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Y2 LCRS Pharmacology and Therapeutics > inflammatory bowel disease > Flashcards

inflammatory bowel disease Flashcards

inflammatory bowel disease medication: list the major classes of drugs used in the treatment of IBD, their mechanisms of action and their associated side-effects

1
Q

3 supportive therapies for acutely sick IBD patient

A

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

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2
Q

3 symptomatic therapies against active disease and prevent remission

A

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

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3
Q

2 potentially curative therapies

A

microbiome manipulation, biologic therapies

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4
Q

2 examples of aminosalicylates used to treat IBD

A

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

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5
Q

role of aminosalicylates

A

anti-inflammatory

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6
Q

where is mesalazine absorbed

A

small bowel and colon

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7
Q

what metabolises olsalazine and where is it absorbed

A

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

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8
Q

describe anti-inflammatory actions of aminosalicylates

A

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)

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9
Q

what are aminosalicylates effective at in UC

A

induction and maintenance of remission with minimal adverse side effects

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10
Q

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

A

combined oral and rectal administration

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11
Q

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

A

rectal

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12
Q

aminosalicylates vs glucocorticoids in treating UC

A

aminosalicylates are better

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13
Q

what are aminosalicylates ineffective at in CD

A

inducing remission

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14
Q

aminosalicylates vs glucocorticoids in treating CD

A

glucocorticoids are better

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15
Q

3 examples of glucocorticoids used to treat IBD

A

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

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16
Q

role of glucocorticoids

A

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

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17
Q

what hormone are glucocorticoids derived from

A

cortisol

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18
Q

mechanism of glucocorticoid action

A

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

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19
Q

impact of glucocorticoids in IBD

A

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

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20
Q

relative safety of budesonide vs prednisolone

A

budesonide safer than prednisolone as not absorbed

21
Q

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

A

standard oral glucocorticoids

22
Q

use of glucocorticoids in UC

A

avoided as aminosalicylates are better

23
Q

use of glucocorticoids in CD

A

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)

24
Q

example of immunosuppresive prodrug used to treat IBD

A

azathioprine

25
Q

what activates azathioprine, and what drug is produced

A

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

26
Q

function of 6-mercaptopurine (6-MP)

A

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

27
Q

what 4 things does 6-mercaptopurine impair in immune response

A

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

28
Q

what does 6-mercaptopurine enhance in immune response

A

T cell apoptosis

29
Q

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

A

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

30
Q

4 unwanted effects of azathioprine

A

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

31
Q

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

A

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)

32
Q

3 strategies used to minimise unwanted side effects of glucocorticoids

A

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

33
Q

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

A

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

34
Q

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

A

anti-TNFa antibodies e.g. infliximab

35
Q

3 therapies which manipulate biome as potentially curative IBD therapy

A

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

36
Q

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

A

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

37
Q

describe nutrition-based (probiotic) therapies

A

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

38
Q

describe use of faecal microbiota replacement

A

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

39
Q

example of antibiotic treatment

A

rifaxamin

40
Q

what does rifaxamin treatment do cellularly

A

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

41
Q

describe use of rifaxamin treatment

A

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)

42
Q

mechanisms of action of anti-TNFa antibodies in IBD

A

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

43
Q

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

A

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

44
Q

what are anti-TNFa very good for maintaining in CD

A

fistula closure

45
Q

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

A

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

46
Q

problem with anti-TNFa antibodies

A

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

47
Q

7 adverse effects of infliximab (anti-TNFa antibody)

A

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

48
Q

what drug reduces immunogenic risk of infliximab

A

azothiaprine (immunosuppressive), so combined early on

49
Q

4 new targets for IBD therapies

A

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

Y2 LCRS Pharmacology and Therapeutics (68 decks)

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