| bioavailability = Rapidly and completely absorbed
| protein_bound = 99.6%
| metabolism = [[Liver|Hepatic]]
| elimination_half-life = 300–650 mg dose: 3.1–3.2hrs<br />1 g dose: 5 hours<br />2 g dose: 9 hours
| excretion = [[Kidney|Renal]]
| pregnancy_AU = C
| pregnancy_US = C
| 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]]
}}
__NOTOC__
{{SI}}
{{CMG}}; '''Associate Editor-In-Chief:''' {{CZ}}
==Overview==
{{DrugProjectFormSinglePage
[[Aspirin]], or '''acetylsalicylic acid''' ({{IPAEng|əˌsɛtɨlsælɨˌsɪlɨk ˈæsɨd}}), (acetosal) is a [[salicylate]] [[medication|drug]] often used as an [[analgesic]] (to relieve minor aches and pains), [[antipyretic]] (to reduce [[fever]]), and as an [[anti-inflammatory]]. It also has an [[Antiplatelet drug|antiplatelet]] ("blood-thinning") effect and is used in long-term, low doses to prevent [[myocardial infarction|heart attacks]] and [[thrombus|blood clot]] formation in people at high risk for developing blood clots.<ref>[http://www.americanheart.org/presenter.jhtml?identifier=4456] American Heart Association: ''Aspirin in Heart Attack and Stroke Prevention'' "The American Heart Association recommends aspirin use for patients who've had a myocardial infarction (heart attack), unstable angina, ischemic stroke (caused by blood clot) or transient ischemic attacks (TIAs or "little strokes"), if not contraindicated. This recommendation is based on sound evidence from clinical trials showing that aspirin helps prevent the recurrence of such events as heart attack, hospitalization for recurrent angina, second strokes, etc. (secondary prevention). Studies show aspirin also helps prevent these events from occurring in people at high risk (primary prevention)."</ref>
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
<!--Non–Guideline-Supported Use (Adult)-->
|offLabelAdultNoGuideSupport======Condition1=====
* Dosing Information
:* Dosage
=====Condition2=====
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
<!--Pediatric Indications and Dosage-->
<!--FDA-Labeled Indications and Dosage (Pediatric)-->
|fdaLIADPed======Condition1=====
* Dosing Information
:* Dosage
=====Condition2=====
There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.
<!--Off-Label Use and Dosage (Pediatric)-->
<!--Guideline-Supported Use (Pediatric)-->
|offLabelPedGuideSupport======Condition1=====
* Developed by:
* Class of Recommendation:
* Strength of Evidence:
* Dosing Information
:* Dosage
=====Condition2=====
There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
<!--Non–Guideline-Supported Use (Pediatric)-->
|offLabelPedNoGuideSupport======Condition1=====
* Dosing Information
:* Dosage
=====Condition2=====
There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
<!--Contraindications-->
|contraindications=* Condition1
<!--Warnings-->
|warnings=* Description
====Precautions====
* Description
<!--Adverse Reactions-->
<!--Clinical Trials Experience-->
|clinicalTrials=There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
=====Body as a Whole=====
=====Cardiovascular=====
=====Digestive=====
=====Endocrine=====
=====Hematologic and Lymphatic=====
=====Metabolic and Nutritional=====
=====Musculoskeletal=====
=====Neurologic=====
=====Respiratory=====
High doses of aspirin may also be given immediately after an acute heart attack; these doses may inhibit the synthesis of [[prothrombin]] and therefore produce a second and different anticoagulant effect,<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| url = http://www.bmj.com/cgi/content/full/313/7070/1429 | accessdate = 2007-10-04}}</ref> although this is not well understood.
=====Skin and Hypersensitivy Reactions=====
The main [[adverse drug reaction|undesirable side effects]] of aspirin are [[gastrointestinal]] distress—including [[gastric ulcer|ulcers]] and stomach bleeding—and [[tinnitus]], especially in higher doses. Another adverse effect is increased bleeding in [[menstruating]] women, due to aspirin's anticoagulant properties. In children under 12 years of age, aspirin is no longer used to control [[Influenza|flu]]-like symptoms or the symptoms of [[chickenpox]], due to 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}}</ref>
Aspirin was the first-discovered member of the class of drugs known as [[non-steroidal anti-inflammatory drugs]] (NSAIDs), not all of which are salicylates, although they all have similar effects and most have some [[Non-steroidal anti-inflammatory drugs#Mode of action|mechanism of action]] which involves non-selective inhibition of the enzyme [[cyclooxygenase]].
