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Aspirin: Mechanism of action, major toxicities, and use in rheumatic diseases

Aspirin: Mechanism of action, major toxicities, and use in rheumatic diseases
Literature review current through: Sep 2023.
This topic last updated: Apr 21, 2021.

INTRODUCTION — Aspirin, an acetylated salicylate (acetylsalicylic acid), is classified among the nonsteroidal antiinflammatory drugs (NSAIDs). These agents reduce the signs and symptoms of inflammation and exhibit a broad range of pharmacologic activities, including analgesic, antipyretic, and antiplatelet properties. Aspirin was first introduced by the drug and dye firm Bayer in 1899. Aspirin and the other NSAIDs do not generally change the course of the disease process in those conditions where they are used for symptomatic relief.

The mechanism of action, efficacy, and toxicity of aspirin in rheumatic and other inflammatory disorders are reviewed here. The nonsalicylate NSAIDs, including nonspecific NSAIDs and cyclooxygenase (COX)-2 selective agents; the use of aspirin for primary and secondary prevention of cardiovascular disease; and the prevention of gastroduodenal and other toxicities from aspirin are discussed in detail elsewhere. (See "Nonselective NSAIDs: Overview of adverse effects" and "Overview of COX-2 selective NSAIDs" and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "NSAIDs (including aspirin): Secondary prevention of gastroduodenal toxicity" and "NSAIDs: Adverse cardiovascular effects" and "NSAIDs (including aspirin): Allergic and pseudoallergic reactions" and "Aspirin in the primary prevention of cardiovascular disease and cancer" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

MECHANISM OF ACTION

Effect of dose — Aspirin's effects and respective mechanisms of action vary with dose:

Low doses (typically 75 to 81 mg/day) are sufficient to irreversibly acetylate serine 530 of cyclooxygenase (COX)-1. This effect inhibits platelet generation of thromboxane A2, resulting in an antithrombotic effect.

Intermediate doses (650 mg to 4 g/day) inhibit COX-1 and COX-2, blocking prostaglandin (PG) production, and have analgesic and antipyretic effects.

High doses (between 4 and 8 g/day) are effective as antiinflammatory agents in rheumatic disorders; the mechanism(s) of action at these high doses may include both PG-dependent (particularly COX-2-dependent PGE2) and independent effects [1]. However, the usefulness of aspirin at these high doses is limited by toxicity, including tinnitus, hearing loss, and gastric intolerance.

Cyclooxygenase inhibition — COX inhibition is central to the mechanism of action of both aspirin and the nonsalicylate nonsteroidal antiinflammatory drugs (NSAIDs). The role of COX inhibition is reviewed briefly below, especially as it pertains to aspirin and other salicylates, and is discussed in further detail elsewhere. (See "NSAIDs: Pharmacology and mechanism of action", section on 'Cyclooxygenase inhibition'.)

PGH2 synthase is a bifunctional enzyme with two adjacent but spatially distinct active sites for peroxidase and COX activities. The COX active site is created by a long hydrophobic channel that is the site of aspirin and nonsalicylate NSAID binding [2]. Mammalian cells contain two related but unique isozymes of COX: PG endoperoxide H2 synthase-1 and -2 (COX-1 and COX-2, respectively). Both catalyze the conversion of arachidonic acid to PGH2, leading to the production of biologically active PGs (figure 1). Both are sensitive to aspirin and nonselective nonsalicylate NSAIDs.

The COX isoforms differ in cellular location and relative inhibition:

COX-1 is a constitutive isozyme found in most tissues, where it is involved in producing PGs that regulate cellular housekeeping functions such as gastric cytoprotection, vascular homeostasis, platelet aggregation, and kidney function. By comparison, COX-2 is preferentially, if not exclusively, expressed in inflamed tissue or following exposure to growth factors, cytokines, or other mediators of inflammation.

Aspirin irreversibly inhibits both COX enzymes, preventing PG production by cells until new enzyme is produced. In COX-2, however, the efficiency by which serine 530 is trans-acetylated by aspirin, resulting in such inhibition, is at least 10-fold less than for COX-1. Thus, higher doses are required for an antiinflammatory effect than for an antithrombotic effect. Because arachidonic acid can be metabolized by either the COX or the lipoxygenase pathways, COX inhibition by aspirin and other NSAIDs may result in the increased synthesis of leukotriene (LT) products such as LTB4, LTC4, and LTD4.

The gastrointestinal side effects of aspirin, caused by COX-1 inhibition, persist if aspirin is given in combination with selective COX-2 inhibitors. Thus, although use of a selective COX-2 inhibitor as an antiinflammatory agent otherwise results in less risk of gastroduodenal ulceration and hemorrhage, the incidence of such complications is similar to that observed with nonselective NSAIDS if the COX-2 selective NSAID is used concurrently with antithrombotic low-dose aspirin therapy [3]. (See "Overview of COX-2 selective NSAIDs".)

