Mechanism of action
Aspirin exerts its effects through irreversible acetylation of serine residues on cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. This covalent modification permanently inactivates the enzymes, preventing the conversion of arachidonic acid to prostaglandin H2, the precursor for prostaglandins, thromboxanes, and prostacyclins.
Antiplatelet effect
Aspirin's antiplatelet action results from irreversible inhibition of COX-1 in platelets, blocking thromboxane A2 (TXA2) synthesis. TXA2 is a potent vasoconstrictor and promoter of platelet aggregation. Because platelets lack nuclei and cannot synthesize new COX-1 enzyme, this inhibition lasts for the entire lifespan of the platelet (approximately 7-10 days). Even low doses of aspirin (75-100 mg daily) achieve near-complete inhibition of platelet COX-1.
Anti-inflammatory and analgesic effects
At higher doses, aspirin inhibits COX-2 in peripheral tissues, reducing prostaglandin synthesis at sites of inflammation and in the central nervous system. Prostaglandins mediate pain, fever, and inflammation, so their reduction produces analgesia, antipyresis, and anti-inflammatory effects. Aspirin also inhibits prostaglandin E2 production in the hypothalamus, contributing to its antipyretic action.
Additional mechanisms
Aspirin has anti-inflammatory effects independent of COX inhibition, including inhibition of nuclear factor-kappa B (NF-κB) activation and modification of gene expression related to inflammation.
- Aspirin irreversibly acetylates COX-1, permanently inhibiting platelet function for 7-10 days.
- Low-dose aspirin (75-100 mg) is sufficient for antiplatelet effect in cardiovascular prophylaxis.
- Reye syndrome: aspirin is contraindicated in children with viral illnesses (influenza, varicella).
- Salicylate toxicity: early respiratory alkalosis, late metabolic acidosis, tinnitus, and hyperventilation.
- Ibuprofen blocks aspirin's antiplatelet effect; take aspirin 2 hours before ibuprofen.
- Aspirin increases bleeding risk when combined with anticoagulants, other antiplatelets, or SSRIs.
- AERD triad: asthma, nasal polyps, aspirin/NSAID hypersensitivity with bronchospasm.
- Alkalinization of urine enhances salicylate excretion in overdose (hemodialysis if severe).
Indications
Cardiovascular prophylaxis
- Secondary prevention of myocardial infarction and stroke in patients with established cardiovascular disease
- Acute coronary syndrome (unstable angina, NSTEMI, STEMI) as part of dual antiplatelet therapy
- Post-percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)
- Atrial fibrillation in select patients (though anticoagulation is preferred)
- Primary prevention in certain high-risk individuals (benefit-risk assessment required)
Analgesic and antipyretic uses
- Mild to moderate pain (headache, musculoskeletal pain, dysmenorrhea)
- Fever reduction
- Inflammatory conditions (though other NSAIDs often preferred)
Rheumatologic conditions
- Rheumatoid arthritis
- Osteoarthritis
- Acute rheumatic fever
- Kawasaki disease (high-dose initially, then low-dose antiplatelet therapy)
- Pericarditis
Other indications
- Preeclampsia prophylaxis in high-risk pregnancies (low-dose)
- Colorectal cancer prevention (emerging evidence, not standard)
Dosing follows the product label and clinical indication. Antiplatelet doses are typically 75-100 mg daily, while anti-inflammatory doses range higher.
Pharmacokinetics
Absorption: Aspirin is rapidly absorbed from the stomach and small intestine. Peak plasma levels occur within 30-40 minutes for immediate-release formulations. Enteric-coated preparations delay absorption but reduce gastric irritation.
Distribution: Aspirin is widely distributed and crosses the blood-brain barrier and placenta. It is highly protein-bound (approximately 80-90%, primarily to albumin).
Metabolism: Aspirin undergoes rapid hydrolysis by esterases in the gastrointestinal mucosa, plasma, and liver to salicylic acid, its active metabolite. Salicylic acid is further metabolized via hepatic conjugation (glycine and glucuronic acid conjugation) and oxidation. At therapeutic doses, metabolism follows first-order kinetics, but at high doses (intoxication), metabolism shifts to zero-order kinetics due to saturation of hepatic enzymes.
Excretion: Salicylates are primarily eliminated by the kidneys. Renal excretion is pH-dependent—alkalinization of urine increases ionization of salicylic acid and enhances excretion. The half-life of aspirin is approximately 15-20 minutes, but salicylic acid has a half-life of 2-3 hours at low doses and up to 15-30 hours at high doses due to saturable metabolism.
Special populations: Renal impairment prolongs salicylate elimination. Use caution in hepatic impairment due to reduced metabolism and increased bleeding risk.
