Acetylsalicylic Acid (Aspirin)

Mechanism

Pharmacological Class and Group

Antiplatelet agent belonging to the group of Irreversible Cyclooxygenase 1 (COX-1) Enzyme Inhibitors.

Mechanism of Action

Platelet activation and aggregation are key stages in the development of arterial thrombosis in coronary or cerebral vessels damaged by atherosclerosis. Thromboxane A₂ Synthesis (TXA₂) is a potent lipid mediator synthesized by platelets that induces aggregation and promotes active local vasoconstriction.

Molecular Mechanism of COX-1 Acetylation

1. Irreversible acetylation of the hydrophobic channel of COX-1: Acetylsalicylic acid selectively and covalently donates its acetyl group to the amino acid residue serine 529 located in the catalytic site of the platelet cyclooxygenase 1 (COX-1) enzyme. This obstructs the entry of arachidonic acid and prevents the intermediate synthesis of prostaglandin H₂ (PGH₂):

Aspirin Covalent acetylation of Ser529 Irreversible inactivation of platelet COX-1

2. Blockade of Thromboxane A₂ Synthesis (TXA₂): By not synthesizing PGH₂, the terminal metabolic cascade of thromboxane synthase is stopped, drastically reducing the platelet availability of TXA₂:

↓ [TXA₂] ↓ Activation of TP Receptors Blockage of platelet aggregation

3. Long-lasting Sustained Effect of Platelet Anucleation: Being anucleated cells, circulating platelets lack the ribosomal machinery necessary to resynthesize new inactivated COX-1 proteins. The blockade of the aggregation of the treated platelets persists irreversibly throughout their useful circulatory half-life in blood (approximately 7 to 10 days).

Pharmacokinetics

High Resolution Pharmacokinetics

• Absorption and Bioavailability: Rapid absorption in the stomach and duodenum by simple passive diffusion. Bioavailability of conventional formulations from 50% to 70%, decreasing slightly with enteric-coated presentations (designed to protect the gastric mucosa, but which delay the onset of systemic absorption).
• Distribution: Wide tissue distribution with moderate to high binding to plasma proteins (mainly albumin, 50% to 90% depending on concentration).
• Metabolism: Rapid and extensive hydrolysis by plasma and liver esterases to its secondary active metabolite, salicylic acid (which has anti-inflammatory effects but is a weak reversible inhibitor of platelet COX).
• Excretion: Renal excretion of salicylic acid and its conjugated metabolites, accelerated by alkalinization of the urine.
• Half-life (t_1/2): The half-life of acetylsalicylic acid is extraordinarily short in plasma (just 15 to 20 minutes of persistence), but its biological pharmacodynamic effect on platelets persists for life (7-10 days).

Indicators and dose

Clinical Indications and Uses

• Secondary Prevention of Ischemic Heart Disease: In patients with a confirmed history of myocardial infarction, stable angina, unstable angina or underlying surgical or percutaneous coronary revascularization.
• Acute Ischemic Heart Disease (ACS): Immediate initial chewable loading dose upon clinical suspicion of acute myocardial infarction.
• Secondary Prevention of Ischemic Stroke and Transient Cerebral Ischemia (TIA): To reduce the risk of recurrent thrombotic occlusions.
• Primary Prevention of Preeclampsia: Indicated at low doses starting from week 12 of gestation in women with identified cardiovascular risk factors.

Dosage and Clinical Adjustment

• Acute Loading Dose (ACS / Stroke): 162 mg to 325 mg chewable starting.
• Chronic Secondary Prevention Dose: 75 mg to 100 mg once daily orally for life, administered with food preferably to mitigate direct local gastric damage.
• Renal/Hepatic Adjustment: Avoid use if eGFR is less than 10 mL/min/1.73 m² or in active decompensated liver disease.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Known hypersensitivity to salicylates or previous history of NSAID-induced asthma (respiratory disease exacerbated by aspirin - Samter's Triad).
• Severe active gastrointestinal bleeding or other risk location.
• Known bleeding diathesis or severe thrombocytopenia.
• Children or adolescents with active viral infections (risk of triggering the deadly Reye Syndrome).

Relative Contraindications

• Active peptic ulcer or history of recurrent gastric bleeding without mucosal protection.
• Concomitant use of oral or high-intensity systemic anticoagulants.
• Moderate underlying renal failure.

Adverse Effects and Toxicity

• Gastrointestinal Bleeding and Gastric Dyspepsia: Due to the concomitant inhibition of COX-1 in the stomach mucosa, reducing protective prostaglandins (PGE₂) that stimulate the secretion of mucus and bicarbonate.
• Systemic Hemorrhage (Hematomas, Epistaxis, Petechiae): Requires clinical monitoring.
• Salicylism / Acute Overdose Toxicity: Presents with tinnitus, vertigo, central hyperventilation due to direct respiratory stimulation and complex mixed metabolic acidosis.

Relevant Drug Interactions

• Ibuprofen and other reversible NSAIDs: If ibuprofen is administered before aspirin, it binds competitively and reversibly to the serine 529 residue of COX-1, blocking the active site and preventing aspirin from irreversibly acetylating it. Once ibuprofen dissociates from the enzyme, platelets regain their normal function, losing the long-term cardiovascular protective effect:

Interaction Alert: AAS / Ibuprofen Administration Rule

To prevent the nullification of the irreversible cardioprotective effect of acetylsalicylic acid, the patient must be educated in strict compliance with the order and physical separation of both doses according to the following temporal separation guidelines:

Take AAS first Wait at least 2 hours Take Ibuprofen or Take Ibuprofen first Wait at least 8 hours Take AAS

In this way, total irreversible acetylation of circulating platelets is ensured before serine 529 of the COX-1 enzyme is occupied by the antagonist with reversible action.

Clinical

Clinical Pearl: Choice of the Type of AAS in the Acute Phase of Infarction

If acute coronary syndrome is suspected in the emergency room, immediate administration of aspirin should ensure rapid systemic absorption to inactivate circulating platelets within minutes. Enteric-coated tablets swallowed whole should not be used as intact gastric passage delays absorption by up to 2-4 hours:

Acute ACS Loading Dose: 162 mg to 325 mg uncoated tablet, chewed and swallowed

Chewing breaks the crystalline structure and increases absorption through the direct oral and gastric mucosa, achieving a complete blockage of platelet aggregation within the first 10 to 20 minutes of administration.