Aspirin is also used long-term to help prevent further heart attacks, ischaemic strokes, and blood clots in people at high risk. For pain or fever, effects typically begin within 30 minutes. Aspirin works similarly to other NSAIDs but also suppresses the normal functioning of platelets.
In 1897, scientists at the Bayer company began studying acetylsalicylic acid as a less-irritating replacement medication for common salicylate medicines.: 69–75  By 1899, Bayer had named it "Aspirin" and sold it around the world.
Aspirin's popularity grew over the first half of the 20th century, leading to competition between many brands and formulations. The word Aspirin was Bayer's brand name; however, their rights to the trademark were lost or sold in many countries. The name is ultimately a blend of the prefix a(cetyl) + spirSpiraea, the meadowsweet plant genus from which the acetylsalicylic acid was originally derived at Bayer + -in, the common chemical suffix.
Reaction between acetic acid and salicylic acid can also form aspirin but this esterification reaction is reversible and the presence of water can lead to hydrolysis of the aspirin. So, an anhydrous reagent is preferred.
Acetylation of salicylic acid, mechanism
Formulations containing high concentrations of aspirin often smell like vinegar because aspirin can decompose through hydrolysis in moist conditions, yielding salicylic and acetic acids.
Aspirin, an acetyl derivative of salicylic acid, is a white, crystalline, weakly acidic substance, which melts at 136 °C (277 °F), and decomposes around 140 °C (284 °F). Its acid dissociation constant (pKa) is 3.5 at 25 °C (77 °F).
Polymorphism, or the ability of a substance to form more than one crystal structure, is important in the development of pharmaceutical ingredients. Many drugs receive regulatory approval for only a single crystal form or polymorph. For a long time, only one crystal structure for aspirin was known. That aspirin might have a second crystalline form was suspected since the 1960s. The elusive second polymorph was first discovered by Vishweshwar and coworkers in 2005, and fine structural details were given by Bond et al. A new crystal type was found during experiments after co-crystallization of aspirin and levetiracetam from hot acetonitrile. The form II is only stable at 100K and reverts to form I at ambient temperature. In the (unambiguous) form I, two salicylic molecules form centrosymmetric dimers through the acetyl groups with the (acidic) methyl proton to carbonylhydrogen bonds, and in the newly claimed form II, each salicylic molecule forms the same hydrogen bonds with two neighboring molecules instead of one. With respect to the hydrogen bonds formed by the carboxylic acid groups, both polymorphs form identical dimer structures.
Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX; officially known as prostaglandin-endoperoxide synthase, PTGS) enzyme required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the PTGS enzyme (Suicide inhibition). This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen), which are reversible inhibitors.
Low-dose aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation during the lifetime of the affected platelet (8–9 days). This antithrombotic property makes aspirin useful for reducing the incidence of heart attacks in people who have had a heart attack, unstable angina, ischemic stroke or transient ischemic attack. 40mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A2 release provoked acutely, with the prostaglandin I2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition.
Prostaglandins, local hormones produced in the body, have diverse effects, including the transmission of pain information to the brain, modulation of the hypothalamic thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets that form blood clots. Heart attacks are caused primarily by blood clots, and low doses of aspirin are seen as an effective medical intervention to prevent a second acute myocardial infarction.
COX-1 and COX-2 inhibition
At least two different types of cyclooxygenases, COX-1 and COX-2, are acted on by aspirin. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. COX-2 normally produces prostanoids, most of which are proinflammatory. Aspirin-modified PTGS2 (prostaglandin-endoperoxide synthase 2) produces lipoxins, most of which are anti-inflammatory.[verification needed] Newer NSAID drugs, COX-2 inhibitors (coxibs), have been developed to inhibit only PTGS2, with the intent to reduce the incidence of gastrointestinal side effects.
Several COX-2 inhibitors, such as rofecoxib (Vioxx), have been withdrawn from the market, after evidence emerged that PTGS2 inhibitors increase the risk of heart attack and stroke. Endothelial cells lining the microvasculature in the body are proposed to express PTGS2, and, by selectively inhibiting PTGS2, prostaglandin production (specifically, PGI2; prostacyclin) is downregulated with respect to thromboxane levels, as PTGS1 in platelets is unaffected. Thus, the protective anticoagulative effect of PGI2 is removed, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new PTGS once aspirin has irreversibly inhibited the enzyme, an important difference as compared with reversible inhibitors.
