Pharmacology of Inflammatory Bowel Disease

This section looks at the pharmacology of inflammatory bowel disease; understanding the drugs involved in the management of both Crohn's disease and ulcerative colitis.

Inflammatory bowel disease is a chronic disorder of the gastrointestinal tract, commonly divided into two main conditions: Crohn’s Disease and Ulcerative Colitis. However, despite the similarities between these two conditions, there are notable distinctions worth considering. This section of PharmaFactz aims to provide you with an overview of the pharmacology of inflammatory bowel disease conditions, looking at their differences as well as the various pharmacological interventions currently available. Progressing further, we’ll also take a look at revision questions to help cement some of these key ideas.

First, however, we’ll begin by analysing the differences within inflammatory bowel disease conditions, as this acts as a convenient backdrop in understanding the pharmacology of inflammatory bowel disease itself.

What is Inflammatory Bowel Disease?

As we briefly alluded to earlier, IBD is a family name for a spectrum of different diseases, the two main types being Crohn’s Disease and Ulcerative Colitis. However, there also exists individual disease phenotype’s within each of these categories, further complicating this pathogenesis landscape. The main site of pathogenesis is, of course, the gastrointestinal tract, and it’s from here that most of the recognisable symptoms originate. However, before we begin to understand these nuances, let’s first gain an understanding of what these conditions are and what differences exist between them.

Ulcerative Colitis is a disorder confined to the mucosa and submucosa of the GI tract, with inflammation usually restricted to the large intestine. The extent of colonic involvement varies depending on the individual; however, we do know that the rectum is always involved. In addition, the extent of inflammation in the large bowel is continuous, in other words, it lacks any patchy inflammatory areas. Typical symptoms of ulcerative colitis include bloody diarrhoea, weight loss, and marked fatigue. However, symptoms are not exclusive to the large intestine, as UC patients regularly suffer from uveitis, sacroiliitis, and various dermatological manifestations.

Unlike ulcerative colitis, Crohn’s disease is a transmural granulomatous condition that can affect any part of your gut; therefore, it is much more dispersed than UC. In addition, Crohn’s disease is characterised by discontinuous, segmental, and patchy inflammation, which contrasts against the continuous nature of UC. Perianal disease, such as abscesses and fissures remain common, as too is fistula formation and other forms of stricture. Symptoms, when it affects the colon, include abdominal pain, fatigue, and diarrhoea. However, symptoms vary depending on which part of the gut is involved, with more proximate segments inducing different symptoms, even those not involving diarrhoea itself.

Understanding the differences between ulcerative colitis and Crohn’s disease is central to any reasonable comprehension of the clinical pharmacology of these conditions. Having knowledge of the pathogenesis will help you grasp the mechanisms of the pharmacology treatment options involved. Before we take a look at these treatment options, we’re first going to take a look at the aetiology of these two conditions.

Aetiology of IBD

Below, you’ll find a series of points aiming to summarise the presumed causative factors for both ulcerative colitis and Crohn's disease:

  • Genetic component is significantly stronger for Crohn’s disease than ulcerative colitis.
  • The actual trigger for the disease in susceptible individuals is currently unknown, however, it’s assumed to arise from a lack of immune tolerance in the gut, such as improper management of microbial antigens by the intestinal immune system.
  • The improper immune response is due to an excessive quantity of T-Helper Cells (Type 1) for Crohn’s disease and T-Helper Cells (Type 2) for ulcerative colitis. Th17 lymphocytes have recently been shown to play a role in inflammation and tissue damage for both conditions.
  • Notable deficiency of regulatory T-Cells coupled with excessive manufacture of pro-inflammatory cytokines resulting in secretion of TNFα, as well as IL-1 and IL-6 production by macrophages.
  • The inflammatory response is also augmented by the presence of natural killer T-Cells as well as neutrophil leucocytes.
  • Smoking increases the risk of Crohn’s disease and the frequency of symptomatic events but this risk is slightly decreased in patients with ulcerative colitis.
  • The enteric nervous system plays a role in conjunction with the immune system in disturbing the bowel as well as maintaining the effects of inflammation.