Other proposed mechanisms of action — COX inhibition does not explain all the antiinflammatory effects of aspirin and related drugs, nor does COX inhibition address the diverse effects of PGs on cells. As examples:

Although aspirin blocks PG synthesis via COX inhibition, stable PGs and their analogues are in fact antiinflammatory.

Sodium salicylate, a nonacetylated salicylate, is an ineffective COX inhibitor but is as potent as aspirin in its antiinflammatory effects.

Higher doses of aspirin and other NSAIDs are required to exert antiinflammatory effects than doses sufficient to markedly inhibit synthesis of PGs [4].

PG-independent actions of aspirin and other salicylates include:

Inhibition of neutrophil activation and responses, including the response to soluble stimuli such as leukotrienes and complement-derived peptides, the synthesis of leukotrienes, superoxide generation, enzyme release, and aggregation and adhesion [4].

Inhibition of the expression of inducible nitric oxide synthase (iNOS) through COX-independent mechanisms, thus inhibiting the generation of nitric oxide, which is important in inflammation, host-defense responses, and tissue repair. While aspirin does not completely inhibit iNOS expression at therapeutic concentrations, partial suppression may be sufficient to inhibit an inflammatory response [5].

Inhibition of the activation of nuclear factor (NF)-kappa B, a transcription factor that participates in inducible expression of multiple cellular and viral gene products involved in inflammation and infection, including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF), and adhesion molecules [6].

Inhibition of Erk kinase activation, which is important in CD11b/CD18 integrin-dependent adhesiveness of human neutrophils, a critical step in inflammation [1].

CLINICAL USE IN RHEUMATIC DISEASES — Aspirin and other salicylates are effective for the treatment of pain, fever, and inflammation. The use of these agents in the treatment of arthritis and other rheumatic diseases is uncommon since high doses are required for antiinflammatory effects, and their use at high doses has been replaced by nonsalicylate nonsteroidal antiinflammatory drugs (NSAIDs) and other agents used for the conditions described below:

Rheumatoid arthritis — High doses of aspirin had been used previously as an effective antiinflammatory and analgesic intervention for treatment of rheumatoid arthritis (RA). Other (nonsalicylate) NSAIDs have supplanted aspirin for the treatment of RA and other inflammatory arthritides. The use of nonsalicylate NSAIDs and nonacetylated salicylates in this disorder is presented separately. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Symptomatic treatment with antiinflammatory drugs'.)

Osteoarthritis — The use of nonsalicylate NSAIDs, rather than aspirin or nonacetylated salicylates, remains a significant part of the pharmacologic treatment for osteoarthritis (OA), although cardiovascular and other risks remain a concern with use of either cyclooxygenase (COX)-2-selective or nonselective NSAIDs. (See "Nonselective NSAIDs: Overview of adverse effects" and "Overview of COX-2 selective NSAIDs" and "NSAIDs: Adverse cardiovascular effects".)

Giant cell arteritis — Aspirin is used in patients with giant cell arteritis in the attempt to decrease the risk of visual loss and cranial ischemic events. (See "Treatment of giant cell arteritis".)

Kawasaki disease — Aspirin is used for the treatment of Kawasaki disease because of its antiinflammatory and anti-platelet effects. (See "Kawasaki disease: Initial treatment and prognosis".)

Co-administration of salicylates with other NSAIDS — Some NSAIDs may reduce the cardioprotective effects of aspirin by interference with aspirin binding to COX or due to their own effects upon cardiovascular risk. The cardiovascular effects of nonselective and COX-2-selective NSAIDs in patients receiving low-dose aspirin are discussed in detail elsewhere. (See "NSAIDs: Adverse cardiovascular effects", section on 'Aspirin and other antithrombotic agents' and "NSAIDs: Adverse cardiovascular effects".)

The use of low-dose aspirin also appears to negate the gastrointestinal protective benefit of treatment with COX-2 inhibitors. (See 'Gastrointestinal toxicity' below and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "NSAIDs (including aspirin): Secondary prevention of gastroduodenal toxicity" and "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Bleeding'.)

OTHER USES OF ASPIRIN — Aspirin use has a number of possible indications related to cardiovascular disease and malignancies. (See "Aspirin in the primary prevention of cardiovascular disease and cancer" and "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

MAJOR SIDE EFFECTS AND OTHER CONCERNS — Nonsteroidal antiinflammatory drugs (NSAIDs) as a group share characteristic side effects and toxicity, while aspirin has additional unique effects.

Gastrointestinal toxicity — Aspirin is rapidly absorbed from the stomach and can have significant local gastric toxicity. The risk and prevention of gastroduodenal toxicity with aspirin is discussed separately [7]. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "NSAIDs (including aspirin): Secondary prevention of gastroduodenal toxicity" and "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Bleeding'.)

