View source for Aspirin

{{Redirect|Asprin|the author|Robert Asprin}}
{{Good article}}
{{drugbox|Watchedfields = changed
| verifiedrevid = 321835873
|
| IUPAC_name = 2-acetoxybenzoic acid
| OtherNames = Acetylsalicylic acid
| image = Aspirin-skeletal.svg
| image2 = Aspirin-B-3D-balls.png
| width = 150
| width2 = 150
| InChI = 1/C9H8O4/c1-6(10)13-8-5-3-2-4-7(8)9(11)12/h2-5H,1H3,(H,11,12)
| InChIKey = BSYNRYMUTXBXSQ-UHFFFAOYAW
| CAS_number = 50-78-2
| CASNo_Ref = {{cascite}}
| ChemSpiderID = 2157
| ATC_prefix = A01
| ATC_suffix = AD05
| ATC_supplemental = {{ATC|B01|AC06}}, {{ATC|N02|BA01}}
| PubChem = 2244
| DrugBank = DB00945
| C=9|H=8|O=4
| molecular_weight = 180.157 g/mol
| smiles = O=C(Oc1ccccc1C(=O)O)C
| synonyms = 2-acetyloxybenzoic acid<br />acetylsalicylate<br />acetylsalicylic acid<br />O-acetylsalicylic acid
| density = 1.40
| melting_point = 135
| boiling_point = 140
| boiling_notes = (decomposes)
| solubility = 3
| bioavailability = Rapidly and completely absorbed
| protein_bound = 99.6%
| metabolism = [[Liver|Hepatic]]
| elimination_half-life = 300–650&nbsp;mg dose: 3.1–3.2 h<br />1 g dose: 5 h<br />2 g dose: 9 h
| excretion = [[Kidney|Renal]]
| pregnancy_AU = C
| pregnancy_US = D
| legal_AU = unscheduled
| legal_CA =
| legal_UK = GSL
| legal_US = OTC
| legal_status =
| routes_of_administration = Most commonly oral, also rectal. [[Lysine acetylsalicylate]] may be given [[intravenous therapy|IV]] or [[intramuscular injection|IM]]
}}
'''Aspirin''' ([[United States Adopted Name|USAN]]), also known as '''acetylsalicylic acid''' ({{pron-en|əˌsɛtəlˌsælɨˈsɪlɨk}} {{respell|ə|SET|əl-sal-i|SIL|ik}}, abbreviated '''ASA'''), is a [[salicylate]] [[medication|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 drug|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 [[myocardial infarction|heart attacks]], [[stroke]]s, and [[thrombus|blood clot]] formation in people at high risk for developing blood clots.<ref>{{Cite journal| doi = 10.1056/NEJM198308183090703| issn = 00284793| volume = 309| issue = 7| pages = 396–403| last = Lewis| first = H D
| coauthors = J W Davis, D G Archibald, W E Steinke, T C Smitherman, J E Doherty, H W Schnaper, M M LeWinter, E Linares, J M Pouget, S C Sabharwal, E Chesler, H DeMots| title = Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study| journal = The New England journal of medicine| date = 1983-08-18| pmid = 6135989}}</ref> 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.<ref name="anticoag">{{Cite journal|last = Julian|first = D G|coauthors = D A Chamberlain, S J Pocock|title = A comparison of aspirin and anticoagulation following thrombolysis for myocardial infarction (the AFTER study): a multicentre unblinded randomised clinical trial|journal = BMJ| volume = 313|issue = 7070|pages = 1429–1431|publisher = British Medical Journal|date = 1996-09-24|pmid = 8973228|pmc = 2353012}}</ref><ref>{{Cite journal| volume = 92| issue = 10| pages = 2841–2847| last = Krumholz| first = Harlan M.| coauthors = Martha J. Radford, Edward F. Ellerbeck, John Hennen, Thomas P. Meehan, Marcia Petrillo, Yun Wang, Timothy F. Kresowik, Stephen F. Jencks| title = Aspirin in the Treatment of Acute Myocardial Infarction in Elderly Medicare Beneficiaries : Patterns of Use and Outcomes| journal = Circulation| year = 1995|pmid = 7586250}}</ref>

The main [[adverse drug reaction|undesirable side effects]] of aspirin are [[gastrointestinal]] [[gastric ulcer|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]].<ref name="BMJ2002-Macdonald">{{Cite journal|author=Macdonald S|title=Aspirin use to be banned in under 16 year olds|journal=BMJ|volume=325|issue=7371|pages=988|year=2002|pmid= 12411346 |pmc=1169585|doi=10.1136/bmj.325.7371.988/c}}</ref>

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 [[nonsteroidal anti-inflammatory drugs#Mechanism of action|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.<ref name='cox3article'>{{Cite journal|title=Cyclooxygenase-3 (COX-3): filling in the gaps toward a COX continuum?|journal=Proc Natl Acad Sci USA|year=2002|coauthors=Warner TD, Mitchell JA.|volume=99|issue=21|pages=13371–3|pmid=12374850 |url=http://www.pnas.org/cgi/content/extract/99/21/13371|doi=10.1073/pnas.222543099|author=Warner, T. D.|pmc=129677}}</ref> In countries where ''Aspirin'' is a registered [[trademark]] owned by [[Bayer]], the generic term is ''acetylsalicylic acid'' (ASA).<ref>http://www.wordconstructions.com/articles/health/aspirin.html</ref><ref>http://www.inta.org/index.php?option=com_content&task=view&id=202&Itemid=126&getcontent=5</ref>

==History==
{{Main|History of aspirin}}

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 anhydride]]s, he mixed [[acetyl chloride]] with a [[sodium]] salt of salicylic acid ([[sodium salicylate]]). A vigorous reaction ensued, and the resulting melt soon solidified.<ref name=gerhardt>{{de icon}} {{Cite journal|author=Gerhardt C |title=Untersuchungen über die wasserfreien organischen Säuren |journal=Annalen der Chemie und Pharmacie|volume=87 |pages=149–179 |year=1853 |doi=10.1002/jlac.18530870107}}</ref> 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.

[[Image:BayerHeroin.png|thumb|right|180px|Advertisement for Aspirin, Heroin, Lycetol, Salophen]]
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.<ref name=gilm>{{de icon}} {{Cite journal|author=von Gilm H |title=Acetylderivate der Phloretin- und Salicylsäure |journal=Annalen der Chemie und Pharmacie|volume=112 |issue=2 |pages=180–185 |year=1859 |doi=10.1002/jlac.18591120207}}</ref> 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.<ref>{{de icon}} {{Cite journal|author= Schröder, Prinzhorn, Kraut K |title=Uber Salicylverbindungen |journal=Annalen der Chemie und Pharmacie|volume=150 |issue=1 |pages=1–20 |year=1869 |doi=10.1002/jlac.18691500102}}</ref>

In 1897, scientists at the drug and dye firm [[Bayer]] began investigating acetylsalicylic acid as a less-irritating replacement for standard common salicylate medicines. By 1899, Bayer had dubbed this drug ''Aspirin'' and was selling it around the world.<ref>{{Cite book|last = Jeffreys |first = Diarmuid |title = Aspirin: The Remarkable Story of a Wonder Drug |publisher = Bloomsbury USA |date = August 11, 2005 |page = 73 |isbn = 1582346003}}</ref> The name Aspirin is derived from ''acetyl'' and ''spirsäure'', an old German name for salicylic acid.<ref>Ueber Aspirin. Pflügers Archiv : European journal of physiology, Volume: 84, Issue: 11-12 (March 1, 1901), pp: 527-546.</ref> The popularity of aspirin grew over the first half of the twentieth 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.<ref>Karen M. Starko. Salicylates and Pandemic Influenza Mortality, 1918%u20131919 Pharmacology, Pathology, and Historic Evidence. Clinical Infectious Diseases, 2009; DOI: 10.1086/606060</ref> 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.<ref>Jeffreys, ''Aspirin'', pp. 136–142 and 151-152</ref><ref>http://www.history.com/this-day-in-history.do?action=VideoArticle&id=52415</ref>

The popularity of aspirin declined after the market releases of [[paracetamol]] (acetaminophen) in 1956 and [[ibuprofen]] in 1969.<ref>Jeffreys, ''Aspirin'', pp. 212–217</ref> In the 1960s and 1970s, [[John Robert Vane|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.<ref>Jeffreys, ''Aspirin'', pp. 226–231</ref> Aspirin sales revived considerably in the last decades of the twentieth century, and remain strong in the twenty-first century, because of its widespread use as a preventive treatment for [[heart attack]]s and [[stroke]]s.<ref>Jeffreys, ''Aspirin'', pp. 267–269</ref>

