Pharmacology 13c – Inflammatory Bowel Disease
Anil Chopra
1. Describe the factors that impinge on the development of peptic ulcer disease.
2. Explain why antibiotics feature prominently in the treatment of peptic ulcer disease.
3. Using named examples, explain, with the use of a clearly labelled diagram, the mechanisms by which proton pump inhibitors and histamine (H2) receptor antagonists promote the healing of gastric ulcers
4. Explain why misoprostol may be used in the treatment of iatrogenic peptic ulcer disease.
5. Describe the mechanisms by which sucralphate and bismuth chelate are thought to be useful anti-ulcer drugs.
6. Provide two examples of ‘triple therapy’ for peptic ulcer disease.
7. What do you understand by the term ‘gastroesophageal reflux disease’ and how may it be treated?
There are 2 main types of bowel disease however the distinction is not definite in all patients:
-Ulcerative colitis
-Crohn’s disease
These are both autoimmune diseases due to defective interaction between mucosal immune system and gut flora. Both are thought to have a genetic component to the cause.
There are no abcesses, fistulae or fissures.
There are over 2 x 104 microbes in the gut and the immune system must distinguish between those which are pathogenic and non-pathogenic. If the response is excessive then inflammation will result.
Ulcerative Colitis
The autoimmune reaction in ulcerative colitis is mediated by Th2 cell (helper cells) releasing cytokines especially IL-3 (interleukin 3). These cells have limited capacity to expand as there is no defect in apoptosis.
The inflammation takes place in the mucosa and submucosa, starting from the rectum it spreads proximally and continuously in the colon.
Surgery is normally curative.
Crohn’s Disease
The autoimmunity in Crohn’s disease is normally mediated by Th1 cells
(t-helper cells) which also release cytokines especially TNFα and IFNγ. These T-cells expand increasingly due a defect in apoptosis.
The inflammation is not confined to the mucosa but can spread anywhere from the large to the small intestine and may be patchy and discontinuous.
Abscesses, fissures and fistulae are common and the inflammation may recur even after surgery and the condition is less responsive to drugs.
Epidemiology
•Incidence: 10 - 20 new cases/100,000 population/year
•Prevalence: 100 - 200 /100,000 population
•UC is more common than CD
•Peak incidence 20 – 40 years
•More common in women
•Increased incidence in first degree relatives
•Marked differences between ethnic groups
Signs and Symptoms
Rectal bleeding with mucous discharge
Diarrhoea, abdominal pain, anorexia
Weight loss, fever, other extra-GIT symptoms
Rarely fatal, but dramatically reduces quality of life.
Medical Treatment for Inflammatory Bowel Disorders
Supportive therapies: acute
Fluid/electrolyte replacement
Blood transfusion/ oral iron
Antibiotics
Maintenance of remission.
Symptom Treatment
Glucocorticoids e.g. prednisolone
Aminosalicylates e.g. Mesalazine
Immunosuppressives e.g. azathioprine
Curative therapies
Anti-TNFαe.g. Infliximab
Glucocorticoids
Names
Prednisolone, Fluticasone, budesonide
Uses
Anti-inflammatory and immunosuppressive, therefore used in IBD.
Mode of Action
As they are derived from the hormone cortisol, they generally have stressor actions. They reduce the influx and activation of pro-inflammatory cells by increasing transcription of genes which code for anti inflammatory proteins (e.g. lipocortin-1) and by decreasing transcription of genes which code for pro-inflammatory cytokines.