Anticoagulant effects — NSAIDs decrease platelet adhesiveness by inhibiting a prostaglandin (PG)-initiated sequence necessary for platelet activation. Aspirin's effects on platelets are discussed in detail separately. (See "Platelet biology and mechanism of anti-platelet drugs".)

Interactions between nonaspirin NSAIDs and aspirin may decrease the potentially beneficial antiplatelet effect and are one of the causes of aspirin resistance, which is a laboratory phenomenon characterized by the inability of aspirin to inhibit one or more in vitro tests of platelet function. This is discussed in more detail elsewhere. (See "Clopidogrel resistance and clopidogrel treatment failure" and "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Potential risks'.)

Use in pregnancy — The use aspirin during pregnancy and lactation is discussed elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'NSAIDs'.)

Other side effects — A number of other complications have been associated with NSAIDs, including aspirin:

Acute renal failure can occur due to either renal vasoconstriction or acute interstitial nephritis, which is often accompanied by the nephrotic syndrome. (See "NSAIDs: Acute kidney injury".)

Systemic vasoconstriction due to reduced production of vasodilator PGs can lead to a small elevation in blood pressure and worsening of congestive heart failure. These complications may be less likely to occur with low-dose aspirin. (See "NSAIDs and acetaminophen: Effects on blood pressure and hypertension" and "NSAIDs: Adverse cardiovascular effects".)

The use of aspirin in children has declined markedly due to the association of aspirin with Reye syndrome, particularly if given to children with influenza or varicella. (See "Acute toxic-metabolic encephalopathy in children", section on 'Reye syndrome'.)

The ingestion of NSAIDs can give rise to several allergic and "pseudoallergic" reactions. Allergic reactions are abnormal immunologic reactions to NSAIDs, while pseudoallergic reactions are nonimmunologic reactions that are believed to result from acquired alterations in the biochemical pathways upon which NSAIDs act. (See "Aspirin-exacerbated respiratory disease" and "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".)

Analgesic or antiinflammatory doses of aspirin, when given in combination with acetaminophen or phenacetin, increase the risk of developing chronic renal failure (analgesic nephropathy). Most studies suggest that aspirin alone does not causes chronic renal failure in patients with normal underlying renal function. (See "Epidemiology and pathogenesis of analgesic-related chronic kidney disease", section on 'Aspirin'.)

Plasma salicylate levels and salicylate toxicity — The plasma salicylate concentration should be measured if the patient has symptoms or signs of salicylism. These include (see "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation", section on 'Clinical manifestations'):

Tinnitus

Confusion (particularly in older adults)

Diarrhea

Abdominal pain, nausea, and/or vomiting

Headache

Lightheadedness

Drowsiness (particularly in children)

Tachypnea or hyperpnea

Flapping of the hands (in older adults)

Increased thirst

Visual problems

Treatment of aspirin overdose is discussed elsewhere. There may be a delay of several hours before maximum blood levels of aspirin are reached if the patient has taken enteric-coated aspirin.

SUMMARY AND RECOMMENDATIONS

Aspirin, an acetylated salicylate (acetylsalicylic acid), is a nonsteroidal antiinflammatory drug (NSAID) with antipyretic, analgesic, and antiplatelet activities, which are dose-dependent. Low doses have antithrombotic effects; intermediate doses have antipyretic and analgesic effects; and high doses have antiinflammatory effects comparable with other NSAIDs. (See 'Introduction' above and 'Effect of dose' above.)

The mechanisms of action by which aspirin and the nonacetylated salicylates act include both cyclooxygenase (COX)-dependent and -independent mechanisms. (See 'Cyclooxygenase inhibition' above and 'Other proposed mechanisms of action' above.)

High doses of aspirin and nonacetylated salicylates exhibit antiinflammatory activity and may be effective in the treatment of rheumatoid arthritis (RA). In addition, low and moderate doses of aspirin and nonacetylated salicylates may be beneficial in osteoarthritis (OA). Aspirin is also used in giant cell arteritis and Kawasaki disease. (See 'Clinical use in rheumatic diseases' above.)

NSAIDs may interfere with the cardioprotective effects of aspirin by interference with aspirin binding to COX or due to their own effects upon cardiovascular risk. (See 'Co-administration of salicylates with other NSAIDS' above.)

Adverse effects of aspirin include gastrointestinal toxicity (NSAID gastropathy), anticoagulant effects, Reye syndrome, and effects on pregnancy, renal function, and both allergic and pseudoallergic reactions. Salicylate toxicity may occur when higher salicylate levels are achieved. (See 'Major side effects and other concerns' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Rennie Howard, MD, who contributed to an earlier version of this topic review.

Topic 7978 Version 19.0

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