===Trademark in most countries===
As part of [[World War I reparations|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 and can be spelled in lower case.<ref>
 {{Cite web
 |url=http://en.wikisource.org/wiki/Treaty_of_Versailles/Part_X#Article_298
 |date=1919-06-28
 |title=Treaty of Versailles, Part X, Section IV, Article 298
 |accessdate=2008-10-25
 |pages= Annex, Paragraph 5
 }}</ref><ref>
 {{Cite journal|last = Mehta|first = Aalok
 |title = Aspirin
 |journal = Chemical & Engineering News|volume = 83|issue = 25
 |year = 2005 |url = http://pubs.acs.org/cen/coverstory/83/8325/8325aspirin.html
 |accessdate = 2008-10-23}}</ref><ref>http://www.ul.ie/~childsp/CinA/Issue59/TOC43_Aspirin.htm</ref> Today, "aspirin" is a generic word in Australia, France, India, Ireland, New Zealand, Pakistan, the Philippines, South Africa, United Kingdom and the United States.<ref>{{Cite book|title = Scientific Style and Format: The CBE Manual for Authors, Editors, and Publishers|author = CBE Style Manual Committee; Huth, Edward J.|publisher = Cambridge University Press|year = 1994|page = 164|url=http://books.google.com/books?id=PoFJ-OhE63UC&pg=PA164|isbn = 9780521471541}}</ref>
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.<ref>{{Cite news| url=http://www.cbc.ca/health/story/2009/05/28/f-aspirin-studies.html | work=CBC News | title=Aspirin: the versatile drug | date=2009-05-28}}</ref><ref>
 {{Cite journal|last = Cheng|first = Tsung O.
 |title = The History of Aspirin
 |journal = Texas Heart Institute Journal|volume = 34|issue = 3|pages = 392–393
 |pmid = 17948100|year=2007| pmc = 1995051}}</ref>

==Therapeutic uses==
===Headache===
Aspirin is one of the [[first-line drug]]s used in the treatment of [[migraine]], bringing relief in 50–60% of the cases.<ref name=tfelt>{{Cite journal|author=Tfelt-Hansen P |title=Triptans vs Other Drugs for Acute Migraine. Are There Differences in Efficacy? A Comment |journal=Headache|volume=48 |pages=601–605 |year=2008|pmid=18377382 |doi=10.1111/j.1526-4610.2008.01064.x |issue=4}}</ref> [[File:Aspirine-1923.jpg|thumb|left|<center>1923 advertisement]] It is as effective as a newer [[triptan]] medication [[sumatriptan]] (Imitrex)<ref name=lampl>{{Cite journal|author=Lampl C, Voelker M, Diener HC|title=Efficacy and safety of 1,000 mg effervescent aspirin: individual patient data meta-analysis of three trials in migraine headache and migraine accompanying symptoms |journal=J Neurol|volume=254 |pages=705–712 |year=2007|pmid=17406776 |doi=10.1007/s00415-007-0547-2 |issue=6}}</ref> and other painkillers such as [[paracetamol]] (acetaminophen)<ref name=diener1>{{Cite journal|author=Diener HC, Bussone G, de Liano H et al|title=The fixed combination of acetylsalicylic acid, paracetamol and caffeine is more effective than single substances and dual combination for the treatment of headache: a multicentre, randomized, double-blind, single-dose, placebo-controlled parallel group study|journal=Cephalalgia|volume=25 |issue = 10|pages=776–787 |year=2004|pmid=16162254 |doi=10.1111/j.1468-2982.2005.00948.x}}</ref> or [[ibuprofen]].<ref name=diener2>{{Cite journal|author=Diener HC, Pfaffenrath V, Pageler L et al|title=Efficacy and safety of 1,000 mg effervescent aspirin: individual patient data meta-analysis of three trials in migraine headache and migraine accompanying symptoms |journal=Cephalalgia|volume=24 |issue = 11|pages=947–54 |year=2004|pmid=15482357 |doi=10.1111/j.1468-2982.2004.00783.x}}</ref> 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,<ref name=diener1/> better than ibuprofen<ref name=goldstein1>{{Cite journal|author=Goldstein J, Silberstein SD, Saper JR et al|title=Acetaminophen, aspirin, and caffeine in combination versus ibuprofen for acute migraine: results from a multicenter, double-blind, randomized, parallel-group, single-dose, placebo-controlled study |journal=Headache|volume=46 |issue = 3|pages=444–53 |year=2006|pmid=16618262 |doi=10.1111/j.1526-4610.2006.00376.x}}</ref> 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.<ref name=goldstein2>{{Cite journal|author=Goldstein J, Silberstein SD, Saper JR et al|title=Acetaminophen, aspirin, and caffeine versus sumatriptan succinate in the early treatment of migraine: results from the ASSET trial |journal=Headache|volume=45 |issue = 8|pages=973–82 |year=2005|pmid=16109110 |doi=10.1111/j.1526-4610.2005.05177.x}}</ref>

Aspirin alleviates pain in 60-75% of patients with episodic [[tension headache]]s.<ref name=pmid11472387>{{Cite pmid|11472387}}</ref><ref name=pmid12534583>{{Cite pmid|12534583}}</ref> It is equivalent to paracetamol (acetaminophen) in that respect, except for the higher frequency of gastrointestinal side effects.<ref name=pmid12534583/> 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 60–130&nbsp;mg to aspirin increases the analgesic effect in headache.<ref name=pmid11472387/><ref name=pmid8706118>{{Cite pmid|8706118}}</ref> The combination of aspirin, paracetamol (acetaminophen) and caffeine (Excedrin) is still more effective, but at the cost of more stomach discomfort, nervousness and dizziness.<ref name=pmid7955822>{{Cite pmid|7955822}}</ref>

===Pain===
In general, aspirin works well for dull, throbbing pain; it is ineffective for pain caused by most muscle [[cramp]]s, [[bloating]], [[gastric distension]] and acute skin irritation.<ref name=pmid14592563>{{Cite pmid|14592563}}</ref> 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), 60&nbsp;mg of [[codeine]] and 5&nbsp;mg 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).<ref name=pmid10868553>{{Cite pmid|10868553}}</ref>

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 (400&nbsp;mg), and this relief does not last as long.<ref name=pmid10868553/> A combination of aspirin and codeine may have a slightly higher analgesic effect than aspirin alone; however, this difference is not clinically meaningful.<ref name=pmid9373807>{{Cite pmid|9373807}}</ref> It appears that ibuprofen is at least equally, and possibly more, effective than this combination.<ref name=pmid6763202>{{Cite pmid|6763202}}</ref>

According to a meta-analysis of clinical trials for [[dysmenorrhea|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.<ref name=pmid9692420>{{Cite pmid|9692420}}</ref>

Aspirin did not ease pain during cycling exercise,<ref name=pmid9268956>{{Cite pmid|9268956}}</ref> while caffeine, surprisingly, was very effective.<ref name=pmid18458355>{{Cite pmid|18458355}}</ref><ref name=pmid14622688>{{Cite pmid|14622688}}</ref> Similarly, aspirin, codeine or paracetamol (acetaminophen) were not better than placebo for muscle soreness after exercise.<ref name=pmid10896014>{{Cite pmid|10896014}}</ref>

===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 [[stroke]]s and [[heart attack]]s in the general population of those who have no diagnosed heart or [[vascular]] problems. Secondary prevention concerns patients with known [[cardiovascular disease]].<ref name="pmid19482214">{{Cite journal|author=Baigent C, Blackwell L, Collins R, ''et al.'' |title=Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials |journal=Lancet |volume=373 |issue=9678 |pages=1849–60 |year=2009 |pmid=19482214 |pmc=2715005 |doi=10.1016/S0140-6736(09)60503-1 }}</ref>

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 [[Stroke#Ischemic_stroke|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 [[Stroke#Hemorrhagic_stroke|hemorrhagic stroke]] and other major [[bleeding|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.<ref name="pmid19482214"/>

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.<ref name="pmid19482214"/> Further trials are in progress.<ref name="pmid19482214"/>

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.<ref name="pmid19293073">{{Cite journal|author=Wolff T, Miller T, Ko S |title=Aspirin for the primary prevention of cardiovascular events: an update of the evidence for the U.S. Preventive Services Task Force |journal=Ann. Intern. Med. |volume=150 |issue=6 |pages=405–10 |year=2009 |pmid=19293073 }}</ref><ref name="pmid19293072">{{Cite journal|title=Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement |journal=Ann. Intern. Med. |volume=150 |issue=6 |pages=396–404 |year=2009 |pmid=19293072 |author1= US Preventive Services Task Force}}</ref> 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 [[statin]]s as the alternative and more effective preventive medication.<ref name="pmid19482214"/>

===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 [[stent]]s 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 [[medical grafting|grafts]] which are [[surgical suture|sutured]] to the arteries to improve blood supply, aspirin is used to keep the grafts open.

