Analgesics and NSAIDs
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Direct answer
Aspirin acetylates cyclo-oxygenase-1 irreversibly, and because the anucleate platelet cannot rebuild the enzyme, a single 75–150 mg dose disables thromboxane production for the platelet's entire seven-to-ten-day lifespan — the fact underlying both its antiplatelet use and the rule of stopping it a week before surgery. Paracetamol, centrally acting with weak peripheral anti-inflammatory action, is the default analgesic of pregnancy, asthma and chronic kidney disease, capped at 4 g per day in adults because glutathione depletion beyond that converts it into a hepatotoxin. The non-selective NSAIDs share gastrointestinal, renal and blood-pressure toxicity in proportion to cyclo-oxygenase-2 inhibition, which is why diclofenac carries the highest cardiac risk and naproxen the lowest, while the COX-2 selective group spares the stomach at the price of the same cardiac risk that withdrew rofecoxib.
What you must remember
- Aspirin antiplatelet dosing is 75–150 mg daily; effects persist 7–10 days (platelet lifespan); stop 7 days before elective surgery.
- Reye syndrome: no aspirin under 16 years with viral illness — replaced by paracetamol or ibuprofen.
- Aspirin-exacerbated respiratory disease: asthma with nasal polyps and urticaria reacts to all COX-1 inhibitors; paracetamol is the safe analgesic.
- Paracetamol: maximum 4 g/day (reduce in low body weight, liver disease, chronic alcohol); N-acetylcysteine replenishes glutathione and works best within 8 hours of overdose.
- NSAID renal risk: prostaglandin-dependent afferent dilation means AKI in the dehydrated, elderly, cirrhotic or chronic kidney disease patient — and the "triple whammy" with an ACE inhibitor and diuretic.
- Cardiovascular ranking within the class: diclofenac highest risk, naproxen lowest; ibuprofen can blunt aspirin's antiplatelet effect — separate doses by at least 2 hours, giving aspirin first.
- COX-2 selective inhibitors (etoricoxib, celecoxib in India): gastrointestinal sparing but similar cardiovascular risk; rofecoxib was withdrawn for myocardial infarctions.
- Interactions: NSAIDs raise lithium and methotrexate levels, potentiate warfarin, and blunt antihypertensives; ketorolac is restricted to about 5 days.
- Aspirin overdose signature: tinnitus, hyperpnoea, then a mixed picture of respiratory alkalosis with high anion-gap metabolic acidosis, hyperthermia and dehydration — treated with alkalinised urine and dialysis in severe cases.
- The WHO analgesic ladder still frames chronic cancer pain: non-opioid (± adjuvants), then weak opioid, then strong opioid, dosed by the clock and by the mouth.
A worked case: analgesia in a cardiac patient
A 65-year-old on aspirin after a stent wants pain relief for knee osteoarthritis. Walk the reasoning: his diclofenac habit — the commonest Indian over-the-counter default — is the worst choice, stacking myocardial risk on his stent and gastric risk on his aspirin. Step one is scheduled paracetamol 1 g three times daily; regular dosing outperforms as-needed dosing because it prevents pain cycling. Step two adds topical diclofenac or ketoprofen gel, which delivers drug to the joint with a fraction of the systemic exposure. Step three, if oral NSAID becomes unavoidable, chooses the lowest-risk agent (naproxen) at the lowest dose for the shortest period, with a proton pump inhibitor for gastroprotection and a review of renal function and blood pressure after two weeks. Physiotherapy and weight management are prescribed, not mentioned.
The contrast stem writes itself: the same man's wife, with chronic kidney disease stage 4 and on ramipril, presents with doubled creatinine after a week of over-the-counter ibuprofen for back pain. Her ladder is paracetamol, topical agents, and non-drug measures — the oral NSAID was never on her ladder at all.
Where students slip
Diclofenac is prescribed by reflex in India and tested against the evidence: among NSAIDs it carries the highest cardiovascular risk, and post-stent patients are exactly the wrong recipients. Second, the aspirin–ibuprofen interaction is missed: ibuprofen competing at the COX-1 channel prevents aspirin's irreversible acetylation, so aspirin must go first by two hours. Third, paracetamol's "safety" collapses above 4 g daily or in the malnourished alcoholic whose glutathione is already low — the overdose question will use a staggered ingestion to hide the timing. Fourth, the triple whammy stem (NSAID + ACE inhibitor + diuretic in a vomiting elderly patient) is read as "contrast nephropathy" or missed entirely. Finally, aspirin overdose acid–base reasoning: the early respiratory alkalosis is a real finding, not a laboratory error, and its persistence into a mixed acidosis marks severity.
Frequently asked questions
Why does a single aspirin dose disable platelets for over a week?
Irreversible acetylation of COX-1 in anucleate platelets, which cannot resynthesise the enzyme; new platelets restore function only as the population turns over in 7–10 days.
What is the maximum daily paracetamol dose and its overdose antidote?
4 grams per day in healthy adults; N-acetylcysteine, ideally within 8 hours, replenishes glutathione and detoxifies the NAPQI metabolite.
Which NSAID carries the lowest cardiovascular risk?
Naproxen; diclofenac carries the highest among common agents — a ranking now printed into prescribing guidance.
Why is aspirin avoided in children with fever?
The association with Reye syndrome — acute encephalopathy and hepatic failure after aspirin use in viral illness, principally influenza and varicella.
What is the "triple whammy" in kidney injury?
Concurrent NSAID, ACE inhibitor or ARB, and diuretic — afferent vasoconstriction plus efferent dilation plus volume depletion, a classic cause of acute kidney injury in the elderly.
How do COX-2 selective inhibitors trade risks?
They spare gastric mucosa (fewer ulcers) but carry cardiovascular risk comparable to or exceeding non-selective agents — the mechanism behind rofecoxib's withdrawal and the caution around etoricoxib in coronary disease.