Routes: Most commonly oral, also rectal. Lysine acetylsalicylate may be given IV or IM
Main: Aspirin (USAN), also known as acetylsalicylic acid (pronounced /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 also has an antiplatelet effect by inhibiting the production of thromboxane, which under normal circumstances binds platelet molecules together to create a patch over damage of the walls within 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 for 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. The main undesirable side effects of aspirin are gastrointestinal ulcers, stomach bleeding, and tinnitus, especially in higher doses. In children and adolescents, aspirin is no longer used to control flu-like symptoms or the symptoms of chickenpox or other viral illnesses, because of the risk of Reye's syndrome. Aspirin was the first discovered member of the class of drugs known as nonsteroidal anti-inflammatory drugs (NSAIDs), not all of which are salicylates, although they all have similar effects and most have inhibition of the enzyme cyclooxygenase as their mechanism of action. 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).
Main article: History of aspirin Plant extracts including willow bark and spiraea, of which salicylic acid was the active ingredient, had been known to help heal headaches, pains and fevers since antiquity. A French chemist, Charles Frederic Gerhardt, was the first to prepare acetylsalicylic acid in 1853. In the course of his work on the synthesis and properties of various acid anhydrides, he mixed acetyl chloride with a sodium salt of salicylic acid (sodium salicylate). A vigorous reaction ensued, and the resulting melt soon solidified. Since no structural theory existed at that time, Gerhardt called the compound he obtained "salicylic-acetic anhydride" (wasserfreie Salicylsäure-Essigsäure). This preparation of aspirin ("salicylic-acetic anhydride") was one of the many reactions Gerhardt conducted for his paper on anhydrides and he did not pursue it further.
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Six years later, in 1859, von Gilm obtained analytically pure acetylsalicylic acid (which he called "acetylierte Salicylsäure", acetylated salicylic acid) by a reaction of salicylic acid and acetyl chloride. In 1869 Schröder, Prinzhorn and Kraut repeated both Gerhardt's (from sodium salicylate) and von Gilm's (from salicylic acid) syntheses and concluded that both reactions gave the same compound—acetylsalicylic acid. They were first to assign to it the correct structure with the acetyl group connected to the phenolic oxygen. In 1897 Felix Hoffmann created a synthetically altered version of salicin, derived from the species, which caused less digestive upset than pure salicylic acid. The new drug, formally Acetylsalicylic acid, was named aspirin by Hoffman's employer Bayer AG after the old botanical name for meadowsweet, Spiraea ulmaria. By 1899, Bayer was selling it around the world. The name Aspirin is derived from acetyl and spirsäure, an old German name for salicylic acid. The popularity of aspirin grew over the first half of the 20th century, spurred by its supposed effectiveness in the wake of the Spanish flu pandemic of 1918. However recent research suggests that the high death toll of the 1918 flu was partly due to aspirin, as the aspirin doses used at times can lead to toxicity, fluid in the lungs, and in some cases contribute to secondary bacterial infections and mortality. Aspirin's profitability led to fierce competition and the proliferation of aspirin brands and products, especially after the American patent held by Bayer expired in 1917. The popularity of aspirin declined after the market releases of paracetamol (acetaminophen) in 1956 and ibuprofen in 1969. In the 1960s and 1970s, John Vane and others discovered the basic mechanism of aspirin's effects, 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. Aspirin sales revived considerably in the last decades of the 20th century, and remain strong in the 21st century, because of its widespread use as a preventive treatment for heart attacks and strokes.
Trademark in most countries
As part of war reparations specified in the 1919 Treaty of Versailles following Germany's surrender after World War I, Aspirin (along with heroin) lost its status as a registered trademark in France, Russia, the United Kingdom, and the United States, where it became a generic name. Today, "aspirin" is a generic word in Australia, France, India, Ireland, New Zealand, Pakistan, Jamaica, the Philippines, South Africa, United Kingdom and the United States. Aspirin, with a capital "A", remains a registered trademark of Bayer in Germany, Canada, Mexico, and in over 80 other countries, where the trademark is owned by Bayer, using a uniform chemical formula for all markets, but adapting the packaging and physical aspects for each.
Aspirin is one of the first-line drugs used in the treatment of migraine, bringing relief in 50–60% of the cases. It is as effective as a newer triptan medication sumatriptan (Imitrex) and other painkillers such as paracetamol (acetaminophen) or ibuprofen. The combination of aspirin, paracetamol (acetaminophen) and caffeine (Excedrin) is even more potent. For the treatment of migraine headache, this formulation works better than any of its three components taken separately, better than ibuprofen and better than sumatriptan. Similarly to all other medications for migraine, it is recommended to take aspirin at the first signs of the headache, and it is the way these medications were used in the comparative clinical trials. Aspirin alleviates pain in 60–75% of patients with episodic tension headaches. It is equivalent to paracetamol (acetaminophen) in that respect, except for the higher frequency of gastrointestinal side effects. Comparative clinical trials indicated that metamizole and ibuprofen may relieve pain faster than aspirin, although the difference becomes insignificant after about 2 hours. The addition of Caffeine in a dose of 60–130mg to aspirin increases the analgesic effect in headache. The combination of aspirin, paracetamol (acetaminophen) and caffeine (Excedrin) is still more effective, but at the cost of more stomach discomfort, nervousness and dizziness.