===Other uses===
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 {{convert|39.0|C|abbr=on}} to {{convert|37.6|C|abbr=on}} after 3 hours. The relief began after 30 minutes, and after 6 hours the temperature still remained below {{convert|37.8|C|abbr=on}}. Aspirin also helped with "achiness", discomfort and headache,<ref name=pmid16154478>{{Cite pmid|16154478}}</ref> and with sore throat pain, for those who had it.<ref name=pmid12873261>{{Cite pmid|12873261}}</ref> Aspirin was indistinguishable from paracetamol (acetaminophen) in any respect, except for, possibly, slightly higher rate of sweating and gastrointestinal side effects.<ref name=pmid16154478/>

Fever and joint pain of [[rheumatic fever|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.<ref name=NHFA>{{Cite web|url=http://www.heartfoundation.org.au/SiteCollectionDocuments/PP-590%20Diagnosis-Management%20ARF-RHD%20Evidence-Based%20Review.pdf |title=Diagnosis and management of acute rheumatic fever and rheumatic heart disease in Australia. An evidence-based review |author=National Heart Foundation of Australia (RF/RHD guideline development working group) and the Cardiac Society of Australia and New Zealand |year=2006 |format=PDF |publisher=National Heart Foundation of Australia |pages=33–37 |accessdate=2009-11-01}}</ref> In addition, the high doses of aspirin used cause liver toxicity in about 20% of the treated children,<ref>{{cite pmid|14651540}}</ref><ref>{{cite pmid|1376585}}</ref> who are the majority of rheumatic fever patients, and increase the risk of them developing [[Reye's syndrome]].<ref name=NHFA/> [[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.<ref name=NHFA/><ref>{{cite pmid|14517527}}</ref>

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.<ref name="pmid15545617">{{Cite journal|author=Hsieh KS, Weng KP, Lin CC, Huang TC, Lee CL, Huang SM |title=Treatment of acute Kawasaki disease: aspirin's role in the febrile stage revisited |journal=Pediatrics |volume=114 |issue=6 |pages=e689–93 |year=2004 |pmid=15545617 |doi=10.1542/peds.2004-1037 |url=http://pediatrics.aappublications.org/cgi/pmidlookup?view=long&pmid=15545617}}</ref> 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]].<ref>{{Cite journal|title=Aspirin in the treatment of acute myocardial infarction in elderly Medicare beneficiaries. Patterns of use and outcomes|journal=Circulation|year=1995|first=HM|last=Krumholz|coauthors=Radford MJ, Ellerbeck EF, Hennen J, Meehan TP, Petrillo M, Wang Y, Kresowik TF, Jencks SF.|volume=92|issue=10|pages=2841–7|pmid=7586250}}</ref><ref name="Lancet1988-ISIS2">{{Cite journal|author=ISIS-2 Collaborative group|title=Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2|journal=Lancet|year=1988|pages=349–60|issue=2|pmid= 2899772|volume=2}}</ref><ref>{{Cite journal|last=Mallinson|first=T|title=Myocardial Infarction|journal=Focus on First Aid|issue=15|pages=15|year=2010|url=http://www.focusonfirstaid.co.uk/Magazine/issue15/index.aspx|accessdate=2010-06-08}}</ref>

===Experimental===
Aspirin has been theorized to reduce [[cataract]] formation in diabetic patients, but one study showed it was ineffective for this purpose.<ref name="chew">{{Cite journal|author=Chew EY, Williams GA, Burton TC, Barton FB, Remaley NA, Ferris FL |title=Aspirin effects on the development of cataracts in patients with diabetes mellitus. Early treatment diabetic retinopathy study report 16 |journal=Arch Ophthalmol |volume=110 |issue=3 |pages=339–42 |year=1992 |pmid=1543449 }}</ref> 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|prostate cancer]].<ref>{{Cite journal|author=Bosetti, ''et al.''|title=Aspirin and the risk of prostate cancer|journal=Eur J Cancer Prev|year=2006|pages=43–5|volume=15|issue=1|pmid= 16374228|doi=10.1097/01.cej.0000180665.04335.de|first2=R|first3=E|first4=S|first5=M|first6=C|last2=Talamini|last3=Negri|last4=Franceschi|last5=Montella|last6=La Vecchia}}</ref><ref>{{Cite journal|author=Menezes, ''et al.''|title=Regular use of aspirin and prostate cancer risk (United States)|journal=Cancer Causes & Control|year=2006|pages=251–6|volume=17|issue=3|pmid= 16489532 |doi=10.1007/s10552-005-0450-z|first2=H|first3=R|first4=KB|last2=Swede|last3=Niles|last4=Moysich}}</ref> 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,<ref>{{Cite journal|author=Schernhammer, ''et al.''|title=A Prospective Study of Aspirin Use and the Risk of Pancreatic Cancer in Women|journal=J Natl Cancer Inst|year=2004|pages=22–28|volume=96|issue=1|pmid= 14709735|url=http://jnci.oxfordjournals.org/cgi/content/full/96/1/22|doi=10.1093/jnci/djh001|first2=JH|first3=AT|first4=DS|first5=HG|first6=E|first7=GA|first8=CS|last2=Kang|last3=Chan|last4=Michaud|last5=Skinner|last6=Giovannucci|last7=Colditz|last8=Fuchs}}</ref> 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.<ref>{{Cite journal|author=Larsson SC, Giovannucci E, Bergkvist L, Wolk A |title=Aspirin and nonsteroidal anti-inflammatory drug use and risk of pancreatic cancer: a meta-analysis |journal=Cancer Epidemiol. Biomarkers Prev. |volume=15 |issue=12 |pages=2561–4 |year=2006 |pmid=17164387 |doi=10.1158/1055-9965.EPI-06-0574 |url=http://cebp.aacrjournals.org/cgi/content/full/15/12/2561}}</ref> The drug may be effective in reduction of risk of various cancers, including those of the [[colon cancer|colon]],<ref name="thun">{{Cite journal|doi=10.1056/NEJM199112053252301 |author=Thun MJ, Namboodiri MM, Heath CW |title=Aspirin use and reduced risk of fatal colon cancer |journal=[[New England Journal of Medicine|N Engl J Med]] |volume=325 |issue=23 |pages=1593–6 |year=1991 |pmid=1669840 }}</ref><ref>{{Cite journal|author=Baron, ''et al.''|title=A randomized trial of aspirin to prevent colorectal adenomas|journal=N Engl J Med|year=2003|pages=891–9|volume=348|issue=10|pmid=12621133|doi=10.1056/NEJMoa021735|first2=BF|first3=RS|first4=RW|first5=D|first6=R|first7=G|first8=RW|first9=R|last2=Cole|last3=Sandler|last4=Haile|last5=Ahnen|last6=Bresalier|last7=McKeown-Eyssen|last8=Summers|last9=Rothstein}}</ref><ref>{{Cite journal|author=Chan, ''et al.''|title=A Prospective Study of Aspirin Use and the Risk for Colorectal Adenoma|journal=Ann Intern Med|year=2004|pages=157–66|volume=140|issue=3|pmid= 14757613|first2=EL|first3=ES|first4=GA|first5=DJ|first6=WC|first7=CS|last2=Giovannucci|last3=Schernhammer|last4=Colditz|last5=Hunter|last6=Willett|last7=Fuchs}}</ref><ref>{{Cite journal|author=Chan, ''et al.''|title=Long-term Use of Aspirin and Nonsteroidal Anti-inflammatory Drugs and Risk of Colorectal Cancer|journal=JAMA|year=2005|pages=914–23|volume=294|issue=8|pmid= 16118381|doi=10.1001/jama.294.8.914|first2=EL|first3=JA|first4=ES|first5=GC|first6=CS|pmc=1550973|last2=Giovannucci|last3=Meyerhardt|last4=Schernhammer|last5=Curhan|last6=Fuchs}}</ref> [[lung cancer|lung]],<ref>{{Cite journal|author=Akhmedkhanov, ''et al.''|title=Aspirin and lung cancer in women|journal=Br J cancer|year=2002|pages=1337–8|volume=87|issue=11|pmid= 12085255|doi=10.1038/sj.bjc.6600370|first2=P|first3=A|first4=KL|first5=RE|pmc=2364276|last2=Toniolo|last3=Zeleniuch-Jacquotte|last4=Koenig|last5=Shore}}</ref><ref>{{Cite journal|author=Moysich KB, Menezes RJ, Ronsani A, ''et al.'' |title=Regular aspirin use and lung cancer risk |journal=BMC Cancer |volume=2 |pages=31 |year=2002 |pmid=12453317 |doi=10.1186/1471-2407-2-31 |pmc=138809}} [http://www.biomedcentral.com/1471-2407/2/31 Free full text]</ref> and possibly the upper GI tract, though some evidence of its effectiveness in preventing cancer of the upper GI tract has been inconclusive.<ref name="'Asprin upper GI cancer'">{{Cite journal|title=Regular aspirin use and esophageal cancer risk|journal=Int J Cancer|year=2006|coauthors=Jayaprakash V, Menezes RJ, Javle MM, McCann SE, Baker JA, Reid ME, Natarajan N, Moysich KB.|volume=119|issue=1|pages=202–7|pmid=16450404 |doi=10.1002/ijc.21814|author=Jayaprakash, Vijayvel}}</ref><ref name="'Asprin upper GI cancer'"/><ref>{{Cite journal|author=Bosetti, ''et al.''|title=Aspirin use and cancers of the upper aerodigestive tract|journal=Br J Cancer|year=2003|pages=672–74|volume=88|issue=5|pmid= 12618872|doi=10.1038/sj.bjc.6600820|first2=R|first3=S|first4=E|first5=W|first6=C|pmc=2376339|last2=Talamini|last3=Franceschi|last4=Negri|last5=Garavello|last6=La Vecchia}}</ref> Its preventative effect against adenocarcinomas may be explained by its inhibition of [[Cyclooxygenase|PTGS2 (COX-2)]] enzymes expressed in them.<ref>{{Cite journal|author=Wolff, ''et al.''|title=Expression of cyclooxygenase-2 in human lung carcinoma|journal=Cancer Research|date=15 November 1998| pages=4997–5001|volume=58|issue=22|url=http://cancerres.aacrjournals.org/cgi/content/abstract/58/22/4997|pmid=9823297|first2=K|first3=S|first4=A|first5=H|first6=A|last2=Saukkonen|last3=Anttila|last4=Karjalainen|last5=Vainio|last6=Ristimäki}}</ref>

