Acetylsalicylic Acid

 
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Aspirin (USAN), also known as acetylsalicylic acid (/əˌsɛtəlˌsælɨˈsɪlɨk/ ə-SET-əl-SAL-i-SIL-ik; abbreviated ASA), is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. Aspirin was first isolated by Felix Hoffmann, a chemist with the German company Bayer in 1897.

Salicylic acid, the main metabolite of aspirin, is an integral part of human and animal metabolism. While in humans much of it is attributable to diet, a substantial part is synthesized endogenously.

Aspirin also has an antiplatelet effect by inhibiting the production of thromboxane, which under normal circumstances binds platelet molecules together to create a patch over damaged walls of blood vessels. Because the platelet patch can become too large and also block blood flow, locally and downstream, aspirin is also used long-term, at low doses, to help prevent heart attacks, strokes, and blood clot formation in people at high risk of developing blood clots. It has also been established that low doses of aspirin may be given immediately after a heart attack to reduce the risk of another heart attack or of the death of cardiac tissue. Aspirin may be effective at preventing certain types of cancer, particularly colorectal cancer.

The main undesirable side effects of aspirin taken by mouth are gastrointestinal ulcers, stomach bleeding, and tinnitus, especially in higher doses. In children and adolescents, aspirin is no longer indicated to control flu-like symptoms or the symptoms of chickenpox or other viral illnesses, because of the risk of Reye's syndrome.

Aspirin is part of a group of medications called nonsteroidal anti-inflammatory drugs (NSAIDs), but differs from most other NSAIDs in the mechanism of action. Though it, and others in its group called the salicylates, have similar effects (antipyretic, anti-inflammatory, analgesic) to the other NSAIDs and inhibit the same enzyme cyclooxygenase, aspirin (but not the other salicylates) does so in an irreversible manner and, unlike others, affects more the COX-1 variant than the COX-2 variant of the enzyme.

Today, aspirin is one of the most widely used medications in the world, with an estimated 40,000 tonnes of it being consumed each year. In countries where Aspirin is a registered trademark owned by Bayer, the generic term is acetylsalicylic acid (ASA).

Medical uses

Aspirin is used in the treatment of a number of conditions, including fever, pain, rheumatic fever, and inflammatory diseases, such as rheumatoid arthritis, pericarditis, and Kawasaki disease. Lower doses of aspirin have also shown to reduce the risk of death from a heart attack, or the risk of stroke in some circumstances. There is some evidence that aspirin is effective at preventing colorectal cancer, though the mechanisms of this effect are unclear.

Pain

In most cases, aspirin is considered inferior to ibuprofen for the alleviation of pain, because aspirin is more likely to cause gastrointestinal bleeding. Aspirin is generally ineffective for those pains caused by muscle cramps, bloating, gastric distension, or acute skin irritation. As with other NSAIDs, combinations of aspirin and caffeine provide slightly greater pain relief than aspirin alone. Effervescent formulations of aspirin, such as Alka-Seltzer or Blowfish, relieve pain faster than aspirin in tablets, which makes them useful for the treatment of migraines.

Topical aspirin may be effective for treating some types of neuropathic pain.

Headache

Aspirin, either by itself or in combined formulation, effectively treats some types of 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 acetaminophen/aspirin/caffeine formulation (e.g., Excedrin Migraine), 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. There is little data that suggest the aspirin is an effective treatment for cluster headache.

Fever

Like its ability to control pain, aspirin's ability to control fever is due to its action on the prostaglandin system through its irreversible inhibition of COX. Although aspirin's use as an antipyretic in adults is well-established, many medical societies and regulatory agencies (including the American Academy of Family Physicians, the American Academy of Pediatrics, and the United States Food and Drug Administration) strongly advise against using aspirin for treatment of fever in children because of the risk of Reye's syndrome, a rare but often fatal illness associated with the use of aspirin or other salicylates in children during episodes of viral or bacterial infection. Because of the risk of Reye's syndrome in children, in 1986, the FDA required labeling on all aspirin-containing medications advising against its use in children and teenagers.

