NSAID Adverse Effects and Selection
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Direct answer
NSAID adverse effects arise because cyclo-oxygenase blockade lowers gastric mucosal protection, renal perfusion and the balance between prostacyclin and thromboxane. Gastrointestinal bleeding, acute kidney injury and thrombotic events are the three adverse effects most often tested. Non-selective agents carry the stomach risk, while COX-2 selective drugs spare the stomach but add cardiovascular risk, so selection depends on the patient's gastric, renal and cardiac profile.
What you must remember
- Gastric mechanism: COX-1 inhibition reduces prostaglandin E2 and I2, lowering mucus, bicarbonate and mucosal blood flow, which leads to ulcers and bleeding.
- Renal effect: prostaglandins keep the afferent arteriole dilated, so NSAIDs cause haemodynamic acute kidney injury, sodium retention and hyperkalaemia.
- Triple whammy: NSAIDs combined with ACE inhibitors or angiotensin receptor blockers and diuretics markedly raise the risk of acute kidney injury.
- Cardiovascular risk: COX-2 selective drugs and high-dose diclofenac suppress prostacyclin more than thromboxane, raising the risk of myocardial infarction and stroke.
- Aspirin interaction: ibuprofen taken before low-dose aspirin blocks its antiplatelet effect at the COX-1 site.
- Reye syndrome: aspirin is avoided in children with viral illness because of the risk of Reye syndrome.
- Pregnancy: NSAIDs are avoided after about 20 weeks because of oligohydramnios and premature closure of the ductus arteriosus.
A selection pathway for a patient with arthritis and a past ulcer
Take a 64-year-old man with knee osteoarthritis, hypertension treated with an ACE inhibitor and a diuretic, and a bleeding duodenal ulcer five years ago.
- Ask whether an NSAID is needed. Paracetamol, topical NSAIDs for the knee and physiotherapy come first, because topical preparations give lower systemic exposure.
- Use the lowest effective oral dose. If an oral NSAID is still required, the lowest effective dose is used for the shortest time, with a proton pump inhibitor because his gastric risk is high.
- Screen the heart. A COX-2 selective drug spares the stomach, but it is avoided if he has ischaemic heart disease, uncontrolled hypertension or heart failure.
- Choose a non-selective drug if COX-2 is unsafe. In that case a non-selective drug with a proton pump inhibitor is chosen, and naproxen is often cited as having a comparatively lower cardiovascular signal.
- Check renal function. Renal function is checked before and after starting, because the triple combination of an NSAID, an ACE inhibitor and a diuretic is a common cause of drug-induced acute kidney injury.
- Protect the mucosa carefully. Misoprostol protects the mucosa but is contraindicated in pregnancy.
Where the exam tries to catch you
Four beliefs repeatedly cost candidates marks in NSAID questions.
- Trap: assuming COX-2 selective drugs are simply safer. Correct: they spare the stomach but not the heart, and rofecoxib was withdrawn from the market because of excess cardiovascular events.
- Trap: calling paracetamol an ulcerogenic NSAID. Correct: it has negligible peripheral COX activity and causes no gastric injury, though it is hepatotoxic in overdose.
- Trap: treating COX-1 inhibiting drugs as safe in aspirin-exacerbated respiratory disease. Correct: they provoke bronchospasm in patients with asthma, nasal polyps and urticaria, while selective COX-2 drugs are usually tolerated.
- Trap: looking only at the stomach. Correct: acute interstitial nephritis and papillary necrosis are classic renal lesions that are easy to miss.
Frequently asked questions
Why do NSAIDs cause peptic ulcers and which drugs protect against them?
NSAIDs inhibit COX-1 in the gastric mucosa, reducing prostaglandins that maintain mucus, bicarbonate and mucosal blood flow. Proton pump inhibitors protect by reducing acid exposure, while misoprostol protects the mucosa but is contraindicated in pregnancy.
Why are COX-2 selective drugs associated with heart attacks?
COX-2 selective drugs suppress endothelial prostacyclin, a vasodilator and platelet inhibitor, while leaving platelet thromboxane A2, made through COX-1, relatively unchecked. This prothrombotic imbalance raises the risk of myocardial infarction and stroke, so these drugs are avoided in ischaemic heart disease.
Which combination of drugs causes NSAID-associated acute kidney injury?
An NSAID combined with an ACE inhibitor or angiotensin receptor blocker and a diuretic, often called the triple whammy, is a classic cause of acute kidney injury. NSAIDs block prostaglandin-mediated dilatation of the afferent arteriole, so a volume-depleted kidney loses its remaining protection.
Is paracetamol classed as an NSAID when selecting analgesics?
Many textbooks classify paracetamol as a non-NSAID analgesic because it has negligible peripheral COX inhibition and does not cause gastric ulceration or platelet dysfunction. It is the usual first choice in peptic ulcer disease, though it does not treat inflammation and is hepatotoxic in overdose.