Pharmacology of Aspirin

1. Introduction/Overview

Aspirin, or acetylsalicylic acid (ASA), represents one of the most historically significant and widely utilized pharmaceutical agents in clinical medicine. Its development from the natural salicylates found in willow bark to a synthetically produced molecule exemplifies the evolution of pharmacotherapy. The drug’s unique pharmacological profile, characterized by dose-dependent therapeutic effects, underpins its diverse clinical applications ranging from analgesia to the prevention of cardiovascular and cerebrovascular events. Aspirin’s enduring clinical relevance is attributed to its efficacy, low cost, and broad availability, securing its position on the World Health Organization’s List of Essential Medicines.

The clinical importance of aspirin extends across multiple medical specialties, including cardiology, neurology, rheumatology, and primary care. Its role in secondary prevention of atherosclerotic cardiovascular disease is well-established, while its utility in primary prevention remains a nuanced topic of ongoing research and guideline refinement. Furthermore, aspirin serves as a foundational agent for understanding fundamental pharmacological principles such as cyclooxygenase inhibition, platelet biology, and the management of drug-induced adverse effects.

Learning Objectives

Upon completion of this chapter, the reader should be able to:

• Describe the molecular mechanism of action of aspirin, including its irreversible acetylation of cyclooxygenase enzymes and the consequent differential inhibition of prostaglandin and thromboxane synthesis.
• Explain the pharmacokinetic properties of aspirin, including its absorption, metabolism, elimination, and the impact of formulation and dose on its bioavailability and half-life.
• Detail the major therapeutic applications of aspirin, distinguishing between the high-dose anti-inflammatory, medium-dose analgesic/antipyretic, and low-dose antiplatelet regimens.
• Identify the spectrum of adverse effects associated with aspirin use, from common gastrointestinal disturbances to rare but serious conditions such as Reye’s syndrome and salicylate intoxication.
• Analyze significant drug interactions and special population considerations, including use in pregnancy, pediatrics, and patients with renal or hepatic impairment.

2. Classification

Aspirin belongs to several overlapping pharmacological and chemical classifications, which inform its therapeutic profile and potential adverse effects.

Pharmacological Classification

• Nonsteroidal Anti-inflammatory Drug (NSAID): Aspirin is considered the prototypical NSAID. It shares the core mechanism of cyclooxygenase (COX) inhibition with other agents in this class, leading to anti-inflammatory, analgesic, and antipyretic effects.
• Antiplatelet Agent: At low doses, aspirin’s primary action is the irreversible inhibition of platelet aggregation, classifying it as an antiplatelet drug. It is often specifically categorized as a platelet aggregation inhibitor.
• Salicylate: Aspirin is a derivative of salicylic acid. While it shares some properties with other salicylates, its acetyl moiety confers a unique, irreversible mechanism of action not possessed by non-acetylated salicylates like sodium salicylate.

Chemical Classification

Chemically, aspirin is known as acetylsalicylic acid (2-acetoxybenzoic acid). It is an organic ester synthesized from the reaction of salicylic acid with acetic anhydride. This acetyl group is pharmacologically critical. Upon administration, aspirin undergoes hydrolysis to yield salicylic acid, its active metabolite responsible for most systemic effects, and acetic acid. However, the acetylation event itself, which occurs before hydrolysis, is responsible for its distinctive antiplatelet action.

3. Mechanism of Action

The pharmacological effects of aspirin are primarily mediated through the irreversible inhibition of the cyclooxygenase (COX) enzyme, also known as prostaglandin-endoperoxide synthase (PTGS). This enzyme exists in at least two major isoforms: COX-1 and COX-2. The differential inhibition of these isoforms, coupled with tissue-specific expression and drug pharmacokinetics, explains aspirin’s dose-dependent therapeutic spectrum.