==Historical Perspective==
{{see also|Salicylic_acid}}
=====Special Senses=====
Derivatives of [[salicylic acid]] have been in medical use since antiquity. In the modern times, a French chemist, Charles Frederic Gerhardt, was the first to prepare acetylsalicylic acid (named aspirin in 1899) 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>{{cite journal |author=Gerhardt C |title=Untersuchungen über die wasserfreien organischen Säuren |journal=Annalen der Chemie und Pharmacie|volume=87 |issue= |pages=149–179 |year=1853}}</ref> Since no structural theory existed at that time Gerhardt called the compound he obtained "salicylic-acetic anhydride" (''wasserfreie Salicylsäure-Essigsäure''). When Gerhardt tried to dissolve the solid in a diluted solution of [[sodium carbonate]] it immediately decomposed to sodium salts of salicylic and acetic acids.<ref name=gerhardt/> 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.
Six years later, in 1859, von Gilm obtained analytically pure acetylsalicylic acid (which he called "acetylirte Salicylsäure", ''acetylated salicylic acid'') by a reaction of salicylic acid and acetyl chloride.<ref name=gilm>{{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}}</ref> In 1869 Schröder, Prinzhorn and Kraut (Prinzhorn is credited in the paper with conducting the experiments) 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>{{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}}</ref>
In 1897, Felix Hoffmann, a chemist at [[Bayer|Friedrich Bayer & Co.]], obtained acetylsalicylic acid<ref name="aspirin wars">{{cite book |author=by Charles C. Mann and Mark L. Plummer |title=The aspirin wars: money, medicine, and 100 years of rampant competition |publisher=Harvard Business School Press |location=Boston, Mass |year=1991 |pages=25–36 |isbn=0-87584-401-4 |oclc= |doi=}}</ref> by a reaction of salicylic acid and acetic anhydride;<ref>{{cite web
| title = US Patent 644,077 dated February 27, 1900
| accessdate = 2007-05-20
| author = Hoffmann H
| authorlink =
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| date =
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| publisher = US Patent Office
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}}</ref> that is, essentially repeating the Gilm/Kraut procedure but substituting acetic anhydride for acetyl chloride. This synthesis served as the basis for Bayer claims to discovery of aspirin. According to a legend publicized by Bayer, Hoffmann made some of the formula and gave it to his father, who was suffering from the pain of arthritis and could not stand the side-effects of salicylic acid.<ref name="aspirin wars"/> Much later, in 1949, another Bayer researcher, Arthur Eichengrün, who was 81, "claimed that he had instructed Hoffmann to synthesise
acetylsalicylic acid and that the latter had done so without knowing the purpose of the work".<ref name=sneader>{{cite journal |author=Sneader W |title=The discovery of aspirin: a reappraisal |journal=BMJ |volume=321 |issue=7276 |pages=1591–4 |year=2000 |pmid=11124191 |doi=}}</ref> In 2000, Walter Sneader of University of Strathclyde in Glasgow reexamined the case and concluded that "Arthur Eichengrün was telling the truth when he wrote that acetylsalicylic acid was
synthesized under his direction and that the drug would not have been introduced in 1899 without his intervention".<ref name=sneader/> Axel Helmstaedter, General Secretary of the International Society for the History of Pharmacy, subsequently questioned the novelty of Sneader’s research, noting that several earlier articles discussed the Hoffmann-Eichengrün controversy in detail.<ref>{{cite web
|title=Aspirin history: Is there a need for a reappraisal ?