In general, aspirin works well for dull, throbbing pain; it is ineffective for pain caused by most muscle cramps, bloating, gastric distension and acute skin irritation. The most studied example is pain after surgery such as tooth extraction, for which the highest allowed dose of aspirin (1 g) is equivalent to 1 g of paracetamol (acetaminophen), 60mg of codeine and 5mg of oxycodone. Combination of aspirin and caffeine, generally, affords greater pain relief than aspirin alone. Effervescent aspirin alleviates pain much faster than aspirin in tablets (15–30 min vs. 45–60 min). Nevertheless, as a post-surgery painkiller, aspirin is inferior to ibuprofen. Aspirin has higher gastrointestinal toxicity than ibuprofen. The maximum dose of aspirin (1 g) provides weaker pain relief than an intermediate dose of ibuprofen (400mg), and this relief does not last as long. A combination of aspirin and codeine may have a slightly higher analgesic effect than aspirin alone; however, this difference is not clinically meaningful. It appears that ibuprofen is at least equally, and possibly more, effective than this combination. According to a meta-analysis of clinical trials for menstrual pain, aspirin demonstrated higher efficacy than placebo but lower one than ibuprofen or naproxen, although maximum doses of aspirin were never used in these trials. The authors concluded that ibuprofen has the best risk-benefit ratio. Aspirin did not ease pain during cycling exercise, while caffeine, surprisingly, was very effective. Similarly, aspirin, codeine or paracetamol (acetaminophen) were not better than placebo for muscle soreness after exercise.
Prevention of heart attacks and strokes
There are two distinct uses of aspirin for prophylaxis of cardiovascular events: primary prevention and secondary prevention. Primary prevention is about decreasing strokes and heart attacks in the general population of those who have no diagnosed heart or vascular problems. Secondary prevention concerns patients with known cardiovascular disease. Low doses of aspirin are recommended for the secondary prevention of strokes and heart attacks. For both males and females diagnosed with cardiovascular disease, aspirin reduces the chance of a heart attack and ischaemic stroke by about a fifth. This translates to an absolute rate reduction from 8.2% to 6.7% of such events per year for people already with cardiovascular disease. Although aspirin also raises the risk of hemorrhagic stroke and other major bleeds by about twofold, these events are rare, and the balance of aspirin's effects is positive. Thus, in secondary prevention trials, aspirin reduced the overall mortality by about a tenth. For persons without cardiovascular problems, the benefits of aspirin are unclear. In the primary prevention trials aspirin decreased the overall incidence of heart attacks and ischaemic strokes by about a tenth. However, since these events were rare, the absolute reduction of their rate was low: from 0.57% to 0.51% per year. In addition, the risks of hemorrhagic strokes and gastrointestinal bleeding almost completely offset the benefits of aspirin. Thus, in the primary prevention trials aspirin did not change the overall mortality rate. Further trials are in progress[update]. The expert bodies diverge in their opinions regarding the use of aspirin for primary prevention, such as can be accomplished by including aspirin in a polypill for the general population. The US Government Preventive Services Task Force recommended making individual case by case choice based on the estimated future risk and patient's preferences. On the other hand, Antithrombotic Trialists’ Collaboration argued that such recommendations are unjustified since the relative reduction of risk in the primary prevention trials of aspirin was same for persons in high- and low-risk groups and did not depend on the blood pressure. The Collaboration suggested statins as the alternative and more effective preventive medication.
Coronary and carotid arteries, bypasses and stents
The coronary arteries supply blood to the heart. Aspirin is recommended for 1 to 6 months after placement of stents in the coronary arteries and for years after a coronary artery bypass graft. The carotid arteries supply blood to the brain. Patients with mild carotid artery stenosis benefit from aspirin. Aspirin is recommended after a carotid endarterectomy or carotid artery stent. After vascular surgery of the lower legs using artificial grafts which are sutured to the arteries to improve blood supply, aspirin is used to keep the grafts open.