Molecular and Cellular Mechanisms

Aspirin’s primary mechanism involves the covalent modification of the COX enzyme. The drug enters the hydrophobic channel of the COX enzyme and transfers its acetyl group to a strategically located serine residue within the active site. For COX-1, this acetylation occurs at serine-529 (Ser529); for COX-2, it occurs at the analogous serine-516 (Ser516). This acetylation event introduces a sterically bulky acetyl group that permanently blocks the channel, preventing the substrate, arachidonic acid, from accessing the catalytic site. Consequently, the conversion of arachidonic acid to prostaglandin G₂ (PGG₂) and subsequently to prostaglandin H₂ (PGH₂) is halted.

PGH₂ is a pivotal precursor for the synthesis of various prostanoids, including:

• Prostaglandins (PGs): e.g., PGE₂, PGI₂ (prostacyclin), PGF_2α
• Thromboxane A₂ (TXA₂): A potent platelet aggregator and vasoconstrictor.
• Prostacyclin (PGI₂): A potent vasodilator and inhibitor of platelet aggregation.

The inhibition of these downstream mediators is responsible for aspirin’s therapeutic and adverse effects.

Dose-Dependent Effects and Isoform Selectivity

The clinical effects of aspirin are profoundly influenced by dosage, which relates to its ability to inhibit COX isoforms in different cell types with varying regenerative capacities.

• Low-Dose (75-100 mg daily): At these doses, aspirin achieves a selective, irreversible inhibition of platelet COX-1. Platelets are anucleate cells incapable of synthesizing new protein. Therefore, once acetylated, platelet COX-1 activity is suppressed for the entire lifespan of the platelet (≈7-10 days). This effectively blocks thromboxane A₂-dependent platelet aggregation, providing antithrombotic protection. Systemic endothelial cells, which produce anti-aggregatory prostacyclin (PGI₂) via COX-2, are nucleated and can regenerate the enzyme, leading to a less profound and more transient inhibition of prostacyclin synthesis. This creates a favorable antithrombotic state.
• Medium-Dose (325-650 mg every 4-6 hours): These analgesic and antipyretic doses inhibit COX in peripheral tissues and the central nervous system. Inhibition of prostaglandin synthesis (particularly PGE₂) in inflamed tissues and the hypothalamus mediates pain relief and fever reduction, respectively.
• High-Dose (3-6 g daily in divided doses): Anti-inflammatory and antirheumatic doses non-selectively inhibit both COX-1 and COX-2 in most tissues. The profound reduction in pro-inflammatory prostaglandins at sites of inflammation underlies its efficacy in conditions like rheumatoid arthritis. However, this broad inhibition also increases the risk of adverse effects, particularly in the gastrointestinal tract and kidneys.

Additional Mechanisms

Beyond COX inhibition, aspirin may exert effects through other pathways, though their clinical significance is less well-defined. These include modulation of NF-κB signaling, induction of nitric oxide synthase, and the acetylation of other proteins (e.g., hemoglobin, albumin). The contribution of these mechanisms to aspirin’s overall pharmacodynamic profile is an area of ongoing investigation.

4. Pharmacokinetics

The pharmacokinetics of aspirin are complex due to its rapid hydrolysis to salicylic acid, which is the primary circulating active species responsible for most systemic effects except for the initial antiplatelet action.

Absorption

Absorption of intact acetylsalicylic acid occurs rapidly from 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 aspirin tablets dissolve in the acidic stomach environment, facilitating absorption. Enteric-coated formulations are designed to resist dissolution in the stomach, delaying absorption until the tablet reaches the higher pH of the duodenum. This can delay the time to peak plasma concentration (t_max) by 3-6 hours but does not significantly alter overall bioavailability. Buffered and effervescent formulations may enhance dissolution and absorption rates. Following oral administration of a standard dose, peak plasma levels of aspirin are typically achieved within 30-40 minutes. The absolute bioavailability of aspirin is approximately 50-70% due to presystemic hydrolysis in the gut wall and liver.

