate colitis)

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2
Q

What are risk factors for IBD

A
  • genetic predisposition
  • environmental factors eg smoking, diet, obesity, gut microbiome
  • obesity
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3
Q

What is the pathogenesis of IBD

A

Defective interactions between the mucosal immune system and the gut flora leading to disrupted innate immunity -> uncontrolled inflammation -> physical damage

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4
Q

What are the differences between ulcerative colitis and crohn’s disease? - 6 points
what mediates it? dependent on? affects? surgery effect? ect

A

Ulcerative colitis:

o Th2-mediated.
o Dependant on IL-5 & IL-13 cytokines.
o Affects mucosa and submucosa.
o Starts in rectum, spreads proximally.
o Always continuous.
o Surgery can be curative.

Crohn’s disease:

o Th1-mediated -> worst inflammatory response.
o Dependant on TNF-a cytokine.
o Penetrates all through gut wall.
o Affects any point of the GI tract.
o Causes patchy (not continuous) inflammation.
- Hard to cure with surgery and often reoccurs.
o Abscesses, fissures and fistula more common.

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5
Q

What are clinical features of inflammatory bowel disease: name 10

A 
Right iliac fossa pain
Skin rash
Diarrhoea, blood, mucus
Weight loss
Arthritis, arthralgia
Abdominal pain
Anaemia
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6
Q

What are classic symptomatic treatments of IBD

A

Glucocorticoids eg prednisolone
Aminosalicylates eg mesalazine
Immunosuppressives eg azathioprine

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7
Q

What are supportive therapies of IBD

A

Fluid/electrolyte replacement
Blood transfusion or oral iron
Nutritional support - as malnutrition is common

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8
Q

what are curative (potentially) treatments of IBD

A

Manipulation of gut microbiome

Drugs - anti-TNF-a eg infliximab or anti-a-4-integrins eg natalizumab

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9
Q

When are aminosalicyates used as therapy in UC and crohn’s?

A

UC - first line in inducing and maintaining remission with good evidence base
Crohn’s - non effective in active disease but may help maintain surgically induced remission

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10
Q

What are examples of aminosalicylates

A

Masalazine

Olsalazine

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11
Q

What is the mechanism of action of aminosalicylates

A
  • Inhibition of IL-1, TNF alpha, and PAF (platelet activating factor)
  • Decrease antibody secretion
  • Non specific cytokine inhibition
  • Reduced cell migration - macrophages
  • Localised inhibition of immune responses
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12
Q

What is the effectiveness of mesalazine at inducing and maintaining remission in UC

A

It is good at maintaining remission, and topical mesalazine is better than topical steroids at inducing remission. Combined topical mesalazine and oral steroids are better at inducing remission than oral 5-ASA alone

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13
Q

How is mesalazine metabolised

A

It does not need to be metabolised and is absorbed by small bowel and colon

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14
Q

How is olsalazine metabolised

A

By gut flora and absorbed by the colon

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15
Q

What are examples of glucocorticoids

A

Prednisolone, fluticasone, budesonide

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16
Q

How are glucocorticoids used as treatment in UC and crohns?

A

In UC - use is in decline, can be used topically or via IV but mesalazine is superior
In Crohn’s it is the drug of choice for inducing remission. SEs likely if used to maintain remission

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17
Q

What are the effects of glucocorticoids when used in IBD

A

Powerful antiinflammatories and immunosuppressives that activate intra cellular GC receptors causing TF +/-

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18
Q

How are glucocorticoids administered in IBD to reduce side effects in long term use

A

Administer topically
Use a low dose in combination with another drug eg a steroid sparing agent
Use an oral/topical drug with HIGH first pass metabolism eg budesonide so little escapes systemically -> budesonide has fewer Ses than prednisolone

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19
Q

What GC are best at inducing crohn’s remission and which are better at preventing relapse

A

Oral GCs are better than budesonide at inducing remission in active crohn’s disease
Budesonide is a better placebo at preventing CD relase

20
Q

What are examples of immunosuppressives used in IBD

A

Azathioprine, methotrexate, cyclosporine

21
Q

When is Azathioprine used as therapy in UC and crohn’s?