Furthermore, aspirin, while inhibiting the ability of COX-2 to form pro-inflammatory products such as the prostaglandins, converts this enzyme's activity from a prostaglandin-forming cyclooxygenase to a lipoxygenase-like enzyme: aspirin-treated COX-2 metabolizes a variety of polyunsaturated fatty acids to hydroperoxy products which are then further metabolized to specialized proresolving mediators such as the aspirin-triggered lipoxins, aspirin-triggered resolvins, and aspirin-triggered maresins. These mediators possess potent anti-inflammatory activity. It is proposed that this aspirin-triggered transition of COX-2 from cyclooxygenase to lipoxygenase activity and the consequential formation of specialized proresolving mediators contributes to the anti-inflammatory effects of aspirin.
Aspirin has been shown to have at least three additional modes of action. It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, by diffusing from the inner membrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once again to release protons. Aspirin buffers and transports the protons. When high doses are given, it may actually cause fever, owing to the heat released from the electron transport chain, as opposed to the antipyretic action of aspirin seen with lower doses. In addition, aspirin induces the formation of NO-radicals in the body, which have been shown in mice to have an independent mechanism of reducing inflammation. This reduced leukocyte adhesion is an important step in the immune response to infection; however, evidence is insufficient to show aspirin helps to fight infection. More recent data also suggest salicylic acid and its derivatives modulate signalling through NF-κB. NF-κB, a transcription factor complex, plays a central role in many biological processes, including inflammation.
Aspirin is readily broken down in the body to salicylic acid, which itself has anti-inflammatory, antipyretic, and analgesic effects. In 2012, salicylic acid was found to activate AMP-activated protein kinase, which has been suggested as a possible explanation for some of the effects of both salicylic acid and aspirin. The acetyl portion of the aspirin molecule has its own targets. Acetylation of cellular proteins is a well-established phenomenon in the regulation of protein function at the post-translational level. Aspirin is able to acetylate several other targets in addition to COX isoenzymes. These acetylation reactions may explain many hitherto unexplained effects of aspirin.
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Aspirin is produced in many formulations, with some differences in effect. In particular, aspirin can cause gastrointestinal bleeding, and formulations are sought which deliver the benefits of aspirin while mitigating harmful bleeding. Formulations may be combined (e.g., buffered + vitamin C).
Tablets, typically of about 75-100mg and 300-320mg of immediate-release aspirin (IR-ASA).
Buffered formulations containing aspirin with one of many buffering agents.
Formulations of aspirin with vitamin C (ASA-VitC)
A phospholipid-aspirin complex liquid formulation, PL-ASA. As of 2023[update] the phospholipid coating was being trialled to determine if it caused less gastrointestinal damage.
Acetylsalicylic acid is a weak acid, and very little of it is ionized in the stomach after oral administration. Acetylsalicylic acid is quickly absorbed through the cell membrane in the acidic conditions of the stomach. The increased pH and larger surface area of the small intestine causes aspirin to be absorbed more slowly there, as more of it is ionized. Owing to the formation of concretions, aspirin is absorbed much more slowly during overdose, and plasma concentrations can continue to rise for up to 24 hours after ingestion.
About 50–80% of salicylate in the blood is bound to human serum albumin, while the rest remains in the active, ionized state; protein binding is concentration-dependent. Saturation of binding sites leads to more free salicylate and increased toxicity. The volume of distribution is 0.1–0.2 L/kg. Acidosis increases the volume of distribution because of enhancement of tissue penetration of salicylates.
As much as 80% of therapeutic doses of salicylic acid is metabolized in the liver. Conjugation with glycine forms salicyluric acid, and with glucuronic acid to form two different glucuronide esters. The conjugate with the acetyl group intact is referred to as the acyl glucuronide; the deacetylated conjugate is the phenolic glucuronide. These metabolic pathways have only a limited capacity. Small amounts of salicylic acid are also hydroxylated to gentisic acid. With large salicylate doses, the kinetics switch from first-order to zero-order, as metabolic pathways become saturated and renal excretion becomes increasingly important.
