Chapter: Pharmacology of Aspirin

1. Introduction/Overview

Aspirin, or acetylsalicylic acid (ASA), represents one of the most historically significant and widely utilized pharmaceutical agents in medical practice. Its development from the natural salicylates found in willow bark to a synthetically produced acetylated derivative marked a pivotal advancement in therapeutics. The drug’s unique pharmacological profile, characterized by its irreversible inhibition of cyclooxygenase (COX) enzymes, confers a diverse range of clinical effects including analgesia, antipyresis, anti-inflammatory action, and antiplatelet activity. This breadth of action underpins its extensive use across numerous medical disciplines, from primary care to specialized cardiology and neurology.

The clinical relevance of aspirin is profound, spanning acute symptomatic relief to chronic disease modification. It serves as a cornerstone in the secondary prevention of atherosclerotic cardiovascular events and cerebrovascular accidents. Furthermore, its role in primary prevention, though more nuanced and subject to ongoing risk-benefit evaluation, remains a critical area of clinical decision-making. The ubiquitous availability of aspirin, both as a prescription and over-the-counter medication, necessitates a thorough understanding of its pharmacology among healthcare professionals to ensure its safe and effective application.

Learning Objectives

• Describe the chemical structure of acetylsalicylic acid and its classification within broader therapeutic categories.
• Explain the molecular mechanism of irreversible cyclooxygenase inhibition and differentiate its effects on COX-1 and COX-2 isoforms.
• Outline the pharmacokinetic profile of aspirin, including absorption, metabolism, elimination, and the impact of formulation and dose.
• Detail the approved therapeutic indications for aspirin, correlating specific doses with distinct clinical applications (analgesic, anti-inflammatory, antiplatelet).
• Identify major adverse effects, contraindications, and drug interactions, with particular emphasis on gastrointestinal and bleeding risks.

2. Classification

Aspirin can be categorized within multiple overlapping classification systems based on its chemical nature, pharmacological action, and therapeutic use.

Chemical and Pharmacological Classification

Chemically, aspirin is designated as acetylsalicylic acid, an acetyl ester derivative of salicylic acid. It belongs to the broader class of compounds known as salicylates. From a pharmacological perspective, it is primarily classified as a nonsteroidal anti-inflammatory drug (NSAID). However, this classification requires qualification due to its distinctive mechanism. Unlike most traditional NSAIDs which are reversible competitive inhibitors of cyclooxygenase, aspirin is an irreversible, covalent modifier of the enzyme. This fundamental difference underpins its unique long-lasting antiplatelet effect, a property not shared by reversible NSAIDs.

Therapeutic Classifications

• Analgesic: Used for the relief of mild to moderate pain such as headache, myalgia, and arthralgia.
• Antipyretic: Employed to reduce elevated body temperature in febrile states.
• Anti-inflammatory: Used in the management of inflammatory conditions like rheumatoid arthritis, albeit at higher doses than for analgesia.
• Antiplatelet Agent: Used at low doses for the primary and secondary prevention of thrombotic cardiovascular and cerebrovascular events. This is its most significant chronic use in modern medicine.

3. Mechanism of Action

The therapeutic and adverse effects of aspirin are predominantly mediated through its inhibition of the cyclooxygenase (COX) enzyme system. COX exists in at least two principal isoforms: COX-1, which is constitutively expressed in most tissues and involved in homeostatic functions, and COX-2, which is inducible by inflammatory stimuli and mediates pain, fever, and inflammation.

Molecular Mechanism of Cyclooxygenase Inhibition

Aspirin exerts its effect through a unique, irreversible acetylation mechanism. The drug enters the hydrophobic channel of the COX enzyme and transfers its acetyl group to a specific serine residue within the active site. For COX-1, this acetylation occurs at serine-530. For COX-2, the acetylation site is serine-516. This covalent modification permanently blocks the channel through which the substrate, arachidonic acid, gains access to the catalytic site. Consequently, the enzyme is unable to convert arachidonic acid to prostaglandin G₂ (PGG₂), the first step in the synthesis of prostanoids, which include prostaglandins, prostacyclin, and thromboxanes.

