NSAIDs — Classification, COX Selectivity, Adverse Effects and Aspirin Toxicity

The main mechanism of NSAIDs is inhibition of cyclooxygenase (COX), the enzyme that converts arachidonic acid into prostaglandins, prostacyclin and thromboxanes. The therapeutic effects come from the loss of these eicosanoids: prostaglandins mediate vasodilation, raise the hypothalamic temperature set-point and take part in nociception, while thromboxane is involved in platelet adhesion (StatPearls). That one idea explains the analgesic, antipyretic, anti-inflammatory and antiplatelet effects, and also most of the adverse effects.

There are two isoenzymes. COX-1 is expressed constitutively and maintains the gastric mucosal lining, kidney function and platelet aggregation. COX-2 is not constitutive; it is induced during inflammation. Most NSAIDs are non-selective and block both, whereas COX-2 selective agents such as celecoxib spare COX-1 and so carry a lower gastric risk (StatPearls).

StatPearls divides NSAIDs by chemical structure and selectivity. The table below is the version worth memorising; each group is a favourite for 'identify the odd one out' questions.

Topical NSAIDs such as diclofenac gel are available for acute tenosynovitis, ankle sprains and soft-tissue injuries. Aspirin's daily limit for over-the-counter analgesia is 4000 mg, per the StatPearls dosing notes.

Aspirin is distinguished from salicylic acid by an acetyl group. This gives it a distinctive, irreversible inhibition of platelet function. Platelets have no nucleus and cannot synthesise new COX enzymes, so aspirin's block of thromboxane A2 synthesis lasts for the life of the platelet. Ibuprofen and naproxen, by contrast, produce reversible COX-1 blockade (StatPearls, Salicylic Acid).

Blocking COX also shunts arachidonic acid towards the lipoxygenase pathway, which raises leukotriene production. This is the explanation offered for aspirin-exacerbated respiratory disease (AERD) — bronchospasm and nasal symptoms triggered by cyclooxygenase inhibition. Low-dose aspirin is used in pregnancy to reduce the risk of pre-eclampsia, and in acute coronary syndrome a loading dose is followed by a daily low-dose regimen; dual antiplatelet therapy with a P2Y12 inhibitor is recommended for at least 12 months in ACS patients who are not at high bleeding risk.

Gastric toxicity is due to COX-1 inhibition: without prostaglandins the protective mucosa is lost, and the damage is more likely when there is a prior history of peptic ulcer. Because the problem is COX-1 specific, COX-2 selective NSAIDs are a lower-risk alternative (StatPearls).

Renal toxicity arises because both COX isoenzymes support renal haemodynamics. In normal kidneys the effect is small, but in renal dysfunction prostaglandins carry a larger share of renal blood flow, and blocking them can cause hypertension, acute renal dysfunction, fluid and electrolyte disorders, renal papillary necrosis, nephrotic syndrome and interstitial nephritis. NSAIDs reduce afferent arteriolar dilation and lower GFR, which blunts the natriuretic effect of diuretics and antagonises the haemodynamic benefit of ACE inhibitors.

• Stomach/duodenum: erosions, ulcers, bleeding — COX-1 loss; risk higher with previous ulcer
• Kidney: reduced GFR, papillary necrosis, interstitial nephritis, nephrotic syndrome
• Fluid balance: sodium and water retention, so pedal oedema and blunted diuretic response
• Blood pressure: NSAIDs can raise BP and oppose ACE-inhibitor action

NSAID use can increase myocardial infarction, thromboembolic events and atrial fibrillation. Diclofenac appears to have the highest reported increase in cardiovascular events. By promoting sodium and water retention NSAIDs raise intravascular volume and preload, so they can worsen congestive heart failure — even COX-2 selective agents like meloxicam can precipitate acute volume overload in heart failure patients (StatPearls).

NSAIDs are contraindicated in patients with NSAID or salicylate hypersensitivity, those who had an allergic reaction (urticaria, asthma) after taking NSAIDs, after coronary artery bypass graft surgery, in the third trimester of pregnancy, and in renal failure. For chronic users the American College of Rheumatology monitoring list in StatPearls is a CBC, renal tests and hepatic panel.

Salicylate directly stimulates the medulla, causing hyperventilation and respiratory alkalosis. It also uncouples oxidative phosphorylation in mitochondria, increasing anaerobic metabolism and lactate; lactic acid plus salicylate metabolites cause metabolic acidosis. The patient hyperventilates harder to compensate until fatigue sets in. At toxic levels the clearance pathways saturate and elimination becomes zero-order, which is why levels can keep rising (StatPearls, Salicylates Toxicity).

Acute overdose symptoms start within 3 to 8 hours. Early blood gas shows a pure respiratory alkalosis; at moderate levels metabolic acidosis with respiratory alkalosis; in severe toxicity the acidosis worsens with an anion gap. Hypokalaemia and hypercalcaemia may occur, and thrombocytopenia may be seen. See ABG interpretation and anion gap.

1. Resuscitate: patients are volume depleted from hyperventilation, fever and hypermetabolism. Use dextrose with sodium bicarbonate (3 ampoules in D5 in the chapter) to correct acidosis and treat CNS hypoglycaemia; target urine output 2 to 3 mL/kg per hour; replace potassium if low.
2. Serum alkalinisation and fluids increase salicylate elimination.
3. Activated charcoal lowers salicylate levels but no morbidity or mortality benefit has been shown; whole bowel irrigation has shown no benefit. Gastric lavage may be considered after enteric-coated aspirin if no aspiration risk.
4. Avoid intubation if possible because the ventilator cannot match the patient's own hyperventilation; if needed give a bolus of 1 to 2 mEq/kg sodium bicarbonate and arrange emergent haemodialysis.
5. Haemodialysis is indicated for severe acidosis or hypotension despite fluids, level above 100 mg/dL, need for mechanical ventilation, or end-organ damage (seizures, rhabdomyolysis and similar).

• Colorectal polyposis: the NSAID sulindac reduced adenomas by nearly 50% and their size by 65% in small studies of familial adenomatous polyposis, but adenomas recurred when it was stopped. See hereditary colorectal cancer.
• Pregnancy: third-trimester NSAIDs are a labelled contraindication; low-dose aspirin is used to reduce pre-eclampsia risk.
• Bronchospasm after an NSAID: think aspirin-exacerbated respiratory disease, explained by leukotriene shunting.
• Heart failure and CKD: avoid NSAIDs; they retain sodium and water and reduce GFR.
• Related drug groups: compare with corticosteroids and the prostaglandin chapter in autacoids.

For a rapid scan of how these questions are framed in recent papers, use the NEET PG PYQ bank and the most repeated topics list.