Aspirin (Acetylsalicylic Acid)

Drug Class

Aspirin belongs to the salicylate subclass of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs). Unlike other NSAIDs, it is an irreversible inhibitor of cyclooxygenase — this distinction is clinically critical.

Mechanism of Action

Aspirin is a weak organic acid that irreversibly acetylates a serine residue near the active site of cyclooxygenase (COX), rendering the enzyme permanently inactive:

COX-1 inhibition (low doses): Blocks thromboxane A₂ (TXA₂) synthesis in platelets → inhibits platelet aggregation and vasoconstriction. Because platelets are anucleate and cannot synthesize new COX, this effect lasts 7–10 days (the entire platelet lifespan).
COX-2 inhibition (high doses, ~1 g/day): Also inhibits COX-2 in endothelial cells → reduces prostacyclin (PGI₂) synthesis, which normally acts as a vasodilator and platelet inhibitor. This partially offsets the antiplatelet benefit at high doses.

Aspirin acetylates COX: the acetyl group from aspirin transfers to cyclooxygenase, rendering it inactive. The drug is then metabolized to salicylic acid.

Metabolism of aspirin and acetylation of cyclooxygenase — Lippincott Illustrated Reviews: Pharmacology

Pharmacological Effects

Effect	Mechanism
Antiplatelet	COX-1 inhibition → ↓ TXA₂ → ↓ platelet aggregation
Analgesic	↓ PG synthesis → ↓ peripheral sensitization
Antipyretic	↓ PGE₂ in hypothalamus → ↓ fever
Anti-inflammatory	↓ prostaglandins/prostacyclin (only at high doses)

Site of Action in Platelet Cascade

Aspirin inhibits COX-1 to block TXA₂ synthesis, while other antiplatelet drugs act on ADP (P2Y12), GpIIb/IIIa, and PAR-1 pathways.

Site of action of antiplatelet drugs — Harrison's Principles of Internal Medicine, 22e (2025)

Clinical Indications

Cardiovascular (Primary Use at Low Doses: 75–325 mg/day)

Secondary prevention of cardiovascular events in patients with established coronary artery disease, cerebrovascular disease, or peripheral arterial disease — produces a ~25% reduction in cardiovascular death, MI, or stroke vs. placebo.
Acute MI / ACS: Initial dose of ≥160 mg for rapid platelet inhibition.
Post-PCI / stent: Often combined with a P2Y12 inhibitor (clopidogrel, ticagrelor) as dual antiplatelet therapy (DAPT).
Primary prevention: No longer routinely recommended. May be considered only in adults aged 40–59 with ≥10% 10-year CVD risk and low bleeding risk, as hemorrhagic risks outweigh benefits in lower-risk individuals.

Analgesic / Antipyretic / Anti-inflammatory

Headache, musculoskeletal pain, fever (at higher doses of 325–650 mg q4–6h)
Rheumatic diseases (at high doses 3–6 g/day, rarely used now)

Other

Kawasaki disease: High-dose aspirin is standard of care
Pericarditis: Used as anti-inflammatory
Pre-eclampsia prevention: Low-dose aspirin in high-risk pregnancies

Dosing

Indication	Dose
Antiplatelet (maintenance)	75–100 mg/day
Antiplatelet (loading)	≥160 mg stat
Analgesic/antipyretic	325–650 mg q4–6h
Anti-inflammatory	3–6 g/day (high-dose, rarely used)

Higher doses are not more effective for cardiovascular protection and increase bleeding risk.

Adverse Effects

Effect	Notes
GI: dyspepsia, erosive gastritis, peptic ulcer, GI bleeding	Dose-related; enteric coating does NOT eliminate risk
Bleeding	Overall ~1–3% major bleeding/year; 2–3× higher with dual antiplatelet or anticoagulant combinations
Aspirin hypersensitivity	Bronchospasm in ~0.3% general population; higher in asthmatics with nasal polyps or chronic rhinitis
Reye's syndrome	Avoid in children with viral illness (encephalopathy + liver failure risk)
Hepatic/renal toxicity	With overdose/high chronic doses

Salicylate Toxicity (Overdose)

Classically causes a mixed respiratory alkalosis + metabolic acidosis
Serum acidosis promotes drug entry into CNS (increases toxicity)
Urinary alkalinization (sodium bicarbonate) is a key treatment to trap salicylate in urine and enhance excretion

Contraindications / Cautions

Active peptic ulcer disease
Bleeding disorders
Aspirin allergy / NSAID hypersensitivity
Children with viral infections (Reye's syndrome risk)
Last trimester of pregnancy (premature closure of ductus arteriosus)

Aspirin Resistance

Failure to inhibit platelet TXA₂ production or aggregation. Causes include poor compliance, reduced absorption, drug interaction with ibuprofen (which competitively blocks COX-1 access), and COX-2 overexpression. Testing for resistance is not yet standardized for clinical use.

Sources: Harrison's Principles of Internal Medicine 22e (2025); Lippincott Illustrated Reviews: Pharmacology; Katzung's Basic & Clinical Pharmacology 16e; Braunwald's Heart Disease; Goodman & Gilman's Pharmacological Basis of Therapeutics

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