Distribution

Once absorbed, aspirin is widely distributed throughout the body. Its volume of distribution (V_d) for salicylate is relatively low, approximately 0.15-0.2 L/kg, indicating distribution primarily within the extracellular fluid. Salicylic acid is highly protein-bound (≈80-90%), primarily to albumin. This binding is saturable within the therapeutic range. At low serum concentrations, binding is high, but as concentration increases (e.g., with high-dose therapy), the fraction of unbound, pharmacologically active drug increases disproportionately. Salicylate readily crosses the placenta and is excreted in breast milk. It also distributes into synovial fluid, cerebrospinal fluid, and other body tissues.

Metabolism

Aspirin undergoes rapid and extensive metabolism. The most critical metabolic step is the enzymatic hydrolysis by esterases in the gastrointestinal mucosa, plasma, and liver to form salicylic acid and acetate. Salicylic acid is the major active metabolite and is subject to further hepatic metabolism via several pathways:

• Conjugation with Glycine: This is the primary metabolic pathway, forming salicyluric acid. It is a capacity-limited (Michaelis-Menten) pathway that becomes saturated at higher salicylate doses.
• Conjugation with Glucuronic Acid: Forms phenolic glucuronide and acyl glucuronide metabolites.
• Oxidation: A minor pathway yielding gentisic acid and other hydroxylated metabolites.

The metabolic fate of salicylate is dose-dependent. At low antiplatelet doses, elimination follows first-order kinetics with a half-life (t_1/2) of salicylate of 2-3 hours. At high anti-inflammatory doses, the glycine conjugation pathway becomes saturated, leading to zero-order (saturation) kinetics. In this scenario, the elimination half-life can increase dramatically to 15-30 hours or more, and small increases in dose can lead to large, non-linear increases in steady-state plasma concentration.

Excretion

Renal excretion is the primary route of elimination for salicylate and its metabolites. The elimination 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, facilitating passive reabsorption in the renal tubules and prolonging its half-life. In alkaline urine (pH > 7.5), the ionized form predominates, trapping the drug in the tubular lumen and enhancing its renal clearance. This principle is utilized therapeutically in the management of salicylate overdose, where urinary alkalinization with sodium bicarbonate is a cornerstone of treatment. Under normal conditions, approximately 10% of a dose is excreted as free salicylic acid, 75% as salicyluric acid, 10% as phenolic glucuronide, and 5% as acyl glucuronide.

5. Therapeutic Uses/Clinical Applications

The therapeutic applications of aspirin are defined by the dose-response relationship stemming from its mechanism of action.

Approved Indications

• Cardiovascular and Cerebrovascular Disease Prevention:
  • Secondary Prevention: This is the most robust indication. Low-dose aspirin (75-100 mg/day) is standard therapy for preventing recurrent myocardial infarction, ischemic stroke, and death in patients with established atherosclerotic cardiovascular disease (ASCVD), including those with a history of MI, stroke, transient ischemic attack (TIA), stable or unstable angina, or peripheral arterial disease.
  • Acute Coronary Syndrome (ACS): A loading dose of 162-325 mg of non-enteric-coated aspirin is administered at presentation for rapid platelet inhibition, followed by a lifelong maintenance dose of 75-100 mg daily.
  • Primary Prevention: The role of aspirin in primary prevention for individuals without known ASCVD is carefully balanced against bleeding risk. Guidelines generally recommend it only for selected adults aged 40-70 years who are at higher ASCVD risk but not at increased bleeding risk.
• Analgesia: Aspirin is effective for mild to moderate pain, such as headache, myalgia, arthralgia, and dysmenorrhea. Typical doses range from 325 mg to 650 mg every 4-6 hours as needed.
• Antipyresis: Used to reduce fever in doses similar to those for analgesia.
• Anti-inflammatory Therapy: High doses (3-6 g/day in divided doses) are used in the management of inflammatory conditions such as rheumatoid arthritis, acute rheumatic fever, and other connective tissue disorders. Its use for this purpose has declined with the availability of other NSAIDs and disease-modifying antirheumatic drugs (DMARDs).
• Prevention of Pre-eclampsia: Low-dose aspirin (81 mg/day) initiated between 12 and 28 weeks of gestation (optimally before 16 weeks) is recommended for women at high risk of pre-eclampsia.

