Inflammatory Bowel Inflammatory Bowel DiseaseDisease

Inflammatory bowel Inflammatory bowel diseasedisease

Ulcerative colitisUlcerative colitis - diffuse mucosal inflammation - diffuse mucosal inflammation

- limited to colon- limited to colon

- defined by location (eg proctitis;pancolitis)- defined by location (eg proctitis;pancolitis) Crohn’s diseaseCrohn’s disease - patchy transmural inflammation- patchy transmural inflammation

- fistulae; strictures- fistulae; strictures

- any part of GI tract- any part of GI tract

- defined by location or pattern- defined by location or pattern

Treatment optionsTreatment options

1.1. AminosalicylatesAminosalicylates

2.2. CorticosteroidsCorticosteroids

3.3. ThiopurinesThiopurines

4.4. CiclosporinCiclosporin

5.5. MethotrexateMethotrexate

6.6. InfliximabInfliximab

7.7. SurgerySurgery

AminosalicylatesAminosalicylates

MOA: MOA:

precise MOA unknownprecise MOA unknown

act on epithelial cells; anti-inflammatoryact on epithelial cells; anti-inflammatory

modulate release of cytokines and modulate release of cytokines and reactive reactive

oxygen speciesoxygen species

SulphasalazineSulphasalazine

Sulfapyridine + 5-aminosalicylic Sulfapyridine + 5-aminosalicylic acidacid

Cleaved in colon by bacterial Cleaved in colon by bacterial actionaction

5-ASA poorly absorbed active 5-ASA poorly absorbed active moietymoiety

Sulfapyridine absorbed Sulfapyridine absorbed side side effectseffects

Newer formulationsNewer formulations

Mesalazine (5-ASA)Mesalazine (5-ASA) Balsalazide (a prodrug of 5-ASA)Balsalazide (a prodrug of 5-ASA) Olsalazine (5-ASA dimer)Olsalazine (5-ASA dimer)

Pharmacological Pharmacological propertiesproperties

Oral; enema; suppositoriesOral; enema; suppositories PH dependent release/resin coated PH dependent release/resin coated

(eg Asacol; caution with lactulose (eg Asacol; caution with lactulose Ph)Ph) Time controlled release (eg Pentasa)Time controlled release (eg Pentasa) Delivery by carrier molecules (eg Delivery by carrier molecules (eg

Sulphasalazine;olsalazine;balsalazide)Sulphasalazine;olsalazine;balsalazide)

IndicationsIndications

Maintaining remission in UCMaintaining remission in UC Reduce risk of colorectal cancer by Reduce risk of colorectal cancer by

75% (long term Rx for extensive 75% (long term Rx for extensive disease)disease)

Less effective for maintenance in CDLess effective for maintenance in CD Inducing remission in mild UC/CD Inducing remission in mild UC/CD

(higher doses)(higher doses)

ContraindicationsContraindications/cautions/cautions 5-ASA5-ASA

- Salicylate hypersensitivity- Salicylate hypersensitivity SulfapyridineSulfapyridine

- G6PD deficiency (haemolysis)- G6PD deficiency (haemolysis)

- Slow acetylator status (- Slow acetylator status ( risk of risk of hepatic and blood disorders)hepatic and blood disorders)

Adverse effects - 5-Adverse effects - 5-ASAASA Dose-related (10-45%)Dose-related (10-45%)

- headache, nausea, epigastric pain, diarrhoea*- headache, nausea, epigastric pain, diarrhoea* Idiosyncratic (rare)Idiosyncratic (rare)

- acute pancreatitis; hepatitis; myocarditis; - acute pancreatitis; hepatitis; myocarditis; pericarditis; eosinophilia; fibrosing alveolitis; pericarditis; eosinophilia; fibrosing alveolitis; interstitial nephritis; nephrotic syndromeinterstitial nephritis; nephrotic syndrome

- peripheral neuropathy- peripheral neuropathy

- blood disorders- blood disorders

- skin reactions – lupus like syndrome; Stevens-- skin reactions – lupus like syndrome; Stevens-Johnson syndrome; alopeciaJohnson syndrome; alopecia

Blood disordersBlood disorders

Agranulocytosis; aplastic anaemia; Agranulocytosis; aplastic anaemia; leucopenia; neutropenia; leucopenia; neutropenia; thrombocytopenia; thrombocytopenia; methaemoglobinemiamethaemoglobinemia

Patients should advised to report any Patients should advised to report any unexplained bleeding; bruising; unexplained bleeding; bruising; purpura; sore throat; fever or malaisepurpura; sore throat; fever or malaise

Steven’s Johnson Steven’s Johnson syndromesyndrome

immune-immune-complex–complex–mediated mediated hypersensitivity hypersensitivity

erythema erythema multiforme multiforme

target lesions, target lesions, mucosal mucosal involvementinvolvement

Adverse effects - Adverse effects - sulfapyridinesulfapyridine

Heinz body anaemia; Megaloblastic Heinz body anaemia; Megaloblastic anaemiaanaemia