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".<ref name=Imaeda2009>{{Cite journal
|last1 = Imaeda|first1 = Avlin B.
|last2 = Watanabe|first2 = Azuma
|last3 = Sohail|first3 = Muhammad A.
|last4 = Mahmood|first4 = Shamail
|last5 = Mohamadnejad|first5 = Mehdi
|last6 = Sutterwala|first6 = Fayyaz S.
|last7 = Flavell|first7 = Richard A.
|last8 = Mehal|first8 = Wajahat Z.
|year = 2009
|title = Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome
|journal = Journal of Clinical Investigation
|doi = 10.1172/JCI35958
|pmid = 19164858
|volume = 119
|issue = 2
|pages = 305–14
|pmc = 2631294
}}</ref>

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.<ref>{{Cite journal|author=Chan, ''et al.''|title=Aspirin Use and Survival After Diagnosis of Colorectal Cancer|journal=JAMA|date=12 August 209| pages=649–658|volume=302|issue=6|url=http://jama.ama-assn.org/cgi/content/short/302/6/649?rss=1|doi=10.1001/jama.2009.1112|pmid=19671906|first2=S|first3=CS|last2=Ogino|last3=Fuchs|pmc=2848289}}</ref><ref>{{Cite web| url=http://www.pgxnews.org/web/pgx-pharmacogenomics-articles-reviews/41-general-literature-review/97-aspirin-use-after-colorectal-cancer-diagnosis-associated-with-improved-survival|title=Aspirin use after colorectal cancer diagnosis associated with improved survival|author=PGxNews.Org| publisher=PGxNews.Org| accessdate=2009-08-11| month= August| year=2009}} {{Dead link|date=September 2010|bot=H3llBot}}</ref>

A 2010 article in the Journal of Clinical Oncology has suggested that aspirin may reduce the risk of death from breast cancer.<ref>Holmes, M et al (2010). "Aspirin intake and survival after breast cancer". ''Journal of Clinical Oncology'' (pre-publication). Available at http://jco.ascopubs.org/cgi/content/abstract/JCO.2009.22.7918v1</ref> While the information has been well-circulated by the media,<ref>"Is aspirin a miracle drug?". ''ABC News'', 2010. Available at http://abcnews.go.com/Health/video/aspirin-miracle-drug-9980248</ref><ref>Coomer, C (2010). "Aspirin battling breast cancer". ''Fox News Health Blog'', available at http://health.blogs.foxnews.com/2010/02/17/aspirin-battling-breast-cancer/</ref> official health bodies and medical groups have expressed concern over the touting of aspirin as "miracle drug".<ref>"Women warned aspirin reports may be misleading". ''National Prescribing Service'' (2010), available at http://www.nps.org.au/news_and_media/media_releases/repository/Women_warned_aspirin</ref>

==Contraindications and resistance==
<!--Note that Contraindications is spelled correctly! It does not need to be changed.-->
Aspirin should not be taken by people who are allergic to [[ibuprofen]] or [[naproxen]],<ref name="drugs.com"/><ref name="personalmd" /> or who have [[salicylate intolerance]]<ref name="pmid16247191">{{Cite journal
| author = Raithel M, Baenkler HW, Naegel A, ''et al.''
| title = Significance of salicylate intolerance in diseases of the lower gastrointestinal tract
| journal = J. Physiol. Pharmacol.
| volume = 56 Suppl 5
| issue =
| pages = 89–102
| year = 2005
| month = September
| pmid = 16247191
| doi =
| url = http://www.jpp.krakow.pl/journal/archive/0905_s5/pdf/89_0905_s5_article.pdf
| issn =
|format=PDF}}</ref><ref name="pmid8566739">{{Cite journal
| author = Senna GE, Andri G, Dama AR, Mezzelani P, Andri L
| title = Tolerability of imidazole salycilate in aspirin-sensitive patients
| journal = Allergy Proc
| volume = 16
| issue = 5
| pages = 251–4
| year = 1995
| pmid = 8566739
| doi = 10.2500/108854195778702675
| url = http://openurl.ingenta.com/content/nlm?genre=article&issn=1088-5412&volume=16&issue=5&spage=251&aulast=Senna
}}</ref> 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 ulcer]]s, mild [[diabetes]], or [[gastritis]] seek medical advice before using aspirin.<ref name="drugs.com"/><ref name="mercksource">{{Cite web| title = PDR Guide to Over the Counter (OTC) Drugs|url=http://www.mercksource.com/pp/us/cns/cns_hl_pdr.jspzQzpgzEzzSzppdocszSzuszSzcnszSzcontentzSzpdrotczSzotc_fullzSzdrugszSzfgotc036zPzhtm| accessdate = 2008-04-28}}.</ref> Even if none of these conditions are present, there is still an increased risk of [[gastrointestinal hemorrhage|stomach bleeding]] when aspirin is taken with [[alcoholic beverage|alcohol]] or [[warfarin]].<ref name="drugs.com"/><ref name="personalmd" /> Patients with [[hemophilia]] or other bleeding tendencies should not take aspirin or other salicylates.<ref name="drugs.com"/><ref name="mercksource" /> 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.<ref>{{Cite book| title = G6PD (Glucose-6-Phosphate Dehydrogenase) Deficiency|url=http://www.healthsystem.virginia.edu/uvahealth/adult_blood/glucose.cfm |accessdate = 2008-05-07|publisher=University of Virginia| isbn = 0195036344| author = Frank B. Livingstone.| year = 1985}}</ref><ref>{{Cite book| title = G6PD (Glucose-6-Phosphate Dehydrogenase) Deficiency|url=http://www.utmbhealthcare.org/Health/Content.asp?PageID=P00091 |accessdate = 2008-05-07 |publisher=University of Texas Medical Branch| isbn = 0195036344| author = Frank B. Livingstone.| year = 1985}}</ref> Use of aspirin during [[dengue fever]] is not recommended owing to increased bleeding tendency.<ref>{{Cite web|title= Dengue and Dengue Hemorrhagic Fever: Information for Health Care Practitioners|url = http://www.cdc.gov/NCIDOD/dvbid/dengue/dengue-hcp.htm| accessdate = 2008-04-28}}</ref> 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]].<ref name="BMJ2002-Macdonald"/>

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<ref>{{Cite journal|author=Dorsch MP, Lee JS, Lynch DR, Dunn SP, Rodgers JE, Schwartz T, Colby E, Montague D, Smyth SS |title=Aspirin Resistance in Patients with Stable Coronary Artery Disease with and without a History of Myocardial Infarction |journal=Ann Pharmacother |volume= 41|issue=May |pages= 737|year=2007 |pmid=17456544 |doi=10.1345/aph.1H621}}</ref> and a different, aggregate study of 2,930 patients found 28% to be resistant.<ref name="pmid18202034">{{Cite journal|author=Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR |title=Aspirin "resistance" and risk of cardiovascular morbidity: systematic review and meta-analysis |journal=BMJ |volume=336 |issue=7637 |pages=195–8 |year=2008 |pmid=18202034 |pmc=2213873 |doi=10.1136/bmj.39430.529549.BE |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=18202034}}</ref>
A study in 100 Italian patients found that of the apparent 31% aspirin resistant subjects, only 5% were truly resistant, and the others were [[Compliance (medicine)|noncompliant]].<ref name="pmid18680540">{{Cite journal|author=Pignatelli P, Di Santo S, Barillà F, Gaudio C, Violi F |title=Multiple anti-atherosclerotic treatments impair aspirin compliance: effects on aspirin resistance |journal=J. Thromb. Haemost. |volume=6 |issue=10 |pages=1832–4 |year=2008 |pmid=18680540 |doi=10.1111/j.1538-7836.2008.03122.x}}</ref>

