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