Hypersensitivity reactionsHypersensitivity reactions Orbital oedemaOrbital oedema Renal reactionsRenal reactions Neurological reactionsNeurological reactions OligospermiaOligospermia Orange coloured urine & tearsOrange coloured urine & tears

SulfasalazineSulfasalazine

Modest therapeutic advantage in Modest therapeutic advantage in maintaining remissionmaintaining remission

Overall newer agents have Overall newer agents have comparable efficacy and better comparable efficacy and better tolerabilitytolerability

Prescribing usually confined to Prescribing usually confined to selected cases selected cases

eg concomitant arthritis eg concomitant arthritis

CorticosteroidsCorticosteroids

MOA: enter cells and bind to and activate MOA: enter cells and bind to and activate specific cytoplasmic receptorsspecific cytoplasmic receptors

Steroid-receptor dimers enter cell nucleusSteroid-receptor dimers enter cell nucleus Activate steroid-responsive elements in Activate steroid-responsive elements in

DNADNA Gene repression or induction Gene repression or induction anti- anti-

inflammatory effectsinflammatory effects Anti-inflammatory effects take several Anti-inflammatory effects take several

hours hours

Pharmacological Pharmacological propertiesproperties Prednisolone oral/ enemaPrednisolone oral/ enema Hydrocortisone ivHydrocortisone iv Budesonide (poorly absorbed – Budesonide (poorly absorbed –

used for iliocaecal CD/ UC)used for iliocaecal CD/ UC)

IndicationsIndications

Moderate to severe relapse UC & Moderate to severe relapse UC & CDCD

No role in maintenance therapyNo role in maintenance therapy Combination oral and rectalCombination oral and rectal No added benefit over 40mg /dayNo added benefit over 40mg /day <15mg ineffective<15mg ineffective Rapid reduction a/w relapseRapid reduction a/w relapse

CorticosteroidsCorticosteroids

inflammationinflammation healinghealing Na retention/ K loss / Ca lossNa retention/ K loss / Ca loss gluconeogenesis – diabetogenicgluconeogenesis – diabetogenic catabolismcatabolism Redistribution of fat – Cushingoid Redistribution of fat – Cushingoid

appearanceappearance Reduced endogenous steroids – withdrawal Reduced endogenous steroids – withdrawal

a/w acute adrenal insufficiencya/w acute adrenal insufficiency

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© 2005 Elsevier

ThiopurinesThiopurines

AzathioprineAzathioprine MOA: inhibit ribonucleotide MOA: inhibit ribonucleotide

synthesis; induce T cell apoptosis synthesis; induce T cell apoptosis by modulating cell (Rac1) by modulating cell (Rac1) signallingsignalling

Metabolised to mercaptopurineMetabolised to mercaptopurine

IndicationsIndications

Unlicensed indication (specialist Unlicensed indication (specialist supervision)supervision)

Steroid sparing agentsSteroid sparing agents two courses of steroids in 1 yeartwo courses of steroids in 1 year

Relapse at steroid dose < 15mgRelapse at steroid dose < 15mg

Relapse within 6 weeks of stoppingRelapse within 6 weeks of stopping

Post-op for complicated CDPost-op for complicated CD

Active disease CD/UCActive disease CD/UC Maintenance of remission CD/UCMaintenance of remission CD/UC Generally continue treatment x 3-4yearsGenerally continue treatment x 3-4years

Adverse effectsAdverse effects

Flu-like symptoms (20%)Flu-like symptoms (20%)

- occur at 2-3 weeks; cease on withdrawal- occur at 2-3 weeks; cease on withdrawal Hepatotoxicity; pancreatitis (<5%)Hepatotoxicity; pancreatitis (<5%) Leucopenia (3%) – myelotoxicityLeucopenia (3%) – myelotoxicity

- determined by TPMT activity- determined by TPMT activity

- weekly FBC x 8 weeks- weekly FBC x 8 weeks

- 3 monthly thereafter- 3 monthly thereafter

- warn patients re: sore throat/fever- warn patients re: sore throat/fever

CiclosporinCiclosporin

Indicated in Severe UC (Unlicensed) Indicated in Severe UC (Unlicensed) No value in CDNo value in CD ControversialControversial MOA:inhibitor of calcineurin preventing MOA:inhibitor of calcineurin preventing

clonal expansion of T cellsclonal expansion of T cells S/E dose dependent S/E dose dependent

nephrotoxicity;hepatotoxicity;hypertensinephrotoxicity;hepatotoxicity;hypertension; hypertrichosis; gingival hypertrophy on; hypertrichosis; gingival hypertrophy etc.etc.

