Treatment of inflammatory bowel disorders Flashcards
Treatment options for IBDs
4 key classes:
Anti-inflammatories
Immunosuppressants
Antibiotics/probiotics
Biologicals
Corticosteroids
Steroid drugs used to treat acute inflammatory effects in IBD
Mechanisms include:
- Reduced expression of COX enzymes
- Reduced prostaglandin synthesis
- Reduced cytokine production → reduces T cell activation amd proliferation and neutrophil chemotaxis
- Reduced T cell activation and proliferation
- Reduced neutrophil chemotaxis → important for bacterial phagocytosis
Corticosteroid drugs
Drugs of choice: prednisolone, budesonide, hydrocortisone (enema)
Corticosteroid side effects
Corticosteroids not suitable for long-term use due to adverse effects:
- Redistribution of body fat - unequal
- Poor wound healing
- Moon face - alteration in face shape
- Thinning of skin
- Osteoporosis
Aminosalicyclates
First-line for chronic treatment of IBDs
Used to maintain remission from symptoms
Marginally more effective in ulcerative colitis than in Crohn’s disease
Aminosalicyclates - mechanism of action
Reduce inflammation by:
Scavenging free radicals
Inhibiting prostaglandin and leukotriene production
Decreasing neutrophil chemotaxis
Blocking superoxide generation - causes stress to cells
Aminosalicyclate drugs
Main compounds: , mesalazine, olsalazine, balsalazine, sulfasalazine
Active moiety is 5-aminosalicylic acid (5-ASA)
Mesalazine = 5-ASA itself
Olsalazine = dimer of 5-ASA
Balsalazine = pro-drug of 5-ASA
Aminosalicyclate - side effects
May cause diarrhoea, salicylate sensitivity and interstitial nephritis
5-ASA not absorbed; systemic side effects caused by sulphapyridine → metabolism, occurs as a result of bacteria that exists in the colon
Immunosuppressants
Used in severe cases of IBD, after failure of aminosalicylates
Drugs more commonly used in rheumatoid arthritis, some leukaemias (and other cancers) and organ transplantation
Thiopurines (azathioprine, 6-mercaptopurine)
Methotrexate
Cyclosporin A
Azathioprine
active metabolite is 6-thioguanine, purine antagonist, interferes with DNA and RNA synthesis, inhibits proliferation of T cells and B cells → due to irregular DNA replication - cell dies
Methotrexate
inhibits purine metabolism, inhibits T cell activation, down-regulates B cells, reduces production of multiple cytokines - particularly pro-inflammatory cytokines
Cyclosporin A
used in ulcerative colitis unresponsive to steroids, reduces T cell activation and reduces release of interleukins - only given when patient is unresponsive to steroids
Antibiotics
Antibiotics used to treat septic complications (i.e. abscesses which cause internal bleeding) in IBD
May also be useful in primary disease process in Crohn’s disease but not effective in ulcerative colitis - although used commonly
Antibiotics - mechanism of action
Benefits assume bacterial involvement in pathogenesis of the disease and include:
Decreased concentrations of bacteria in the gut lumen → attempt to favour good bacteria in gut but immune system may still react to these
Altered composition of microbiota to favour beneficial bacteria
Decreased bacterial tissue invasion
Treatment of micro-abscesses
Probiotics
Probiotic drinks (i.e. yogurts) suggested to be beneficial
Main antibiotics used in Crohn’s disease
Metronidazole
Ciprofloxacin
Clarithromycin
Clarithromycin
may have an additional immunomodulatory action; alters cytokine expression and macrophage activation
Fecal microbiota transplantation
used in C. difficile infection, may be effective in Crohn’s disease
Biologics
use of antibodies
increasingly common, particularly patients with late stage IBD
Treatment of many immune and inflammatory disorders has been revolutionised by use of monoclonal antibodies (mAbs)
Infliximab, adalimumab and certolizumab licensed for treatment of Crohn’s disease and ulcerative colitis
Monoclonal antibodies against TNF-a; bind with high affinity to soluble & transmembrane forms of TNF-a and prevent interaction with its receptor → stimulates pro-inflammatory pathways, stops TNF receptor signalling
Expensive, often restricted to severe IBD that is unresponsive to other medications
Infliximab
chimera of mouse and human antibodies, human backbone with mouse recognition sites – anti-TNFa
Adalimumab
fully human mAb, less effective than infliximab - anti-TNFa
Certolizumab
human Fab (fragment antigen binding) – anti-TNFa
Vedolizumab
Acts on T helper cell-specific integrins to inhibit their localisation through the epithelial layer - inhibits downstream activation
Thereby stopping excessive inflammation
Ustekinumab
Binds IL-12 and IL-23
Inhibits cytokine binding to receptor on immune cells - competitive inhibitor for these receptors, preventing IL-23 and IL-12 binding
Decreases activation of immune system
