inflammatory bowel disease

Question 1

3 supportive therapies for acutely sick IBD patient

Answer 1

fluids (and electrolyte), blood transfusion/oral iron, nutritional support (malnutrition common)

Question 2

3 symptomatic therapies against active disease and prevent remission

Answer 2

glucocorticoids, aminosalicylates (especially UC), immunosuppressives (especially with biologics/steroids)

Question 3

2 potentially curative therapies

Answer 3

microbiome manipulation, biologic therapies

Question 4

2 examples of aminosalicylates used to treat IBD

Answer 4

mesalazine (5-ASA), olsalazine (2x 5-ASA)

Question 5

role of aminosalicylates

Answer 5

anti-inflammatory

Question 6

where is mesalazine absorbed

Answer 6

small bowel and colon

Question 7

what metabolises olsalazine and where is it absorbed

Answer 7

metabolised by colonic flora into 2 5-ASA molecules, so absorbed in colon

Question 8

describe anti-inflammatory actions of aminosalicylates

Answer 8

binds to membrane receptors and acts as transcription modular to downregulate pro-inflammatory cytokines e.g. TNFa and IL-6 via NF-kB/MAPK pathway, as well as COX-2, so downregulates pro-inflammatory prostaglandins (e.g. PGE2)

Question 9

what are aminosalicylates effective at in UC

Answer 9

induction and maintenance of remission with minimal adverse side effects

Question 10

what routes of administration of aminosalicylates are most effective for generalised UC

Answer 10

combined oral and rectal administration

Question 11

what route of administration of aminosalicylates is most effective for localised UC (proctitis)

Answer 11

rectal

Question 12

aminosalicylates vs glucocorticoids in treating UC

Answer 12

aminosalicylates are better

Question 13

what are aminosalicylates ineffective at in CD

Answer 13

inducing remission

Question 14

aminosalicylates vs glucocorticoids in treating CD

Answer 14

glucocorticoids are better

Question 15

3 examples of glucocorticoids used to treat IBD

Answer 15

prednisolone, fluticasone, budesonide (not absorbed so fewer side effects)

Question 16

role of glucocorticoids

Answer 16

very potent anti-inflammatory and immunosuppressive (if given systemically, chronic administration causes unwanted side effects)

Question 17

what hormone are glucocorticoids derived from

Answer 17

cortisol

Question 18

mechanism of glucocorticoid action

Answer 18

activate IC glucocorticoid receptors which then act as positive or negative transcription factors

Question 19

impact of glucocorticoids in IBD

Answer 19

downregulate pro-inflammatory cytokines, macrophages, T cells etc.

Question 20

relative safety of budesonide vs prednisolone

Answer 20

budesonide safer than prednisolone as not absorbed

Question 21

what glucocorticoids are better than budesondie at inducing remission in active CD

Answer 21

standard oral glucocorticoids

Question 22

use of glucocorticoids in UC

Answer 22

avoided as aminosalicylates are better

Question 23

use of glucocorticoids in CD

Answer 23

induce remission (but likely to get side effects if used to maintain remission), with budesonide preferred if mild (similar potency but metabolised and inactivated locally)

Question 24

example of immunosuppresive prodrug used to treat IBD

Answer 24

azathioprine

Question 25

what activates azathioprine, and what drug is produced

Answer 25

gut flora, producing 6-mercaptopurine (this can also be given directly)

Question 26

function of 6-mercaptopurine (6-MP)

Answer 26

purine antagonist so interferes with DNA synthesis and cell cycle by being metabolised further (inhibit de novo purine synthesis and incorporate itself into DNA)

Question 27

what 4 things does 6-mercaptopurine impair in immune response

Answer 27

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

Question 28

what does 6-mercaptopurine enhance in immune response

Answer 28

T cell apoptosis

Question 29

azathioprine use in IBD, speed of therapeutic onset, and what happens if ineffective