|accessdate=2007-05-20
|author=Helmstaedter A
|authorlink=
|coauthors
|date=2001
|format=
|work=
|publisher=bmj.com Rapid Responses for Sneader, 321 (7276) 1591–1594
|pages=
|language=
|archiveurl=
|archivedate=
|quote=
}}</ref> Bayer countered Sneader in a press release stating that according to the records, Hoffmann and Eichengrün held equal positions, and Eichengrün was not Hoffmann's supervisor. Hoffmann was named on the US Patent as the inventor, which Sneader did not mention. Eichengrün, who left Bayer in 1908, had multiple opportunities to claim the priority and had never before 1949 done it; he neither claimed nor received any percentage of the profit from aspirin sales.<ref>{{cite web
|title=Bayer AG: Zum Vortrag von Dr. Walter Sneader über die Entwicklung der Acetylsalicylsäure
|accessdate=2007-05-20
|author=
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|coauthors=
|date=
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|publisher=
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|language=German
|archiveurl=
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}}</ref> This argument did much to obscure the real history of aspirin, whose origin is not the pharmaceutical industry but earlier academic research. Despite the fact that pure aspirin was synthesized by von Gilm and by Kraut's group many years before Hoffmann, Bayer continues to insist that "The active ingredient in Aspirin®, acetylsalicylic acid, was synthesized for the first time in a chemically pure and thus stable form in 1897 by a young chemist working for Bayer, Dr. Felix Hoffmann."<ref>{{cite web
|url=http://www.aspirin.com/faq_en.html
|title=Aspirin FAQ's
|accessdate=2007-05-20
|author=
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}}</ref>
It was not until the 1970s that the [[Aspirin#Mechanism of action|mechanism of action]] of aspirin and other NSAIDs was elucidated.
=====Urogenital=====
===Trademark issues===
The brand name ''Aspirin'' was coined by the [[Bayer]] company of Germany. The name "aspirin" is composed of ''a-'' (from ''acetylirte'', meaning [[acetylation|acetylated]]) ''-spir-'' (from the plant genus ''Spiraea'') and ''-in'' (a common, easily pronounceable ending for drug names at the time). On March 6, 1899, [[Bayer]] registered the name ''Aspirin'' as a trademark.
Bayer began marketing aspirin in July 1899. It was originally sold as a powder (which is still the preferred form in many European countries) and was an instant success; in 1914, Bayer introduced aspirin tablets.<ref name="aspirin wars"/>
[[Image:BayerHeroin.png|thumb|left|180px|Advertisement for Aspirin, Heroin, Lycetol, Salophen]]
=====Miscellaneous=====
Although Bayer had registered Aspirin as a trademark in 1899, the German Patent Office refused to grant Bayer a patent for the drug based on the grounds that neither the product nor the process of preparation were novel.<ref name="aspirin wars"/> In 1905, Bayer sued Chemische Fabrik von Heyden in Britain for infringing the British patent on aspirin granted to it in 1900. Hayden claimed that existing prior art, in particular Kraut's work, invalidated Bayer's patent. Bayer advanced the argument that they were first to prepare a pure form of aspirin. The judge agreed with Hayden and invalidated the Bayer patent. A similar struggle took place in the U.S. Circuit court in Chicago; however, in the U.S., Bayer's patent was upheld in 1909.<ref name="aspirin wars"/> This created a situation where aspirin in the U.S. was three times more expensive than in Canada, and ten times more expensive than in Europe, resulting in rampant smuggling of aspirin, which Bayer unsuccessfully tried to contain.<ref name="aspirin wars"/>
After World War I, Bayer lost the right to use the trademark in many countries because the Allies seized and resold its foreign assets. The right to use the aspirin trademark in the United States (along with all other Bayer trademarks) was purchased from the U.S. government by Sterling Drug in 1918. Even before the patent for the drug expired in 1917, Bayer had been unable to stop competitors from copying the formula and using the name elsewhere, so, with a flooded market, the public was unable to recognize aspirin as coming from only one manufacturer, and in 1921, a landmark ruling by Billings Learned Hand established "aspirin" as a genericized trademark.<ref>''[http://cyber.law.harvard.edu/metaschool/fisher/domain/tmcases/bayer.htm Bayer Co. v. United Drug Co.]'', 272 F. 505 (United States District Court for the Southern District of New York 1921). Free full text at Harvard Law School's Berkman Center for Internet & Society. Retrieved on 2007-09-07.</ref> Sterling was ultimately acquired by Bayer in 1994, but this did not restore the U.S. trademark. Other countries (such as Canada and many countries in Europe) still consider aspirin a protected trademark.
In some countries the name ''Aspirin'' is used as a generic name for the drug instead of the manufacturer's trademark. In countries in which Aspirin remains a trademark, the initialism '''ASA''' (for ''acetylsalicylic acid''), or another initialism that matches the local-language term, is used as a generic term.