Adverse effects
Gastrointestinal
- Dyspepsia, nausea, gastric erosion (common even at low doses)
- Peptic ulcer disease and gastrointestinal bleeding (increased risk, especially at higher doses and with prolonged use)
- Esophagitis
Hematologic
- Increased bleeding risk due to irreversible platelet inhibition
- Prolonged bleeding time (not prothrombin time or aPTT)
- Risk of hemorrhagic stroke (rare but serious)
Reye syndrome
- Rare but life-threatening hepatoencephalopathy in children and adolescents with viral infections (especially influenza and varicella). Aspirin is contraindicated in children with febrile illnesses due to this risk.
Hypersensitivity reactions
- Aspirin-exacerbated respiratory disease (AERD): triad of asthma, chronic rhinosinusitis with nasal polyps, and respiratory reactions to aspirin/NSAIDs
- Urticaria, angioedema, anaphylaxis (rare)
- Cross-reactivity with other NSAIDs may occur
Renal
- Acute interstitial nephritis
- Reduced renal function, especially in volume-depleted patients or those with pre-existing renal disease (due to inhibition of prostaglandin-mediated renal blood flow)
Salicylism
- Chronic toxicity with tinnitus, hearing loss, vertigo, confusion, hyperventilation (mixed respiratory alkalosis and metabolic acidosis)
Other
- Hepatotoxicity (rare, dose-related)
- Iron deficiency anemia from chronic gastrointestinal blood loss
Contraindications and warnings
Absolute contraindications
- Hypersensitivity to aspirin or other salicylates
- Active peptic ulcer disease or gastrointestinal bleeding
- Severe renal or hepatic impairment
- Bleeding disorders (hemophilia, severe thrombocytopenia, vitamin K deficiency)
- Children and adolescents with viral infections (risk of Reye syndrome)
- Third trimester of pregnancy (risk of premature closure of ductus arteriosus, bleeding complications, delayed labor)
Relative contraindications and warnings
- Asthma or nasal polyps: increased risk of bronchospasm (AERD)
- Gout: high-dose aspirin may precipitate attacks by decreasing uric acid excretion
- Concurrent anticoagulation: increased bleeding risk
- Glucose-6-phosphate dehydrogenase (G6PD) deficiency: risk of hemolysis at high doses
- Surgery: aspirin is often discontinued 5-7 days preoperatively to reduce bleeding risk, though cardiac stents may require continuation
- First and second trimester pregnancy: generally avoided unless specifically indicated (e.g., low-dose for preeclampsia prophylaxis)
Black box warnings
While aspirin does not carry a formal black box warning in many countries, NSAIDs as a class have warnings regarding increased cardiovascular thrombotic events and gastrointestinal bleeding. Reye syndrome risk in children is prominently highlighted.
Drug interactions
Anticoagulants and antiplatelets
- Warfarin, heparin, direct oral anticoagulants (DOACs): additive bleeding risk
- Clopidogrel, ticagrelor, prasugrel: often used together intentionally (dual antiplatelet therapy) but increase bleeding risk
- SSRIs, SNRIs: increased risk of gastrointestinal bleeding
Other NSAIDs
- Ibuprofen: may interfere with aspirin's irreversible antiplatelet effect by competing for the COX-1 active site. Ibuprofen should be taken at least 2 hours after aspirin or avoided.
- Other NSAIDs: additive gastrointestinal and renal toxicity
Antihypertensives
- ACE inhibitors, ARBs, diuretics: aspirin may reduce their antihypertensive efficacy by inhibiting renal prostaglandin synthesis
Methotrexate
- Aspirin reduces renal clearance of methotrexate, increasing toxicity risk
Uricosuric agents
- Probenecid, sulfinpyrazone: aspirin antagonizes their uric acid-lowering effects
Alcohol
- Increased risk of gastrointestinal bleeding and hepatotoxicity
Corticosteroids
- Additive gastrointestinal bleeding risk; corticosteroids may also increase aspirin clearance
Valproic acid
- Aspirin displaces valproic acid from protein binding, increasing free drug levels and risk of toxicity
Clinical pearls
- Irreversible vs. reversible COX inhibition: Aspirin is unique among NSAIDs in permanently acetylating COX enzymes. Other NSAIDs (ibuprofen, naproxen) reversibly inhibit COX, so their effects cease once the drug is cleared from plasma.
- Kawasaki disease: Aspirin is used in high doses during the acute phase for anti-inflammatory effect, then switched to low-dose for antiplatelet effect to prevent coronary artery thrombosis.
- Aspirin resistance: A subset of patients do not achieve adequate platelet inhibition with standard aspirin doses. True aspirin resistance is rare; non-adherence is more common.
