Inflammation: Pharmacology of Aspirin

1. Introduction/Overview

Acetylsalicylic acid (ASA) is among the most widely utilized medications worldwide, serving roles that span from symptom relief in mild inflammatory conditions to secondary prevention of cardiovascular events. The importance of aspirin in contemporary practice is underscored by its inclusion in standard treatment algorithms for acute coronary syndrome, stroke prevention, rheumatoid arthritis, and various other inflammatory disorders. Understanding its pharmacological profile is essential for clinicians and pharmacists, as it informs dosing strategies, risk–benefit assessments, and patient counseling.

Learning objectives for this chapter include:

• Describe the classification and chemical nature of aspirin.
• Explain the pharmacodynamic and pharmacokinetic properties of the drug.
• Detail the therapeutic indications and off‑label applications.
• Identify common and serious adverse effects, including black‑box warnings.
• Recognize key drug interactions and contraindications.
• Apply knowledge of special patient populations to optimize therapy.

2. Classification

Drug Classes and Categories

Aspirin belongs to the nonsteroidal anti‑inflammatory drug (NSAID) class, specifically categorized as a salicylate. Within the broader NSAID grouping, ASA is considered a non‑selective inhibitor of cyclooxygenase (COX) enzymes, lacking the preferential COX‑2 inhibition characteristic of newer agents such as celecoxib.

Chemical Classification

As a small, lipophilic organic acid, acetylsalicylic acid is structurally related to salicylic acid, differing by an acetyl group attached to the phenolic hydroxyl. The acetyl moiety is critical for its pharmacological activity, as it enables irreversible acetylation of COX enzymes upon hydrolysis, thereby conferring a unique antiplatelet effect. The drug is typically formulated as a free base or as a salt (e.g., potassium salicylate) for enhanced solubility in certain preparations.

3. Mechanism of Action

Pharmacodynamics

Aspirin exerts its therapeutic effects through a dual mechanism: inhibition of cyclooxygenase enzymes and modulation of arachidonic acid metabolism. The irreversible acetylation of COX‑1 and COX‑2 reduces the synthesis of prostaglandins and thromboxane A₂ (TXA₂). In platelets, the blockade of TXA₂ synthesis results in a prolonged antiplatelet effect, as platelets lack the capacity for resynthesis of COX enzymes. This property underlies the drug’s efficacy in preventing arterial thrombotic events.

Receptor Interactions

While aspirin does not directly bind to prostaglandin receptors, its downstream effect of decreasing prostaglandin production indirectly modulates receptor-mediated pathways involved in inflammation, pain transmission, and vascular tone. The suppression of prostaglandin E₂ (PGE₂) contributes to analgesic and antipyretic actions, whereas reduced thromboxane B₂ (TXB₂), the stable metabolite of TXA₂, mediates its antithrombotic effect.

Molecular and Cellular Mechanisms

At the cellular level, aspirin’s acetylation of serine residues within the active sites of COX enzymes (Ser530 in COX‑1 and Ser516 in COX‑2) prevents the conversion of arachidonic acid to prostaglandin H₂ (PGH₂). The resulting deficit in PGH₂ limits the substrate availability for downstream synthases, thereby decreasing prostaglandin and thromboxane output. Additionally, aspirin may exert COX‑independent effects, such as modulation of nuclear factor‑κB (NF‑κB) signaling, activation of AMP‑activated protein kinase (AMPK), and induction of cyclin‑dependent kinase inhibition, which can contribute to anti‑cancer and anti‑inflammatory properties. However, these mechanisms are less pronounced clinically compared to COX inhibition.

4. Pharmacokinetics

Absorption

Orally administered aspirin is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations typically achieved within 30–60 minutes. The absolute oral bioavailability is approximately 40–70%, varying with dose and formulation; higher doses may exhibit slightly reduced absorption due to saturation of transport mechanisms. Gastric irritation can transiently reduce absorption, particularly when taken with food, yet the overall impact on systemic exposure remains modest.

Distribution

After absorption, aspirin distributes widely throughout body tissues. It is highly protein‑bound (∼99% to plasma albumin), which limits the free fraction available for pharmacologic action. The drug’s lipophilic nature facilitates penetration across cellular membranes, including the blood–brain barrier, though central nervous system concentrations remain low relative to plasma levels. Distribution to tissues such as the liver, kidney, and spleen is achieved rapidly, contributing to metabolic clearance.

