10.02.3.2 Non-Selective Cyclooxygenase Inhibitors

Aspirin is a non-selective inhibitor of cyclooxygenase (COX), which leads to reduced production of prostaglandins, and thromboxanes, but not leukotrienes. There are a group of non-selective inhibitors of COX, which are known as the NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs), to distinguish them from the steroid anti-inflammatory drugs (the glucocorticoids). NSAIDs include aspirin, paracetamol, ibuprofen, and piroxicam. The NSAIDs are probably the most commonly used drugs.

Aspirin is an irreversible non-selective inhibitor of COX, whereas all the other NSAIDs are reversible inhibitors of COX. Aspirin reverses the effects of the prostaglandins, to be a mild analgesic, anti-pyretic, and partially anti-inflammatory. Aspirin is only partially anti-inflammatory as it only prevents the inflammatory effects to prostaglandins, not those to leukotrienes or other inflammatory mediators. A novel action of aspirin is that low dose it inhibits platelet aggregation to be an anti-coagulant, by preferentially blocking synthesis of TXA₂. This preferential action may be related to the irreversible nature of aspirin. Low dose inhibits platelet aggregation by preferentially blocking synthesis of TXA₂, and this will be discussed more fully in the section on Cardiovascular Therapeutics. Aspirin is used to prevent myocardial infarction/thrombosis.

The two main problems with aspirin are ulcers and hypersensitivity. Thus, chronic users of aspirin for its antithrombotic effect or of the other NSAIDs for analgesia, have a 2-4% of developing an ulcer. The ulcers are due to removal of the cytoprotective effects of prostaglandins in the stomach.

The hypersensitivity to aspirin is due to the inhibition of cyclooxygenase leading to a build up of arachidonic acid, which is then metabolised by the lipooxygenase pathway to leukotrienes (Figure 10.7)

Figure 10.7 NSAIDs and hypersensitivity (Copyright QUT, Sheila Doggrell)

Leukotrienes are potent mediators of hypersensitivity reactions such as rhinitis and asthma. Thus, the use of NSAIDs can be associated with hypersensitivity reactions, especially if people are susceptible. For instance, 5-10% of asthmatics are sensitive to aspirin.

Paracetamol is an inhibitor of COX, and consequently reduces the levels of prostaglandins. Thus, paracetamol is effective as a mild analgesic, and as an antipyretic, and is usually preferred to aspirin for these indications, as it is milder on the stomach. Paracetamol is NOT anti-inflammatory, possibly because some products of inflammation stop paracetamol from inhibiting COX. Thus, paracetamol is not indicated for inflammation, and you need to use aspirin or other NSAIDs in the treatment of inflammation. Paracetamol also has no effect on platelet aggregation or clotting, possibly because the effect of low dose aspirin to inhibit platelet aggregation and clotting may depend on aspirin being an irreversible inhibitor. In contrast, paracetamol is a reversible inhibitor of COX and does not inhibit platelet aggregation. The outcome of this is that you cannot substitute paracetamol for aspirin for cardioprotection, as it is not anti-thrombotic.

Ibuprofen (Nurofen) is a non-selective COX inhibitor. Ibuprofen can be used as an analgesic, an anti-pyretics and an anti-inflammatory agent in similar way as aspirin. Ibuprofen is effective in pain of low-to-moderate intensity, such as nonspecific relief of minor aches and pain (headache, arthritis, dysmenorrhea, neuralgia, myalgia). Ibuprofen is also used in chronic conditions such as rheumatoid arthritis and osteoarthritis, where they are only partially effective as anti-inflammatory agents due to the mediators, other than prostaglandins, of inflammation. Ibuprofen has a similar efficacy in these conditions as aspirin. However, ibuprofen is generally preferred to aspirin as an analgesic, an anti-pyretics and an anti-inflammatory agent as it has greater tolerability than aspirin on chronic use i.e. less likely to cause ulcers. However, ibuprofen has a lesser ability to inhibit platelet aggregation than aspirin, and is not suitable as agents to inhibit platelet aggregation e.g. in the secondary prevention of myocardial infarction or stroke.

Piroxicam is a non-selective COX inhibitor, which is predominantly used as an anti-inflammatory agent. Independently of COX inhibition, piroxicam inhibits the activation of neutrophils, which is another anti-inflammatory mechanism, and contributes, to the anti-inflammatory action of piroxicam. Thus, piroxicam has more anti-inflammatory activity that the agents that just inhibit COX. Piroxicam, like the other NSAIDs discussed above, is active after oral administration. However, unlike the other NSAIDs discussed, piroxicam has a slow onset of action, and is slow to reach steady state (7-12 days), and has a t_1/2 (half-life) of elimination is about 50 hours. Because of the slow onset of action, piroxicam is not used in acute conditions (pain, fever), but is used in the long term treatment of chronic conditions such as rheumatoid arthritis and osteoarthritis.

The major problem with non-selective NSAIDs is ulcers and gastrointestinal bleeding, especially with aspirin. COX has too forms, COX-1 is constitutively expressed (always active e.g. stomach) whereas COX-2 is induced in response to stimuli. NSAIDs inhibit COX-2 to reduce pain and inflammation, which are its beneficial effects, but NSAIDs also inhibit COX-1 to reduce levels of the cytoprotective prostaglandins, which is detrimental (Figure 10.8).

Figure 10.8 NSAIDs and COX-1 and COX-2 (Copyright QUT, Sheila Doggrell)

Thus, drugs that are selective COX-2 inhibitors should give still be able to reduce pain and inflammation, but cause less COX-1 inhibition and less bleeding. This was the rationale for developing selective COX-2 inhibitors.