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
3 supportive therapies for acutely sick IBD patient
fluids (and electrolyte), blood transfusion/oral iron, nutritional support (malnutrition common)
3 symptomatic therapies against active disease and prevent remission
glucocorticoids, aminosalicylates (especially UC), immunosuppressives (especially with biologics/steroids)
2 potentially curative therapies
microbiome manipulation, biologic therapies
2 examples of aminosalicylates used to treat IBD
mesalazine (5-ASA), olsalazine (2x 5-ASA)
role of aminosalicylates
anti-inflammatory
where is mesalazine absorbed
small bowel and colon
what metabolises olsalazine and where is it absorbed
metabolised by colonic flora into 2 5-ASA molecules, so absorbed in colon
describe anti-inflammatory actions of aminosalicylates
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)
what are aminosalicylates effective at in UC
induction and maintenance of remission with minimal adverse side effects
what routes of administration of aminosalicylates are most effective for generalised UC
combined oral and rectal administration
what route of administration of aminosalicylates is most effective for localised UC (proctitis)
rectal
aminosalicylates vs glucocorticoids in treating UC
aminosalicylates are better
what are aminosalicylates ineffective at in CD
inducing remission
aminosalicylates vs glucocorticoids in treating CD
glucocorticoids are better
3 examples of glucocorticoids used to treat IBD
prednisolone, fluticasone, budesonide (not absorbed so fewer side effects)
role of glucocorticoids
very potent anti-inflammatory and immunosuppressive (if given systemically, chronic administration causes unwanted side effects)
what hormone are glucocorticoids derived from
cortisol
mechanism of glucocorticoid action
activate IC glucocorticoid receptors which then act as positive or negative transcription factors
impact of glucocorticoids in IBD
downregulate pro-inflammatory cytokines, macrophages, T cells etc.
relative safety of budesonide vs prednisolone
budesonide safer than prednisolone as not absorbed
what glucocorticoids are better than budesondie at inducing remission in active CD
standard oral glucocorticoids
use of glucocorticoids in UC
avoided as aminosalicylates are better
use of glucocorticoids in CD
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)
example of immunosuppresive prodrug used to treat IBD
azathioprine
what activates azathioprine, and what drug is produced
gut flora, producing 6-mercaptopurine (this can also be given directly)
function of 6-mercaptopurine (6-MP)
purine antagonist so interferes with DNA synthesis and cell cycle by being metabolised further (inhibit de novo purine synthesis and incorporate itself into DNA)
what 4 things does 6-mercaptopurine impair in immune response
cell and antibody mediated immune responses, lymphocyte proliferation, mononuclear cell infiltration, synthesis of antibodies
what does 6-mercaptopurine enhance in immune response
T cell apoptosis
azathioprine use in IBD, speed of therapeutic onset, and what happens if ineffective
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
4 unwanted effects of azathioprine
pancreatitis, bone marrow suppression, hepatotoxicity, 4x increased risk of lymphoma and skin cancer
what causes unwanted effects of azathioprine, and consequence of using with allopurinol to treat gout
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)
3 strategies used to minimise unwanted side effects of glucocorticoids
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
4 strategies which give better targeting of drugs to areas of inflammation in long colon with different environments
based on coating system: pH-dependent, pressure/osmotic controlled, time-dependent, prodrug based (some can combine these features)
example of biologic therapies (adults) as potentially curative IBD therapy
anti-TNFa antibodies e.g. infliximab
3 therapies which manipulate biome as potentially curative IBD therapy
nutrition-based (exclusive enteral nutrition and probiotic therapies), faecal microbiota replacement, antibiotic treatment
describe use of nutrition-based (exclusive enteral nutrition) therapies
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
describe nutrition-based (probiotic) therapies
different organisms have different effects so difficult to generalise, no evidence for probiotics in CD, weak evidence for maintenance of remission of UC
describe use of faecal microbiota replacement
unclear if changed microbiome is cause or effect of IBD; weak evidence for induction in UC, none for maintenance
example of antibiotic treatment
rifaxamin
what does rifaxamin treatment do cellularly
interfere with bacterial transcription by binding to RNA polymerase (reduces inflammatory mediator mRNA)
describe use of rifaxamin treatment
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)
mechanisms of action of anti-TNFa antibodies in IBD
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
pharmacokinetics of infliximab (route of administration, half-life, duration between infusions)
given i.v., long half-life (9.5 days), most patients relapse after 8-12 weeks so repeat infusion every 8 weeks
what are anti-TNFa very good for maintaining in CD
fistula closure
efficacy of anti-TNFa antibodies for induction and maintaining mucosal healing in UC
benefit, indicating UC may have some Th1 ability as well as Th2
problem with anti-TNFa antibodies
up to 50% responders lose response within 3 years due to production of anti-drug antibodies and increased drug clearance
7 adverse effects of infliximab (anti-TNFa antibody)
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
what drug reduces immunogenic risk of infliximab
azothiaprine (immunosuppressive), so combined early on
4 new targets for IBD therapies
integrins, interleukins, interleukin receptors, Janus kinase cytoplasmic cell signalling