A

CD - maintain remission and is superior to placebo and budesonide in CD
UC - useful for maining remission in some patients

22
Q

What is the onset of action of azathioprine for IBD

A

3-4 months treatment needed before clinical benefits are seen

23
Q

What is methotrexate

A

A folate antagonist that reduces the synthesis of thymidine and other purines

24
Q

Why is methotrexate not used to treat IBD often

A

Due to significant side effects in over 40% of patients

25
Q

What condition is cyclosporine used in

A

UC

26
Q

What is the mechanism of action of azathioprine

A

Aza is a pro drug activated in vivo by the gut flora into 6 mercaptopurine (6-MP) which is a purine antagonist that interferes with DNA synthesis and cell replication. 6MP can also be given directly

27
Q

What does azathioprine impair

A

Humoural and innate immune responses, lymphocyte proliferation, mononuclear cell infiltration and synthesis of antibodies

28
Q

What does azathioprine promote

A

T cell apoptosis

29
Q

What are unwanted effects of azathioprine

A

Pancreatitis, bone marrow suppression, hepatotoxicity and a x4 risk increase of lymphoma and skin cancer

30
Q

What are the 3 main routes of metabolism of 6Mp

A

HPRT- beneficial but causes myelosuppression
TPMT - hepatotoxic metabolites
XO - inert metabolites - ideal and main pathway but a drug allopurinol inhibits CO and blocks the pathway (treats gout)

31
Q

What are the ways of using microbiome manipulation to treat IBD

A

(adults only)
Nutrition based therapies
Faecal microbiota replacement (FMT)
Antibiotic treatment (rifaximin)

32
Q

What IBD is affected by probiotics

A

UC has evidence for probiotics in the induction and maintenance of remission

33
Q

What is the problem with using faecal microbiota replacement as a treatment for IBD

A

Insufficient evidence for FMT - 1 study showing remission/cure

34
Q

What does antibiotic treatment do in IBD

A

CD - induces and sustains remission in moderate cases

UC - may be beneficial

35
Q

How does antibiotic treatment work for IBD

A

Interferes with bacterial transcription by binding to RNA polymerase - reducing mRNA coding by inflammatory mediators

36
Q

What are biological therapies used for IBD

A

Anti TNF alpha:
Infliximab (IV) or Adalimumab (SC)
Other antibodies are effective but also have more side effects

37
Q

What happens when anti TNF alpha antibodies are used in different IBDs?

A

CD - used successfully and 60% response

UC - some evidence of effectiveness but UC is not TNF alpha mediated and mainly IL mediated

38
Q

How does Infliximab used to treat IBD

A

It binds to soluble TNFa and receptor bound TNFa and it can strip away already TNFa bound onto cells

39
Q

MoA of biological therapies for IBD - anti TNFa

A

Reduces activation of TNFa receptors in the gut
As TNFa activates other cytokines, TNFa inactivation downregulates other cytokines and infiltration and activation of leukocytes
It binds to membrane associated TNFa as well as soluble TNFa, (inducing cytolysis of cells expressing TNFa and promotes apoptosis of activated T cells)

40
Q

What is the effect of biological therapies of IBD?

A

Induces cytolysis of cells expressing TNFa and promotes apoptosis of activated T cells

41
Q

What are the half life, benefits and relapse time of biological IBD therapies?

A

very long half life 9.5 days, benefits last 30 weeks after infusion and patients relapse after 8-12 weeks

42
Q

What are problems with anti TNF a antibodies used in IBD

A

~50% of patients lose response to drug after 3 years and due to an increased metabolism and anti drug ABs

43
Q

What are adverse effects of biological therapies for IBD due to

A

Due to consequences of knocking out the key cytokine inflammatory cascades

44
Q

what are the adverse effects of biological therapies for IBD

A
  • 4-5x increased incidence of Tb and other infections - and risk of reactivating dormant TB
  • increased risk of septicaemia - downregulates inflammation
  • worsening heart failure
  • increased risk of demyelinating disease and malignancy
  • can be immunogenic - azathioprine reduces risk but raises TB/malignancy risk
45
Q

What are other targets for therapies used for IBD

A
  • alpha 4 integrin -cell adhesion molecule
  • IL 13 particularly in UC
  • Janus kinases 1,2,3 - block signalling by IL 2, 4, 9, 15, 21 (lymphocyte activation and function) and IL6 and INF gamma (pro inflammatory) good in UC

Year 2 Pharma (34 decks)

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