Clinical pharmacology treatment options for inflammatory bowel disease have two main intentions: to induce remission as well as to maintain this remission. In the pharmacology options laid out below, you’ll find that Crohn’s disease is less responsive to many of these drugs in comparison to ulcerative colitis.

Drugs for Inflammatory Bowel Disease

In this section, we’re going to take a look at the clinical pharmacology of both Crohn’s disease and ulcerative colitis by studying five categories of drugs involved in both its treatment and management.

ü Aminosalicylates
ü Corticosteroids
ü Cytokine Inhibitors
ü Immunosuppressants
ü Antibacterials

 

Aminosalicylates

Examples: Balsalazide, Mesalazine, Olsalazine, Sulfasalazine

The aminosalicylate drugs all share one common anti-inflammatory constituent: 5-Aminosalicylic Acid. The drugs listed above are all designed with the core idea of delivering 5-ASA to the lower bowel.

Sulfasalazine was the first drug to demonstrate efficacy against inflammatory bowel disease. It works through the use of colonic bacteria which act to cleave the azo bond into two further components: 5-ASA and Sulfapyridine. This latter component, of course, is also responsible for most of the unwanted effects of Sulfasalazine, such as folate deficiency, temporary infertility, agranulocytosis and anaemia. However, sulfapyridine itself has no therapeutic benefit.

The mechanism of action of this class of drugs has not yet been fully elucidated. However, they are thought to operate according to the following:

ü Inhibition of leucocyte chemotaxis via reduced cytokine formation.
ü Inhibition of the production of pro-inflammatory mediators such as thromboxanes, prostaglandins, leukotrienes, and PAF.

The aminosalicylates are commonly used as first-line treatment for mild to moderate ulcerative colitis, markedly reducing relapse rate in a lot of cases. However, the clinical pharmacology of the aminosalicylates also shows a less well established efficacy in Crohn’s disease, especially if the cause of Crohn’s is of non-colonic origin.

From a pharmacokinetic perspective, let’s take a look at some of the key factors in the operation of this class of drugs:

  • Sulfasalazine is partially absorbed from the gut and undergoes reduction by gut bacteria to cleave the azo bond, forming sulfapyridine and 5-ASA.
  • Sulfapyridine and approximately 20% of the 5-ASA is absorbed from the colon and further metabolized by the liver.
  • Both components have half-lives of 5-10 hours.
  • Mesalazine (5-ASA itself) is formulated as an enteric coated, or modified-release, formulation to limit the absorption from the small bowel, thereby delivering more active drug to the colon.
  • Olsalazine is a drug comprising 2 molecules of 5-ASA merged together by an azo bond. This drug is not absorbed from the upper gut and, instead, the 5-ASA is released after reductive splitting by the azo bond in the presence of colonic flora.
  • Balsalazide acts as a prodrug in which (again, through the use of an azo bond) 5-ASA is linked to a carrier molecule, 4-amino-benzoyl-β-alanine, a link cleaved by colonic flora.
  • Mesalazine and Sulfasalazine can be administered by suppository or enema in the treatment of distal disease of the colon.

The table below details the most common side-effects in the clinical pharmacology of these drugs – with symptoms occurring in approximately 40% of patients taking Sulfasalazine and 15% of those taking Mesalazine.

Nausea, Vomiting, Diarrhoea, Abdominal Pain
Headache
Rashes
Agranulocytosis, Thrombocytopenia
Anorexia, Oligospermia (Sulfasalazine)

Corticosteroids

Examples: Budenoside, Hydrocortisone, Prednisolone

The clinical pharmacology of these drugs in the treatment of inflammatory bowel disease show marked efficacy for inducing remission in active IBD. However, evidence also shows these drugs lack any significant relapse prophylaxis, at least at doses that would also induce major side-effects. Relatively newer drugs, such as budenoside, act as a potential alternative to hydrocortisone and prednisolone, with topical treatments for local rectal disease proving beneficial. Although, oral or parenteral administration would be required for more severe or extensive disease.

