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Pharm > IBD > Flashcards

IBD Flashcards

1
Q

Types of IBD

A

Ulcerative Colitis (UC)

Crohn’s Disease (CD)

Distinction incomplete in ~10% patients (Indeterminate Colitis)

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2
Q

Where is IBD most common

A

Western europe more than eastern

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3
Q

Are there genetic risk factors for IBD?

A

Genetic predisposition

201 loci identified

People of White European origin most susceptible

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4
Q

Cell types and molecular mechanisms

A

Treg IL10: T‐cell immunodeficiencies with bowel inflammation and Defects in Tregs or IL10 signaling.

Phagocytes: Congenital defects of phagocyte number or function.

Complement: Complement deficiencies.

Bacterial recognition: Defects in host‐microbiota interactions, bacterial sensing.

Epithelial barrier: Epithelial barrier defects.

B cells and antibodies: Predominantly antibody deficiencies with IBD.

Innate immune cells: Systemic autoinflammatory diseases and IBD.

PRR: pattern‐recognition receptor

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5
Q

What are the main environmental risk factors for IBD

A

Smoking
Diet
MICROBIOME

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6
Q

How many gut bacteria

A

10 x more gut bacteria than host cells

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7
Q

Outline the autoimmune basis of IBD

A

Complex interplay between host and microbes

Disrupted innate immunity and impaired clearance

Pro-inflammatory compensatory responses

Physical damage and chronic inflammation

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8
Q

What occurs in each of the following layers in IBD:

Intestinal lumen
Mucus layer
Epithelial barrier
Lamina propria

A

lumen:
Increased pathogen number. Diet/antibiotics/stress. Dysbiosis

mucus:
Reduces mucus in IBD. Reduced anti-inflammatory bacteria in the mucus

Epithelial layer:
Tight junctions inpaired so pathogens can permeate the epithelial barrier

Lamina propria:
Normally there would be physiological inflammation with upregulated Th17/Th1/barrier function and also increased Tregs and IL-10 (anti-inflammatory)

In IBD, TH17 and TH1 greatly increased, reduced Treg, IL10 though

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9
Q

Differentiate Crohns and UC

A

AI disease: Chrohn’s is Th1 (TNF-a), UC is Th2 (IL-13). Chrohn’s is T cell expansion, defective T cell apoptosis. In UC, limited clonal expansion and normal T cell apoptosis.

Gut layers: Chrohn’s- all layers, UC: mucosa/submucosa

Regions: Crohn’s any part of GI, UC rectum spreading proximally

Inflamed areas patchy in chrohn’s but continuous in UC

Abcesses and fissures and fistulae are common in Crohn’s but not in UC

Surgery is curative in UC but not crohn;s

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10
Q

What are the systemic and GI effects of IBD

A

SYSTEMIC

Skin rashes, night sweats, fevers, arthritis, weight loss

GI:
Pain
Diarrhoea
Mouth ulcers

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11
Q

Types of therapy for IBD

A

Supportive,

Symptomatic:
Active disease

Symptomatic:
prevention of remission

Potentially curative

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12
Q

What are supportive therapies

A

Acutely unwell

  • Fluid/electrolyte replacement
  • Blood transfusion/ oral iron
  • Nutritional support (malnutrition common)
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13
Q

What are the
Symptomatic:
Active disease
therapy

A

Aminosalicylates eg
Mesalazine

Glucocorticoids eg Prednisolone

Immunosuppressives eg Azathioprine

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14
Q

Give examples of aminosalicylates

A

Mesalazine or 5-aminosalicylic acid (5-ASA)

Olsalazine (2 linked 5-ASA molecules)

Anti-inflammatory

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15
Q

What is the difference between mesalazine and olsalazine in terms of where they are absorbed and their metabolism

A

Olsalazine must be metabolised to active form in the colon by COLONIC FLORA

Mesalizine absorbed throughout small bowel and colon

Olsalazine only absorbed in the colon

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16
Q

Mechanism of action of aminosalicylates, including the receptor they act on

A

PPAR receptor activation by 5-ASA.

  1. Downregulate NFkB/MAPK and thus TNFa, IL1 and IL6
  2. Downregulate COX2 and thus PGE2 and PGF2
  3. Also scavenge oxidants
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17
Q

What is the effectiveness of aminosalicylates in UC

A

Effective at induction and maintenance of remission

Combined oral and rectal administration probably more effective than either alone for generalised disease across colon

Rectal delivery better for localised disease

Probably better than glucortocoids

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18
Q

What is the effectiveness of aminosalicylates in CD

A

Unclear

Ineffective in inducing remission

Glucorticoids probably better

May be effective in a subgroup of patients

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19
Q

Examples of glucocorticoids

A

Prednisolone, Fluticasone, budesonide

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20
Q

What is the action of glucocorticoids

A

Powerful anti-inflammatory and immunosuppressive drugs

Activate intracellular Glucocorticoid Receptors which can then act as positive or negative transcription factors

21
Q

Why might GC be useful in IBD

A

GC come through blood stream,

can downregulate dendritic cells and the TNFa and IL1 they produce

Downregulate production of Th1/Th2 and Th17 cytokines

Modulate macrophage an downregulate their cytokines (TNFa, IL12, IL6)

Inhibit inflammatory effects
Promote regulatory effects

22
Q

What is the problem with GCs

A

When given systemically, chronic glucocorticoid administration causes many unwanted effects
(endo)

SO YOU GIVE IT TO INDUCE REMISSION AND THEN MAINTAIN THE REMISSION WITH SOMETHING ELSE.