The inhibition is considered irreversible because the acetyl-enzyme bond is stable and the inactivated enzyme cannot be reactivated. Recovery of prostanoid synthesis depends entirely on the synthesis of new enzyme protein by the cell. The turnover time for COX varies by cell type, which explains the duration of action differences between its antiplatelet effect (lasting the lifespan of the platelet, 7-10 days) and its analgesic effect (lasting several hours).

Differential Effects on COX-1 and COX-2

Aspirin is not a selective inhibitor; it acetylates both COX-1 and COX-2. However, the biochemical consequence differs between the isoforms. Acetylation of COX-1 completely abolishes its ability to produce any prostanoids. In contrast, acetylation of COX-2 not only inhibits its normal cyclooxygenase activity but also may confer a novel function, enabling the enzyme to convert certain unsaturated fatty acids like arachidonic acid and docosahexaenoic acid (DHA) to specialized pro-resolving mediators such as 15(R)-hydroxyeicosatetraenoic acid [15(R)-HETE] and 17(R)-hydroxy-DHA. These metabolites can be further converted by other cells into lipoxins and resolvins, which are potent anti-inflammatory and pro-resolution molecules. This alternate activity may contribute to some of aspirin’s anti-inflammatory effects beyond simple prostanoid suppression.

Consequences of Prostanoid Inhibition

The clinical effects of aspirin are directly attributable to the inhibition of specific prostanoids synthesized via the COX pathway.

• Analgesic Effect: Mediated primarily through reduced synthesis of prostaglandin E₂ (PGE₂) and prostacyclin (PGI₂) at peripheral sensory nerve endings. These prostaglandins sensitize nociceptors to mechanical and chemical stimulation and to the pain-producing effects of other mediators like bradykinin and histamine.
• Antipyretic Effect: Exerted within the hypothalamus. Pyrogens released during infection or inflammation stimulate the synthesis of PGE₂ in the preoptic area of the anterior hypothalamus, which resets the body’s thermoregulatory set-point upward. By inhibiting this PGE₂ synthesis, aspirin promotes the return of the set-point to normal, initiating heat-dissipating processes such as vasodilation and sweating.
• Anti-inflammatory Effect: Results from the inhibition of prostaglandin and thromboxane synthesis at sites of inflammation. Prostaglandins, particularly PGE₂ and PGI₂, contribute to vasodilation, edema, and the potentiating effects on other mediators. This effect requires higher doses to sufficiently inhibit COX in inflamed tissues.
• Antiplatelet Effect: This is the most dose-sensitive action. At low doses (75-100 mg daily), aspirin selectively inhibits thromboxane A₂ (TXA₂) synthesis in platelets. Platelets are anucleate and lack the capacity for protein synthesis; therefore, the irreversible acetylation of COX-1 permanently disables TXA₂ production for the cell’s entire 7-10 day lifespan. TXA₂ is a potent promoter of platelet aggregation and vasoconstriction. Inhibition of platelet COX-1 is achieved in the presystemic (portal) circulation before aspirin is deacetylated to salicylate by esterases in the liver. Higher doses may also inhibit vascular endothelial synthesis of prostacyclin (PGI₂), a potent inhibitor of platelet aggregation and a vasodilator. The theoretical concern is that loss of this protective PGI₂ could attenuate the net antithrombotic benefit, providing the rationale for using the lowest effective antiplatelet dose.

4. Pharmacokinetics

The pharmacokinetics of aspirin are complex due to its rapid hydrolysis to salicylic acid (salicylate), which is the primary active moiety for anti-inflammatory and analgesic effects, though not for antiplatelet action. The parent drug, acetylsalicylic acid, is responsible for the irreversible acetylation of COX.

