DRUG TREATMENT OF INFLAMMATORY BOWEL DISEASE. Objectives Describe the mechanism of action, pharmacokinetics and adverse effects of drugs in IBD.

DRUG TREATMENT OF

INFLAMMATORY BOWEL

DISEASE

Objectives Describe the mechanism of action,

pharmacokinetics and adverse effects of drugs in IBD

INFLAMMATORY BOWEL DISEASE

Ulcerative Colitis

Crohn’s disease

Inflammatory bowel disease

Inappropriate inflammatory response to intestinal microbes in a genetically susceptible host

Ulcerative colitis

- diffuse mucosal inflammation

- limited to colon

- defined by location (eg proctitis;pancolitis)

Crohn’s disease

- patchy transmural inflammation

- fistulae, strictures

- any part of GI tract

AIMS OF THERAPY

Suppress inflammatory response

Suppress the immune reaction

Aminosalicylates corticosteroids

Acute maintenance acute

Aminosalicylates

• precise MOA unknown

• act on epithelial cells

• anti-inflammatory

• modulate release of cytokines and reactive oxygen species

Aminosalicylates Local effect on mucosa in reducing inflammation

Sulfasalazine Mesalamine

Olsalazine

Aminosalicylates

Sulfasalazine Mesalamine

Olsalazine

Aminosalicylates

Sulphasalazine Broken down by gut bacterial azoreductase to 5-

aminosalicylate & sulphapyridine

SULFASALAZINE

Bacterial Flora (Colon)

Bacterial azoreductase

Sulfapyridine 5-aminosalicylic Acid

Absorbed Acts through the lumen

Systemic Adverse Effect Anti-inflammatory Effect

Aminosalicylates

5-ASA absorbed in small intestine

Acetylated by N- acetyltransferase-1

Excreted in urine

Indications 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 5-ASA

- Salicylate hypersensitivity Sulfapyridine

- G6PD deficiency (haemolysis)

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

Adverse effects

Dose-related

Idiosyncratic (rare)

- blood disorders

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

Blood disorders 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 immune-complex–

mediated hypersensitivity

erythema multiforme

target lesions, mucosal involvement

Newer formulations Mesalazine (5-ASA)

Balsalazide (a prodrug of 5-ASA)

Olsalazine (5-ASA dimer)

Mesalazine Available as

Enteric-coated tablets (for ileal Crohn’s disease) Slow release tablets (for proximal bowel Crohn’s) Enemas, suppositories (for distal colonic disease)

Used when sulphasalazine can not be tolerated

Sulfasalazine Oral use

Mesalamine (5-aminosalicylic acid). Oral delayed release capsules Enema

Olsalazine. 5-ASA-n=n-5-ASA Bacterial flora breaks it into 5-ASA

Aminosalicylates

Anti-inflammatory &Immunosuppressive Drugs

Corticosteroids

Prednisolone

Hydrocortisone

Corticosteroids

USES Remission Induction

Route of Administration

Oral

Intravenous

Topical (Enema)

Indications Moderate to severe relapse UC & CD

No role in maintenance therapy

Combination oral and rectal

Indications

Immunomodulators

Azathioprine

Cyclosporine

Infliximab (Anti-TNF-)

Thiopurines

Azathioprine

MOA: inhibit ribonucleotide synthesis; induce T cell apoptosis by modulating cell (Rac1) signalling

Indications Steroid sparing agents

Active disease CD/UC

Maintenance of remission CD/UC

Generally continue treatment x 3-4years

Ciclosporin MOA:inhibitor of calcineurin

preventing clonal expansion of T cells

Indicated in Severe UC

No value in CD

Methotrexate MOA: inhibitor of dihyrofolate reductase;

anti-inflammatory

Inducing remission/preventing relapse in CD

Refractory to or intolerant of Azathioprine

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

of steroids & immunosupressants - for whom surgery is inappropriate

MOA: anti-TNF monoclonal antibody

Potent anti-inflammatory

Antibiotics Metronidazole Ciprofloxacin Clarithromycin

“Probiotics” (administration of “healthy” bacteria)

Summary

Drugs for IBD Aminosalicylates Glucocorticoids Immunosuppressives Cytokine modulators Antibiotics

Management of UC

to induce remission

1. oral +- topical 5-ASA

2. +- oral corticosteroids

3. Azathioprine

4. iv steroids/Colectomy/ ciclosporin (severe)

Maintaining remission

1. oral +- topical 5-ASA

2. +- Azathioprine (frequent relapses)

Management of CD

to induce remission

1. oral high dose of 5-ASA

1. +- oral corticosteroids reducing over 8/52

2. Azathioprine

3. iv steroids/ metronidazole/elemental diet/surgery/infliximab

Maintaining remission

+- Azathioprine (frequent relapses)

Methotrexate (intolerant of azathioprine)

Infliximab infusions (8 weekly)