Off-Label and Evolving Uses

• Colorectal Cancer Prevention: Long-term, low-dose aspirin use may be associated with a reduced risk of colorectal adenomas and cancer. This potential benefit is sometimes considered in shared decision-making for select patients, particularly those with a high cardiovascular risk profile where the cardioprotective benefit already justifies its use.
• Atrial Fibrillation Stroke Prevention: Aspirin has a limited role and is generally inferior to oral anticoagulants (e.g., warfarin, direct oral anticoagulants) for stroke prevention in non-valvular atrial fibrillation. It may be considered only in patients with a very low stroke risk (CHA₂DS₂-VASc score of 1 in men or 2 in women) or with absolute contraindications to anticoagulation.

6. Adverse Effects

The adverse effect profile of aspirin is extensive and correlates with its inhibition of physiologically important prostaglandins.

Common Side Effects

• Gastrointestinal (GI) Effects: The most frequent adverse effects are GI in nature, including dyspepsia, nausea, epigastric pain, and heartburn. These are often dose-related and result from both a direct topical irritant effect on the gastric mucosa and the systemic inhibition of COX-1. COX-1 inhibition reduces the synthesis of gastroprotective prostaglandins (PGE₂ and PGI₂) that stimulate mucus and bicarbonate secretion and maintain mucosal blood flow.
• Increased Bleeding Tendency: Due to its irreversible antiplatelet effect, aspirin prolongs bleeding time. This can manifest as easy bruising, gingival bleeding, or prolonged bleeding from cuts. It is a predictable pharmacodynamic effect, not an idiosyncratic reaction.

Serious and Rare Adverse Reactions

• Gastrointestinal Ulceration and Bleeding: This is the most significant common serious adverse effect. Aspirin use increases the risk of gastroduodenal ulcers, perforation, and life-threatening GI hemorrhage. The risk is dose-dependent and heightened in elderly patients, those with a history of ulcer disease, and individuals concurrently using other NSAIDs, corticosteroids, or anticoagulants.
• Hypersensitivity Reactions: True immunological hypersensitivity to aspirin occurs in a subset of patients, particularly those with asthma, chronic urticaria, or nasal polyps (a triad known as Samter’s triad or aspirin-exacerbated respiratory disease). Reactions can range from bronchospasm and urticaria to angioedema and anaphylaxis. This reaction is thought to involve shunting of arachidonic acid metabolism toward leukotriene production due to COX inhibition.
• Reye’s Syndrome: A rare but severe and potentially fatal condition characterized by acute encephalopathy and fatty liver degeneration. It has a strong epidemiological association with the use of aspirin (and other salicylates) in children and adolescents with viral infections, particularly influenza and varicella. Consequently, aspirin is contraindicated in this population for febrile illnesses.
• Salicylate Intoxication (Salicylism): Can occur with acute overdose or chronic high-dose therapy. Early symptoms include tinnitus, hearing loss, vertigo, sweating, nausea, and vomiting (a condition often termed “cinchonism”). Severe intoxication leads to hyperventilation (from direct respiratory center stimulation), metabolic acidosis, hyperthermia, cerebral edema, seizures, coma, and death.
• Renal Effects: Inhibition of renal COX can impair renal blood flow and glomerular filtration rate, particularly in states of decreased effective circulating volume (e.g., heart failure, cirrhosis, dehydration). This can lead to fluid retention, edema, and in susceptible individuals, acute kidney injury. Papillary necrosis and interstitial nephritis are rare complications associated with chronic, high-dose use.
• Hepatotoxicity: Mild, asymptomatic elevations in hepatic transaminases can occur, especially with high-dose therapy. Overt hepatitis is rare.

