Acetylsalicylic acid (ASA)

Mechanism

Mechanism of Action

Acetylsalicylic acid is a classic antiplatelet agent that acts by inhibiting the synthesis of proaggregant mediators in platelets.

Molecular Physiology: Irreversible Acetylation of COX-1

1. ASA selectively and irreversibly inhibits the enzyme cyclooxygenase-1 (COX-1) within the circulating platelet.
2. The acetyl group of the AAS molecule is covalently transferred to the Serine 529 residue in the COX-1 catalytic channel, sterically blocking the entry of its physiological substrate: arachidonic acid.
3. This prevents the intermediate synthesis of Prostaglandin Endoperoxides and the subsequent generation of Thromboxane A2 (TXA2), a potent platelet granule-releasing agonist and systemic vasoconstrictor.
4. Lacking a chromosome nucleus, platelets are incapable of resynthesizing new COX-1 enzyme. Therefore, the blockage persists for the entire lifespan of the exposed platelet (approx. 7 to 10 days). Normal platelet aggregation only recovers progressively as the bone marrow releases new functional platelets into the circulation (approximately 10% of the total platelets released daily).

Pharmacokinetics

Pharmacokinetics

• Route of administration: Oral; enteric-coated formulations are marketed to limit direct erosive damage to the gastric mucosa.
• Bioavailability (F): Approximately 50 - 70% due to significant gastric and hepatic first-pass clearance mediated by hydrolysis to salicylic acid.
• Distribution: Widely distributed in most body tissues. Concentration-dependent binding to plasma proteins (~50-90% albumin).
• Metabolism: Rapid hydrolysis in plasma by nonspecific esterases to salicylic acid (active metabolite with anti-inflammatory and analgesic properties, but with little antiaggregant effect). Salicylic acid is conjugated in the liver to salicyluric acid.
• Excretion: Renal, dependent on urinary pH (urinary alkalinization ionizes salicylate, increasing its urinary clearance drastically in acute poisoning).
• Half-life (t_1/2): Unaltered ASA has an ultra-short plasma half-life of 15 to 20 minutes; its main metabolite, salicylic acid, has a dose-dependent half-life of 2 to 3 hours at low doses, extending to more than 20 hours in therapeutic overdose due to saturation of hepatic clearance.

Indicators and dose

Indications

• Secondary prevention of atherothrombotic events: AMI, ischemic stroke and transient ischemic attack (TIA).
• Primary prevention of ischemic events in patients at high cardiovascular risk (e.g., diabetes mellitus with high risk scores).
• Acute treatment of AMI and after coronary angioplasty (PCI) as part of dual antiplatelet therapy (DAPT).
• Treatment of Kawasaki disease in pediatrics (acute and immunological phase).

Dosage and Adjustments

• Usual antiplatelet prophylaxis: 75 mg to 100 mg orally once a day.
• Loading dose in ACS: 150 mg to 325 mg (preferably chewed non-enteric tablets to accelerate onset of action to < 10 min).
• Kidney adjustment: Avoid use if the glomerular filtration rate is less than 10 mL/min due to metabolic accumulation and potential nephrotoxicity due to inhibition of renal vasodilatory prostaglandins.

Pregnancy and Breastfeeding

FDA Category D for classic analgesic doses (associated with premature closure of the fetal ductus arteriosus, pulmonary hypertension and renal dysfunction in utero in the third trimester). However, the use of low doses (75 - 150 mg) is prescribed in a safe and scheduled manner in the first and second trimester for the prevention of preeclampsia in high-risk pregnant women. It is not recommended during prolonged breastfeeding due to the theoretical risk of inducing Reye's syndrome in the exposed infant.

Security

Contraindications

Absolute

• Hypersensitivity to ASA or salicylates.
• History of salicylate-induced asthma or bronchospasm attacks associated with NSAIDs (Samter's triad).
• Active peptic ulcer or history of recurrent gastrointestinal bleeding.
• Third trimester of pregnancy (high doses).
• Active bleeding diathesis (e.g., hemophilia).
• Active viral infections in children or adolescents (risk of Reye's Syndrome).

Relative

• Severe kidney or liver failure.
• Previous gout or hyperuricemia (low doses of ASA decrease uric acid excretion by competing in the renal anion transporter).
• Concomitant use of systemic anticoagulants.

Adverse effects (ADRs)

• Gastrointestinal hemorrhage: Most common adverse effect. Results from topical injury by a weak acid and gastric COX-1 inhibition, reducing prostaglandin E2 synthesis (PGE₂) y Prostaciclina (PGI₂), which supports bicarbonate and mucus secretion and mucosal blood flow.
• Bronchospasm (Aspirin-exacerbated respiratory disease): Cyclooxygenase blockade diverts arachidonic acid metabolism toward the lipoxygenase pathway, increasing synthesis of cysteine leukotrienes proinflamatorios y broncoconstrictores potentes.
• Reye Syndrome: Severe acute encephalopathy and fatty hepatic degeneration in children with viral infections such as influenza or chickenpox treated with aspirin.
• Salicylism (Acute overdose toxicity): Tinnitus, hearing loss and initial respiratory alkalosis followed by high-anion-gap metabolic acidosis.

Interactions

Competitive interaction with other NSAIDs. Ibuprofen taken before aspirin may reversibly block the serine 529 binding site on COX-1, preventing the irreversible cardioprotective antiplatelet effect of aspirin. Timing depends on the NSAID, aspirin formulation and dosing schedule. Do not extrapolate a 2-hour rule to all NSAIDs or enteric-coated aspirin; check product information and consider an alternative analgesic.