Describe the pharmacology of aspirin including its dose-dependent actions, uses, adverse effects and poisoning.

Pharmacokinetics

• Rapidly absorbed from the stomach and upper intestine; hydrolysed to salicylic acid, which is the active moiety for most effects
• Highly bound to plasma albumin (80–90%), and displaces warfarin, sulphonylureas, methotrexate and bilirubin
• Metabolism shows a change of order — first-order at low doses, zero-order at anti-inflammatory and toxic doses, because conjugation with glycine and glucuronic acid saturates. Hence a small dose increase can cause a large rise in level
• Excretion is greatly increased by alkalinising the urine, since the ionised salicylate cannot be reabsorbed — the basis of treatment in poisoning

Dose-dependent Actions

Therapeutic Uses

• Cardiovascular prophylaxis — acute coronary syndrome (300 mg chewed), and lifelong secondary prevention after infarction, stroke or transient ischaemic attack
• Analgesic and antipyretic — now largely replaced by paracetamol and ibuprofen
• Acute rheumatic fever — still a standard treatment for the arthritis, in which the response is dramatic and almost diagnostic
• Kawasaki disease — one of the few paediatric indications, given with intravenous immunoglobulin
• Pre-eclampsia prophylaxis — low-dose aspirin from early pregnancy in women at high risk
• Possible reduction in colorectal cancer with long-term use, though not an accepted indication on its own

Adverse Effects

• Gastrointestinal — dyspepsia, erosions, ulceration and bleeding; even low doses cause occult blood loss and iron deficiency
• Salicylism — the syndrome of mild chronic overdose: tinnitus and deafness (the earliest and most reliable sign), headache, dizziness, nausea, sweating and mental confusion. Reversible on stopping
• REYE syndrome — acute encephalopathy with fatty liver in children given aspirin during a viral illness, particularly influenza and varicella; often fatal. Aspirin is therefore contraindicated under 16 except in Kawasaki disease and rheumatic fever
• Aspirin-sensitive asthma and urticaria; part of Samter triad with nasal polyps
• Hypersensitivity, bleeding, and hepatic and renal effects as for other NSAIDs
• In G6PD deficiency high doses may precipitate haemolysis

Salicylate Poisoning

Salicylate directly stimulates the respiratory centre → Hyperventilation → respiratory alkalosis — the first disturbance, and the dominant picture in adults → Renal compensation excretes bicarbonate, potassium and sodium → Salicylate uncouples oxidative phosphorylation → increased metabolic rate, hyperthermia, and accumulation of lactic and keto acids → Metabolic acidosis supervenes — the picture in young children from the outset → The result is a mixed respiratory alkalosis with metabolic acidosis → Acidosis increases the unionised fraction, which enters the brain → convulsions, coma and death

• Other features — vomiting, dehydration, hyperpyrexia, tinnitus, sweating, hypoglycaemia or hyperglycaemia, pulmonary oedema, bleeding
• Treatment — activated charcoal if early; correction of dehydration, glucose and potassium; alkalinisation of the urine with sodium bicarbonate (aiming for a urine pH above 7.5), which both traps salicylate in the tubule and keeps it out of the brain; cooling; and haemodialysis for severe poisoning — salicylate has a small volume of distribution and low protein binding at high concentrations, so dialysis works well
• Potassium must be replaced before alkalinisation succeeds, since in hypokalaemia the kidney exchanges hydrogen for sodium and the urine cannot be alkalinised

Drug Interactions of Aspirin

Applied Aspects

• Aspirin must be chewed, not swallowed, in suspected infarction, so that it acts within minutes
• Do not give aspirin to a child with fever; paracetamol is the appropriate antipyretic
• Ask about NSAID use in any patient with unexplained anaemia — chronic occult blood loss from low-dose aspirin is easily overlooked
• NSAIDs taken shortly before aspirin block its antiplatelet effect by competing for the COX-1 site; aspirin should be taken first, or a different analgesic chosen
• Do not stop aspirin unnecessarily before minor surgery — the thrombotic risk of stopping usually exceeds the bleeding risk of continuing
• Salicylate poisoning is easily misdiagnosed, since the early picture of hyperventilation and confusion suggests sepsis or a primary respiratory problem; the level must be measured and repeated, as absorption may be prolonged
• Methyl salicylate (oil of wintergreen) is highly concentrated — a teaspoonful contains the equivalent of many aspirin tablets, and it is a recognised cause of fatal poisoning in children
• Enteric-coated aspirin delays absorption unpredictably in overdose, so levels must be repeated over several hours rather than accepting a single reassuring result
• Aspirin should be stopped about a week before major surgery where bleeding risk is high, but continued for most vascular indications; the decision is made jointly with the surgeon
• Tinnitus is the practical bedside marker of salicylate excess, and in the days when aspirin was used for rheumatoid arthritis the dose was titrated up until it appeared, then reduced slightly
• Aspirin remains one of the highest-value drugs in medicine — cheap, universally available, and life-saving in acute coronary syndrome; its correct use matters more than any newer agent
• Low-dose aspirin is no longer recommended for primary prevention in people without established vascular disease, since the bleeding risk broadly offsets the benefit
• Check for concurrent anticoagulants and SSRIs before adding aspirin; each independently raises bleeding risk and the combination is frequently overlooked
• True aspirin allergy is uncommon; most reported reactions are dyspepsia or bronchospasm, and only the latter is a genuine class contraindication