Transcript Inflammatory Bowel Disease

Inflammatory Bowel
Disease
Inflammatory bowel disease
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Ulcerative colitis
- diffuse mucosal inflammation
- limited to colon
- defined by location (eg proctitis;pancolitis)
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Crohn’s disease
-
patchy transmural inflammation
fistulae; strictures
any part of GI tract
defined by location or pattern
Treatment options
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2.
3.
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7.
Aminosalicylates
Corticosteroids
Thiopurines
Ciclosporin
Methotrexate
Infliximab
Surgery
Aminosalicylates
MOA:
precise MOA unknown
act on epithelial cells; anti-inflammatory
modulate release of cytokines and reactive
oxygen species
Sulphasalazine
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Sulfapyridine + 5-aminosalicylic acid
Cleaved in colon by bacterial action
5-ASA poorly absorbed active moiety
Sulfapyridine absorbed side effects
Newer formulations
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Mesalazine (5-ASA)
Balsalazide (a prodrug of 5-ASA)
Olsalazine (5-ASA dimer)
Pharmacological properties
Oral; enema; suppositories
 PH dependent release/resin coated
(eg Asacol; caution with lactulose Ph)
 Time controlled release (eg Pentasa)
 Delivery by carrier molecules (eg
Sulphasalazine;olsalazine;balsalazide)
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Indications
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Maintaining remission in UC
Reduce risk of colorectal cancer by 75%
(long term Rx for extensive disease)
Less effective for maintenance in CD
Inducing remission in mild UC/CD
(higher doses)
Contraindications
/cautions
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5-ASA
- Salicylate hypersensitivity
Sulfapyridine
- G6PD deficiency (haemolysis)
- Slow acetylator status ( risk of
hepatic and blood disorders)
Adverse effects - 5-ASA
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Dose-related (10-45%)
- headache, nausea, epigastric pain, diarrhoea*
Idiosyncratic (rare)
- acute pancreatitis; hepatitis; myocarditis;
pericarditis; eosinophilia; fibrosing alveolitis;
interstitial nephritis; nephrotic syndrome
- peripheral neuropathy
- blood disorders
- skin reactions – lupus like syndrome; StevensJohnson syndrome; alopecia
Blood disorders
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Agranulocytosis; aplastic anaemia;
leucopenia; neutropenia;
thrombocytopenia; methaemoglobinemia
Patients should advised to report any
unexplained bleeding; bruising; purpura;
sore throat; fever or malaise
Steven’s Johnson
syndrome
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immune-complex–
mediated
hypersensitivity
erythema
multiforme
target lesions,
mucosal
involvement
Adverse effects - sulfapyridine
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Heinz body anaemia; Megaloblastic anaemia
Hypersensitivity reactions
Orbital oedema
Renal reactions
Neurological reactions
Oligospermia
Orange coloured urine & tears
Sulfasalazine
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Modest therapeutic advantage in
maintaining remission
Overall newer agents have comparable
efficacy and better tolerability
Prescribing usually confined to
selected cases
eg concomitant arthritis
Corticosteroids
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MOA: enter cells and bind to and activate
specific cytoplasmic receptors
Steroid-receptor dimers enter cell nucleus
Activate steroid-responsive elements in DNA
Gene repression or induction  antiinflammatory effects
Anti-inflammatory effects take several hours
Pharmacological
properties
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Prednisolone oral/ enema
Hydrocortisone iv
Budesonide (poorly absorbed – used
for iliocaecal CD/ UC)
Indications
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Moderate to severe relapse UC & CD
No role in maintenance therapy
Combination oral and rectal
No added benefit over 40mg /day
<15mg ineffective
Rapid reduction a/w relapse
Corticosteroids
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 inflammation
 healing
Na retention/ K loss / Ca loss
 gluconeogenesis – diabetogenic
 catabolism
Redistribution of fat – Cushingoid appearance
Reduced endogenous steroids – withdrawal
a/w acute adrenal insufficiency
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© 2005 Elsevier
Thiopurines
Azathioprine
 MOA: inhibit ribonucleotide synthesis;
induce T cell apoptosis by modulating
cell (Rac1) signalling
 Metabolised to mercaptopurine
Indications
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Unlicensed indication (specialist supervision)
Steroid sparing agents
 two courses of steroids in 1 year
Relapse at steroid dose < 15mg
Relapse within 6 weeks of stopping
Post-op for complicated CD
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Active disease CD/UC
Maintenance of remission CD/UC
Generally continue treatment x 3-4years
Adverse effects
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Flu-like symptoms (20%)
- occur at 2-3 weeks; cease on withdrawal
Hepatotoxicity; pancreatitis (<5%)
Leucopenia (3%) – myelotoxicity
- determined by TPMT activity
- weekly FBC x 8 weeks
- 3 monthly thereafter
- warn patients re: sore throat/fever
Ciclosporin
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Indicated in Severe UC (Unlicensed)
No value in CD
Controversial
MOA:inhibitor of calcineurin preventing
clonal expansion of T cells
S/E dose dependent
nephrotoxicity;hepatotoxicity;hypertension;
hypertrichosis; gingival hypertrophy etc.
Need to monitor BP; FBC/ RF and levels
Methotrexate
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Inducing remission/preventing relapse in CD
(Unlicensed indication)
Refractory to or intolerant of Azathioprine
MOA: inhibitor of dihyrofolate reductase;
anti-inflammatory
S/E: myelosupression*;mucositis;GI;
hepatotoxicity; pneumonitis
Co-administration of folinic acid reduces
myelosupression;mucositis
Infliximab
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Indicated active and fistulating CD
- in severe CD refractory or intolerant
of steroids & immunosupressants
- for whom surgery is inappropriate
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MOA: anti-TNF monoclonal antibody
Potent anti-inflammatory
S/E: infusion reactions/anaphylaxis;
infection (TB reactivation; overwhelming
sepsis) ?malignancy
Management of UC
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Acute to induce remission
4.
oral +- topical 5-ASA
+- oral corticosteroids eg 40mg prednisolone
Azathioprine (Chronic active)
iv steroids/Colectomy/ ciclosporin (severe)
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Maintaining remission
1.
2.
3.
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oral +- topical 5-ASA
+- Azathioprine (frequent relapses)
Management of CD
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Acute to induce remission
oral high dose5-ASA
+- oral corticosteroids reducing over 8/52
Azathioprine (Chronic active)
Methotrexate (intolerant of azathioprine)
iv steroids/ metronidazole/elemental diet/surgery/infliximab
Maintaining remission
Smoking cessation
oral 5-ASA limited role
+- Azathioprine (frequent relapses)
Methotrexate (intolerant of azathioprine)
Infliximab infusions (8 weekly)
Biliary disease
Gallstones
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Laparoscopic cholecystectomy
ERCP
Bile acids
Ursodeoxycholic acid
Chenodeoxycholic acid
MOA: dissolve non-calcified cholesterol
gallstones
Ursodeoxycholic acid
Indications
1. Gallstones
- unimpaired gallbladder function
- small radioleucent stones
- mild symptoms unamenable surgery
- recur in 25%
2. Primary biliary cirrhosis
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S/E diarhoea
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Colestyramine
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Anion exchange resin
MOA: Non-absorbed, forms insoluble
complex with bile acids
Ind: pruritis of primary biliary
cirrhosis; diarrhoea in Crohn’s disease;
hyperlipidaemia
S/E: hyperchloraemic acidosis
Int: impairs drug absorption
Pancreatic supplements
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Pancreatin – porcine pancreatin
Ind: cystic fibrosis; chronic pancreatitis
Inactivated by gastric acid
S/E GI; hypersensitivity