Absorption

Absorption of aspirin is rapid and occurs primarily in the stomach and upper small intestine via passive diffusion of the non-ionized form. The rate and extent of absorption are influenced by formulation, gastric pH, and gastric emptying time. Plain, uncoated aspirin tablets dissolve readily in gastric acid and are absorbed quickly, with peak plasma concentrations of salicylate occurring within 30-60 minutes. Enteric-coated formulations are designed to resist dissolution in the acidic gastric environment and dissolve in the more alkaline duodenum, thereby delaying absorption and peak concentrations by 3-6 hours. This can reduce acute gastric mucosal irritation but may also delay the onset of analgesic or antiplatelet effect. Buffered and effervescent formulations enhance solubility and may accelerate absorption.

The presence of food can delay gastric emptying, thereby slowing the absorption of plain aspirin but having less effect on enteric-coated products. Antacids that raise gastric pH can increase the fraction of ionized aspirin, potentially slowing its absorption from the stomach.

Distribution

Following absorption and hydrolysis, salicylate is widely distributed throughout most body tissues and fluids, including synovial fluid, cerebrospinal fluid, and saliva. It readily crosses the placenta. The volume of distribution for salicylate is approximately 0.15-0.2 L/kg. Salicylate is highly bound to plasma albumin (≈80-90% at therapeutic concentrations). This binding is saturable and concentration-dependent. At low therapeutic doses, binding is high. As total salicylate concentration increases into the anti-inflammatory range (≥150 mg/L), the binding sites on albumin become saturated, leading to a disproportionate increase in the free, pharmacologically active fraction. This has important clinical implications: a small increase in dose can lead to a large increase in free drug concentration and the potential for toxicity.

Metabolism

Aspirin itself has a very short half-life of approximately 15-20 minutes due to rapid and extensive presystemic and systemic hydrolysis by esterases in the gut wall, liver, and plasma, converting it to salicylic acid. Therefore, systemic circulation contains predominantly salicylate, not the parent compound.

Salicylic acid undergoes hepatic metabolism via several pathways, the capacity of which is limited and can become saturated within the therapeutic range. The primary metabolic pathways are:

1. Conjugation with Glycine: Forming salicyluric acid. This is the major pathway but becomes saturated at moderate salicylate levels.
2. Conjugation with Glucuronic Acid: Forming phenolic and acyl glucuronides.
3. Hydroxylation: Forming gentisic acid, a minor pathway.

The Michaelis-Menten kinetics of these pathways mean that the elimination half-life of salicylate is dose-dependent. At low analgesic doses (≈600 mg), the half-life is approximately 2-3 hours. At high anti-inflammatory doses (3-5 g/day), the metabolic pathways become saturated, and elimination shifts from first-order to zero-order kinetics, causing the half-life to increase dramatically to 15-30 hours. This kinetic nonlinearity necessitates careful dose titration and monitoring when using high-dose regimens.

Excretion

Renal excretion of unchanged salicylic acid is highly dependent on urinary pH. Salicylic acid is a weak acid with a pK_a of approximately 3.0. In acidic urine (pH < 6.5), the drug is predominantly non-ionized and undergoes passive reabsorption in the renal tubules, minimizing excretion. In alkaline urine (pH > 7.5), the ionized form predominates, trapping the drug in the tubular lumen and enhancing its renal clearance. Alkalinization of urine can increase salicylate clearance by a factor of four or more, a principle employed in the management of salicylate overdose. Under normal conditions, only about 10% of a dose is excreted unchanged in urine at low doses, but this fraction increases as metabolic pathways become saturated at higher doses.

Pharmacokinetic Parameters and Dosing Considerations

• Bioavailability: Approximately 80-100% for plain aspirin, but lower and more variable for enteric-coated products.
• Time to Peak (C_max): 30-60 min (plain); 3-6 hours (enteric-coated).
• Half-life (t_1/2): Aspirin: 15-20 min. Salicylate: 2-3 hours (low dose) to 15-30 hours (high dose).
• Dosing: Dosing intervals vary with indication. Analgesic/antipyretic doses (325-650 mg) are typically given every 4-6 hours as needed. Anti-inflammatory doses (3-6 g/day in divided doses) require careful titration. Antiplatelet doses (75-100 mg once daily) exploit the irreversible platelet inhibition, allowing for once-daily dosing despite the short plasma half-life of the parent compound.