Need to monitor BP; FBC/ RF and levelsNeed to monitor BP; FBC/ RF and levels

MethotrexateMethotrexate

Inducing remission/preventing relapse Inducing remission/preventing relapse in CD (Unlicensed indication) in CD (Unlicensed indication)

Refractory to or intolerant of Refractory to or intolerant of AzathioprineAzathioprine

MOA: inhibitor of dihyrofolate MOA: inhibitor of dihyrofolate reductase; anti-inflammatoryreductase; anti-inflammatory

S/E: myelosupression*;mucositis;GI; S/E: myelosupression*;mucositis;GI; hepatotoxicity; pneumonitishepatotoxicity; pneumonitis

Co-administration of folinic acid Co-administration of folinic acid reduces myelosupression;mucositisreduces myelosupression;mucositis

InfliximabInfliximab

Indicated active and fistulating CDIndicated active and fistulating CD - in severe CD refractory or intolerant- in severe CD refractory or intolerant

of steroids & immunosupressantsof steroids & immunosupressants - for whom surgery is inappropriate- for whom surgery is inappropriate

MOA: anti-TNF monoclonal antibodyMOA: anti-TNF monoclonal antibody Potent anti-inflammatoryPotent anti-inflammatory S/E: infusion reactions/anaphylaxis; S/E: infusion reactions/anaphylaxis;

infection (TB reactivation; infection (TB reactivation; overwhelming sepsis) ?malignancyoverwhelming sepsis) ?malignancy

Management of UCManagement of UC

Acute to induce remissionAcute to induce remission1.1. oral +- topical 5-ASAoral +- topical 5-ASA

2.2. +- oral corticosteroids eg 40mg +- oral corticosteroids eg 40mg prednisoloneprednisolone

3.3. Azathioprine (Chronic active)Azathioprine (Chronic active)

4.4. iv steroids/Colectomy/ ciclosporin (severe)iv steroids/Colectomy/ ciclosporin (severe)

Maintaining remissionMaintaining remission1.1. oral +- topical 5-ASAoral +- topical 5-ASA

2.2. +- Azathioprine (frequent relapses)+- Azathioprine (frequent relapses)

Management of CDManagement of CD

Acute to induce remissionAcute to induce remission1.1. oral high dose5-ASAoral high dose5-ASA2.2. +- oral corticosteroids reducing over 8/52+- oral corticosteroids reducing over 8/523.3. Azathioprine (Chronic active)Azathioprine (Chronic active)4.4. Methotrexate (intolerant of azathioprine)Methotrexate (intolerant of azathioprine)5.5. iv steroids/ metronidazole/elemental iv steroids/ metronidazole/elemental

diet/surgery/infliximabdiet/surgery/infliximab Maintaining remissionMaintaining remission1.1. Smoking cessationSmoking cessation2.2. oral 5-ASA limited roleoral 5-ASA limited role3.3. +- Azathioprine (frequent relapses)+- Azathioprine (frequent relapses)4.4. Methotrexate (intolerant of azathioprine)Methotrexate (intolerant of azathioprine)5.5. Infliximab infusions (8 weekly)Infliximab infusions (8 weekly)

Biliary diseaseBiliary disease

GallstonesGallstones

Laparoscopic cholecystectomyLaparoscopic cholecystectomy ERCPERCP Bile acidsBile acids Ursodeoxycholic acidUrsodeoxycholic acid Chenodeoxycholic acidChenodeoxycholic acid MOA: dissolve non-calcified MOA: dissolve non-calcified

cholesterol gallstonescholesterol gallstones

Ursodeoxycholic acid Ursodeoxycholic acid

IndicationsIndications

1. Gallstones1. Gallstones

- unimpaired gallbladder function- unimpaired gallbladder function

- small radioleucent stones- small radioleucent stones

- mild symptoms unamenable surgery- mild symptoms unamenable surgery

- recur in 25%- recur in 25%

2. Primary biliary cirrhosis2. Primary biliary cirrhosis S/E diarhoeaS/E diarhoea

ColestyramineColestyramine

Anion exchange resinAnion exchange resin MOA: Non-absorbed, forms MOA: Non-absorbed, forms

insoluble complex with bile acidsinsoluble complex with bile acids Ind: pruritis of primary biliary Ind: pruritis of primary biliary

cirrhosis; diarrhoea in Crohn’s cirrhosis; diarrhoea in Crohn’s disease; hyperlipidaemiadisease; hyperlipidaemia

S/E: hyperchloraemic acidosisS/E: hyperchloraemic acidosis Int: impairs drug absorptionInt: impairs drug absorption

Pancreatic Pancreatic supplementssupplements Pancreatin – porcine pancreatinPancreatin – porcine pancreatin Ind: cystic fibrosis; chronic Ind: cystic fibrosis; chronic

pancreatitispancreatitis Inactivated by gastric acidInactivated by gastric acid S/E GI; hypersensitivityS/E GI; hypersensitivity