==Adverse effects==
===Gastrointestinal===
Aspirin use has been shown to increase the risk of [[gastrointestinal bleeding]].<ref name="H Toft">{{Cite journal|author=Sørensen HT, Mellemkjaer L, Blot WJ, ''et al.'' |title=Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin |journal=Am. J. Gastroenterol. |volume=95 |issue=9 |pages=2218–24 |year=2000 |pmid=11007221 |doi=10.1111/j.1572-0241.2000.02248.x |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0002-9270&date=2000&volume=95&issue=9&spage=2218}}</ref> 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.<ref name="H Toft" /> Combining aspirin with other [[NSAID]]s has also been shown to further increase this risk.<ref name="H Toft" /> Using aspirin in combination with [[clopidogrel]] or [[warfarin]] also increases the risk of upper gastrointestinal bleeding.<ref>{{Cite journal|author=Delaney JA, Opatrny L, Brophy JM & Suissa S |year=2007 |title=Drug drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding |journal=CMAJ |volume=177 |issue=4 |pages=347–51 |pmid=17698822 |doi=10.1503/cmaj.070186 |pmc=1942107}}</ref>

====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 prevent 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.<ref>http://antoine.frostburg.edu/chem/senese/101/acidbase/faq/buffered-aspirin.shtml</ref>

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.<ref name="Dammann">{{Cite journal|author= Dammann''et al.'' |title=Effects of buffered and plain acetylsalicylic acid formulations with and without ascorbic acid on gastric mucosa in healthy subjects. |journal=Aliment Pharmacol Ther. |year=2004 |issue=19 |pages=367–74 }}</ref>

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).<ref name="Reese">{{Cite journal|author= Reese''et al.'' |title=Effect of deglycyrrhinized liquorice on gastric mucosal damage by aspirin. |journal=Scand J Gastroenterol |year=1979 |issue=14 |pages=605–07 }}</ref>

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.<ref name="Laudanno">{{Cite journal|author=Laudanno ''et al.'' |title=Prostaglandin E1 (misoprostol) and S-adenosylmethionine in the prevention of hemorrhagic gastritis induced by aspirin in the human. Endoscopic, histologic and histochemical study. |journal=Acta Gastroenterol Latinoam |year=1984 |issue=14 |pages=289–93 }}</ref>

===Central effects===
Large doses of salicylate, a metabolite of aspirin, have been proposed to cause [[tinnitus]] (ringing in the ears) based on the experiments in rats, via the action on [[arachidonic acid]] and [[NMDA receptor]]s cascade.<ref name="Gutton">{{Cite journal|author=Guitton MJ, Caston J, Ruel J, Johnson RM, Pujol R, Puel JL |title=Salicylate induces tinnitus through activation of cochlear NMDA receptors |journal=J. Neurosci. |volume=23 |issue=9 |pages=3944–52 |year=2003 |pmid=12736364 |url=http://www.jneurosci.org/cgi/content/full/23/9/3944}}</ref>

===Reye's syndrome===
{{Main|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 tract infection (disambiguation)|respiratory infection]], [[chickenpox]], or [[diarrhea]]. Salicylates were detectable in 81.9% of children for whom test results were reported.<ref name=Belay>{{Cite journal|author=Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB |title=Reye's syndrome in the United States from 1981 through 1997 |journal=N. Engl. J. Med. |volume=340 |issue=18 |pages=1377–82 |year=1999 |pmid=10228187 |doi= 10.1056/NEJM199905063401801|url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=10228187&promo=ONFLNS19}}</ref> After the association between Reye's syndrome and aspirin was reported and safety measures to prevent it (including a [[Surgeon General of the United States|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.<ref name=Belay/> The United States [[Food and Drug Administration (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,<ref name="BMJ2002-Macdonald"/> 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.<ref>NHS Choices: Reye's syndrome. Last reviewed: 16 December 2008 http://www.nhs.uk/conditions/Reyes-syndrome/Pages/Introduction.aspx</ref>

===Hives/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 [[Aspirin#Overdose|overdose]].

===Other effects===
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.<ref>{{Cite journal|author=Berges-Gimeno MP & Stevenson DD |year=2004 |title=Nonsteroidal anti-inflammatory drug-induced reactions and desensitization |journal=J Asthma |volume=41 |issue=4 |pages=375–84 |pmid=15281324 |doi=10.1081/JAS-120037650}}</ref>

Aspirin causes an increased risk of cerebral microbleeds that is the appearance on [[MRI]] scans of 5–10&nbsp;mm or smaller hypointense (dark holes) patches.<ref>Vernooij MW, Haag MD, van der Lugt A, Hofman A, Krestin GP, Stricker BH, Breteler MM. (2009). Use of antithrombotic drugs and the presence of cerebral microbleeds: the Rotterdam Scan Study. Arch Neurol. 66(6):714-20. PMID 19364926</ref><ref>Gorelick PB. (2009). Cerebral microbleeds: evidence of heightened risk associated with aspirin use.
Arch Neurol. 66(6):691-3. PMID 19506128</ref> 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, thirty patients were observed after their various surgeries. Twenty of the thirty patients had to have an additional unplanned operation because of postoperative bleeding.<ref>{{Cite journal|author=Scher, K.S. |year=1996 |title=Unplanned reoperation for bleeding |journal=Am Surg |volume=62 |issue=1 |pages=52–55 |pmid=8540646}}</ref> This diffuse bleeding was associated with aspirin alone or in combination with another NSAID in 19 out of the 20 who had to have another operation owing to bleeding after their operation. The average recovery time for the second operation was 11 days.

{{Bleeding worksheet}}

==Dosage==
[[Image:Regular strength enteric coated aspirin tablets.jpg|thumb|Coated 325&nbsp;mg aspirin tablets]]
For adults doses are generally taken four times a day for fever or arthritis,<ref name=BNF>{{Cite book|title=[[British National Formulary]]|edition=45|year=2003|publisher= [[British Medical Journal]] and [[Royal Pharmaceutical Society of Great Britain]]}}</ref> with doses near the maximal daily dose used historically for the treatment of rheumatic fever.<ref>[http://www.medscape.com/druginfo/monograph?cid=med&drugid=3881&drugname=Aspirin+EC+Oral&monotype=monograph Aspirin monograph: dosages, etc]</ref> For the prevention of myocardial infarction in someone with documented or suspected coronary artery disease, much lower doses are taken once daily.<ref name=BNF />

New recommendations from the US Preventive Services Task Force (USPSTF, March, 2009) 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. Regular low dose (75 to 81&nbsp;mg) aspirin 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 to 81&nbsp;mg/day) may optimize efficacy and safety for patients requiring aspirin for long-term prevention.<ref>[http://cme.medscape.com/viewarticle/589895?src=cmemp]</ref>

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.<ref>{{Cite book|title=[[British National Formulary for Children]]|year=2006|publisher= [[British Medical Journal]] and [[Royal Pharmaceutical Society of Great Britain]]}}</ref>

==Overdose==
{{Main|Aspirin poisoning}}

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.<ref name="Pediatrics1982-gaudreault">{{Cite journal|author=Gaudreault P, Temple AR, Lovejoy FH Jr.|title=The relative severity of acute versus chronic salicylate poisoning in children: a clinical comparison |journal=Pediatrics|year=1982|pages=566–9|volume=70|issue=4|pmid= 7122154}}</ref> Toxicity is managed with a number of potential treatments including: [[activated charcoal]], intravenous dextrose and normal saline, [[sodium bicarbonate]], and dialysis.<ref>{{Cite book|title=Rosen's emergency medicine: concepts and clinical practice |last=Marx |first=John |year=2006 |publisher=Mosby/Elsevier |isbn=9780323028455 |page=2242 }}</ref>

==Mechanism of action==
{{Main|Mechanism of action of aspirin}}
<!--[[Image:PTGS2 inhibited by Aspirin.png|thumb|Structure of PTGS2 inactivated by Aspirin. In the active site of each of the two monomers, Serine 530 has been acetylated. Also visible is the salicylic acid which has transferred the acyl group, and the heme cofactor.]]-->

===Discovery of the mechanism===
In 1971, British [[pharmacologist]] [[John Robert Vane]], then employed by the [[Royal College of Surgeons of England|Royal College of Surgeons]] in London, showed that aspirin suppressed the production of [[prostaglandin]]s and [[thromboxane]]s.<ref>{{Cite journal|title = Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs|author = John Robert Vane| journal = Nature - New Biology| year = 1971| volume = 231| issue = 25| pages = 232–5| pmid= 5284360}}</ref><ref>{{Cite journal|author=Vane JR, Botting RM |year=2003 |title=The mechanism of action of aspirin |journal=Thromb Res |volume=110 |issue=5–6 |pages=255–8 |pmid=14592543 |doi=10.1016/S0049-3848(03)00379-7 |url=http://www.eao.chups.jussieu.fr/polys/certifopt/saule_coxib/theme/1vane2003.pdf|format=PDF}}</ref> For this discovery, he was awarded both a [[Nobel Prize]] in [[Nobel Prize in Physiology or Medicine|Physiology or Medicine]] in 1982 and a [[knighthood]].