Salicylates are excreted mainly by the kidneys as salicyluric acid (75%), free salicylic acid (10%), salicylic phenol (10%), and acyl glucuronides (5%), gentisic acid (< 1%), and 2,3-dihydroxybenzoic acid. When small doses (less than 250mg in an adult) are ingested, all pathways proceed by first-order kinetics, with an elimination half-life of about 2.0 h to 4.5 h. When higher doses of salicylate are ingested (more than 4 g), the half-life becomes much longer (15 h to 30 h), because the biotransformation pathways concerned with the formation of salicyluric acid and salicyl phenolic glucuronide become saturated. Renal excretion of salicylic acid becomes increasingly important as the metabolic pathways become saturated, because it is extremely sensitive to changes in urinary pH. A 10- to 20-fold increase in renal clearance occurs when urine pH is increased from 5 to 8. The use of urinary alkalinization exploits this particular aspect of salicylate elimination. It was found that short-term aspirin use in therapeutic doses might precipitate reversible acute kidney injury when the patient was ill with glomerulonephritis or cirrhosis. Aspirin for some patients with chronic kidney disease and some children with congestive heart failure was contraindicated.
Medicines made from willow and other salicylate-rich plants appear in clay tablets from ancient Sumer as well as the Ebers Papyrus from ancient Egypt.: 8–13  Hippocrates referred to the use of salicylic tea to reduce fevers around 400 BC, and willow bark preparations were part of the pharmacopoeia of Western medicine in classical antiquity and the Middle Ages. Willow bark extract became recognized for its specific effects on fever, pain, and inflammation in the mid-eighteenth century. By the nineteenth century, pharmacists were experimenting with and prescribing a variety of chemicals related to salicylic acid, the active component of willow extract.: 46–55
Old package. "Export from Germany is prohibited"
In 1853, chemist Charles Frédéric Gerhardt treated sodium salicylate with acetyl chloride to produce acetylsalicylic acid for the first time;: 46–48 in the second half of the 19th century, other academic chemists established the compound's chemical structure and devised more efficient methods of synthesis. In 1897, scientists at the drug and dye firm Bayer began investigating acetylsalicylic acid as a less-irritating replacement for standard common salicylate medicines, and identified a new way to synthesize it.: 69–75 By 1899, Bayer had dubbed this drug Aspirin and was selling it globally.: 27 The word Aspirin was Bayer's brand name, rather than the generic name of the drug; however, Bayer's rights to the trademark were lost or sold in many countries. Aspirin's popularity grew over the first half of the 20th century leading to fierce competition with the proliferation of aspirin brands and products.
Aspirin's popularity declined after the development of acetaminophen/paracetamol in 1956 and ibuprofen in 1962. In the 1960s and 1970s, John Vane and others discovered the basic mechanism of aspirin's effects,: 226–231 while clinical trials and other studies from the 1960s to the 1980s established aspirin's efficacy as an anti-clotting agent that reduces the risk of clotting diseases.: 247–257 The initial large studies on the use of low-dose aspirin to prevent heart attacks that were published in the 1970s and 1980s helped spur reform in clinical research ethics and guidelines for human subject research and US federal law, and are often cited as examples of clinical trials that included only men, but from which people drew general conclusions that did not hold true for women.
Aspirin sales revived considerably in the last decades of the 20th century, and remain strong in the 21st century with widespread use as a preventive treatment for heart attacks and strokes.: 267–269
In Canada and many other countries, "Aspirin" remains a trademark, so generic aspirin is sold as "ASA" (acetylsalicylic acid).
In the US., "aspirin" is a generic name.
Bayer lost its trademark for Aspirin in the United States in actions taken between 1918 and 1921 because it had failed to use the name for its own product correctly and had for years allowed the use of "Aspirin" by other manufacturers without defending the intellectual property rights. Today, aspirin is a generic trademark in many countries. Aspirin, with a capital "A", remains a registered trademark of Bayer in Germany, Canada, Mexico, and in over 80 other countries, for acetylsalicylic acid in all markets, but using different packaging and physical aspects for each.