Heart attacks and strokes

For a subset of the population, aspirin may help prevent heart attacks and strokes. In lower doses, aspirin has been known to prevent the progression of existing cardiovascular disease, and reduce the frequency of these events for those with a history of them. (This is known as secondary prevention.)

Aspirin appears to offer little benefit to those at lower risk of heart attack or stroke—for instance, those without a history of these events or with pre-existing disease. (This is called primary prevention.) Some studies recommend aspirin on a case-by-case basis, while others have suggested that the risks of other events, such as gastrointestinal bleeding, were significant enough to outweigh any potential benefit, and recommended against using aspirin for primary prevention entirely.

Complicating the use of aspirin for prevention is the phenomenon of aspirin resistance. For patients who are resistant, aspirin's efficacy is reduced, which can cause an increased risk of stroke. Some authors have suggested testing regimes to identify those patients who are resistant to aspirin or other anti-thrombotic drugs (such as clopidogrel).

Aspirin has also been suggested as a component of a polypill for prevention of cardiovascular disease.

Post-surgery

After percutaneous coronary interventions (PCIs), such as the placement of a coronary artery stent, a US 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 anti-platelet therapy (DAPT). US and EU guidelines disagree somewhat about how long, and for what indications this combined therapy should be continued post-surgery. US guidelines recommend DAPT for at least 12 months while EU guidelines recommend DAPT for 6–12 months after drug eluting stent. However, they agree that aspirin be continued indefinitely after DAPT is complete.

Cancer prevention

Aspirin's effect on cancer has been widely studied, particularly its effect on colorectal cancer (CRC). Multiple meta-analyses and reviews have concluded that regular use of aspirin reduces the long-term risk of CRC incidence and mortality.However, the relationships of aspirin dose and duration of use to the various types of CRC risk, including mortality, progression, and incidence, are not well-defined. While the majority of data on aspirin and CRC risk comes from observational studies, rather than randomized controlled trials (RCTs), the available data from RCTs suggests that long-term use of low dose aspirin may be effective at preventing some types of CRC. In the 2007 United States Preventive Services Task Force (USPSTF) guidelines on this topic, use of aspirin for prevention of CRC was given a "D" rating, advising healthcare practitioners against routinely using aspirin for this purpose.

An online news story posted and accessed on Tuesday, June 18, 2013 by Jeffrey Norris at the University of California at San Francisco (UCSF) stated: "Aspirin is known to lower risk for some cancers, and a new study led by a UC San Francisco scientist points to a possible explanation, with the discovery that aspirin slows the accumulation of DNA mutations in abnormal cells in at least one pre-cancerous condition. 'Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), which are commonly available and cost-effective medications, may exert cancer-preventing effects by lowering mutation rates,' said Dr. Carlo Maley, Ph.D., a member of the UCSF Helen Diller Family Comprehensive Cancer Center, and an expert on how cancers evolve in the body over time. In the study, published June 13 in the online journal PLOS Genetics, Maley – working with gastroenterologist and geneticist Dr. Brian Reid, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center– analyzed biopsy samples from 13 patients with a pre-cancerous condition called Barrett’s esophagus who were tracked for six to 19 years. In an 'observational crossover' study design, some patients started out taking daily aspirin for several years, and then stopped, while others started taking aspirin for the first time during observation. The goal was to track the rate of mutations in tissues sampled at different times. The researchers found that biopsies taken while patients were on an aspirin regimen had on average accumulated new mutations about 10 times more slowly than biopsies obtained during years when patients were not taking aspirin. 'This is the first study to measure genome-wide mutation rates of a pre-malignant tissue within patients for more than a decade, and the first to evaluate how aspirin affects those rates,' Maley said. Gender and ethnic distribution of study patients reflected the known demographics of esophageal cancer, which predominantly affects white, middle-aged and elderly men, he said. Barrett’s esophagus only occasionally progresses to esophageal cancer."

Other uses

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.

