Cyclooxygenase Platelet Inhibitors

Cyclooxygenase platelet inhibitors block formation of thromboxane A2, a platelet activator and vasoconstrictor. Aspirin (acetylsalicylic acid) is the main member. Because platelets have no nucleus, irreversible inhibition lasts for the platelet lifespan of 7 to 10 days, and about 10% of platelets are renewed each day, so full recovery of function takes about 7 days after the last dose.

Members. Aspirin, and in some regions indobufen and triflusal. Other NSAIDs inhibit platelet COX reversibly and are not used for antiplatelet purposes.

Mechanism. Aspirin acetylates serine 529 of cyclooxygenase-1, blocking conversion of arachidonic acid to prostaglandin H2 and then to thromboxane A2. Low doses (75 to 100 mg) inhibit platelet COX-1 in the portal circulation, with relative sparing of endothelial prostacyclin. Higher doses add anti-inflammatory and analgesic effect through COX-2 inhibition.

Pharmacokinetics. Aspirin is absorbed in the stomach and small intestine, with an antiplatelet effect within 30 to 60 minutes (faster when chewed or when non-enteric-coated). Plasma half-life is 15 to 20 minutes, and salicylate half-life lengthens from 2 to 3 hours at low doses to 15 to 30 hours at high doses because of saturable metabolism. Enteric coating delays and may reduce absorption.

Variable response. Some patients show a poor platelet response. Missed doses and enteric-coated formulations contribute, so adherence should be checked before changing therapy.

• Aspirin: the reference drug.
• Indobufen, triflusal: reversible alternatives in some regions, with less gastric toxicity.

• Acute coronary syndrome and suspected acute myocardial infarction: 300 mg chewed as soon as possible unless allergic.
• Long-term secondary prevention after infarction, stroke, transient ischaemic attack or peripheral artery disease: 75 to 100 mg daily.
• Acute ischaemic stroke: aspirin 300 mg once intracranial haemorrhage is excluded and thrombolysis considerations are settled, usually for 14 days, then a long-term regimen.
• Primary prevention: no routine use in people without vascular disease, because bleeding offsets benefit. Consider in selected high-risk adults with low bleeding risk after discussion.
• Pre-eclampsia prevention: 75 to 150 mg nightly from 12 weeks until delivery in women at high risk.
• Kawasaki disease: high-dose aspirin early with immunoglobulin, then low dose, under specialist care.
• Analgesia and fever: 300 to 900 mg every 4 to 6 hours in adults (maximum 4 g daily).
• Selection: use the lowest effective dose with food, and add a proton pump inhibitor in patients at gastrointestinal risk. Where dengue is possible, avoid aspirin and NSAIDs for fever.

Contraindications. Active peptic ulcer or gastrointestinal bleeding, aspirin-exacerbated respiratory disease (nasal polyps, asthma, aspirin sensitivity), bleeding disorders, severe hepatic or renal impairment, children and adolescents under 16 years with viral illness (Reye syndrome risk), gout flares at higher doses, and the last trimester of pregnancy at analgesic doses.

Adverse effects. Dyspepsia, ulceration, gastrointestinal and intracranial bleeding, bronchospasm, urticaria, tinnitus and deafness at higher doses, and fluid retention. Low doses reduce uric acid excretion.

Salicylate poisoning. Early features: tinnitus, vomiting, sweating, hyperventilation. Later features: respiratory alkalosis then metabolic acidosis, hyperthermia, confusion, seizures and pulmonary oedema.

Treat with activated charcoal 50 g within 1 to 2 hours (repeat in large ingestions), intravenous fluids, glucose, sodium bicarbonate to alkalinise urine to pH 7.5 to 8.5 with potassium correction, and haemodialysis for levels over 700 mg/L (lower thresholds in renal impairment, altered mental state or pulmonary oedema). Avoid intubation unless essential, since loss of respiratory compensation worsens acidosis.

Interactions. Warfarin, direct oral anticoagulants, clopidogrel, SSRIs, corticosteroids and other NSAIDs raise bleeding risk. Ibuprofen can block aspirin antiplatelet effect if taken before it. Methotrexate toxicity rises with salicylates. Aspirin lessens the effect of ACE inhibitors, diuretics and spironolactone, and raises valproate and phenytoin free levels.

Monitoring. Haemoglobin, signs of bleeding, kidney function in higher doses, and blood pressure.

Referral and escalation. Black stools, haematemesis, severe headache or neurological change on aspirin needs emergency care.

Special groups. Pregnancy: low-dose use is safe, analgesic doses are avoided from 20 weeks. Older adults: higher bleeding risk. Asthma: ask about aspirin sensitivity. G6PD deficiency: low doses are tolerated, high doses risk haemolysis. Surgery: usually continue low-dose aspirin unless bleeding would be dangerous, for example in neurosurgery.