This results in a reduction in the production of adhesion molecules on endothelial cells and leukocytes and a reduction in production of some chemokines. There is a reduction in the mediates with cause vasodilation, swelling, inflammatory cell recruitment and tissue degredation. Other proteins that are inhibited include:
–Some cytokines and their receptors (such as IL-1 and TNFα)
–Proteolytic enzymes (such as elastase)
–Enzymes catalysing mediator synthesis (eg cyclo-oxygenase)
–Eicosanoids (such as prostaglandins and leukotrienes)
–Nitric oxide
Their immunosuppressive functions are brought about by:
•Reduced antigen presentation
•Reduced production of mediators (e.g. IL-2, IL-4, IFNγ ) resulting in …
•Reduced cell proliferation and clonal expansion
Side Effects
Osteoporosis
- increase osteoclast activity
- decrease osteoblast activity
Increased risk of Gastric ulceration
- decrease prostaglandins in stomach
Suppression of HPA axis
- negative feedback on pituitary & hypothalamus
Type II diabetes
- oppose actions of insulin; increase gluconeogenesis
- increase glycogenolysis
Hypertension
- cause Na+, Cl-, water retention, increase adrenoceptors & thus response to catecholamines
Susceptibility to infection
- immunosuppression
Skin thinning, bruising and slow wound healing
- reduced connective tissue turnover and repair
Muscle wasting and buffalo hump
- reduced storage of glucose in muscle
- increased fat deposition
Minimising Side Effects
•Start with high dose and taper down
•Use drug with high therapeutic index (e.g. Fluticasone)
•Administer topically - fluid or foam enemas or suppositories
•Use an oral or topically administered drug which is degraded locally e.g.Budesonide
Aminosalicylates
Name
Sulfasalazine, Mesalazine, olsalazine,
Usage
•Mainly used to maintain remission and prevent relapse
•Limited use in the treatment of active IBD
•Anti-inflammatory
•No immunosuppressive action
Mode of Action
Act by reducing the recruitment of inflammatory leukocytes and reduction in production of inflammatory mediators.
Reduce synthesis of eicosanoids
Reduce free radical levels
Reduce inflammatory cytokine production
Reduce leukocyte infiltration
No immunosuppressive effects
Sulfasalazine was the first aminosalicylate. It was split into 2 parts:
•5-aminosalicylic acid (5-ASA) which caused the therapeutic effects
•Sulfapyridine caused the side effects
The other drugs were developed using the active part. These are activated by gut flora therefore NO SIDE EFFECTS
Mesalazine Purely active 5- ASA
Olsalazine 2 linked 5 – ASA molecules
Pharmacokinetics
-Administered topically or orally in capsules that are pH dependent and therefore are only activated when they get into the small intestine.
-Mesalazine is release slowly as it travels through the bowel as it can come in slow release microspheres
Immunosuppressive Agents
Name - azathioprine
Usage–an immunosuppressant. Mainly used in Crohn’s disease to maintain remission.
Mode of Action
It is degraded by the gut flora to its active compound (6 – mercaptopurine) where it interferes with purine biosynthesis and hence DNA synthesis and hence the cell cycle. It therefore inhibits
–cell- and antibody-mediated immune responses
–lymphocyte proliferation
–mononuclear cell infiltration
–synthesis of antibodies
Also enhances T-cell apoptosis
Side effects and Pharmacokinetics
Bone marrow suppression
If administered with drugs which inhibit xanthine oxidase e.g. allopurinolas blood dyscrasias can result (simply means abnormal blood mixtures).
Curative Therapies
Name – Infliximab
Usage–used as treatment for Crohn’s disease.
Mode of Action–It is an anti TNFα. TNFα plays a major role in the pathogenesis of Crohn’s disease with regards to the synthesis of cytokines and activation of leukocytes. With TNFα inhibited, these will not occur and the progression of the disease will be halted. As it also binds to the TNFα associated with the membrane it inhibits complement activation and promotes apoptosis of T cells.
Side Effects and Pharmacokinetics
-Administered i.v.
-½ life of 9.5 days
-effects last for up to a month therefore given once every 8 weeks.
Side effects
•4x - 5x increase in incidence of tuberculosis and other infections
•Must not be used if there is evidence of sepsis (e.g. an abcess) because of the risk of septicaemia
•Worsening of heart failure
•Can be immunogenic – therefore given with azathioprine
•Should only be used by specialists where adequate resuscitation facilities available because of the risk of anaphylaxis