Although aspirin has been used to combat fever and pains associated with common cold for more than 100 years, only recently its efficacy was confirmed in controlled clinical trials on adults. 1 g of aspirin, on average, reduced the oral body temperature from 39.0°C (102.2°F) to 37.6°C (99.7°F) after 3 hours. The relief began after 30 minutes, and after 6 hours the temperature still remained below 37.8°C (100.0°F). Aspirin also helped with "achiness", discomfort and headache, and with sore throat pain, for those who had it. Aspirin was indistinguishable from paracetamol (acetaminophen) in any respect, except for, possibly, slightly higher rate of sweating and gastrointestinal side effects. Fever and joint pain of acute rheumatic fever respond extremely well, often within three days, to high doses of aspirin. The therapy usually lasts for 1–2 weeks; and only in about 5% of the cases it has to continue for longer than six months. After fever and pain have subsided, the aspirin treatment is unnecessary as it does not decrease the incidence of heart complications and residual rheumatic heart disease. In addition, the high doses of aspirin used cause liver toxicity in about 20% of the treated children, who are the majority of rheumatic fever patients, and increase the risk of them developing Reye's syndrome. Naproxen was shown to be as effective as aspirin and less toxic; however, 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, although even this use has been questioned by some authors. In the United Kingdom, the only indications for aspirin use in children and adolescents under 16 are Kawasaki disease and prevention of blood clot formation. Aspirin is also used in the treatment of pericarditis, coronary artery disease, and acute myocardial infarction. There have been suggestions that taking aspirin before air travel in cramped conditions may decrease the risk of deep-vein thrombosis (DVT). The reason for taking aspirin is the long period of sitting without exercise, not air travel in itself. A large, randomized, controlled trial in 2000 of aspirin against placebo in 13,000 patients with hip fractures found "a 29% relative risk reduction in DVT with 160 mg of aspirin taken daily for 5 weeks. Although there are obvious problems with extrapolating the data to long-distance travelers, this is the best evidence we could find to justify aspirin use".
Aspirin has been theorized to reduce cataract formation in diabetic patients, but one study showed it was ineffective for this purpose. The role of aspirin in reducing the incidence of many forms of cancer has also been widely studied. In several studies, aspirin use did not reduce the incidence of prostate cancer. Its effects on the incidence of pancreatic cancer are mixed; one study published in 2004 found a statistically significant increase in the risk of pancreatic cancer among women, while a meta-analysis of several studies, published in 2006, found no evidence that aspirin or other NSAIDs are associated with an increased risk for the disease. The drug may be effective in reduction of risk of various cancers, including those of the colon, lung, and possibly the upper GI tract, though some evidence of its effectiveness in preventing cancer of the upper GI tract has been inconclusive. Its preventative effect against adenocarcinomas may be explained by its inhibition of PTGS2 (COX-2) enzymes expressed in them. In a 2009 article published by the Journal of Clinical Investigation it was found that aspirin might prevent liver damage. In their experiment, scientists from Yale University and The University of Iowa induced damage in certain liver cells called hepatocytes using excessive doses of acetaminophen. This caused hepatoxicity and hepatocyte death which triggered an increase in the production of TLR9. The expression of TLR9 caused an inflammatory cascade involving pro–IL-1β and pro-IL-18. Aspirin was found to have a protective effect on hepatocytes because it led to the "downregulation of proinflammatory cytokines". In another 2009 article published by the Journal of the American Medical Association, it was found that men and women who regularly took aspirin after colorectal cancer diagnosis had lower risk of overall and colorectal cancer death compared to patients not using aspirin. A 2010 article in the Journal of Clinical Oncology has suggested that aspirin may reduce the risk of death from breast cancer. While the information has been well-circulated by the media, official health bodies and medical groups have expressed concern over the touting of aspirin as a "miracle drug".
Contraindications and resistance
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 that people with peptic ulcers, mild diabetes, or gastritis seek medical advice before using aspirin. Even if none of these conditions are present, there is still an increased risk of stomach bleeding 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 (G6PD), 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 aspirin 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. 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 that women are more likely to be resistant than men and a different, aggregate study of 2,930 patients found 28% to be resistant. A study in 100 Italian patients found that of the apparent 31% aspirin resistant subjects, only 5% were truly resistant, and the others were noncompliant.
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.
Mitigation of gastrointestinal bleeding
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 that is used in antacids can be used; Bufferin, for example, uses MgO. Other preparations use CaCO3. Taking with Vitamin C is a more recently investigated method of protecting the stomach lining. According to research done at a German university taking equal doses of vitamin C and aspirin decreases the amount of stomach damage that occurs when compared to taking aspirin alone. DGL, Deglycyrrhizinated licorice, an extract of the popular herb licorice reportedly helps relieve the symptoms of gastritis. In a 1979 research study a dose of 350 milligrams of DGL was shown to decrease the amount of gastrointestinal bleeding induced by 3 adult-strength aspirin tablets (750 milligrams). A dose of 500 milligrams of SAMe (S-adenosyl-methionine,is an amino acid naturally formed in the body) given together with a large dose of aspirin (1300 milligrams) in a research study reduced the amount of stomach damage by 90 percent.
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.
Main article: Reye's syndrome Reye's syndrome, a 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 U.S. 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 United States Food and Drug Administration now recommends that 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 (MHRA) recommends that 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, aspirin can result in symptoms that resemble an allergic reaction and include 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.
Aspirin can induce angioedema in some people. In one study, angioedema appeared 1–6 hours after ingesting aspirin in some of the patients participating in the study. 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 that has the appearance on MRI scans of 5–10mm 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 Alzheimers Disease. 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. 20 had diffuse bleeding and 10 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.