Answer 29

some success in UC, but mainly used to maintain remission in CD as glucocorticoid-sparing (however has slow onset of 3-4 months); if ineffective, move to biological therapies

Question 30

4 unwanted effects of azathioprine

Answer 30

pancreatitis, bone marrow suppression, hepatotoxicity, 4x increased risk of lymphoma and skin cancer

Question 31

what causes unwanted effects of azathioprine, and consequence of using with allopurinol to treat gout

Answer 31

some metabolites (inactive 6-MeMP causes hepatotoxicity, 6-TGN which incorporates into DNA causes myelosuppression); xanthine oxidase converts 6MP to inactive compound, which is inhibited by allopurinol (used to treat gout)

Question 32

3 strategies used to minimise unwanted side effects of glucocorticoids

Answer 32

administer topically (e.g. fluid/foam enema), use low dose in combination with other drug, use oral/topically administered drug with high hepatic first pass metabolism e.g. budesonide so little escapes into systemic circulation

Question 33

4 strategies which give better targeting of drugs to areas of inflammation in long colon with different environments

Answer 33

based on coating system: pH-dependent, pressure/osmotic controlled, time-dependent, prodrug based (some can combine these features)

Question 34

example of biologic therapies (adults) as potentially curative IBD therapy

Answer 34

anti-TNFa antibodies e.g. infliximab

Question 35

3 therapies which manipulate biome as potentially curative IBD therapy

Answer 35

nutrition-based (exclusive enteral nutrition and probiotic therapies), faecal microbiota replacement, antibiotic treatment

Question 36

describe use of nutrition-based (exclusive enteral nutrition) therapies

Answer 36

liquid diet, allows resting of mucosa and recovery of gut flora, unpalatable and hard to maintain, only if patient cannot take steroids for induction of remission

Question 37

describe nutrition-based (probiotic) therapies

Answer 37

different organisms have different effects so difficult to generalise, no evidence for probiotics in CD, weak evidence for maintenance of remission of UC

Question 38

describe use of faecal microbiota replacement

Answer 38

unclear if changed microbiome is cause or effect of IBD; weak evidence for induction in UC, none for maintenance

Question 39

example of antibiotic treatment

Answer 39

rifaxamin

Question 40

what does rifaxamin treatment do cellularly

Answer 40

interfere with bacterial transcription by binding to RNA polymerase (reduces inflammatory mediator mRNA)

Question 41

describe use of rifaxamin treatment

Answer 41

not absorbed from gut, some evidence it induces and sustains remission in moderate CD, may be microbiome modulator (only recommended if complications relating to infection)

Question 42

mechanisms of action of anti-TNFa antibodies in IBD

Answer 42

reduces activation of TNFa receptors in gut (reduces downstream inflammatory events), and binds to membrane associated TNFa to induce cytolysis of cells expressing TNFa and promotes apoptosis of activated T cells

Question 43

pharmacokinetics of infliximab (route of administration, half-life, duration between infusions)

Answer 43

given i.v., long half-life (9.5 days), most patients relapse after 8-12 weeks so repeat infusion every 8 weeks

Question 44

what are anti-TNFa very good for maintaining in CD

Answer 44

fistula closure

Question 45

efficacy of anti-TNFa antibodies for induction and maintaining mucosal healing in UC

Answer 45

benefit, indicating UC may have some Th1 ability as well as Th2

Question 46

problem with anti-TNFa antibodies

Answer 46

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

Question 47

7 adverse effects of infliximab (anti-TNFa antibody)

Answer 47

4-5x increase in TB, risk of reactivating dormant TB, increased risk of septicaemia, worsening heart failure, increased risk of demyelinating disease, increased risk of malignancy, can be immunogenic

Question 48

what drug reduces immunogenic risk of infliximab

Answer 48

azothiaprine (immunosuppressive), so combined early on

Question 49

4 new targets for IBD therapies

Answer 49

integrins, interleukins, interleukin receptors, Janus kinase cytoplasmic cell signalling