Resistance

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 patients found 28% were resistant. A study in 100 Italian patients, on the other hand, found that, 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."

Dosage

Adult aspirin tablets are produced in standardised sizes, which vary slightly from country to country, for example 300 mg in Britain and 325 mg in the USA. Smaller doses are based on these standards (e.g., 75 mg and 81 mg tablets.) The 81 mg tablets are called "baby-strength." There is no medical significance in the slight difference in dosage between the 75 mg and the 81 mg tablets. Of historical interest, in the US, a 325 mg dose is equivalent to the historic 5 grain aspirin tablet in use prior to the metric system.

In general, for adults, doses are taken four times a day for fever or arthritis, with doses near the maximal daily dose used historically for the treatment of rheumatic fever. For the prevention of myocardial infarction in someone with documented or suspected coronary artery disease, much lower doses are taken once daily.

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 myocardial infarction (MI) for men or stroke for women outweighs the potential harm of an increase in gastrointestinal hemorrhage. The WHI study said regular low dose (75 or 81 mg) aspirin female users had a 25% lower risk of death from cardiovascular disease and a 14% lower risk of death from any cause. Low dose aspirin use was also associated with a trend toward lower risk of cardiovascular events, and lower aspirin doses (75 or 81 mg/day) may optimize efficacy and safety for patients 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.

Adverse effects

Contraindications

Aspirin should not be taken by people who are allergic to ibuprofen or naproxen, or who have salicylate intolerance or a more generalized drug intolerance to NSAIDs, and caution should be exercised in those with asthma or NSAID-precipitated bronchospasm. Owing to its effect on the stomach lining, manufacturers recommend people with peptic ulcers, mild diabetes, or gastritis seek medical advice before using aspirin. Even if none of these conditions is present, the risk of stomach bleeding is still increased when aspirin is taken with alcohol or warfarin. Patients with hemophilia or other bleeding tendencies should not take aspirin or other salicylates. Aspirin is known to cause hemolytic anemia in people who have the genetic disease glucose-6-phosphate dehydrogenase deficiency, particularly in large doses and depending on the severity of the disease. Use of aspirin during dengue fever is not recommended owing to increased bleeding tendency. People with kidney disease, hyperuricemia, or gout should not take aspirin because it inhibits the kidneys' ability to excrete uric acid, and thus may exacerbate these conditions. Aspirin should not be given to children or adolescents to control cold or influenza symptoms, as this has been linked with Reye's syndrome.

Gastrointestinal

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. Combining aspirin with other NSAIDs has also been shown to further increase this risk. Using aspirin in combination with clopidogrel or warfarin also increases the risk of upper gastrointestinal bleeding.

It appears that blockade of COX-1 by aspirin results in the upregulation of COX-2 as part of a gastric defense and that taking COX-2 inhibitors concurrently with aspirin increases the gastric mucosal erosion. 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.

In addition to enteric coating, "buffering" is the other main method companies have used to try to mitigate the problem of gastrointestinal bleeding. Buffering agents are intended to work by preventing the aspirin from concentrating in the walls of the stomach, although the benefits of buffered aspirin are disputed. Almost any buffering agent used in antacids can be used; Bufferin, for example, uses MgO. Other preparations use CaCO3.

Taking it with vitamin C is a more recently investigated method of protecting the stomach lining. Taking equal doses of vitamin C and aspirin may decrease the amount of stomach damage that occurs compared to taking aspirin alone.

Central effects

Large doses of salicylate, a metabolite of aspirin, have been proposed to cause tinnitus (ringing in the ears) based on experiments in rats, via the action on arachidonic acid and NMDA receptors cascade.

Reye's syndrome

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 illnesses or infections. From 1981 through 1997, 1207 cases of Reye's syndrome in under-18 patients were reported to the US Centers for Disease Control and Prevention. Of these, 93% reported being ill in the three weeks preceding 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 now recommends aspirin (or aspirin-containing products) should not be given to anyone under the age of 12 who has a fever, and the British Medicines and Healthcare products Regulatory Agency recommends children who are under 16 years of age should not take aspirin, unless it is on the advice of a doctor.