Aspirin is used in the treatment of a number of conditions, including fever, pain, rheumatic fever, and inflammatory conditions, such as rheumatoid arthritis, pericarditis, and Kawasaki disease. Lower doses of aspirin have also been shown to reduce the risk of death from a heart attack, or the risk of stroke in people who are at high risk or who have cardiovascular disease, but not in elderly people who are otherwise healthy. There is some evidence that aspirin is effective at preventing colorectal cancer, though the mechanisms of this effect are unclear. In the United States, the selective initiation of low-dose aspirin, based on an individualised assessment, has been deemed reasonable for the primary prevention of cardiovascular disease in people aged between 40 and 59 who have a 10% or greater risk of developing cardiovascular disease over the next 10 years and are not at an increased risk of bleeding.
Aspirin, either by itself or in a combined formulation, effectively treats certain types of a headache, but its efficacy may be questionable for others. Secondary headaches, meaning those caused by another disorder or trauma, should be promptly treated by a medical provider. Among primary headaches, the International Classification of Headache Disorders distinguishes between tension headache (the most common), migraine, and cluster headache. Aspirin or other over-the-counter analgesics are widely recognized as effective for the treatment of tension headache. Aspirin, especially as a component of an aspirin/paracetamol/caffeinecombination, is considered a first-line therapy in the treatment of migraine, and comparable to lower doses of sumatriptan. It is most effective at stopping migraines when they are first beginning.
Aspirin is an important part of the treatment of those who have had a heart attack. It is generally not recommended for routine use by people with no other health problems, including those over the age of 70.
The 2009 Antithrombotic Trialists' Collaboration published in Lancet evaluated the efficacy and safety of low dose aspirin in secondary prevention. In those with prior ischaemic stroke or acute myocardial infarction, daily low dose aspirin was associated with a 19% relative risk reduction of serious cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death). This did come at the expense of a 0.19% absolute risk increase in gastrointestinal bleeding; however, the benefits outweigh the hazard risk in this case. Data from early trials of aspirin in primary prevention suggested low dose aspirin is more beneficial for people <70kg and high dose aspirin is more beneficial for those ≥70kg. However, more recent trials have suggested lower dose aspirin is not more efficacious in people with a low body weight and more evidence is required to determine the effect of higher dose aspirin in people with a high body weight.
After percutaneous coronary interventions (PCIs), such as the placement of a coronary arterystent, a U.S. Agency for Healthcare Research and Quality guideline recommends that aspirin be taken indefinitely. Frequently, aspirin is combined with an ADP receptor inhibitor, such as clopidogrel, prasugrel, or ticagrelor to prevent blood clots. This is called dual antiplatelet therapy (DAPT). Duration of DAPT was advised in the United States and European Union guidelines after the CURE  and PRODIGY  studies . In 2020, the systematic review and network meta-analysis from Khan et al. showed promising benefits of short-term (< 6 months) DAPT followed by P2Y12 inhibitors in selected patients, as well as the benefits of extended-term (> 12 months) DAPT in high risk patients. In conclusion, the optimal duration of DAPT after PCIs should be personalized after outweighing each patient's risks of ischemic events and risks of bleeding events with consideration of multiple patient-related and procedure-related factors. Moreover, aspirin should be continued indefinitely after DAPT is complete.
The status of the use of aspirin for the primary prevention in cardiovascular disease is conflicting and inconsistent, with recent changes from previously recommending it widely decades ago, and that some referenced newer trials in clinical guidelines show less of benefit of adding aspirin alongside other anti-hypertensive and cholesterol lowering therapies. The ASCEND study demonstrated that in high-bleeding risk diabetics with no prior cardiovascular disease, there is no overall clinical benefit (12% decrease in risk of ischaemic events v/s 29% increase in GI bleeding) of low dose aspirin in preventing the serious vascular events over a period of 7.4 years. Similarly, the results of the ARRIVE study also showed no benefit of same dose of aspirin in reducing the time to first cardiovascular outcome in patients with moderate risk of cardiovascular disease over a period of five years. Aspirin has also been suggested as a component of a polypill for prevention of cardiovascular disease. Complicating the use of aspirin for prevention is the phenomenon of aspirin resistance. For people who are resistant, aspirin's efficacy is reduced. Some authors have suggested testing regimens to identify people who are resistant to aspirin.