===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. Cyclooxygenase is 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|thromboxane A<sub>2</sub>]] in [[platelet]]s, producing an inhibitory effect on [[platelet|platelet aggregation]]. This anticoagulant property makes aspirin useful for reducing the incidence of heart attacks.<ref>{{Cite web|url=http://www.americanheart.org/presenter.jhtml?identifier=4456 |title=Aspirin in Heart Attack and Stroke Prevention |accessdate=2008-05-08 |publisher=American Heart Association}}</ref> 40&nbsp;mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A<sub>2</sub> release provoked acutely, with the prostaglandin I2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition.<ref>{{Cite journal|last = Tohgi| first = H| coauthors = S Konno, K Tamura, B Kimura and K Kawano|year = 1992|title = Effects of low-to-high doses of aspirin on platelet aggregability and metabolites of thromboxane A2 and prostacyclin|journal = Stroke| volume = 23|pages = 1400–1403 |pmid=1412574|issue = 10}}</ref>

Prostaglandins are local [[hormone]]s produced in the body and have diverse effects in the body, including the transmission of pain information to the brain, modulation of the [[hypothalamus|hypothalamic]] thermostat, and inflammation. Thromboxanes are responsible for the aggregation of [[platelet]]s that form [[clot|blood clots]]. Heart attacks are primarily caused by blood clots, and low doses of aspirin are seen as an effective medical intervention for acute [[myocardial infarction]]. The major side effect of this is that because the ability of blood to clot is reduced, excessive bleeding may result from the use of aspirin.

===PTGS1 [COX-1] and PTGS2 [COX-2] inhibition===
There are at least two different types of cyclooxygenase: PTGS1 and PTGS2. Aspirin irreversibly inhibits PTGS1 and modifies the enzymatic activity of PTGS2. Normally PTGS2 produces prostanoids, most of which are pro-inflammatory. Aspirin-modified PTGS2 produces lipoxins, most of which are anti-inflammatory. Newer NSAID drugs called [[PTGS2 selective inhibitor]]s have been developed that inhibit only PTGS2, with the intent to reduce the incidence of gastrointestinal side effects.<ref name="cox3article" />

However, several of the new [[PTGS2 selective inhibitor]]s, such as [[Vioxx]], have been withdrawn recently, after evidence emerged that PTGS2 inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the microvasculature in the body 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 anti-coagulative 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.<ref name="SomasundaramS">{{Cite journal|last=Somasundaram, S. et al.|year=2000|title=Uncoupling of intestinal mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase are required for the development of NSAID-enteropathy in the rat|journal=Aliment Pharmacol Ther|volume=14|pages=639–650|doi=10.1046/j.1365-2036.2000.00723.x|pmid=10792129|author1=Somasundaram|first2=G|first3=RJ|first4=J|first5=M|first6=IA|first7=S|first8=A|first9=R|issue=5|last2=Sigthorsson|last3=Simpson|last4=Watts|last5=Jacob|last6=Tavares|last7=Rafi|last8=Roseth|last9=Foster}}</ref> In short, aspirin buffers and transports the protons. When high doses of aspirin are given, aspirin 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. Additionally, 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.<ref>{{Cite journal|first=Mark J. |last=Paul-Clark |first2=Thong van |last2=Cao |first3=Niloufar |last3=Moradi-Bidhendi |first4=Dianne |last4=Cooper |first5=Derek W. |last5=Gilroy |lastauthoramp=yes |title=15-epi-lipoxin A4–mediated Induction of Nitric Oxide Explains How Aspirin Inhibits Acute Inflammation |journal=J. Exp. Med. |year=2004 |volume=200 |issue=1 |pages=69–78 |doi=10.1084/jem.20040566 |pmid=15238606 |pmc=2213311}}</ref> More recent data also suggests that salicylic acid and its derivatives modulate signaling through [[NF-κB]].<ref>{{Cite journal|last=McCarty |first=M. F. |first2=K. I. |last2=Block |year=2006 |title=Preadministration of high-dose salicylates, suppressors of NF-kappaB activation, may increase the chemosensitivity of many cancers: an example of proapoptotic signal modulation therapy |journal=Integr Cancer Ther. |volume=5 |issue=3 |pages=252–268 |pmid=16880431 |doi=10.1177/1534735406291499}}</ref> NF-κB is a [[transcription factor]] complex that plays a central role in many biological processes, including inflammation.

===Effects upon Hypothalamic-Pituitary-Adrenal Activity===
Aspirin reduces the effects of [[vasopressin]]<ref name="Nye">
{{Cite journal
| author = Nye EJ, Hockings GI, Grice JE, Torpy DJ, Walters MM, Crosbie GV, Wagenaar M, Cooper M, Jackson RV
| title = Aspirin inhibits vasopressin-induced hypothalamic-pituitary-adrenal activity in normal humans
| journal = J. Clin. Endocrinol. Metab.
| volume = 82
| issue = 3
| pages = 812–7
| year = 1997
| doi = 10.1210/jc.82.3.812
| pmid = 9062488
}}</ref> and increases those of [[naloxone]]<ref>
{{Cite journal
| author = Hockings GI, Grice JE, Crosbie GV, Walters MM, Jackson AJ, Jackson RV
| title = Aspirin increases the human hypothalamic-pituitary-adrenal axis response to naloxone stimulation
| journal = J. Clin. Endocrinol. Metab.
| volume = 77
| issue = 2
| pages = 404–8
| year = 1993
| doi = 10.1210/jc.77.2.404
| pmid = 8393884
}}</ref> upon the secretion of [[ACTH]] and [[cortisol]] by the [[hypothalamic-pituitary-adrenal axis]]. It has been suggested that this occurs through an interaction with endogenous prostaglandins and their role in regulating the HPA axis.<ref name="Nye"/>

==Pharmacokinetics==
[[Salicylic acid]] is a weak acid, and very little of it is [[Acid dissociation constant|ionized]] in the [[stomach]] after oral administration. Acetylsalicylic acid is poorly soluble in the [[pH|acidic]] conditions of the stomach, which can delay absorption of high doses for 8 to 24 hours. In addition to the increased pH of the [[small intestine]], aspirin is rapidly absorbed there owing to the increased surface area, which in turn allows more of the salicylate to dissolve. Owing to the issue of solubility, however, aspirin is absorbed much more slowly during overdose, and [[blood plasma|plasma]] concentrations can continue to rise for up to 24 hours after ingestion.<ref name="'RK Ferguson'">{{Cite journal|title=Death following self-poisoning with aspirin|journal=Journal of the American Medical Association|date=1970-08-17|first=RK|last=Ferguson|coauthors=Boutros, AR|volume=213|issue=7|pages=1186–8|pmid=5468267|doi=10.1001/jama.213.7.1186}}</ref><ref name="'FL Kaufman'">{{Cite journal|title=Darvon poisoning with delayed salicylism: a case report|journal=Pediatrics|date=1970-04|first=FL|last=Kaufman|coauthors=Dubansky, AS|volume=49|issue=4|pages=610–1|pmid=5013423}}</ref><ref name="G Levy">{{Cite journal|doi=10.1056/NEJM197208312870903|title=Salicylate accumulation kinetics in man|journal=New England Journal of Medicine|date=1972-09-31|first=G|last=Levy|coauthors=Tsuchiya, T|volume=287|issue=9|pages=430–2|pmid=5044917 }}</ref>

About 50–80% of salicylate in the blood is bound by [[protein]] 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.<ref name="G Levy"/>

As much as 80% of therapeutic doses of salicylic acid is [[metabolism|metabolized]] in the [[liver]]. Conjugation with [[glycine]] forms [[salicyluric acid]] and with [[glucuronic acid]] forms salicyl acyl and 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 pathway]]s become saturated and [[kidneys|renal]] excretion becomes increasingly important.<ref name="G Levy"/>