Cytokine Inhibitors

Examples: Adalimumab, Infliximab

Infliximab (Remicade) was the first such monoclonal antibody to be used in the treatment of Crohn’s disease. However, if Infliximab is poorly tolerated, or in those whose condition has since become refractory, Adalimumab (Humira) acts as a convenient alternative. Given that TNFα induces pro-inflammatory cytokines, reduction of this factor remains a key development in current clinical pharmacology of IBD. Infliximab, too, may be used in severe cases of ulcerative colitis.

Immunosuppressants

Examples: Azathioprine, Mercaptopurine, Methotrexate

Azathioprine (Imuran), and less commonly, Mercaptopurine (Purithenol) have proven to be useful in some patients with active inflammatory bowel disease and also harbour the benefit of requiring less corticosteroid dose. Azathioprine therapy should be considered if IBD control necessitates more than two 6-week courses of oral corticosteroid use per year. Alternatively, if the disease relapses as the dose of corticosteroid is being reduced, this can also justify the use of immunosuppressants. 

The height of therapeutic effect for both Azathioprine and Mercaptopurine (used more in North America and harbours a lower risk of nausea) is achieved after 6-12 weeks of use. Clinical pharmacology research shows that 10% of patients are likely to suffer from nausea, vomiting, rashes and hypersensitivity syndrome within the first 6 weeks of therapy. Serious complications include pancreatitis and liver toxicity, though the risk of these is sufficiently small.

Methotrexate has proven beneficial in both ulcerative colitis and Crohn's disease. It's administered intramuscularly and is mostly only employed when Azathioprine has proven ineffective.

Antibacterials

Examples: Metronidazole, Clarithromycin, Ciprofloxacin

Metronidazole has proven to be moderately effective in treating some aspects of Crohn's disease, particularly the perianal symptoms that often result. However, the mechanism of action of this benefit is currently unknown. Clinical pharmacology research shows that other antibacterials, such as Clarithromycin and Ciprofloxacin, is conflicted, and therefore more research needs to be performed in this regard. Nonetheless, antibacterials do have a place in modern inflammatory bowel disease treatment options.

Management of Ulcerative Colitis

In this section, we're going to draw all the threads together and come to some conclusions about how ulcerative colitis is managed over the course of the disease. Later, we'll do the same with Crohn's disease - thereby presenting you with a clear contrast between the two conditions. The subject of inflammatory bowel disease is, of course, under intense clinical pharmacology studies and, therefore, the options for management are changing rapidly and in the right direction.

  • NSAID's and COX-2 Inhibitors have been shown to make symptoms worse and therefore should be avoided in patients with severe colitis.
  • Opioids should be avoided in the treatment of diarrhoea caused by extensive colitis given the risk of precipitating toxic megacolon.
  • If the disease is limited to the rectum or distal colon, rectal drug delivery often proves successful.
  • Topical Mesalazine is more effective than topical corticosteroid when treating mild symptoms. Foam enemas or suppositories will treat inflammation should the inflammation remain within 12-20cm of the anus. Liquid enemas, on the other hand, treat within 30-60cm (up to the splenic flexure). 
  • Oral corticosteroids may be required in induce remission and, thereafter, the dose will be gradually reduced to control unwanted effects. Once this is achieved, maintenance therapy can resume with topical Mesalazine or an oral aminosalicylate drug.
  • If symptoms are mild to moderate, an oral aminosalicylate should alleviate these symptoms within 6-8 weeks.
  • Severe colitis requires intense fluid and electrolyte replacement; anaemia remains a high risk and should be corrected by transfusion. 
  • Infliximab can be used for severe refractory disease as well as for subsequent maintenance therapy.
  • Surgery, however, is necessitated in approximately 20% of patients.
  • Azathioprine has been shown, due to clinical pharmacology studies, to be the only immunosuppressant agent with a strong evidence base of therapeutic efficacy.