As of April 2022[update], the United States Preventive Services Task Force (USPSTF) determined that there was a "small net benefit" for patients aged 40-59 with a 10% or greater 10-year cardiovascular disease (CVD) risk, and "no net benefit" for patients aged over 60. Determining the net benefit was based on balancing the risk reduction of taking aspirin for heart attacks and ischaemic strokes, with the increased risk of gastrointestinal bleeding, intracranial bleeding, and hemorrhagic strokes. Their recommendations state that age changes the risk of the medicine, with the magnitude of the benefit of aspirin coming from starting at a younger age, while the risk of bleeding, while small, increases with age, particular for adults over 60, and can be compounded by other risk factors such as diabetes and a history of gastrointestinal bleeding. As a result, the USPSTF suggests that "people ages 40 to 59 who are at higher risk for CVD should decide with their clinician whether to start taking aspirin; people 60 or older should not start taking aspirin to prevent a first heart attack or stroke." Primary prevention guidelines from September 2019[update] made by the American College of Cardiology and the American Heart Association state they might consider aspirin for patients aged 40-69 with a higher risk of atherosclerotic CVD, without an increased bleeding risk, while stating they would not recommend aspirin for patients aged over 70 or adults of any age with an increased bleeding risk. They state a CVD risk estimation and a risk discussion should be done before starting on aspirin, while stating aspirin should be used "infrequently in the routine primary prevention of (atherosclerotic CVD) because of lack of net benefit". As of August 2021[update], the European Society of Cardiology made similar recommendations; considering aspirin specifically to patients aged less than 70 at high or very high CVD risk, without any clear contraindications, on a case-by-case basis considering both ischemic risk and bleeding risk.
Some conclude the benefits are greater than the risks due to bleeding in those at average risk. Others are unclear if the benefits are greater than the risk. Given this uncertainty, the 2007 United States Preventive Services Task Force (USPSTF) guidelines on this topic recommended against the use of aspirin for prevention of CRC in people with average risk. Nine years later however, the USPSTF issued a grade B recommendation for the use of low-dose aspirin (75 to 100mg/day) "for the primary prevention of CVD [cardiovascular disease] and CRC in adults 50 to 59 years of age who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years".
A meta-analysis through 2019 said that there was an association between taking aspirin and lower risk of cancer of the colorectum, esophagus, and stomach.
In 2021, the U.S. Preventive services Task Force raised questions about the use of aspirin in cancer prevention. It notes the results of the 2018 ASPREE (Aspirin in Reducing Events in the Elderly) Trial, in which the risk of cancer-related death was higher in the aspirin-treated group than in the placebo group.
Aspirin, along with several other agents with anti-inflammatory properties, has been repurposed as an add-on treatment for depressive episodes in subjects with bipolar disorder in light of the possible role of inflammation in the pathogenesis of severe mental disorders. However, meta-analytic evidence is based on very few studies and does not suggest any efficacy of aspirin in the treatment of bipolar depression. Thus, notwithstanding the biological rationale, the clinical perspectives of aspirin and anti-inflammatory agents in the treatment of bipolar depression remain uncertain.
Although cohort and longitudinal studies have shown low-dose aspirin has a greater likelihood of reducing the incidence of dementia, numerous randomised controlled trials have not validated this.
Aspirin is a first-line treatment for the fever and joint-pain symptoms of acute rheumatic fever. The therapy often lasts for one to two weeks, and is rarely indicated for longer periods. After fever and pain have subsided, the aspirin is no longer necessary, since it does not decrease the incidence of heart complications and residual rheumatic heart disease.Naproxen has been shown to be as effective as aspirin and less toxic, but due to the limited clinical experience, naproxen is recommended only as a second-line treatment.
Along with rheumatic fever, Kawasaki disease remains one of the few indications for aspirin use in children in spite of a lack of high quality evidence for its effectiveness.
Low-dose aspirin supplementation has moderate benefits when used for prevention of pre-eclampsia. This benefit is greater when started in early pregnancy.
Aspirin has also demonstrated anti-tumoral effects, via inhibition of the PTTG1 gene, which is often overexpressed in tumors.