- Timing with ibuprofen: Ibuprofen can block aspirin's access to the COX-1 active site. To preserve aspirin's cardioprotective effect, take aspirin at least 2 hours before ibuprofen or use alternative analgesics.
- Salicylate toxicity: Presents with respiratory alkalosis (early, from direct medullary stimulation) followed by metabolic acidosis (late, from uncoupling of oxidative phosphorylation). Classic findings include tinnitus, hyperventilation, and altered mental status. Treatment includes alkalinization of urine and hemodialysis in severe cases.
- Pregnancy: Low-dose aspirin (81 mg daily) started before 16 weeks gestation reduces preeclampsia risk in high-risk pregnancies. Avoid in the third trimester due to fetal risks.
- Aspirin desensitization: Patients with AERD who require aspirin for cardiovascular indications can undergo desensitization protocols under specialist supervision.
- Enteric coating: Reduces gastric irritation but delays absorption and may not significantly reduce ulcer risk with chronic use.
- Colorectal cancer: Observational data suggest aspirin may reduce colorectal cancer incidence, but routine use for cancer prevention is not currently recommended due to bleeding risks.
ASPIRIN toxicity: Acidosis, Seizures, Pyrexia (fever), Irritability, Respiratory alkalosis (early) then acidosis, INcreased anion gap, Nausea/tinnitus.
Practice questions
1. A 62-year-old man with a history of coronary artery disease presents to the emergency department with chest pain. He is diagnosed with acute myocardial infarction and started on dual antiplatelet therapy. Four days later, he requires urgent coronary artery bypass grafting. Despite stopping all antiplatelet agents 24 hours before surgery, he experiences excessive intraoperative bleeding. Which property of one of his medications most likely contributed to this complication?
2. A 14-year-old girl is brought to the clinic with a 2-day history of fever, headache, and myalgias. Her mother reports the patient has been taking aspirin every 4 hours for symptom relief. Physical examination reveals mild hepatomegaly and confusion. Laboratory studies show elevated aminotransferases and ammonia. Influenza A is confirmed by rapid testing. Which pathophysiological process best explains this patient's presentation?
3. A 68-year-old woman on low-dose aspirin for secondary stroke prevention is prescribed ibuprofen for osteoarthritis pain. Two weeks later, she experiences an ischemic stroke. Her medication adherence is confirmed. Which mechanism most likely contributed to the loss of aspirin's protective effect?
Frequently asked questions
How does aspirin work?
Aspirin irreversibly inhibits cyclooxygenase (COX) enzymes by acetylating a serine residue, permanently blocking prostaglandin and thromboxane synthesis. In platelets, this prevents thromboxane A2 production, inhibiting platelet aggregation for the platelet's lifespan (7-10 days). At higher doses, aspirin also reduces prostaglandin-mediated pain, fever, and inflammation.
What are the side effects of aspirin?
Common side effects include gastrointestinal upset, gastric erosion, and increased bleeding risk due to platelet inhibition. Serious adverse effects include peptic ulcer disease, gastrointestinal bleeding, hemorrhagic stroke, Reye syndrome in children with viral infections, and hypersensitivity reactions such as aspirin-exacerbated respiratory disease (asthma, nasal polyps, bronchospasm). Chronic use may cause salicylism (tinnitus, confusion, metabolic disturbances).
Is aspirin a controlled substance?
No, aspirin is not a controlled substance. It is available over-the-counter in most countries for analgesic, antipyretic, and anti-inflammatory purposes. Low-dose aspirin for cardiovascular prophylaxis is also widely accessible without prescription, though its use should be guided by a healthcare provider for appropriate indications.
Aspirin vs ibuprofen — what is the difference?
Aspirin irreversibly inhibits COX enzymes, leading to permanent antiplatelet effects lasting 7-10 days, making it ideal for cardiovascular prophylaxis. Ibuprofen reversibly inhibits COX, so its antiplatelet effect is shorter and dose-dependent, making it unsuitable for long-term cardiovascular protection. Importantly, ibuprofen can block aspirin's antiplatelet action by competing for the COX-1 active site, so timing is critical if both are used. Both have analgesic and anti-inflammatory properties.
Why is aspirin contraindicated in children?
Aspirin is contraindicated in children and adolescents with viral infections (especially influenza and varicella) due to the risk of Reye syndrome, a rare but life-threatening condition causing acute hepatic failure and encephalopathy. The exact mechanism is unclear but involves mitochondrial dysfunction. Exceptions include specific indications like Kawasaki disease, where aspirin is used under close medical supervision.
Conditions it is used for
Related drugs
Sources and further reading
DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: A01AD05WHO ATC/DDD index: B01AC06
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.