Hives and swelling

For a small number of people, taking aspirin can result in symptoms resembling an allergic reaction, including hives, swelling and headache. The reaction is caused by salicylate intolerance and is not a true allergy, but rather an inability to metabolize even small amounts of aspirin, resulting in an overdose.

Other adverse effects

Aspirin can induce angioedema (swelling of skin tissues) in some people. In one study, angioedema appeared one to six hours after ingesting aspirin in some of the patients. However, when the aspirin was taken alone, it did not cause angioedema in these patients; 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 10 mm or smaller, hypointense (dark holes) patches. Such cerebral microbleeds are important, since they often occur prior to ischemic stroke or intracerebral hemorrhage, Binswanger disease and Alzheimer's disease.

A study of a group with a mean dosage of aspirin of 270 mg 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 approximately 250 mg per day resulting in a relative risk of death within three months after the ICH of approximately 2.5 (95% confidence interval 1.3 to 4.6).

Aspirin and other NSAIDs can cause hyperkalemia by inducing a hyporenin hypoaldosteronic state via inhibition of prostaglandin synthesis; however, these agents do not typically cause hyperkalemia by themselves in the setting of normal renal function and euvolemic state.

Aspirin can cause prolonged bleeding after operations for up to 10 days. In one study, 30 of 6499 elective surgical patients required reoperations to control bleeding. Twenty had diffuse bleeding and 10 had bleeding from a site. Diffuse, but not discrete, bleeding was associated with the preoperative use of aspirin alone or in combination with other NSAIDS in 19 of the 20 diffuse bleeding patients.

Mechanism of action

Discovery of the mechanism

In 1971, British pharmacologist John Robert Vane, then employed by the Royal College of Surgeons in London, showed aspirin suppressed the production of prostaglandins and thromboxanes. For this discovery he was awarded the 1982 Nobel Prize in Physiology or Medicine, jointly with Sune K. Bergström and Bengt I. Samuelsson. In 1984 he was made a Knight Bachelor.

Suppression of prostaglandins and thromboxanes

Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (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. This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen), which are reversible inhibitors.

Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation. This antithrombotic property makes aspirin useful for reducing the incidence of heart attacks. 40 mg 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 for acute myocardial infarction. An unwanted side effect of the effective anticlotting action of aspirin is that it may cause excessive bleeding.

COX-1 and COX-2 inhibition

There are at least two different types of cyclooxygenase: COX-1 and COX-2. 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 produces lipoxins, most of which are anti-inflammatory. 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.

However, several of the new COX-2 inhibitors, such as rofecoxib (Vioxx), have been withdrawn recently, 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 with reversible inhibitors.

Additional mechanisms

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. In short, aspirin buffers and transports the protons. When high doses of aspirin 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, which is an important step in immune response to infection; however, there is currently insufficient evidence to show that aspirin helps to fight infection. More recent data also suggest salicylic acid and its derivatives modulate signaling 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, and this 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 is not without its own targets. Acetylation of cellular proteins is a well-established phenomenon in the regulation of protein function at the posttranslational level. Recent studies have reported aspirin is able to acetylate several other targets in addition to COX isoenzymes. These acetylation reactions may explain many hitherto unexplained effects of aspirin.

Hypothalamic-pituitary-adrenal activity

Aspirin, like other medications affecting prostaglandin synthesis, has profound effects on the pituitary gland, which indirectly affects a number of other hormones and physiological functions. Effects on growth hormone, prolactin, and TSH (with relevant effect on T3 and T4) were observed directly. Aspirin reduces the effects of vasopressin and increases those of naloxone upon the secretion of ACTH and cortisol by the hypothalamic-pituitary-adrenal axis (HPA axis), which has been suggested to occur through an interaction with endogenous prostaglandins and their role in regulating the HPA axis.

This article uses material from the Wikipedia article Acetylsalicylic Acid, which is released under the Creative Commons Attribution-Share-Alike License 3.0.

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