For some people, aspirin does not have as strong an effect on platelets as for others, an effect known as aspirin-resistance or insensitivity. One study has suggested women are more likely to be resistant than men, and a different, aggregate study of 2,930 people found 28% were resistant.
A study in 100 Italian people found, of the apparent 31% aspirin-resistant subjects, only 5% were truly resistant, and the others were noncompliant.
Another study of 400 healthy volunteers found no subjects who were truly resistant, but some had "pseudoresistance, reflecting delayed and reduced drug absorption".
Meta-analysis and systematic reviews have concluded that laboratory confirmed aspirin resistance confers increased rates of poorer outcomes in cardiovascular and neurovascular diseases. Although the majority of research conducted has surrounded cardiovascular and neurovascular, there is emerging research into the risk of aspirin resistance after orthopaedic surgery where aspirin is used for venous thromboembolism prophylaxis. Aspirin resistance in orthopaedic surgery, specifically after total hip and knee arthroplasties, is of interest as risk factors for aspirin resistance are also risk factors for venous thromboembolisms and osteoarthritis; the sequalae of requiring a total hip or knee arthroplasty. Some of these risk factors include obesity, advancing age, diabetes mellitus, dyslipidaemia and inflammatory diseases.
Adult aspirin tablets are produced in standardised sizes, which vary slightly from country to country, for example 300mg in Britain and 325mg (or 5 grains) in the United States. Smaller doses are based on these standards, e.g., 75mg and 81mg tablets. The 81-milligram (1+1⁄4-grain) tablets are commonly called "baby aspirin" or "baby-strength", because they were originally – but no longer – intended to be administered to infants and children. No medical significance occurs due to the slight difference in dosage between the 75mg and the 81mg tablets. The dose required for benefit appears to depend on a person's weight. For those weighing less than 70 kilograms (154 lb), low dose is effective for preventing cardiovascular disease; for patients above this weight, higher doses are required.
March 2009 recommendations from the USPSTF on the use of aspirin for the primary prevention of coronary heart disease encourage men aged 45–79 and women aged 55–79 to use aspirin when the potential benefit of a reduction in MI for men or stroke for women outweighs the potential harm of an increase in gastrointestinal hemorrhage.[needs update] The WHI study of postmenopausal women found that aspirin resulted in a 25% lower risk of death from cardiovascular disease and a 14% lower risk of death from any cause, though there was no significant difference between 81mg and 325mg aspirin doses. The 2021 ADAPTABLE study also showed no significant difference in cardiovascular events or major bleeding between 81mg and 325mg doses of aspirin in patients (both men and women) with established cardiovascular disease.
Low-dose aspirin use was also associated with a trend toward lower risk of cardiovascular events, and lower aspirin doses (75 or 81mg/day) may optimize efficacy and safety for people requiring aspirin for long-term prevention.
In children with Kawasaki disease, aspirin is taken at dosages based on body weight, initially four times a day for up to two weeks and then at a lower dose once daily for a further six to eight weeks.
In October 2020, the US Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy. One exception to the recommendation is the use of low-dose 81mg aspirin at any point in pregnancy under the direction of a health care professional.
Aspirin use has been shown to increase the risk of gastrointestinal bleeding. Although some enteric-coated formulations of aspirin are advertised as being "gentle to the stomach", in one study, enteric coating did not seem to reduce this risk; the Mayo Clinic agree with this, and report that coated aspirin may also not be as effective at reducing blood clot risk.
Combining aspirin with other NSAIDs has been shown to further increase the risk of gastrointestinal bleeding. Using aspirin in combination with clopidogrel or warfarin also increases the risk of upper gastrointestinal bleeding.
Blockade of COX-1 by aspirin apparently results in the upregulation of COX-2 as part of a gastric defense. Several trials suggest that the simultaneous use of a COX-2 inhibitor with aspirin may increase the risk of gastrointestinal injury. However, currently available evidence has been unable to prove that this effect is consistently repeatable in everyday clinical practice. More dedicated research is required to provide greater clarity on the subject. Therefore, caution should be exercised if combining aspirin with any "natural" supplements with COX-2-inhibiting properties, such as garlic extracts, curcumin, bilberry, pine bark, ginkgo, fish oil, resveratrol, genistein, quercetin, resorcinol, and others.