23
Q

Why is budesonide good over prednisolone

Why isn’t it

A

It is metabolised locally (HIGH fpm) and doesn’t escape into systemic circulation so less side effects.

Not as effective though compared to prednisiolone in inducing remission

24
Q

When is comparison of GCs useful

A

In Crohn’s patients (not using GCs in UC patients as they have aminosalicylates working well )

25
Q

What is the drug treatment for chrohn’s

A

GCs remain drugs of choice for inducing remission

Budesonide preferred if mild

Likely to get side effects if used to maintain remisson

26
Q

What is azathioprine

A

Prodrug

Immunosuppressive

27
Q

How does azathrioprine work

A

A pro-drug

Activated by gut flora to 6-mercaptopurine

Give 6-mercaptopurine directly

Purine antagonist
Immunosuppressive

28
Q

How can Azathriprine work on DNA

A

6-MP converted o 6-TIMP which can then inhibit de novo pruine synthesis

and can be incoroporated into the DNA

29
Q

Azathioprine impacts what

A

It impairs:
1. cell- and antibody-mediated immune responses

  1. lymphocyte proliferation
  2. mononuclear cell infiltration
  3. synthesis of antibodies

It enhances:
1. T cell apoptosis

30
Q

When is azathiprine used in IBD

A

Not really needed in UC

Weak benefit in inducing remission, but better in inducing remission when combined for Crohn’s

Maintains remission

31
Q

Downside of azathioprine

A

Slow onset – 3 to 4 months treatment for clinical benefit

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

32
Q

What is causing hepatoxicity and myelosuppression

A

6-MeMP (an inactive metabolite of 6-MP) is hepatotoxic

Even the wanted metabolite of 6-TGN causes myelosuppression

33
Q

What are the strategies for minimising unwanted effects of the IBD drugs

A

Administer topically - fluid or foam enemas or suppositories

Use a low dose in combination with another drug

Use an oral or topically administered drug with high hepatic first pass metabolism e.g.Budesonide so little escapes into the systemic circulation

34
Q

What are the strateiges for targeted drug dlivery

A

Packaging that degrades at certain pH

Packaging that degrades at a certain time (self destructs after a period of time)

Prodrugs (i.e activated by enzymatic degradation in colon lumen incl. azathiprine (to 6MP) and olsalazine (to 5ASA) both by gut flora)

Osmosis (fluid flows into the tablet and pushes drug out the other side)

35
Q

How else can drugs be targeted

A

E.g nanoparticles

Those that are time dependent might have premature release into the release into stomach

Those that are pH dependent you could get complete drug release at small intestine (as it is the same pH as the colon)

If pH/time, the nanoparticals avoid complete drug release and seliver drug to inflamed colon

36
Q

What are the potentally curative therapies

A
  1. Manipulation of the microbiome

2. Biologic Therapies

37
Q

How can the microbiome be manipulated as a curative therapy

A
  1. Nutrition based therapies
    - No evidence for probiotics in CD
    - Some evidence for maintaining remission for UC (but not for induction)
  2. Faecal microbiota replacement (weak evidence)
  3. Antibiotics RIFAXIMIN
38
Q

How does rifaximin work

A
  • Interferes with bacterial transcription by binding to RNA polymerase
  • Induces and sustains remission in moderate CD
  • May be beneficial in UC
  • May be microbiome modulator

Bear in mind don’t want to kill off the commensals

39
Q

What are the biologic therapies in IBD

A

Infliximab (iv)

Anti- TNFa antibodies

Many others

Have to do repeatedly

New humanised antibodies coming on stream eg Entanacept

40
Q

How does infliximab work

A

Anti- TNFa reduces activation of TNF a receptors in the gut

Reduces downstream inflammatory events

Also binds to membrane associated TNFa

Induces cytolysis of cells expressing TNFa

Promotes apoptosis of activated T cells

41
Q

How is infliximab given

A

Infliximab given intravenously

Very long half-life (9.5 days)

Most patients relapse after 8 –
12 weeks

Therefore repeat infusion every 8 weeks

42
Q

When is anti-TNF useful in Chrohn’s

What proportion of CD patients respond to TNFa

A

Used successfully in the treatment of CD

Only 60% patients respond within 6 weeks

Successful in some patients with refractory disease and fistulae

Very good for maintaining fistula closure

43
Q

Why might Anti-TNFa be less useful in UC than Chroh’s

A

Because in Crohn’s it’s TNF-a mediated due to Th1,

but in UC it’s mainly Th2 where there’s less role for TNFa

44
Q

Problems with TNFa

A

50% responders lose response within 3 years time due to production of anti-drug antibodies and increased drug clearance.

45
Q

Adverse effects of TNFa

A

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 – combination with azothiaprine reduces risk, but raises TB /maligancy risk

(I Said Hi To Dr Carrot….. Immunogenic, Septicaemia, Heart failure, TB, Demyelinating disease, Cancer)

46
Q

When is infliximab best used in IBD

A

Early use better than last resort

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

(but think of malignancy/TB risk)

Remember it maintains remission, and may induce remission in moderate CD

47
Q

Potential new targets for IBD

A

Integrins (needed for cells to migrate)

Interleukins (IL12; IL17;IL23)

Interleukin receptors

Janus kinase (JAK) cytoplasmic cell signalling

48
Q

T/f azathriopine increases side effects of infliximab

A

F…. it reduces them

49
Q

T/F azathiopine needs pro-drug activation by metabolism to 5-ASA

A

Olsalazine needs pro-drug activation by metabolism to 5-ASA

untrue becaise azathioprine– it needs activation to 6-mercaptopurine

Pharm (33 decks)

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