Clinical Pharmacology and Therapeutics

INFLAMMATORY BOWEL DISEASE 255
cortical centres affecting vomiting via descending pathways
seems probable. There is some evidence that opioid pathways
are involved in these actions. They are only moderately
effective.
Adverse effects
Adverse effects include sedation, confusion, loss of coordination,
dry mouth and hypotension. These effects are more
prominent in older patients.
MISCELLANEOUS AGENTS
Large doses of glucocorticosteroids exert some anti-emetic
action when used with cytotoxic drugs and the efficacy of the
5HT 3 -antagonists has been shown to be improved when concomitant
dexamethasone is given. Their mode of action is not
known. Benzodiazepines given before treatment with cytotoxics
reduce vomiting, although whether this is a specific antiemetic
action or a reduction in anxiety is unknown.
INFLAMMATORY BOWEL DISEASE
Mediators of the inflammatory response in ulcerative colitis
and Crohn’s disease include kinins and prostaglandins. The
latter stimulate adenylyl cyclase, which induces active ion
secretion and thus diarrhoea. Synthesis of prostaglandin E 2 ,
thromboxane A 2 and prostacyclin by the gut increases during
disease activity, but not during remission. The aminosalicylates
influence the synthesis and metabolism of these
eicosanoids, and influence the course of disease activity.
Apart from correction of dehydration, nutritional and electrolyte
imbalance (which in an acute exacerbation is potentially
life-saving) and other non-specific treatment, glucocorticosteroids,
aminosalicylates and immunosuppressive drugs are
valuable.
GLUCOCORTICOSTEROIDS
Steroids modify every part of the inflammatory response and
glucocorticosteroids (see Chapter 40) remain the standard by
which other drugs are judged. Prednisolone and hydrocortisone
given orally or intravenously are of proven value in the
treatment of acute colitis or exacerbation of Crohn’s disease.
Topical therapy in the form of a rectal drip, foam or enema of
hydrocortisone or prednisolone is very effective in milder
attacks of ulcerative colitis and Crohn’s colitis; some systemic
absorption may occur.
Diffuse inflammatory bowel disease or disease that does not
respond to local therapy may require oral glucocorticosteroid
treatment, e.g. prednisolone for four to eight weeks.
Prednisolone is preferred to hydrocortisone as it has less mineralocorticoid
effect at equipotent anti-inflammatory doses.
Modified-release budesonide is licensed for Crohn’s disease
affecting the ileum and the ascending colon; it causes fewer
systemic side effects than oral prednisolone, due to extensive
hepatic first-pass metabolism, but may be less effective.
Glucocorticosteroids are not suitable for maintenance treatment
because of side effects.
AMINOSALICYLATES
5-Aminosalicylic acid (5ASA) acts at many points in the
inflammatory process and has a local effect on the colonic
mucosa. However, as it is very readily absorbed from the
small intestine, it has to be attached to another compound or
coated in resin to ensure that it is released in the large bowel.
Although these drugs are only effective for controlling mild
to moderate ulcerative colitis when given orally, they are
very effective for reducing the incidence of relapse per year
from about 70 to 20%. The aminosalicylates are not effective in
small-bowel Crohn’s disease. For rectosigmoid disease, suppository
or enema preparations are as effective as systemic
steroids.
Drugs currently available in this group are sulfasalazine,
mesalazine, balsalazide and olsalazine. Sulfasalazine
remains the standard agent, but mesalazine, balsalazide and
olsalazine avoid the unwanted effects of the sulphonamide
carrier molecule (sulphapyridine) of sulfasalazine, while
delivering 5ASA to the colon. Although usually well tolerated,
the adverse effects of sulfasalazine are nausea, vomiting,
epigastric discomfort, headache and rashes (including toxic
dermal necrolysis). All of the adverse effects associated with
sulphonamides can occur with sulfasalazine, and they are
more pronounced in slow acetylators. Toxic effects on red cells
are common (70% of cases) and in some cases lead to haemolysis,
anisocytosis and methaemoglobinaemia. Sulfasalazine
should be avoided in patients with glucose-6-phosphate dehydrogenase
(G6PD) deficiency. Temporary oligospermia with
decreased sperm motility and infertility occurs in up to 70% of
males who are treated for over three years. Uncommon adverse
effects include pancreatitis, hepatitis, fever, thrombocytopenia,
agranulocytosis, Stevens–Johnson syndrome, neurotoxicity,
photosensitization, a systemic lupus erythematosus (SLE)-like
syndrome, myocarditis, pulmonary fibrosis, and renal effects
including proteinuria, haematuria, orange urine and nephrotic
syndrome.
The newer agents are useful in patients who cannot tolerate
sulfasalazine and in men who wish to remain fertile.
Key points
Aminosalicylates and blood dyscrasias
• Any patient who is receiving aminosalicylates must be
advised to report unexplained bleeding, bruising,
purpura, sore throat, fever or malaise.
• If the above symptoms occur, a blood count should be
performed.
• If there is suspicion of blood dyscrasia, stop
aminosalicylates.
• Aminosalicylates are associated with agranulocytosis,
aplastic anaemia, leukopenia, neutropenia and
thrombocytopenia.