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NSAID interactions that get forgotten

Professor Hugh McGavock explains why NSAIDs account for 30 per cent of adverse reaction reports

When the first two NSAIDs were launched in 1971 it was one of the outstanding breakthroughs. For the first time we had a drug that could control most cases of rheumatoid arthritis and inflammatory osteoarthritis, without the risks of high-potency steroids.

Within a few years there were many on the market, all with the same basic action of blocking the synthesis of potent mediators of inflammation, the prostaglandins. These drugs quickly became the most frequently prescribed items in general practice.

On the back of this important discovery scientists unravelled the physiology of the prostanoids. Five natural prostanoids were discovered ­ PGD2, PGE2, PGF2, PGI2 and TXA2 (thromboxane). Cellular receptors were discovered corresponding to each of these intercellular signalling chemicals.

In fact, as often happens with the body's limited range of chemical signals, there are several receptors for each of the prostaglandins, each giving a different effect.

In the presence of any inflammatory stimuli, cells produce prostaglandins, which cause the inflammatory response in a highly controlled manner, appropriate to the level of inflammation. This occurs through the Cox-2 enzyme (cyclo-oxygenase-2). Cox-2 inhibitor NSAIDs are quite selective for this enzyme but by no means entirely selective. Whether a Cox-2 selective NSAID or a non-selective NSAID is used the therapeutic effect results from switching off production of inflammatory prostaglandins.

Potential dangers of NSAIDs

NSAIDs were discovered to have widespread non-inflammatory physiological regulatory functions. For example, PGE2 is involved in regulation of smooth muscle in the bronchial tree. It also regulates gastrointestinal smooth muscle, some intestinal fluid secretion, inhibits gastric acid secretion and increases gastric mucus secretion.

Because of physiological control functions in normal tissues, non-selective NSAIDs produce many unwanted and sometimes life-threatening effects. Given as non-therapy to the healthy adult, there is a relatively small risk of harm, but these drugs can be dangerous in a variety of patients.

 · NSAIDS given to a patient who is well-controlled on warfarin are likely to block production of thromboxanes, leading to bruising or bleeding of varying severity.

 · Patients with any degree of renal failure should not receive NSAIDs, which can precipitate acute renal failure (acute tubular necrosis) due to disruption of the blood supply to the renal tubules.

 · Avoid giving NSAIDs to asthmatic patients ­ they block the prostaglandin responsible for bronchodilation (see BNF for Committee on Safety of Medicines advice).

 · No patient with ulcerative colitis should get a NSAID ­ it may cause an exacerbation (although the mechanism is unclear).

 · Prescription of a NSAID to a hypertensive patient is likely to cause some degree of loss of antihypertensive control. NSAIDs reduce the effect of all antihypertensives.

 · Consider drugs other than NSAIDs for patients in heart failure as they have a direct effect on cardiac muscle and cause retention of fluid by the kidneys.

 · NSAIDs may cause a flare-up of quiescent psoriasis.

 · A particular drug interaction: a patient who is taking an ACE inhibitor and a thiazide diuretic who is given an NSAID may develop severe hyperkalaemia. All three drugs lead to potassium retention.

 · Finally, everyone knows conventional NSAIDs can lead to gastric bleeding and peptic ulceration as they block the protective prostaglandin PGE2 action on the stomach mucosa.

The NSAID epidemic

Within four years of the introduction of NSAIDs yellow card reports began to pour into the Medicines Control Agency. By 1990 NSAIDs accounted for about 30 per cent of total adverse event reports received in the UK. That situation continues to this day, and sadly, for all the excellent efforts of the drug industry to produce safer Cox-2 NSAIDs, these very drugs are now number one in the adverse report league. What can be done? We will always need anti-inflammatories and surely risk must be balanced against benefit in every case.

Simple guidelines

 · Do not use NSAIDs in any patient unless it is certain or highly probable that inflammation is present. If the problem is pain only, give a simple analgesic.

 · If the patient is already on maintenance medication, check for the possibility of drug interactions. Appendix 1 of the BNF is the GP's authority.

 · Be particularly careful when prescribing a NSAID for an older patient ­ remember that over the age of 70 many physiological mechanisms are much less efficient and disrupting them by blocking production of a prostaglandin regulator may lead to trouble.

 · Remember the likely advantages of the selective Cox-2 inhibitor NSAIDs in such patients. But remember also that the selectivity is partial, not complete.

 · Tag the records of all patients on NSAIDs and warn colleagues to listen for symptoms that suggest trouble is brewing.

 · NSAIDs are now a very common form of self-medication. Tell all patients on the maintenance regimens above never to take an over-the-counter NSAID and repeat the message at every opportunity.

 · If there is loss of control think NSAID ­ from a colleague or pharmacist.

 · Prescribe NSAIDs with care!

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