Metabolism

In the liver, aspirin undergoes rapid hydrolysis to salicylic acid, mediated primarily by esterases. Salicylic acid is further metabolized via conjugation pathways: glucuronidation (via UDP‑glucuronosyltransferases) and sulfation (by sulfotransferases). The resulting conjugates are more water‑soluble and facilitate renal excretion. Minor oxidative pathways, mediated by cytochrome P450 enzymes, can produce intermediates such as 2‑hydroxybenzoic acid, yet these routes represent a small fraction of overall metabolism.

Excretion

Renal excretion dominates the elimination of aspirin metabolites. Approximately 70–80% of the administered dose is recovered in the urine as conjugated salicylates within 24 hours. The terminal half‑life of aspirin is relatively short (∼15–20 minutes for the parent drug), whereas the half‑life of salicylate conjugates extends to 3–4 hours, reflecting the slower clearance of metabolites. In patients with renal impairment, the excretion of salicylate derivatives may be delayed, necessitating dose adjustment or alternative therapy.

Half‑Life and Dosing Considerations

The pharmacodynamic effect of aspirin on platelet function persists for the lifespan of the platelet (∼7–10 days), as newly formed platelets are not exposed to the drug. Consequently, a single daily dose can maintain antiplatelet activity for an entire platelet lifespan. Standard antiplatelet dosing ranges from 75–162 mg for cardiovascular prevention, whereas higher doses (≥500 mg) are employed for analgesic or anti‑inflammatory indications. Dose regimens are tailored to therapeutic objectives, tolerability, and patient comorbidities. Frequent dosing at low levels may be preferred to minimize gastrointestinal irritation while preserving efficacy.

5. Therapeutic Uses/Clinical Applications

Approved Indications

Aspirin’s antiplatelet activity underpins its primary indication for secondary prevention of myocardial infarction, ischemic stroke, and peripheral arterial disease. Low‑dose aspirin (75–162 mg) is routinely prescribed for patients with established atherosclerotic disease, acute coronary syndrome, or undergoing percutaneous coronary interventions. In addition, aspirin is approved for the treatment of acute pain, fever, and inflammation in musculoskeletal disorders, including osteoarthritis and rheumatoid arthritis, typically at doses ranging from 300–1000 mg daily.

Off‑Label Uses

Clinicians frequently employ aspirin beyond its formal indications. Off‑label applications include:

• Primary prevention of cardiovascular events in high‑risk but otherwise healthy individuals, although current guidelines recommend careful risk assessment.
• Management of menstrual pain and dysmenorrhea, leveraging its analgesic properties.
• Adjunctive therapy in certain inflammatory dermatoses (e.g., psoriasis) and gastrointestinal disorders (e.g., Helicobacter pylori eradication regimens).
• Potential chemopreventive role in colorectal cancer, especially when combined with low‑dose daily aspirin in older adults, although evidence remains evolving.

6. Adverse Effects

Common Side Effects

Gastrointestinal disturbances are the most frequently reported adverse events. Oral aspirin can cause dyspepsia, epigastric pain, nausea, and, in susceptible individuals, ulceration or bleeding. The risk is dose‑dependent and increases with concurrent use of other NSAIDs or corticosteroids. Minor dermatologic reactions, such as contact dermatitis or skin rash, may occur, particularly with topical preparations.

Serious or Rare Adverse Reactions

Bleeding complications represent the most serious class of adverse effects, encompassing mucosal hemorrhage, intracranial bleeding, and gastrointestinal perforation. Aspirin’s antiplatelet action predisposes patients to acute hemorrhagic events, especially when combined with anticoagulants or in individuals with bleeding disorders. In rare instances, hypersensitivity reactions such as anaphylaxis, angioedema, or bronchospasm may manifest, particularly in patients with aspirin‑exacerbated respiratory disease. Aspirin can also induce acute kidney injury in susceptible individuals due to renal vasoconstriction, especially when administered in high doses or in the setting of dehydration.

Black Box Warnings

Regulatory authorities have issued a black‑box warning regarding the increased risk of serious gastrointestinal bleeding and hemorrhagic stroke associated with aspirin therapy. The warning emphasizes careful patient selection, particularly in the elderly, those with a history of peptic ulcer disease, or concomitant use of anticoagulants. Monitoring for signs of bleeding and periodic reassessment of therapeutic necessity are recommended. Additionally, the risk of Reye’s syndrome in children and adolescents receiving aspirin for viral illnesses is underscored, prompting contraindication in this demographic.

