Selective COX-2 inhibitors (coxibs): fewer ulcers but more cardiovascular risk
Coxibs are NSAIDs (anti-inflammatory drugs) selective for COX-2, one of two cyclo-oxygenase (COX) enzymes: they cause fewer ulcers than drugs blocking both enzymes but raise cardiovascular risk.
Remember
Coxibs cause fewer ulcers than drugs blocking both enzymes, but they raise cardiovascular risk, because they take away the anti-clotting signal from the blood vessel wall while the clotting signal from platelets continues.
Memory aid
a coxib removes the brake (prostacyclin) but leaves the accelerator (thromboxane A2) on
Think of prostacyclin as the brake on clotting and thromboxane A2 as the accelerator: a coxib weakens the brake while the accelerator keeps running.
Clotting is kept in check by two opposing chemicals, each made by a different cyclo-oxygenase (COX) enzyme. Protection of the stomach depends mainly on COX-1, and so does the making of thromboxane A2 by platelets (the small cell fragments that form the first plug of a clot), which narrows vessels and makes platelets clump. COX-2 is active in the lining of blood vessels (the vascular endothelium), where it makes prostacyclin, a chemical messenger that widens vessels and discourages platelets from sticking together.
Coxibs are selective for COX-2, meaning they largely spare COX-1. Celecoxib and etoricoxib are coxibs available in the UK. They lower prostacyclin but leave platelet thromboxane A2 largely unaffected, so the balance tips toward thrombosis (a clot forming inside a vessel). That raises the risk of myocardial infarction (a heart attack) and stroke. Unlike low-dose aspirin, a coxib has no antiplatelet effect (it does not stop platelets sticking together), so it gives no protection against clots.
The benefit is gastrointestinal. Because COX-1 is spared, coxibs cause fewer ulcers and bleeds than non-selective NSAIDs (anti-inflammatory drugs that block both COX enzymes), which was the original rationale for the class. Renal (kidney) side effects are similar to those of non-selective NSAIDs, so they do not explain the extra cardiovascular risk. Among non-selective NSAIDs, diclofenac carries a cardiovascular risk similar to that of the coxibs, whereas naproxen and low-dose ibuprofen (1,200 mg a day or less) have a comparatively favourable profile for thrombosis, although neither is risk-free.
For people at high gastrointestinal risk and low cardiovascular risk who specifically need an NSAID, NICE advises a coxib with a proton pump inhibitor (a drug that reduces stomach acid) alongside. Rofecoxib, another coxib, was withdrawn worldwide in 2004 because of excess myocardial infarctions.
Key facts
- Target
- Coxibs are selective for COX-2 and largely spare COX-1.
- Gastrointestinal benefit
- Fewer ulcers and bleeds than with non-selective NSAIDs, because COX-1 protection of the stomach is spared.
- Clotting balance
- Prostacyclin falls while platelet thromboxane A2 is largely spared, so thrombosis is favoured.
- Kidney effects
- Renal (kidney) side effects are similar to those of non-selective NSAIDs, so they do not explain the extra cardiovascular risk.
- Aspirin contrast
- A coxib has no antiplatelet effect, so it gives no protection against clots, unlike low-dose aspirin.
- Prescribing
- For people at high gastrointestinal risk and low cardiovascular risk who specifically need an NSAID, NICE advises a coxib with a proton pump inhibitor alongside.
- Evidence
- Rofecoxib was withdrawn worldwide in 2004 because of excess myocardial infarctions.
Exam traps
- Aspirin lowers platelet thromboxane A2 by blocking COX-1, which makes platelets less sticky, but a coxib spares COX-1, so a rise in heart attacks and strokes is not explained by reduced thromboxane A2.
- Retention of salt and water and a higher blood pressure are real kidney effects of NSAIDs, but renal side effects are similar for coxibs and non-selective NSAIDs, so they do not explain the extra risk with coxibs.
- Stomach bleeding does not explain the cardiovascular risk of coxibs, because coxibs spare COX-1 and cause fewer ulcers, so losing stomach protection is the problem of non-selective NSAIDs.
Read the full notes
Tested in 7 SimpleMed+ questions
Practice it in Pharmacology, with the answer and a full explanation after every question.
Practice these questions