Adverse Reactions

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Gastrointestinal effects

Gastric and intestinal mucosal damage is the commonest adverse effect of NSAIDs. The physiological function of mucosal prostaglandins is cytoprotective, by inhibiting acid secretion, by promoting the secretion of mucus and by strengthening resistance of the mucosal barrier to back-diffusion of acid from the gastric lumen into the submucosal tissues where it causes damage. Inhibition of prostaglandin biosynthesis removes this protection. Indigestion, gastro-oesophageal reflux, erosions, peptic ulcer, gastrointestinal haemorrhage and perforation, and small and large bowel ulceration occur.

In the UK an estimated 12 000 peptic ulcer complications and 1200 deaths per year are attributable to NSAID use.3 Toxicity relates to anti-

3 Hawkey C J 1996 Scandinavian Journal of Gastroenterology (Suppl.) 220:124-127,221: 23-24.

inflammatory efficacy. A meta-analysis of 12 controlled epidemiological studies ranked common NSAIDs according to their propensity for causing gastrointestinal complications.4 Azapropazone, pir-oxicam, ketoprofen and indomethacin were associated with high risk (and azapropazone was 9.2 times more likely than low-dose ibuprofen to cause such adverse effects).

Clinical trial evidence in general appears to support the theory that COX-2 selective inhibitors are as effective as, but have fewer adverse effects than, non-COX-2 selective compounds; for example meloxicam is better tolerated than diclofenac or piroxicam.5-6 The relative risk of serious gastrointestinal effects (bleeding peptic ulcers) due to rofecoxib (COX-2 selective) was 0.51 compared with conventional NSAIDs.7 COX-2 selective drugs are yet associated with significant dyspeptic symptoms (indigestion, heartburn), and these effects may result from inhibition of the (protective) constitutively expressed COX-2 in the stomach.

In practice, a minority of patients are intolerant of all NSAIDs. They may benefit from the coadministration of a proton pump inhibitor, a H2-receptor blocker or the prostaglandin analogue, misoprostol. To address this problem, some NSAIDs are presented in combination with misoprostol, e.g. diclofenac with misoprostol (Arthrotec) and naproxen with misoprostol (Napratec). Some patients experience abdominal pain and diarrhoea from the misoprostol component.

Ulceration and stricture of the small bowel may also be caused by NSAIDs, and in some patients there is occult blood loss, diarrhoea and malabsorption, i.e. a clinical syndrome indistinguishable from Crohn's disease.

Renal effects

Renal blood flow is reduced because the synthesis of vasodilator renal prostaglandins is inhibited; the

4 Henry D et al 1996 British Medical Journal 312:1563.

5 Hawkey C J et al 1998 British Journal of Rheumatology 37: 937.

6 Dequeker J et al 1998 British Journal of Rheumatology 37: 946.

7 Langman M J et al 1999 Journal of the American Medical

Association 282: 1929.

result is sodium and fluid retention and arterial blood pressure may rise. Renal failure may occur when glomerular filtration is dependent on the vasodilator action of prostaglandins, e.g. in the elderly, those with pre-existing renal disease, hepatic cirrhosis, cardiac failure, or on diuretic therapy sufficient to reduce intravascular volume.

Analgesic nephropathy. Mixtures of NSAIDs (rather than single agents) taken repeatedly cause grave and often irreversible renal damage, notably chronic interstitial nephritis, renal papillary necrosis and acute renal failure; these effects appear to be due at least in part to ischaemia through inhibition of formation of locally produced vasodilator prostaglandins. The condition is most common in people who take high doses over years, e.g. for severe chronic rheumatism and patients with personality disorder. Whilst analgesic nephropathy appears to be associated with long-term abuse of NSAID mixtures, the strong evidence that phenacetin was particularly responsible has rendered this drug obsolete.8

Cutaneous effects

Urticaria, severe rhinitis and asthma occur in susceptible individuals, e.g. with nasal polyposis, who are exposed to NSAIDs, notably aspirin; the

8 During the influenza pandemic of 1918 a physician to a big factory in a Swedish town prescribed an antipyretic powder containing phenacetin, phenazone (both NSAIDs) and caffeine. Survivors of the epidemic thought they felt fitter and reinvigorated during convalescence if they took the powder and they continued to take it after recovery. Consumption increased and many families 'could not think of beginning the day without a powder. Attractively wrapped packages of powder were often given as birthday presents'. Deaths from renal insufficiency rose in the 'phenacetin town', but not in a similar Swedish town, and in the decade of 1952-61 they were more than 3 times as many. An investigation was resisted by the factory workers to the extent that there was an organised burning of a questionnaire on powder-taking. It was eventually discovered that most of those who used the powders did so, not for pain, but to maintain a high working pace, from 'habit', or to counter fatigue (an effect probably due to the caffeine). Eventually the rising death rate brought home to the consumers the gravity of the matter, something that has yet to be achieved for tobacco smoking or alcohol drinking (Grimlund K 1964 Acta Medica Scandinavica 174: suppl. 405).

mechanism may involve inhibition of synthesis of bronchodilator prostaglandins, notably PGE2 (see Pseudoallergie reactions, p. 146). Other effects on the skin include photosensitivity, erythema multiforme, urticaria, and toxic epidermal necrolysis.

Other general effects include cholestasis, hepatocellular toxicity, thrombocytopenia, neutropenia, red cell aplasia, and haemolytic anaemia. Ovulation may be reduced or delayed (reversibly).

An account of adverse reactions that probably relate to individual chemical classes of NSAID is given later.

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