NSAIDs
Examples
- Ibuprofen
- Naproxen
- Diclofenac
- COX-2 Inhibitors (celecoxib)
Indications
Pain (particularly musculoskeletal pain), fever, inflammation.
Contraindications
Contraindications
- Hypersensitivity to NSAIDs, including some asthmatic patients who may develop wheeze when exposed.
- NSAIDs should be avoided in renal disease, hepatic disease and coagulation disorders.
- NSAIDs should be avoided in pregnancy, but can be used with care in breast-feeding.
- All NSAIDs can cause gastro-intestinal side effects. In theory, non-selective NSAIDs vary in potential for adverse effects and COX-2 inhibitors are safer, however, all should be avoided if possible or used with extreme care in high risk patients. The BNF states that non-selective NSAIDs are contra-indicated in patients who have active or previous peptic ulceration, whilst selective COX-2 inhibitors are contra-indicated in those with active peptic ulcer disease.
- All NSAIDs also have the potential to adversely affect the cardiovascular system, and again may have different potential for harm. All are contraindicated in those with severe heart failure, and selective COX-2 inhibitors are contraindicated in patients with ischaemic heart disease, cerebrovascular disease, peripheral vascular disease, or moderate heart failure. In patients with oedema or risk factors for heart disease, selective COX-2 inhibitors should be used with caution.
Mechanism
NSAIDs act on the Cyclooxygenase pathway to inhibit the 2 isoenzymes of cyclooxygenase: COX-1 and COX-2.
Normally, COX-1 and COX-2 act by converting Arachidonic Acid into various prostaglandins and thromboxanes. These prostaglandins are pro-inflammatory and also promote fever and pain. The rationale for prescribing drugs which block COX-1 and COX-2 is that they prevent prostaglandins from being produced, therefore preventing inflammation, fever and pain.
Obviously, this demonstrates how NSAIDs can have an analgesic effect. Very simply, if you block COX-1 and COX-2 enzymes, you prevent the production of compounds which cause pain.
Whilst traditional NSAIDs such as aspirin and diclofenac inhibit both COX-1 and COX-2, selective COX-2 inhibitors do also exist. The rationale behind their use is that prostaglandins which are synthesised via the COX-1 pathway are thought to be primarily involved in the maintenance and protection of the GI tract, whilst those synthesised via the COX-2 pathway are responsible for inflammation and pain. So by solely blocking the COX-2 pathway, unwanted GI side effects could be avoided, whilst still having the desirable analgesic effects.
Unfortunately it seems that it is not as simple as this, and there remain real problems with selective COX-2 inhibitors. Despite a decrease in GI side-effects these still occur, and in addition there seems to be an increase in cardiovascular side-effects compared to traditional NSAIDs. The full detail of how these drugs work is yet to be worked out.
Administration
Oral.
Diclofenac can also be given per rectum.
Some NSAIDs can be given by IM or IV injections, but remember that this does not avoid the adverse gastro-intestinal effects.
Some NSAIDs can also be applied topically via medicated plasters or as a gel. The incidence of systemic side effects are much less common with these formulations.
Adverse Reactions
The major side effects associated with NSAIDs are irritation of the gastrointestinal mucosa, leading to gastric or duodenal ulcers. This occurs because one of the prostaglandins produced by COX actually has protective properties in the gastrointestinal tract and by inhibiting its production, there is less protection against the formation of ulcers which can then go on to bleed.
Renal damage due to NSAIDs is also a major issue and patients with pre-existing renal disease should have their renal function monitored whilst drugs are used for the shortest possible time. NSAIDs can cause renal failure.
NSAIDs can precipitate asthma, through an effect on leukotrienes.
Other side effects which are rare, but can occur include:
- Hypertension
- Nausea and diarrhoea
- Headache
- Dizziness
- Drowsiness
- Insomnia
- Fluid retention
- Stevens-Johnson Syndrome
Interactions
Due to their effects on the kidneys, NSAIDs can cause decreased elimination of both lithium and methotrexate. They may also reduce the efficacy of diuretics.
Some documentation has suggested that NSAIDs can amplify the effect of warfarin when used in conjunction. Ideally, those on warfarin should try to avoid long term use of NSAIDs.
Due to the possibility of causing hypertension, long term use of NSAIDs in patients who are on anti-hypertensives should be considered carefully.
Education
The risk of GI problems with non-selective NSAIDs should be explained to patients, and the risk of cardiac problems with selective COX-2 inhibitors should also be explained. Although the risks don't appear to be huge, they are significant and patients need to be aware of these risks if they are considering long term use of NSAIDs.
Patients should be advised to take NSAIDs with or just after food.
Patients should also be advised to stop taking their NSAID temporarily during periods of dehydrating illness such as vomiting or diarrhoea due to the risk of acute kidney injury.
Pharmacokinetics
The majority of NSAIDs are metabolised in the liver via the cytochrome P450 pathways.
Other Systems