7. Drug Interactions

Major Drug–Drug Interactions

Aspirin’s pharmacologic profile predisposes it to interactions that may enhance bleeding risk or diminish therapeutic efficacy. Key interactions include:

• Anticoagulants (warfarin, direct oral anticoagulants) – additive antithrombotic effect increases bleeding risk.
• Other NSAIDs or COX‑inhibitors – cumulative gastrointestinal irritation and reduced renal perfusion.
• Selective serotonin reuptake inhibitors (SSRIs) and serotonin‑neurotransmitter reuptake inhibitors (SNRIs) – combined antiplatelet effects heighten bleeding potential.
• Corticosteroids – enhanced risk of gastric ulceration.
• Cytochrome P450 inhibitors or inducers – modest effects on aspirin metabolism, primarily via alterations in salicylate conjugation pathways.

Contraindications

Aspirin is contraindicated in patients with known hypersensitivity to salicylates, active peptic ulcer disease, bleeding diatheses, severe hepatic impairment, uncontrolled hypertension, or those undergoing major surgery where hemostasis is critical. In pediatric and adolescent populations, aspirin is contraindicated in the setting of viral illness due to the risk of Reye’s syndrome. Careful review of concomitant medications and underlying conditions is essential before initiating therapy.

8. Special Considerations

Pregnancy and Lactation

In pregnancy, low‑dose aspirin is occasionally prescribed in the second and third trimesters for prevention of preeclampsia in high‑risk women, under obstetric guidance. High‑dose aspirin is avoided due to teratogenic potential and risk of fetal platelet dysfunction. Aspirin is excreted into breast milk; however, the concentrations are low and generally considered safe for lactating mothers when used at therapeutic doses. Nonetheless, alternative antiplatelet agents may be preferred when appropriate.

Pediatric Considerations

In children, aspirin is reserved for specific indications such as Kawasaki disease or severe infections, due to the risk of Reye’s syndrome. Pediatric dosing is weight‑based, typically ranging from 10–15 mg/kg every 6–8 hours for anti‑inflammatory effects, yet caution is advised regarding dosing frequency and cumulative exposure. Monitoring for signs of hepatic dysfunction and bleeding is essential in this population.

Geriatric Considerations

Older adults exhibit increased susceptibility to gastrointestinal bleeding, renal impairment, and drug interactions. Low‑dose aspirin remains the standard for cardiovascular prophylaxis in this group, but the decision should balance cardiovascular benefit against bleeding risk. Proton pump inhibitor co‑therapy may mitigate gastrointestinal adverse events, though evidence for routine use is mixed. Renal function should be monitored regularly, and dose adjustments may be warranted in chronic kidney disease.

Renal and Hepatic Impairment

In renal insufficiency, the elimination of salicylate conjugates is delayed, potentially increasing systemic exposure. Dose reduction or alternative antiplatelet agents may be considered in severe renal dysfunction. Hepatic impairment can alter hepatic esterases and conjugation pathways, leading to accumulation of salicylate. Caution and dose modification are advised in patients with significant hepatic disease, particularly cirrhosis or acute liver injury.

9. Summary/Key Points

• Aspirin, a nonselective COX inhibitor, achieves antiplatelet effect through irreversible acetylation of COX‑1, reducing thromboxane A₂ synthesis.
• Rapid absorption and extensive hepatic metabolism to salicylate form the basis of its pharmacokinetic profile; renal excretion dominates elimination.
• Low‑dose aspirin (75–162 mg) is the cornerstone for secondary prevention of cardiovascular events, whereas higher doses address pain and inflammation.
• Gastrointestinal bleeding remains the most significant adverse effect; careful patient selection and monitoring are imperative.
• Drug interactions that enhance bleeding risk (e.g., anticoagulants, SSRIs) warrant vigilance; contraindications include hypersensitivity, active ulcers, and Reye’s syndrome.
• Special populations—pregnant, lactating, pediatric, geriatric, and patients with renal or hepatic impairment—require individualized dosing and monitoring strategies.

Clinical pearls: In patients requiring both antiplatelet and anticoagulant therapy, consider low‑dose aspirin with anticoagulation only when benefits outweigh bleeding risk, and evaluate for gastroprotective strategies. For patients with a history of peptic ulcer disease, concurrent proton pump inhibitor therapy may reduce gastrointestinal complications. In the elderly, renal function should be assessed before initiating aspirin therapy to prevent accumulation of salicylate metabolites. When used for primary prevention, risk stratification tools (e.g., ASCVD risk calculator) should guide decision‑making, given the potential for harm in low‑risk individuals.

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