7. Drug Interactions

Aspirin participates in numerous pharmacokinetic and pharmacodynamic drug interactions, many of which are clinically significant.

Major Pharmacodynamic Interactions

• Anticoagulants and Other Antiplatelet Agents: Concurrent use with warfarin, heparin, direct oral anticoagulants (DOACs), or other antiplatelet drugs (e.g., clopidogrel, ticagrelor) synergistically increases the risk of bleeding, including intracranial and gastrointestinal hemorrhage. This combination requires careful monitoring and is typically reserved for specific high-risk clinical scenarios (e.g., coronary stenting).
• Other NSAIDs: Concomitant use of other NSAIDs (e.g., ibuprofen, naproxen) may competitively interfere with aspirin’s access to the platelet COX-1 active site, potentially attenuating its antiplatelet effect. Furthermore, combining NSAIDs increases the risk of GI toxicity and renal impairment.
• Corticosteroids: Concurrent use increases the risk of GI ulceration and bleeding.
• Selective Serotonin Reuptake Inhibitors (SSRIs): SSRIs impair platelet serotonin uptake and may have a mild antiplatelet effect. Combined with aspirin, this can increase bleeding risk.
• Methotrexate: Aspirin can reduce the renal clearance of methotrexate by competitively inhibiting tubular secretion, potentially leading to methotrexate toxicity (myelosuppression, mucositis).

Major Pharmacokinetic Interactions

• Urinary Alkalinizers (e.g., Sodium Bicarbonate, Acetazolamide): Increase the renal clearance of salicylate by ion-trapping, reducing its plasma concentration and therapeutic effect.
• Urinary Acidifiers (e.g., Ammonium Chloride, High-Dose Vitamin C): Decrease renal clearance of salicylate, increasing the risk of toxicity.
• Probenecid: Competitively inhibits the renal tubular secretion of salicylate, potentially increasing salicylate levels.
• Valproic Acid: Aspirin may displace valproic acid from plasma protein binding sites and inhibit its metabolism, potentially increasing the risk of valproate toxicity.

Contraindications

Absolute contraindications to aspirin therapy include:

• Active peptic ulcer disease or history of severe GI bleeding related to prior NSAID use.
• Known hypersensitivity to aspirin or other NSAIDs (including patients with aspirin-exacerbated respiratory disease).
• Hemophilia and other severe bleeding disorders.
• Severe hepatic failure.
• Severe renal failure.
• Children and adolescents (<16-19 years, depending on guideline) with viral infections (due to Reye’s syndrome risk).
• Third trimester of pregnancy (risk of premature ductus arteriosus closure and increased maternal bleeding risk).

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 pre-eclampsia prevention in high-risk women. However, high-dose aspirin should be avoided, particularly after 30 weeks gestation, due to risks including premature closure of the fetal ductus arteriosus, oligohydramnios, increased maternal and fetal bleeding risks, and potential prolongation of labor.

Lactation: Salicylate is excreted in breast milk in low concentrations. While occasional use of low-dose aspirin is generally considered compatible with breastfeeding, high-dose, chronic therapy may pose a risk to the infant, including potential metabolic acidosis and impaired platelet function. The American Academy of Pediatrics classifies aspirin as a drug to be used with caution during nursing.

Pediatric Considerations

The use of aspirin in the pediatric population is restricted due to the established link with Reye’s syndrome. Aspirin is contraindicated for the treatment of febrile illnesses in children and adolescents. Its use is generally reserved for specific conditions where the benefit outweighs the risk, such as Kawasaki disease (high-dose regimen with intravenous immunoglobulin) and certain rheumatologic conditions (e.g., juvenile idiopathic arthritis). In these cases, close monitoring is essential.

Geriatric Considerations

Elderly patients (≥65 years) are at increased risk for both the therapeutic benefits and adverse effects of aspirin. Age-related declines in renal function can lead to salicylate accumulation, even with standard doses. The risk of GI bleeding is significantly higher in this population due to age-related changes in GI mucosa and a higher prevalence of comorbid conditions and concomitant medications (e.g., corticosteroids, anticoagulants). Dosing for analgesia or anti-inflammatory effects should generally start at the low end of the range, and patients should be monitored closely for GI bleeding and renal impairment.

