Anti Inflammatory Drugs Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin are amongst the oldest drugs known to Western European medicine. They appear in 16C herbals such as Culpeper in the form of willow bark – Salix alba. This is where aspirin’s chemical name of acetylsalicylic acid originates. Modern NSAIDs include ibuprofen, indometacin, naproxen and diclofenac. NSAIDs are targeted at COX-2 enzymes in the prostanoid synthesis pathway. COX-2 converts arachidonic acid to a prostaglandin precursor. NSAIDs block the active site of COX-2 enzymes so reducing the production of PGE2.
NSAIDs - Effects NSAIDs reduce the production of inflammatory prostaglandins and so attenuate their inflammatory effects…
reduction in oedema reduces dull pain
attenuation of bradykinin induced pain
reduction in allodynia (tenderness of skin)
reduction in fever (anti-pyretic effect)
NSAIDS - Side Effects
COX-1 and COX-2 are isozymes – very similar in structure.
Anti-inflammatory drugs that target COX-2 are thus likely to bind to COX-1
Inflammatory PGE2 prostaglandin levels are reduced
Unfortunately, so are the prostaglandins produced by COX-1 – the non-inflammatory “housekeeping” prostaglandins
A reduction in levels of “housekeeping” prostaglandins can produce disturbances in homoeostasis – side effects
The most common side-effect is…
GI problems (remember PGE2 protects the stomach by promoting gastric mucus secretion and inhibiting gastric acid secretion)
NSAIDs are contra-indicated in patients with peptic ulcers, hypersensitivity reactions to aspirin, coagulation defects etc. (refer to BNF for full list)
NSAIDs vary in their selectivity for COX-1 and COX-2…
Flurbiprofen and indometacin are more selective for COX-1
Ibuprofen and naproxen have similar selectivity, biased towards COX-1
Diclofenac is more biased towards COX-2
Unfortunately, the theoretical COX-1 / COX-2 selectivity is not always reflected in their propensity to produce side-effects.
Aspirin Asprin is one of the oldest NSAIDs (originally extracted from willow bark), it is relatively selective for COX-1 and less popular now as an anti-inflammatory due to GI effects. Asprin is increasingly popular as an anti-platelet drug for patients with CAD at risk of thrombosis. Asprin inhibits thromboxane production in platelets and reduces their ability to coagulate with fibrin (anti-inflammatory activity also contributes to benefit). As an anti-platelet drug, lower doses can be used to avoid GI problems
Selective COX-2 Inhibitors These drugs are highly specific for COX-2 enzyme and do not inhibit COX-1 produced prostanoids. Long-term use is possible with less chance of side-effects, particularly GI problems. Selective COX-2 inhibitors have been useful in the treatment of chronic inflammatory diseases such as rheumatoid arthritis. At the time of writing (May 2007) celecoxib (Celebrex), etoricoxib (Arcoxia) and lumiracoxib (Prexige) appear in the BNF. In 2004 rofecoxib (Vioxx) and valdecoxib (Bextra) were withdrawn as they appeared to cause an increase in the incidence of coronary thrombosis. PGI2 (prostacyclin) results in vasodilation and inhibition of platelet aggregation in the clotting process. Unfortunately PGI2 is produced by a previously unrecognised constitutive action mediated by COX-2. Current COX-2 inhibitors are contra-indicated in coronary artery disease
Paracetamol Paracetamol is a non-anti-inflammatory NSAID that has mainly anti-pyretic and analgesic properties. It probably inhibits COX-3 isozymes in the central nervous system. A reduction in prostaglandins in the hypothalamus reduces pyresis. The short-term usage of paracetamol at therapeutic doses produces relatively few side effects. Hepatotoxicity can occur at only 2-3 times the therapeutic dose. The toxic metabolite (N-acetyl-p-benzoquinone) accumulates causing necrosis in the liver.
Compound Analgesic Combinations NSAIDs, paracetamol and opioids attenuate pain by different mechanisms, in combination their effects can be additive and improve pain relief. Examples…
Co-codamol/co-dydramol – codeine and paracetamol
Co-codaprin – codeine and aspirin
OTC preparations contain many different combinations of analgesics
(Co-proxamol – being withdrawn on advice from CSM)