5. Therapeutic Uses/Clinical Applications

The clinical applications of aspirin are defined by dose-response relationships, with different dose ranges employed for distinct therapeutic goals.

Analgesia and Antipyresis

For the relief of mild to moderate pain (e.g., headache, dental pain, musculoskeletal pain) and reduction of fever, doses of 325 mg to 1000 mg are typically used every 4 to 6 hours, not to exceed 4 g per day in adults. Its efficacy is comparable to other NSAIDs for many types of pain, though it is generally avoided in children and adolescents due to the association with Reye’s syndrome.

Anti-inflammatory Therapy

In inflammatory conditions such as rheumatoid arthritis, rheumatic fever, and osteoarthritis, higher doses are required to maintain sufficient salicylate concentrations to suppress prostaglandin synthesis in inflamed tissues. Doses range from 3 to 6 g per day in divided doses, targeting a therapeutic serum salicylate level of 150-300 mg/L. Therapeutic drug monitoring may be useful due to nonlinear kinetics. Its use in these conditions has largely been supplanted by other NSAIDs and disease-modifying agents due to the high incidence of gastrointestinal toxicity at these doses.

Antiplatelet and Antithrombotic Therapy

This represents the most critical and evidence-based application of aspirin in contemporary medicine.

• Secondary Prevention: Low-dose aspirin (75-100 mg daily) is a standard of care for the secondary prevention of myocardial infarction, stroke, and other thrombotic events in patients with established atherosclerotic cardiovascular disease (ASCVD), including those with a history of acute coronary syndrome (ACS), percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), stable angina, transient ischemic attack (TIA), or ischemic stroke. The benefit in reducing the risk of major adverse cardiovascular events (MACE) is well-established and outweighs the bleeding risk in this population.
• Acute Coronary Syndrome (ACS): A loading dose of 162 mg to 325 mg of non-enteric-coated aspirin is administered as soon as possible upon presentation, chewed or crushed to facilitate rapid absorption, followed by a daily maintenance dose of 75-100 mg indefinitely.
• Primary Prevention: The role of aspirin in primary prevention (for individuals without known ASCVD) is more controversial. Current guidelines generally recommend it only for selected adults aged 40-70 years who are at higher atherosclerotic cardiovascular disease risk but not at increased bleeding risk. The decision requires careful individual assessment of the balance between the absolute reduction in cardiovascular risk and the absolute increase in major bleeding, particularly gastrointestinal.
• Other Cardiovascular Indications: Used in the management of atrial fibrillation when oral anticoagulation is contraindicated (though direct oral anticoagulants are preferred), and in patients with prosthetic heart valves (often in combination with warfarin).
• Pre-eclampsia Prophylaxis: Low-dose aspirin (81 mg daily) initiated between 12 and 28 weeks of gestation (optimally before 16 weeks) is recommended for women at high risk of pre-eclampsia.

Other Uses

Off-label or less common uses include its role in the prevention of colorectal adenomas and cancer in certain high-risk populations, an effect thought to be related to prolonged COX-2 inhibition. It may also be used in the acute treatment of pericarditis and in Kawasaki disease (in combination with intravenous immunoglobulin) to reduce inflammation and prevent coronary artery aneurysms.

6. Adverse Effects

The adverse effect profile of aspirin is extensive and is largely a direct extension of its pharmacological action—the inhibition of cytoprotective and homeostatic prostaglandins.

Gastrointestinal Effects

Gastrointestinal disturbances are the most common adverse effects. They range from dyspepsia, nausea, and epigastric pain to more serious complications like gastric and duodenal ulceration, bleeding, and perforation. The mechanisms involve both local and systemic actions. Locally, the acidic nature of the drug can cause direct mucosal irritation. Systemically, and more importantly, inhibition of COX-1 reduces the synthesis of gastroprotective prostaglandins (PGE₂ and PGI₂) that maintain mucosal blood flow, stimulate bicarbonate and mucus secretion, and enhance epithelial cell turnover. The risk is dose-dependent and duration-dependent. Concomitant use of other NSAIDs, corticosteroids, or anticoagulants significantly increases the risk. Enteric-coated or buffered formulations do not eliminate the risk of serious ulcer complications, as the systemic anti-prostaglandin effect is the principal culprit.