<!--Postmarketing Experience-->
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
==Synthesis==
=====Body as a Whole=====
The synthesis of aspirin is classified as an [[esterification]] reaction, where the alcohol group from the salicylic acid reacts with an acid derivative ([[acetic anhydride]]) to form an ester. Aspirin is commercially synthesized using a two-step process. First, [[phenol]] (generally extracted from coal tar) is treated with a sodium base which generates sodium phenolate, which is then reacted with [[carbon dioxide]] under high temperature and pressure to yield [[salicylate]], which is acidified, yielding [[salicylic acid]]. This process is known as the [[Kolbe-Schmitt reaction]].
:[[Image:Kolbe-Schmitt.png|400px]]
Salicylic acid is then [[acetylation|acetylated]] using [[acetic anhydride]], yielding aspirin and [[acetic acid]] as a byproduct. This generally tends to produce low yields due to the relative difficulty of its extraction from an aqueous state. A method of extracting higher yields is to acidify with [[phosphoric acid]] and heat the reagents under reflux with a boiling water bath for between 40 to 60 minutes.
=====Cardiovascular=====
The original synthesis of aspirin from salicylic acid involved acetylation with [[acetyl chloride]]. The byproduct from this is hydrochloric acid, which is corrosive and environmentally hazardous. As described above, it was then later found that acetic anhydride was a better acylating agent, with the byproduct acetic acid formed, which does not have the unwanted properties of hydrochloric acid and can also be recycled. The salicylic acid/acetic anhydride method is commonly employed in undergraduate teaching labs.
:[[Image:Aspirin synthesis.png|490px]]
Formulations containing high concentrations of aspirin often smell like [[vinegar]]. This is because aspirin can undergo autocatalytic degradation to salicylic acid in moist conditions, yielding salicylic acid and [[acetic acid]].
=====Digestive=====
The acid dissociation constant (pK<sub>a</sub>) for Acetylsalicylic acid is 3.5 at 25 °C.<ref name="asaaciddissconst">{{cite web | last = | first = | 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> ASA, being a weak [[monoprotic acid]], dissociates as shown by the following reaction equation:
Aspirin is one of the most frequently used drugs in the treatment of mild to moderate pain, including that of [[migraine]]s,<ref>{{cite journal |author=Aukerman G, Knutson D, Miser WF |title=Management of the acute migraine headache |journal=Am Fam Physician |volume=66 |issue=11 |pages=2123–30 |year=2002 |pmid=12484694 |doi=}} [http://www.aafp.org/afp/20021201/2123.html Free full text]</ref> and [[fever]]. It is often combined with other analgesics, even though this has never been shown to be more effective or less toxic than aspirin alone. Aspirin has, however, been used in addition to other [[non-steroidal anti-inflammatory drug]]s and opioid analgesics in the treatment of pain associated with [[cancer]].<ref name="katzung">Katzung, Bertram G. (1998). "Basic and Clinical Pharmacology", 7<sup>th</sup> ed., Stamford, Connecticut: Appleton & Lange. ISBN 0-8385-0565-1.</ref>
In high doses, aspirin and other salicylates are used in the treatment of [[rheumatic fever]], [[arthritis|rheumatic arthritis]], and other inflammatory joint conditions. In lower doses, aspirin also has properties as an inhibitor of [[platelet]] aggregation, and has been shown to decrease the incidence of transient ischemic attacks and unstable [[Angina pectoris|angina]] in men, and can be used prophylactically. It is also used in the treatment of [[pericarditis]], [[coronary artery disease]], and acute [[myocardial infarction]].<ref name="katzung"/><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}}</ref>
====Low Dose Aspirin as Primary Prevention of Cardiovascular Disease====
=====Hematologic and Lymphatic=====
The 2009 U.S. Preventive Services Task Force recommendation statement is as follows<ref name="pmid19293072">{{cite journal| author=US Preventive Services Task Force| title=Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. | journal=Ann Intern Med | year= 2009 | volume= 150 | issue= 6 | pages= 396-404 | pmid=19293072 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19293072 }} </ref>:
{{cquote|