Management of Crohn's Disease

You'll find that the management of both conditions contains some degree of overlap. Nonetheless, the conditions need to be considered separately. As you study the management of both conditions, compare and contrast the differences and this will aid your overall understanding in the long-term. Click here to find an algorithm of the overall treatment options.

  • Corticosteroids, particularly oral Prednisolone, is the typical treatment option in those with active Crohn's disease. However, maintenance corticosteroid therapy does not reduce the rate of relapse, so every effort needs to be taken to withdraw the drug once disease activity has been controlled.
  • Given that corticosteroid dependence occurs in almost half of people who take the drug to induce remission, use of immunosuppressive drugs such as Azathioprine can aid in the withdrawal of the corticosteroid once disease activity has been managed.
  • If the disease is confined to the distal colon, topical corticosteroid use or an oral aminosalicylate such as Sulfasalazine can also be efficacious.
  • Antibacterials such as Metronidazole have also proven effective in some aspects of Crohn's disease, particularly perianal disease.
  • Infliximab has proven effective both to induce and maintain remission, particularly if the patient has been resistant to conventional therapy. An infusion of Infliximab can induce remission for up to 3 months - this is augmented with intermittent 2-monthly maintenance infusions to reduce the severity yet further.
  • Should the disease prove refractory to conventional medical therapy, then surgery is an alternative option. Surgery is required in up to 80% in patients with Crohn's disease and, therefore, will remain a core part of their long-term management plan.

Assessment Questions

The following fifteen questions all relate to the material outlined above and all require either a True or False answer. The questions cover clinical pharmacology, aetiology of inflammatory bowel disease, and management of IBD. You'll find the answers located below.

  1. The active constituent of Sulfasalazine is 5-ASA.
  2. Mesalazine can be given rectally.
  3. Cigarette smoking increases the risk of ulcerative colitis.
  4. Mesalazine is equally as efficacious in the small bowel and colon of patients with Crohn's disease.
  5. In ulcerative colitis, corticosteroids such as Prednisolone are effective in maintaining remission.
  6. Azathioprine is ineffective in the treatment of Crohn's disease.
  7. Sulfapyridine is efficacious in Crohn's disease but not ulcerative colitis.
  8. Infliximab is useful for both the induction and maintenance of Crohn's disease.
  9. Immunosuppressants are useful in reducing corticosteroid dependence in patients with Crohn's disease.
  10. NSAID's and COX-2 Inhibitors are recommended in the treatment of severe colitis.
  11. Life-threatening toxic megacolon may occur in patients taking opioids in the treatment of diarrhoea in extensive colitis.
  12. Excessive numbers of T-helper type 1 lymphocytes is indicative of Crohn's disease.
  13. Ulcerative colitis is a transmural granulomatous condition that can involve any part of the gut.
  14. Aminosalicylates are more effective in Crohn's disease, particularly for non-colonic disease.
  15. Olsalazine is a drug comprising of two 5-ASA molecules joined by an azo bond.

Answers
1. True 2. True 3. False 4. False 5. False 6. False 7. False 8. True 9. True 10. False 11. True 12. True 13. False 14. False 15. True

Conclusion

In this section, we focussed on providing you with a comprehensive overview of the pharmacology of inflammatory bowel disease. Initially, we looked at the factors that differentiate ulcerative colitis from Crohn's disease - taking their pathogenesis into consideration. Then, we took a look at some of the major classes of drugs used in their treatment and, finally, the management of both ulcerative colitis and Crohn's disease was taken into consideration.

By | 2015-11-24T15:21:43+00:00 December 4th, 2014|Pharmacology Guides|0 Comments

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