Bleeding and Hematologic Effects

Increased bleeding tendency is a direct consequence of irreversible platelet inhibition. This manifests as easy bruising, prolonged bleeding time, and increased risk of perioperative, gastrointestinal, and intracranial hemorrhage. The antiplatelet effect increases the severity of bleeding from any source, including peptic ulcers. While the absolute increase in major bleeding risk with low-dose aspirin is modest, it remains a critical consideration. Rarely, aspirin can cause other hematologic effects such as iron-deficiency anemia from chronic occult blood loss or, very rarely, hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Renal Effects

Inhibition of renal COX can impair renal function, particularly in states of decreased effective circulating volume (e.g., heart failure, cirrhosis, dehydration, concomitant diuretic use). Renal prostaglandins (PGE₂ and PGI₂) promote vasodilation of the afferent arteriole, counteracting the vasoconstrictive effects of angiotensin II and catecholamines. Their inhibition can lead to reduced renal blood flow and glomerular filtration rate, potentially causing fluid retention, edema, and in susceptible individuals, acute kidney injury. Chronic, high-dose use has been associated with analgesic nephropathy, characterized by papillary necrosis and chronic interstitial nephritis.

Hypersensitivity Reactions

True immunological hypersensitivity to aspirin is uncommon. More frequent is aspirin-exacerbated respiratory disease (AERD), also known as Samter’s triad, which comprises asthma, chronic rhinosinusitis with nasal polyps, and acute respiratory reactions (bronchospasm, rhinorrhea) upon ingestion of aspirin or other COX-1 inhibiting NSAIDs. The mechanism is related to shunting of arachidonic acid metabolism toward leukotriene synthesis when the COX pathway is blocked. Aspirin can also cause urticaria, angioedema, and, in severe cases, anaphylaxis.

Central Nervous System Effects

At high therapeutic doses, salicylism can occur, characterized by tinnitus, hearing loss, vertigo, headache, confusion, and lethargy. Tinnitus is a useful clinical sign of approaching toxicity and often correlates with serum salicylate levels >200 mg/L. These symptoms are usually reversible upon dose reduction.

Reye’s Syndrome

This rare but severe condition of acute encephalopathy and fatty liver degeneration is associated with the use of aspirin in children and adolescents with viral infections, particularly influenza and varicella. The mechanism is unknown, but the association has led to the strong recommendation to avoid aspirin in this age group for febrile illnesses. Acetaminophen or ibuprofen are preferred antipyretics in pediatric patients.

Metabolic Effects

High doses can uncouple oxidative phosphorylation in mitochondria, leading to increased oxygen consumption, carbon dioxide production, and heat generation. This can contribute to the hyperthermia sometimes seen in severe salicylate poisoning. Salicylates can also cause a mixed acid-base disturbance: early respiratory alkalosis due to direct stimulation of the respiratory center, followed by a high-anion-gap metabolic acidosis due to accumulation of organic acids (including salicylate itself, lactic acid, and ketone bodies).

7. Drug Interactions

Aspirin participates in numerous clinically significant drug interactions, primarily through pharmacodynamic synergism or antagonism, and to a lesser extent through pharmacokinetic mechanisms.