Taking vitamin C with aspirin has been investigated as a method of protecting the stomach lining. In trials vitamin C-releasing aspirin (ASA-VitC) or a buffered aspirin formulation containing vitamin C was found to cause less stomach damage than aspirin alone.
Retinal vein occlusion
It is a widespread habit among eye specialists (ophthalmologists) to prescribe aspirin as an add-on medication for patients with retinal vein occlusion (RVO), such as central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO). The reason of this widespread use is the evidence of its proven effectiveness in major systemic venous thrombotic disorders, and it has been assumed that may be similarly beneficial in various types of retinal vein occlusion.
However, a large-scale investigation based on data of nearly 700 patients showed "that aspirin or other antiplatelet aggregating agents or anticoagulants adversely influence the visual outcome in patients with CRVO and hemi-CRVO, without any evidence of protective or beneficial effect". Several expert groups, including the Royal College of Ophthalmologists, recommended against the use of antithrombotic drugs (incl. aspirin) for patients with RVO.
Reye's syndrome, a rare but severe illness characterized by acute encephalopathy and fatty liver, can occur when children or adolescents are given aspirin for a fever or other illness or infection. From 1981 to 1997, 1207 cases of Reye's syndrome in people younger than 18 were reported to the US Centers for Disease Control and Prevention (CDC). Of these, 93% reported being ill in the three weeks preceding the onset of Reye's syndrome, most commonly with a respiratory infection, chickenpox, or diarrhea. Salicylates were detectable in 81.9% of children for whom test results were reported. After the association between Reye's syndrome and aspirin was reported, and safety measures to prevent it (including a Surgeon General's warning, and changes to the labeling of aspirin-containing drugs) were implemented, aspirin taken by children declined considerably in the United States, as did the number of reported cases of Reye's syndrome; a similar decline was found in the United Kingdom after warnings against pediatric aspirin use were issued. The US Food and Drug Administration recommends aspirin (or aspirin-containing products) should not be given to anyone under the age of 12 who has a fever, and the UK National Health Service recommends children who are under 16 years of age should not take aspirin, unless it is on the advice of a doctor.
For a small number of people, taking aspirin can result in symptoms including hives, swelling, and headache. Aspirin can exacerbate symptoms among those with chronic hives, or create acute symptoms of hives. These responses can be due to allergic reactions to aspirin, or more often due to its effect of inhibiting the COX-1 enzyme. Skin reactions may also tie to systemic contraindications, seen with NSAID-precipitated bronchospasm, or those with atopy.
Aspirin and other NSAIDs, such as ibuprofen, may delay the healing of skin wounds. Earlier findings from two small, low-quality trials suggested a benefit with aspirin (alongside compression therapy) on venous leg ulcer healing time and leg ulcer size, however larger, more recent studies of higher quality have been unable to corroborate these outcomes. As such, further research is required to clarify the role of aspirin in this context.
Other adverse effects
Aspirin can induce swelling of skin tissues in some people. In one study, angioedema appeared one to six hours after ingesting aspirin in some of the people. However, when the aspirin was taken alone, it did not cause angioedema in these people; the aspirin had been taken in combination with another NSAID-induced drug when angioedema appeared.
Aspirin causes an increased risk of cerebral microbleeds having the appearance on MRI scans of 5 to 10mm or smaller, hypointense (dark holes) patches.
A study of a group with a mean dosage of aspirin of 270mg per day estimated an average absolute risk increase in intracerebral hemorrhage (ICH) of 12 events per 10,000 persons. In comparison, the estimated absolute risk reduction in myocardial infarction was 137 events per 10,000 persons, and a reduction of 39 events per 10,000 persons in ischemic stroke. In cases where ICH already has occurred, aspirin use results in higher mortality, with a dose of about 250mg per day resulting in a relative risk of death within three months after the ICH around 2.5 (95% confidence interval 1.3 to 4.6).
Use of low-dose aspirin before a surgical procedure has been associated with an increased risk of bleeding events in some patients, however, ceasing aspirin prior to surgery has also been associated with an increase in major adverse cardiac events. An analysis of multiple studies found a three-fold increase in adverse events such as myocardial infarction in patients who ceased aspirin prior to surgery. The analysis found that the risk is dependent on the type of surgery being performed and the patient indication for aspirin use.
