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YR2 LCRS Pharmacology > 20. Inflammatory bowel disease > Flashcards

20. 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

when does IBD most commonly first present and occur?

A

in late adolescents and young adults

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3
Q

what environmental factors are risks in IBD?

A

smoking
diet
microbiome

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4
Q

why does IBD occur?

A
  • occurs as a result of a defective interaction between the mucosal immune system and the gut flora
  • the conditions begin as an infection
  • if the innate immunity becomes disrupted you get pro-inflammatory compensatory responses –> physical damage and chronic inflammation
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5
Q

what is the difference between crohn’s disease and ulcerative colitis?

A
  • CD is Th1-mediated whereas UC is Th2-mediated
  • in CD all layers of the gut are affected, in UC only the mucosa and submucosa are affected
  • in CD any part of the GI can be affected, in UC primarily the rectum is affected (spreading proximally)
  • abscesses/fissures are common in CD not UC
  • surgery is curative in UC but not necessarily in CD
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6
Q

what are the clinical features of CD and UC?

A
  • fevers
  • sweating
  • anaemia
  • arthritis
  • weight loss
  • skin rashes
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7
Q

what types of treatments are there for UC and CD?

A

supportive: fluids, blood, nutritional support

symptomatic (active disease/prevention of remission): glucocorticoids, aminosalicylates, immunosuppressives

potentially curative: microbiome management, biologic therapies

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8
Q

what are aminosalicylates?

A

compounds that contain mesalazine (5-aminosalicylic acid (5-ASA))

this is the active component which interferes with the body’s ability to control inflammation

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9
Q

what is olsalazine?

A

drug consisting of 2 linked 5-ASA molecules

also has anti-inflammatory actions

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10
Q

describe the pharmacokinetics of aminosalicylates

A

OLSALAZINE: has to be activated by gut flora (metabolised by colonic flora) so only works in the colon - if the inflammation is most serious in the colon it is best to give this

MESALAZINE: will be absorbed all the way through the gut

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11
Q

what is inflammation regulated by?

A
  • NF-KB/MAPK pathway: down-regulates pro-inflammatory cytokines (TNF-a, IL-1B, IL-6)
  • COX-2 pathway: down-regulates prostaglandins (PGE2 and PGF2)
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12
Q

how effective is the treatment of UC with aminosalicylates?

A

first line for inducing and maintaining remission

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13
Q

how effective is the treatment of CD with aminosalicylates?

A
  • ineffective in inducing remission

- may be effective in a subgroup of patients

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14
Q

what do glucocorticoids do? give some examples of glucocorticoids

A
  • powerful anti-inflammatory and immunosuppressive drugs
  • activate intracellular glucocorticoid receptors which can act as positive or negative TFs

prednisolone, fluticasone, budesonide

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15
Q

what is the impact of glucocorticoids in IBD?

A
  • inhibit the production of IL-1 and TNF-a by dendritic cells (dendritic cells have an important role in IBD)
  • inhibit the production of IL-6, IL-12 and IL-17
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16
Q

what strategies are there for minimising unwanted effects of glucocorticoids?

A
  • topically administer glucocorticoids (fluid, foam enemas, suppositories, oral preparations)
  • use a lower dose in combination with another drug
  • use an oral or topically administered drug with high hepatic first pass metabolism
17
Q

how effective is the treatment of UC with glucocorticoids?

A
  • use is in decline due to evidence that aminosalicytes are better
  • avoided due to their side effects
18
Q

how effective is the treatment of CD with glucocorticoids?

A
  • drug of choice
  • budesonide is preferred if the disease is mild
  • likely to get side effects if glucocorticoids are used to maintain remission (long-term use)
19
Q

what is azathioprine?

A
  • a pro-inflammatory drug that has to be activated by the gut flora to 6-mercaptopurine
  • 6-mercaptopurine can be given directly - it is a purine antagonist that is therefore immunosuppressive
20
Q

what can 6-mercaptopurine be metabolised to form?

A
  • can be metabolised by multiple routes
  • when it is metabolised to 6-TIMP it is further metabolised to 6-MeMPN or 6-TGN
  • 6-MeMPN inhibits de novo purine synthesis
  • 6-TGN acts like a false purine molecule and gets incorporated into DNA
21
Q

what are the effects of azathioprine on immune response?

A

IMPAIRS:

  • cell-mediated and antibody-mediated immune responses
  • lymphocyte proliferation
  • mononuclear cell infiltration
  • synthesis of antibodies

ENHANCES:
- T-cell apoptosis

22
Q

how effective is the treatment of UC with azathioprine?

A
  • some success

- no real reason to use it if response is good with 5-ASA

23
Q

how effective is the treatment of CD with azathioprine?

A
  • no benefit at all in active disease

- mainly used to maintain remission

24
Q

what are the unwanted effects of azathioprine?

A
  • pancreatitis
  • bone marrow suppression
  • hepatotoxicity
  • increased risk of lymphoma and skin cancers
25
Q

what metabolites of azathioprine specifically cause unwanted effects?

A
  • 6-MeMPN is hepatotoxic
  • 6-TU becomes toxic when taken with allopurinol (used to treat gout)
  • 6-TGN causes myelosuppression
26
Q

how can the microbiome be manipulated?

A
  1. nutrition based therapies (e.g. consuming probiotic-rich foods)
  2. faecal microbiota replacement therapies (FMT) - repopulating a patient’s bowel with healthy gut flora
  3. antibiotic treatment with rifaximin - interferes with bacterial transcription by binding to RNA polymerase, induces and sustains remission in moderate Crohn’s disease
27
Q

what biologic therapies now exist to treat IBD?

A
  • anti-TNF-a antibodies
  • other antibodies (though some have more side-effects)
  • humanised antibodies
28
Q

how do anti-TNF-a antibodies work in IBD?

A
  • antibodies mop up any soluble TNF-a before it can bind and activate receptors
  • reduces downstream inflammatory events
  • also binds to membrane associated TNF-a –> induces cytolysis of cells expressing TNF-a
  • promotes apoptosis of activated T cells
29
Q

describe the pharmacokinetics of infliximab (anti-TNF-a antibody)

A
  • given intravenously
  • has a very long half life (9.5 days)
  • most patients relapse after 8-12 weeks so an infusion needs to be repeated every 8 weeks
30
Q

what are the problems with anti-TNF-a antibodies?

A
  • evidence that up to 50% of responders lose response within 3yrs
  • loss of response is due to production of anti-drug antibodies and increased drug clearance
31
Q

what are the adverse effects associated with anti-TNF-a?

A
  • increase in incidence of TB
  • risk of reactivating dormant TB
  • increased risk of septicaemia
  • worsening heart failure
  • risk of demyelinating disease (MS)
  • increased risk of malignancy
  • can be immunogenic

YR2 LCRS Pharmacology (32 decks)

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