Renal Impairment

Salicylate elimination is reduced in patients with renal impairment (glomerular filtration rate < 30 mL/min). Accumulation can occur, increasing the risk of toxicity. Furthermore, the inhibition of renal prostaglandin synthesis by aspirin can precipitate acute kidney injury in patients with compromised renal blood flow. Aspirin should be used with caution, at the lowest effective dose, and with close monitoring of renal function and salicylate levels if high-dose therapy is necessary. Low-dose antiplatelet therapy is often used cautiously in patients with chronic kidney disease, balancing cardiovascular benefit against bleeding risk, which is inherently higher in this population.

Hepatic Impairment

Patients with severe hepatic impairment have a reduced capacity to metabolize salicylate, particularly via the glycine conjugation pathway. This can lead to prolonged half-life and accumulation. Additionally, the reduced synthesis of clotting factors and albumin in liver disease can exacerbate the bleeding risk and alter salicylate protein binding, respectively. Aspirin is generally contraindicated in severe hepatic failure and should be used with great caution in patients with significant cirrhosis.

9. Summary/Key Points

• Aspirin (acetylsalicylic acid) is a nonsteroidal anti-inflammatory drug (NSAID), antiplatelet agent, and salicylate derivative whose effects are mediated through the irreversible acetylation and inhibition of cyclooxygenase (COX) enzymes.
• Its clinical effects are dose-dependent: low doses (75-100 mg/day) selectively inhibit platelet thromboxane A₂ production for antiplatelet effects; medium doses (325-650 mg) provide analgesia and antipyresis; high doses (3-6 g/day) exert anti-inflammatory actions.
• Pharmacokinetically, aspirin is rapidly hydrolyzed to salicylic acid. Salicylate metabolism follows first-order kinetics at low doses but shifts to zero-order (saturable) kinetics at high doses, leading to a disproportionate increase in plasma levels with dose increments. Renal excretion is highly pH-dependent.
• Primary therapeutic uses include secondary prevention of cardiovascular events, acute coronary syndrome, analgesia, antipyresis, and, in high-risk pregnancies, prevention of pre-eclampsia.
• The most common adverse effects are gastrointestinal (dyspepsia, ulceration, bleeding). Serious risks include hypersensitivity reactions (especially in asthmatics), Reye’s syndrome in children, salicylate intoxication, and increased bleeding tendency.
• Significant drug interactions occur with anticoagulants (increased bleeding), other NSAIDs (potential attenuation of antiplatelet effect, increased GI risk), and drugs that alter urinary pH (affecting salicylate clearance).
• Special population considerations mandate avoidance in children with viral fevers (Reye’s syndrome), caution in the elderly and those with renal/hepatic impairment, and restricted use in pregnancy, particularly during the third trimester.

Clinical Pearls

• For rapid antiplatelet effect in acute coronary syndrome, a non-enteric-coated, chewable aspirin formulation (162-325 mg) should be administered to ensure prompt absorption.
• The antiplatelet effect of a single low dose persists for the lifespan of the platelet (7-10 days), which is why it is administered once daily.
• Tinnitus and hearing loss are classic early signs of salicylate toxicity and can be used as a clinical guide to dosage adjustment in patients on high-dose therapy.
• When discontinuing aspirin prior to elective surgery, a balance must be struck between bleeding risk and thrombotic risk. For most patients on aspirin for secondary prevention, continuing aspirin is often recommended, except for procedures with a high risk of bleeding in closed spaces (e.g., intracranial, posterior eye chamber).
• The decision to use aspirin for primary cardiovascular prevention requires an individualized assessment, weighing the estimated reduction in atherosclerotic events against the absolute increase in major bleeding risk.

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