Aspirin overdose can be acute or chronic. In acute poisoning, a single large dose is taken; in chronic poisoning, higher than normal doses are taken over a period of time. Acute overdose has a mortality rate of 2%. Chronic overdose is more commonly lethal, with a mortality rate of 25%; chronic overdose may be especially severe in children. Toxicity is managed with a number of potential treatments, including activated charcoal, intravenous dextrose and normal saline, sodium bicarbonate, and dialysis. The diagnosis of poisoning usually involves measurement of plasma salicylate, the active metabolite of aspirin, by automated spectrophotometric methods. Plasma salicylate levels in general range from 30 to 100mg/L after usual therapeutic doses, 50–300mg/L in people taking high doses and 700–1400mg/L following acute overdose. Salicylate is also produced as a result of exposure to bismuth subsalicylate, methyl salicylate, and sodium salicylate.
Aspirin is known to interact with other drugs. For example, acetazolamide and ammonium chloride are known to enhance the intoxicating effect of salicylates, and alcohol also increases the gastrointestinal bleeding associated with these types of drugs. Aspirin is known to displace a number of drugs from protein-binding sites in the blood, including the antidiabetic drugstolbutamide and chlorpropamide, warfarin, methotrexate, phenytoin, probenecid, valproic acid (as well as interfering with beta oxidation, an important part of valproate metabolism), and other NSAIDs. Corticosteroids may also reduce the concentration of aspirin. Other NSAIDs, such as ibuprofen and naproxen, may reduce the antiplatelet effect of aspirin. Although limited evidence suggests this may not result in a reduced cardioprotective effect of aspirin. Analgesic doses of aspirin decrease sodium loss induced by spironolactone in the urine, however this does not reduce the antihypertensive effects of spironolactone. Furthermore, antiplatelet doses of aspirin are deemed too small to produce an interaction with spironolactone. Aspirin is known to compete with penicillin G for renal tubular secretion. Aspirin may also inhibit the absorption of vitamin C.[unreliable medical source?]
The ISIS-2 trial demonstrated that aspirin at doses of 160mg daily for one month, decreased the mortality by 21% of participants with a suspected myocardial infarction in the first five weeks. A single daily dose of 324mg of aspirin for 12 weeks has a highly protective effect against acute myocardial infarction and death in men with unstable angina.
Aspirin has been repurposed as an add-on treatment for depressive episodes in subjects with bipolar disorder. However, meta-analytic evidence is based on very few studies and does not suggest any efficacy of aspirin in the treatment of bipolar depression. Thus, notwithstanding the biological rationale, the clinical perspectives of aspirin and anti-inflammatory agents in the treatment of bipolar depression remain uncertain.
Several studies investigated the anti-infective properties of aspirin for bacterial, viral and parasitic infections. Aspirin was demonstrated to limit platelet activation induced by Staphylococcus aureus and Enterococcus faecalis and to reduce streptococcal adhesion to heart valves. In patients with tuberculous meningitis, the addition of aspirin reduced the risk of new cerebral infarction [RR = 0.52 (0.29-0.92)]. A role of aspirin on bacterial and fungal biofilm is also being supported by growing evidence.
There are a many anecdotal reportings that aspirin can improve plant's growth and resistance though most research involved salicylic acid instead of aspirin.
Aspirin is sometimes used in veterinary medicine as an anticoagulant or to relieve pain associated with musculoskeletal inflammation or osteoarthritis. Aspirin should only be given to animals under the direct supervision of a veterinarian, as adverse effects—including gastrointestinal issues—are common. An aspirin overdose in any species may result in salicylate poisoning, characterized by hemorrhaging, seizures, coma, and even death.
Dogs are better able to tolerate aspirin than cats are. Cats metabolize aspirin slowly because they lack the glucuronide conjugates that aid in the excretion of aspirin, making it potentially toxic if dosing is not spaced out properly. No clinical signs of toxicosis occurred when cats were given 25mg/kg of aspirin every 48 hours for 4 weeks, but the recommended dose for relief of pain and fever and for treating blood clotting diseases in cats is 10mg/kg every 48 hours to allow for metabolization.
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