Salicylates are excreted mainly by the [[kidneys]] as salicyluric acid (75%), free salicylic acid (10%), salicylic phenol (10%) and acyl (5%) glucuronides, and gentisic acid (< 1%). When small doses (less than 250&nbsp;mg in an adult) are ingested, all pathways proceed by first-order kinetics, with an elimination half-life of about 2 to 4.5 hours.<ref name="'O Hartwig'">{{Cite journal|title=Pharmacokinetic considerations of common analgesics and antipyretics|journal=American Journal of Medicine|date=1983-11-14|first=Otto H|last=Hartwig|volume=75|issue=5A|pages=30–7|pmid=6606362 |pmc=1725844 |doi=10.1016/0002-9343(83)90230-9}}</ref><ref name="'AK Done'">{{Cite journal|title=Salicylate intoxication. Significance of measurements of salicylate in blood in cases of acute ingestion|journal=Pediatrics|date=1960-11|first=AK|last=Done|volume=26|pages=800–7|pmid=13723722}}</ref> When higher doses of salicylate are ingested (more than 4 g), the half-life becomes much longer (15–30 hours)<ref name="Chyka2007">{{Cite journal|author=Chyka PA, Erdman AR, Christianson G, Wax PM, Booze LL, Manoguerra AS, Caravati EM, Nelson LS, Olson KR, Cobaugh DJ, Scharman EJ, Woolf AD, Troutman WG; Americal Association of Poison Control Centers; Healthcare Systems Bureau, Health Resources and Services Administration, Department of Health and Human Services. |title=Salicylate poisoning: an evidence-based consensus guideline for out-of-hospital management |journal=Clin Toxicol (Phila) |volume=45 |issue=2 |pages=95–131 |year=2007 |pmid=17364628 |doi=10.1080/15563650600907140 }}</ref> because the biotransformation pathways concerned with the formation of salicyluric acid and salicyl phenolic glucuronide become saturated.<ref>{{Cite journal|author=Prescott LF, Balali-Mood M, Critchley JA, Johnstone AF, Proudfoot AT |title=Diuresis or urinary alkalinisation for salicylate poisoning? |journal=Br Med J (Clin Res Ed) |volume=285 |issue=6352 |pages=1383–6 |year=1982 |pmid=6291695 |pmc=1500395 |doi=10.1136/bmj.285.6352.1383}}</ref> Renal excretion of salicylic acid becomes increasingly important as the metabolic pathways become saturated, because it is extremely sensitive to changes in [[urine|urinary]] pH. There is a 10 to 20 fold increase in renal clearance when urine pH is increased from 5 to 8. The use of urinary alkalinization exploits this particular aspect of salicylate elimination.<ref name="EmergMed2002-Dargan">{{Cite journal|author=Dargan PI, Wallace CI, Jones AL.|title=An evidenced based flowchart to guide the management of acute salicylate (aspirin) overdose|journal=Emerg Med J|year=2002|pages=206–9|volume=19|issue=3|pmid= 11971828 |doi=10.1136/emj.19.3.206|pmc=1725844}}</ref>

==Interactions==
Aspirin is known to [[Drug interaction|interact]] with other drugs. For example, [[acetazolamide]] and [[ammonium chloride]] have been known to enhance the intoxicating effect of salicyclates, and [[alcohol]] also increases the gastrointestinal bleeding associated with these types of drugs.<ref name='drugs.com'>{{Cite web|url=http://www.drugs.com/aspirin.html |title=Aspirin information from Drugs.com |accessdate=2008-05-08 |publisher=Drugs.com}}</ref><ref name='personalmd'>{{Cite web|url=http://www.personalmd.com/drgdb/3.htm |title=Oral Aspirin information |accessdate=2008-05-08 |publisher=First DataBank}}</ref> Aspirin is known to displace a number of drugs from protein binding sites in the blood, including the [[anti-diabetic drug]]s [[tolbutamide]] and [[chlorpropamide]], the [[immunosuppressant]] [[methotrexate]], [[phenytoin]], [[probenecid]], [[valproic acid]] (as well as interfering with [[beta oxidation]], an important part of valproate metabolism) and any [[NSAID|nonsteroidal anti-inflammatory drug]]. Corticosteroids may also reduce the concentration of aspirin. The pharmacological activity of [[spironolactone]] may be reduced by taking aspirin, and aspirin is known to compete with [[Penicillin|Penicillin G]] for renal tubular secretion.<ref name="interactions">Katzung (1998), p. 584.</ref> Aspirin may also inhibit the absorption of [[vitamin C]].<ref>{{Cite journal|author=Loh HS, Watters K & Wilson CW |date=1 November 1973|title=The Effects of Aspirin on the Metabolic Availability of Ascorbic Acid in Human Beings |journal=J Clin Pharmacol |volume=13 |issue=11 |pages=480–6 |pmid=4490672 |url=http://jcp.sagepub.com/cgi/content/abstract/13/11/480}}</ref><ref>{{Cite journal|author=Basu TK |year=1982 |title=Vitamin C-aspirin interactions |journal=Int J Vitam Nutr Res Suppl |volume=23 |pages=83–90 |pmid=6811490}}</ref><ref>{{Cite journal|author=Ioannides C, Stone AN, Breacker PJ & Basu TK |year=1982 |title=Impairment of absorption of ascorbic acid following ingestion of aspirin in guinea pigs |journal=Biochem Pharmacol |volume=31 |issue=24 |pages=4035–8 |pmid=6818974 |doi=10.1016/0006-2952(82)90652-9}}</ref>

==Veterinary uses==
Aspirin has been used to treat pain and arthritis in veterinary medicine, primarily in [[dog]]s, although it is often not recommended for this purpose, as there are newer medications available with fewer side effects in these animals. Dogs, for example, are particularly susceptible to the gastrointestinal side effects associated with salicylates.<ref>{{Cite web|last = Crosby|first = Janet Tobiassen|title = Veterinary Questions and Answers|publisher = About.com|year = 2006|url = http://vetmedicine.about.com/cs/altvetmedgeneral/a/dogcataspirin.htm|accessdate = 2007-09-05}}</ref> [[Horse]]s have also been given aspirin for pain relief, although it is not commonly used owing to its relatively short-lived analgesic effects. Horses are also fairly sensitive to the gastrointestinal side effects. Nevertheless, it has shown promise in its use as an [[anticoagulant]], mostly in cases of [[laminitis]].<ref name="CambridgeH">{{Cite journal|author=Cambridge H, Lees P, Hooke RE, Russell CS |title=Antithrombotic actions of aspirin in the horse |journal=Equine Vet J |volume=23 |issue=2 |pages=123–7 |year=1991 |pmid=1904347 |doi=10.1111/j.2042-3306.1991.tb02736.x}}</ref> Aspirin should only be used in animals under the direct supervision of a [[veterinarian]]. Aspirin should never be given to [[cats]] because they lack the ability to form [[glucuronide]] conjugates, which makes it more likely that aspirin will be toxic. Toxicity may be reduced by administering dosages at longer intervals.<ref>Lappin, p. 160</ref>

==Chemistry==
Aspirin is an [[acetyl]] derivative of salicylic acid that is a white, crystalline, weakly acidic substance, with a [[melting point]] of {{convert|135|C|0|abbr=on}}. Acetylsalicylic acid decomposes rapidly in solutions of [[ammonium acetate]] or of the [[acetates]], [[carbonates]], [[citrates]] or [[hydroxides]] of the [[alkali metals]]. Acetylsalicylic acid is stable in dry air, but gradually [[hydrolyses]] in contact with moisture to acetic and salicylic [[acids]]. In solution with alkalis, the hydrolysis proceeds rapidly and the clear solutions formed may consist entirely of acetate and salicylate.<ref>
Reynolds EF (ed) (1982). Aspirin and similar analgesic and anti-inflammatory agents. Martindale, The Extra Pharmacopoeia 28 Ed, 234-82.</ref>

===Synthesis===
The synthesis of aspirin is classified as an [[esterification]] reaction. [[Salicylic acid]] is treated with [[acetic anhydride]], an acid derivative, causing a [[chemical reaction]] that turns salicylic acid's [[hydroxyl]] group into an [[acetyl]] group, (R-OH → R-OCOCH3). This process yields aspirin and [[acetic acid]], which is considered a [[byproduct]] of this reaction. Small amounts of [[sulfuric acid]] (and occasionally [[phosphoric acid]]) are almost always used as a [[catalyst]]. This method is commonly employed in undergraduate teaching labs.<ref>{{Cite book|title=Experimental Organic Chemistry |last=Palleros |first=Daniel R. |year=2000 |publisher=John Wiley & Sons|location=New York|isbn=0-471-28250-2 |pages=494}}</ref>

:[[Image:Aspirin synthesis.png|490px]]