Pharmacodynamic Interactions

• Anticoagulants and Other Antiplatelet Agents: Concurrent use with warfarin, direct oral anticoagulants (DOACs), heparin, or other antiplatelet drugs (e.g., clopidogrel, ticagrelor) dramatically increases the risk of bleeding, including life-threatening intracranial and gastrointestinal hemorrhage. Such combinations require stringent justification and careful monitoring.
• Other NSAIDs: Concomitant use with other NSAIDs (e.g., ibuprofen, naproxen) may increase the risk of GI ulceration and bleeding additively. Furthermore, some NSAIDs like ibuprofen may competitively block access to the serine residue in platelet COX-1, potentially interfering with aspirin’s antiplatelet effect if taken closely before aspirin. It is generally advised to separate doses if both must be used.
• Corticosteroids: Increase the risk of GI ulceration and bleeding when combined with aspirin.
• Selective Serotonin Reuptake Inhibitors (SSRIs): May increase bleeding risk due to impaired platelet serotonin storage and function, an effect additive to aspirin’s antiplatelet action.
• Methotrexate: Aspirin can reduce renal clearance of methotrexate by inhibiting renal prostaglandin synthesis, potentially leading to methotrexate toxicity (myelosuppression, mucositis). This interaction is more likely with high-dose aspirin.
• Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin II Receptor Blockers (ARBs): The antihypertensive effect of these agents may be attenuated by aspirin, possibly due to inhibition of vasodilatory prostaglandins. The clinical significance of this interaction is debated but may be relevant in patients with heart failure.
• Uricosuric Agents (Probenecid, Sulfinpyrazone): Salicylates at low doses may antagonize the uricosuric effect of these drugs, reducing their efficacy in gout. High-dose salicylates (>3 g/day) are themselves uricosuric.

Pharmacokinetic Interactions

• Drugs Affecting Urinary pH: Drugs that alkalinize urine (e.g., acetazolamide, sodium bicarbonate, high-dose antacids) increase renal salicylate clearance and can lower serum levels. Drugs that acidify urine (e.g., ascorbic acid in high doses) decrease clearance and can increase the risk of salicylate accumulation.

Contraindications

Absolute contraindications to aspirin include:

• Active peptic ulcer disease or history of recurrent ulceration.
• History of aspirin or NSAID-induced asthma, urticaria, or other hypersensitivity reactions.
• Hemophilia and other bleeding diatheses.
• Severe hepatic or renal failure.
• Children and adolescents under 16-19 years (depending on jurisdiction) with viral infections, due to the risk of Reye’s syndrome.
• Third trimester of pregnancy (risk of premature ductus arteriosus closure and increased maternal bleeding risk).

Relative contraindications require careful risk-benefit assessment and include a history of GI bleeding, uncontrolled hypertension, concurrent anticoagulant use, and planned surgical procedures.

8. Special Considerations

Pregnancy and Lactation

Pregnancy: Aspirin is classified as FDA Pregnancy Category D in the third trimester and Category C in the first and second trimesters. Low-dose aspirin (81 mg/day) is considered acceptable and is recommended for specific indications like pre-eclampsia prophylaxis in high-risk women. However, high-dose aspirin should be avoided, especially in the third trimester. Risks include:

• First Trimester: Possible association with gastroschisis (data inconsistent).
• Third Trimester: Risk of premature closure of the fetal ductus arteriosus, leading to pulmonary hypertension; potential for prolonged gestation and labor; increased risk of maternal and neonatal bleeding complications, including intracranial hemorrhage in premature infants.

Lactation: Salicylate is excreted in breast milk in small amounts. With occasional analgesic doses, the risk to a healthy infant is considered low. However, chronic, high-dose therapy may lead to accumulation in the infant and could theoretically cause metabolic acidosis or bleeding. Caution is advised, and monitoring of the infant for signs of salicylism (e.g., rash, bleeding) is recommended if the mother requires long-term, high-dose treatment.

Pediatric Use

The use of aspirin is generally contraindicated in children and adolescents under the age of 16-19 years for febrile or viral illnesses due to the established link with Reye’s syndrome. Exceptions exist for specific conditions where the benefit outweighs the risk, such as Kawasaki disease (high-dose for anti-inflammatory effect, followed by low-dose for antiplatelet effect), certain rheumatic diseases, and prophylaxis of thromboembolism in children with congenital heart disease or prosthetic valves. In these cases, use should be under specialist supervision.