*Encourage men age 45 to 79 years to use aspirin when the potential benefit of a reduction in myocardial infarctions outweighs the potential harm of an increase in gastrointestinal hemorrhage. (A recommendation)
*Encourage women age 55 to 79 years to use aspirin when the potential benefit of a reduction in ischemic strokes outweighs the potential harm of an increase in gastrointestinal hemorrhage. (A recommendation)
*Evidence is insufficient to assess the balance of benefits and harms of aspirin for cardiovascular disease prevention in men and women 80 years or older. (I statement)
*Do not encourage aspirin use for cardiovascular disease prevention in women younger than 55 years and in men younger than 45 years. (D recommendation).}}
====ACC/AHA Guidelines- ADA/AHA/ACCF Aspirin for Primary Prevention of Cardiovascular Events in People With Diabetes <ref name="pmid20508178">{{cite journal| author=Pignone M, Alberts MJ, Colwell JA, Cushman M, Inzucchi SE, Mukherjee D et al.| title=Aspirin for primary prevention of cardiovascular events in people with diabetes: a position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. | journal=Circulation | year= 2010 | volume= 121 | issue= 24 | pages= 2694-701 | pmid=20508178 | doi=10.1161/CIR.0b013e3181e3b133 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20508178 }} </ref> (DO NOT EDIT)====
=====Metabolic and Nutritional=====
{{cquote|
:# Low-dose (75–162 mg/d) aspirin use for prevention is reasonable for adults with diabetes and no previous history of vascular disease who are at increased CVD risk (10 year risk of CVD events over 10%) and who are not at increased risk for bleeding (based on a history of previous gastrointestinal bleeding or peptic ulcer disease or concurrent use of other medications that increase bleeding risk, such as NSAIDS or warfarin). Those adults with diabetes at increased CVD risk include most men over age 50 years and women over age 60 years who have 1 or more of the following additional major risk factors: smoking, hypertension, dyslipidemia, family history of premature CVD, and albuminuria. (ACCF/AHA Class IIa, Level of Evidence: B) (ADA Level of Evidence: C)
:# Aspirin should not be recommended for CVD prevention for adults with diabetes at low CVD risk (men under age 50 years and women under 60 years with no major additional CVD risk factors; 10-year CVD risk under 5%) as the potential adverse effects from bleeding offset the potential benefits. (ACCF/AHA Class III, Level of Evidence: C) (ADA Level of Evidence: C)
:# Low-dose (75–162 mg/d) aspirin use for prevention might be considered for those with diabetes at intermediate CVD risk (younger patients with 1 or more risk factors, or older patients with no risk factors, or patients with 10-year CVD risk of 5–10%) until further research is available. (ACCF/AHA Class IIb, Level of Evidence: C) (ADA Level of Evidence: E)
}}
====Secondary Prevention of Cardiovascular Disease====
Low doses of aspirin are also recommended for the prevention of [[stroke]], and myocardial infarction in patients with either diagnosed coronary artery disease or who have an elevated risk of [[cardiovascular disease]]. It is also possible that women may benefit less from aspirin than men.<ref>{{cite news | title=Aspirin may be less effective heart treatment for women than men | date=April 26, 2007. | publisher= | url =http://www.ns.umich.edu/htdocs/releases/story.php?id=5825 | work =University of Michigan | pages = | accessdate = 2007-09-09 | language = }}</ref><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= |issue=May |pages= |year=2007 |month=24 Apr |pmid=17456544 |doi=10.1345/aph.1H621.}}</ref>
===Veterinary Uses===
=====Musculoskeletal=====
Aspirin has been used to treat pain and arthritis in veterinary medicine, primarily in cats and dogs, although it is not particularly recommended, as there are better medications available. Also, dogs 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 | date = 2006 | url = http://vetmedicine.about.com/cs/altvetmedgeneral/a/dogcataspirin.htm | accessdate = 2007-09-05}}</ref> Horses have also been given aspirin for pain relief, although it is not commonly used due to its relatively short-lived analgesic effects. Horses are also fairly sensitive to the gastrointestinal side effects as well. 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=}}</ref> Aspirin's use in animals should only be done under the direct supervision of a [[veterinarian]].