Formulations containing high concentrations of aspirin often smell like [[vinegar]].<ref>{{Cite web|url=http://www.newton.dep.anl.gov/askasci/chem00/chem00314.htm |title=Aspirin Aging |accessdate=2008-05-08 |last=Barrans |first=Richard |publisher=Newton BBS}}</ref> This is because aspirin can decompose through hydrolysis in moist conditions, yielding salicylic acid and [[acetic acid]].<ref>{{Cite journal
 |last = Carstensen
 |first = J.T.
 |coauthors = F Attarchi and XP Hou
 |title = Decomposition of aspirin in the solid state in the presence of limited amounts of moisture
 |journal = Journal of Pharmaceutical Sciences
 |volume = 77
 |issue = 4
 |pages = 318–21|year = 1985 |pmid=4032246
 |doi = 10.1002/jps.2600770407}}</ref>

The acid dissociation constant ([[Acid dissociation constant|pK<sub>a</sub>]]) for acetylsalicylic acid is 3.5 at {{convert|25|C|0|abbr=on}}.<ref name="asaaciddissconst">{{Cite web|title = Acetylsalicylic acid|publisher = Jinno Laboratory, School of Materials Science, Toyohashi University of Technology|date = March 1, 1996|url = http://chrom.tutms.tut.ac.jp/JINNO/DRUGDATA/07acetylsalicylic_acid.html|accessdate = 2007-09-07}}</ref>

===Polymorphism===
[[Polymorphism (materials science)|Polymorphism]], or the ability of a substance to form more than one [[crystal structure]], is important in the development of pharmaceutical ingredients. Many drugs are receiving regulatory approval for only a single crystal form or polymorph. For a long time, only one crystal structure for aspirin was known, although there had been indications that aspirin might have a second crystalline form since the 1960s. The elusive second polymorph was first discovered by Vishweshwar and coworkers in 2005,<ref>{{Cite journal|author= Peddy Vishweshwar, Jennifer A. McMahon, Mark Oliveira, Matthew L. Peterson, and Michael J. Zaworotko| title = The Predictably Elusive Form II of Aspirin|journal = [[J. Am. Chem. Soc.]]|year = 2005|volume = 127|issue = 48|pages = 16802–16803|doi = 10.1021/ja056455b|pmid= 16316223}}</ref> and fine structural details were given by Bond et al.<ref>{{Cite journal|author= Andrew D. Bond, Roland Boese, Gautam R. Desiraju|title = On the Polymorphism of Aspirin: Crystalline Aspirin as Intergrowths of Two "Polymorphic" Domains|journal = [[Angewandte Chemie International Edition]]|year = 2007|volume = 46|issue = 4|pages = 618–622|doi = 10.1002/anie.200603373|pmid= 17139692}}</ref> A new crystal type was found after attempted co-crystallization of aspirin and [[levetiracetam]] from hot [[acetonitrile]]. The form II is only stable at 100 [[Kelvin|K]] and reverts back to form I at ambient temperature. In the (unambiguous) form I, two salicylic molecules form centrosymmetric [[Dimer (chemistry)|dimer]]s through the [[acetyl]] groups with the (acidic) [[methyl]] proton to [[carbonyl]] [[hydrogen bond]]s, 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.

==Compendial status==
* [[United States Pharmacopeia]] <ref name=asa>{{Cite web
 |last = [[Sigma Aldrich]]
 |title = Aspirin
 |url = http://www.sigmaaldrich.com/catalog/ProductDetail.do?lang=en&N4=A2093|SIGMA&N5=SEARCH_CONCAT_PNO|BRAND_KEY&F=SPEC
 |accessdate = 13 July 2009}}</ref> {{Clarify|date=July 2009}}
* [[British Pharmacopoeia]] <ref name=ibp>{{Cite web
 |last = [[British Pharmacopoeia]]
 |title = Index BP 2009
 |url = http://www.pharmacopoeia.co.uk/pdf/2009_index.pdf
 |accessdate = 13 July 2009}}</ref>

==See also==
{{Portal|Pharmacy and Pharmacology}}
* [[Aspergum]]
* [[blood platelets]]
* [[copper aspirinate]]
* [[nonsteroidal anti-inflammatory drug]]
* [[history of aspirin]]
* [[salicylic acid]]
* [[thrombocytopenic purpura]]
* [[ibuprofen]]
* [[paracetamol]] (acetaminophen)
* [[naproxen]]
* [[Choline Magnesium Trisalicylate]] (Trilisate)

==Notes and references==
{{Reflist|colwidth=30em}}

==References==
* Lappin, Michael R. (2001). ''Feline Internal Medicine Secrets''. Elsevier Health Sciences. ISBN 1560534613.

==External links==
{{Commons|Aspirin}}
* [http://www.nextbio.com/b/home/home.nb?q=aspirin NextBio Aspirin Entry]
* [http://www.wellcome.ac.uk/en/bia/gallery.html?image=24 Colour-enhanced scanning electron micrograph of aspirin crystals]
* [http://www.bruker-axs.de/fileadmin/user_upload/SMART_X2S_Structure_Gallery/Structures/aspirin_1006_1432.html Interactive 3D-structure of aspirin] with detailed x-ray crystal structure data
* [http://www.med.mcgill.ca/mjm/issues/v02n02/aspirin.html The History of Aspirin]
* [http://www.howstuffworks.com/aspirin How Aspirin works]
* [http://www.creatingtechnology.org/biomed/aspirin.htm The science behind aspirin]
* [http://pubs.acs.org/subscribe/journals/mdd/v03/i08/html/10health.html Take two: Aspirin], New uses and new dangers are still being discovered as aspirin enters its second century. Shauna Roberts, American Chemical Society
* {{Cite encyclopedia|last = Ling|first = Greg|title = Aspirin|encyclopedia = How Products are Made|volume = 1|publisher = Thomson Gale|year = 2005|url = http://www.madehow.com/Volume-1/Aspirin.html}}
* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Aspirin U.S. National Library of Medicine: Drug Information Portal - Aspirin]

{{-}}
{{Antithrombotics}}
{{Anti-inflammatory and antirheumatic products}}
{{NSAIDs}}
{{analgesics}}
{{Acne Agents}}
{{Salicylates}}

[[Category:Aspirin| ]]
[[Category:Non-steroidal anti-inflammatory drugs]]
[[Category:Antiplatelet drugs]]
[[Category:Benzoic acids]]
[[Category:Equine medications]]
[[Category:Salicylates]]
[[Category:World Health Organization essential medicines]]
[[Category:Acetate esters]]

{{Link GA|es}}
{{Link FA|bs}}
[[ar:أسبرين]]
[[ast:Aspirina]]
[[bn:অ্যাসপিরিন]]
[[zh-min-nan:Aspirin]]
[[bs:Aspirin]]
[[bg:Ацетилсалицилова киселина]]
[[ca:Aspirina]]
[[cs:Kyselina acetylsalicylová]]
[[da:Acetylsalicylsyre]]
[[de:Acetylsalicylsäure]]
[[et:Aspiriin]]
[[el:Ασπιρίνη]]
[[es:Ácido acetilsalicílico]]
[[eo:Aspirino]]
[[eu:Azido azetilsaliziliko]]
[[fa:استیل سالیسیلیک اسید]]
[[fr:Acide acétylsalicylique]]
[[gl:Aspirina]]
[[ko:아스피린]]
[[hi:एस्पिरिन]]
[[hr:Acetilsalicilna kiselina]]
[[io:Aspirino]]
[[id:Aspirin]]
[[is:Acetýlsalicýlsýra]]
[[it:Acido acetilsalicilico]]
[[he:אספירין]]
[[kn:ಆಸ್ಪಿರಿನ್‌]]
[[kk:Салицилді қышқыл]]
[[ht:Aspirin]]
[[ku:Aspîrîn]]
[[lt:Aspirinas]]
[[hu:Acetilszalicilsav]]
[[mk:Аспирин]]
[[ml:ആസ്പിരിൻ]]
[[ms:Aspirin]]
[[nl:Acetylsalicylzuur]]
[[ja:アセチルサリチル酸]]
[[no:Acetylsalisylsyre]]
[[nn:Acetylsalisylsyre]]
[[pl:Kwas acetylosalicylowy]]
[[pt:Ácido acetilsalicílico]]
[[ro:Aspirină]]
[[ru:Ацетилсалициловая кислота]]
[[simple:Aspirin]]
[[sk:Kyselina acetylsalicylová]]
[[sl:Aspirin]]
[[sr:Аспирин]]
[[sh:Aspirin]]
[[fi:Asetyylisalisyylihappo]]
[[sv:Acetylsalicylsyra]]
[[ta:ஆஸ்பிரின்]]
[[th:แอสไพริน]]
[[tr:Aspirin]]
[[uk:Ацетилсаліцилова кислота]]
[[ur:Aspirin]]
[[vi:Aspirin]]
[[wa:Aspirene]]
[[yi:אספירין]]
[[zh-yue:阿士匹靈]]
[[bat-smg:Eksperins]]
[[zh:阿司匹林]]
[[Category:2Fix]]