A Textbook of Clinical Pharmacology and Therapeutics

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 coordina-
tion, 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 con-
comitantdexamethasoneis given. Their mode of action is not
known. Benzodiazepines given before treatment with cytotox-
ics reduce vomiting, although whether this is a specific anti-
emetic 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 aminosalicy-
lates influence the synthesis and metabolism of these
eicosanoids, and influence the course of disease activity.
Apart from correction of dehydration, nutritional and elec-
trolyte imbalance (which in an acute exacerbation is potentially
life-saving) and other non-specific treatment, glucocorticos-
teroids, 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. Prednisoloneandhydrocorti-
sonegiven 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
hydrocortisoneorprednisoloneis 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.
Prednisoloneis preferred to hydrocortisoneas it has less min-
eralocorticoid effect at equipotent anti-inflammatory doses.
Modified-release budesonideis 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, sup-

pository 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,balsalazideand

olsalazineavoid 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 sulfasalazineare 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 haemoly-

sis, anisocytosis and methaemoglobinaemia. Sulfasalazine

should be avoided in patients with glucose-6-phosphate dehy-

drogenase (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 toler-

atesulfasalazineand in men who wish to remain fertile.

INFLAMMATORYBOWELDISEASE 255

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.