Geriatric Use

Older adults are at increased risk for both the therapeutic benefits (higher prevalence of ASCVD) and adverse effects of aspirin. Age-related declines in renal and hepatic function can alter salicylate clearance. The risk of GI bleeding and hemorrhagic stroke is significantly higher in the elderly. Furthermore, the presence of comorbidities and polypharmacy increases the potential for drug interactions. Dosing for analgesia or anti-inflammatory effects should start at the low end of the range. The decision for primary prevention with low-dose aspirin requires particularly careful individualization in this population.

Renal Impairment

Patients with chronic kidney disease (CKD) are at increased risk for aspirin-related adverse effects. The accumulation of salicylate is possible if glomerular filtration is significantly reduced, though hepatic metabolism remains the primary elimination route. More importantly, patients with CKD, especially those with decreased effective circulating volume (e.g., on diuretics, with heart failure), are highly dependent on renal prostaglandins to maintain glomerular filtration. Inhibition by aspirin can precipitate acute kidney injury or worsen pre-existing CKD. Furthermore, patients with CKD have an inherently elevated bleeding risk, which is compounded by antiplatelet therapy. Low-dose aspirin may be used cautiously for cardiovascular protection, but high doses should be avoided, and renal function should be monitored.

Hepatic Impairment

Severe hepatic impairment can reduce the metabolism of salicylate, potentially leading to accumulation and toxicity. Additionally, patients with advanced liver disease often have coagulopathies and portal hypertension with varices, making them exceptionally vulnerable to aspirin-induced bleeding. Aspirin is generally contraindicated in patients with severe liver failure and should be used with extreme caution, if at all, in those with significant hepatic impairment.

9. Summary/Key Points

• Aspirin (acetylsalicylic acid) is a nonsteroidal anti-inflammatory drug that irreversibly acetylates cyclooxygenase (COX) enzymes, inhibiting the synthesis of prostaglandins, thromboxanes, and prostacyclin.
• Its effects are dose-dependent: low doses (75-100 mg/day) selectively inhibit platelet thromboxane A₂ for antiplatelet action; higher doses (325-1000 mg) provide analgesia and antipyresis; even higher doses (3-6 g/day) are required for anti-inflammatory effects.
• Pharmacokinetics are complex: aspirin is rapidly hydrolyzed to salicylate, which exhibits nonlinear, dose-dependent elimination due to saturable metabolism. Its half-life ranges from 3 hours (low dose) to over 30 hours (high dose).
• Primary therapeutic uses include secondary prevention of cardiovascular and cerebrovascular events (low dose), acute treatment of ACS (loading dose), and analgesia/antipyresis. Its role in primary prevention is limited to selected individuals after careful risk-benefit assessment.
• Major adverse effects are gastrointestinal ulceration/bleeding (due to loss of cytoprotective prostaglandins) and increased bleeding risk (due to irreversible platelet inhibition). Reye’s syndrome is a rare but serious risk in children with viral infections.
• Significant drug interactions occur primarily through pharmacodynamic synergism with other anticoagulants, antiplatelet agents, and NSAIDs (increased bleeding risk), and with methotrexate (reduced renal clearance).
• Special populations require caution: contraindicated in children with viral illnesses; used at low dose only in specific scenarios in pregnancy; requires careful individualization in the elderly and those with renal or hepatic impairment due to increased risks of toxicity and bleeding.

Clinical Pearls

• For rapid antiplatelet effect in ACS, administer a non-enteric-coated 162-325 mg tablet, chewed or crushed.
• Tinnitus is a useful clinical sign of salicylate toxicity and often precedes more serious neurological symptoms.
• The antiplatelet effect of a single low dose persists for the lifespan of the platelet (7-10 days); this is why once-daily dosing is effective.
• Enteric coating does not eliminate the risk of GI ulceration, as this is primarily a systemic effect.
• When assessing a patient for primary prevention aspirin therapy, quantitatively estimate both the 10-year ASCVD risk and the risk of major bleeding (consider age, history, concomitant medications) to inform the shared decision-making process.

References

1. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
2. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
3. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
4. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
5. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
6. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.