===Experimental Uses===
There have been some studies in the late 20th century indicating that aspirin may reduce [[cataract]] formation, although this is disputed.<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 |doi=}}</ref> The role of aspirin in reducing the incidence of many forms of [[cancer]] has also been widely studied. The drug may be effective in reduction of risk of various cancers, including those of the [[prostate cancer|prostate]],<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}}</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}}</ref> [[colon cancer|colon]],<ref name="thun">{{cite journal |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 |doi=}}</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}}</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}}</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}}</ref> [[pancreatic cancer|pancreas]],<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}}</ref> upper GI tract,<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}}</ref> and [[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}}</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 |issue= |pages=31 |year=2002 |pmid=12453317 |doi=}} [http://www.biomedcentral.com/1471-2407/2/31 Free full text]</ref> Its potency against [[tumor]]s of the [[lung]] may be due to the fact that such tumors have high amounts of [[Cyclooxygenase|COX-2]] enzymes expressed in them, especially adenocarcinomas and tumors caused by [[asbestosis]], and aspirin is known to inhibit both the COX-1 and COX-2 [[enzyme]]s.<ref>{{cite journal | author=Wolff, ''et al.'' | title=Expression of cyclooxygenase-2 in human lung carcinoma | journal=Cancer Research | year=1998 | pages=4997–5001 | volume=58 | issue=22 | url=http://cancerres.aacrjournals.org/cgi/content/abstract/58/22/4997}}</ref> Likewise, if there is a specific connection between COX-2 and lung cancer, other COX-2 inhibitors might also have the same effect. It should be pointed out, however, that this research is not complete, and there is currently no well-established medical recommendation on the use of aspirin or other [[NSAID]]s for use in the treatment or prevention of cancer.
=====Neurologic=====
In a 1998 article on [[hippocampus|hippocampal]] [[neurotoxicity]] published in the ''Journal of Neuroscience'', it is suggested that aspirin, among other substances, might inhibit the neural [[death]] caused in the [[hippocampus]] by THC, which is the main psychoactive component of [[cannabis]]. "Neuron death induced by THC was inhibited by nonsteroidal anti-inflammatory drugs, including indomethacin and aspirin, as well as vitamin E and other antioxidants."<ref>{{cite journal |author=Chan GC, Hinds TR, Impey S, Storm DR |title=Hippocampal neurotoxicity of Δ<sup>9</sup>-tetrahydrocannabinol |journal=J Neurosci |volume=18 |issue=14 |pages=5322–32 |year=1998 |pmid=9651215}} [http://www.jneurosci.org/cgi/content/full/18/14/5322 Free full text]</ref>
==Contraindications==
* Aspirin should be avoided by those known to be allergic to [[ibuprofen]] or [[naproxen]]. see [[Aspirin desensitization]]
=====Respiratory=====
* Caution should be exercised in those with [[asthma]] or [[NSAID]]-precipitated [[bronchospasm]]. see [[Aspirin desensitization]]
* It is generally recommended that one seek medical help if symptoms do not improve after a few days of therapy.
* Caution should be taken in patients with [[kidney disease]], [[peptic ulcer]]s, mild [[diabetes]], [[gout]] or [[gastritis]]; manufacturers recommend talking to one's doctor before using this medicine.
* Taking aspirin with [[alcoholic beverage|alcohol]] or [[warfarin]] increases the chance of gastrointestinal hemorrhage (stomach bleeding).
* Children under the age of 12 are discouraged from using aspirin to control cold or influenza symptoms as this has been linked with [[Reye's syndrome]].<ref name="BMJ2002-Macdonald"/>
* Patients with [[hemophilia]] or other bleeding tendencies should not take salicylates.
* Some sources recommend that patients with [[hyperthyroidism]] avoid aspirin because it elevates [[Thyroxine|T4]] levels.<ref>{{cite web|url=http://www.patient.co.uk/showdoc/40001339/|title=www.patient.co.uk/showdoc/40001339/<!--INSERT TITLE-->}}</ref>
* 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.
* People living in tropical-weather countries should discontinue use while symptoms or suspicion of Dengue Fever exist, due to an irreversible syndrome relating aspirin and that disease.
==Adverse effects==
===Gastrointestinal complaints===
Aspirin can cause blood loss. Delaney <ref>Delaney, J.A., & Opatrny, L., & Brophy, J.M., & Suissa, S. (2007). Drug drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. Canadian Medical Association Journal, 177, 347-351.</ref> studied that when aspirin is combined with other anticoagulants (an agent that prevents blood clots from forming) it can lead to great risk of gastrointestinal bleeding. Patients 18 years of age or above were chosen from the United Kingdom Research Database from 2000 to 2005. Out of 4,028 cases of gastrointestinal bleeding 53% had used a combination of over the counter drugs (2007). When using a combination of drugs there is 1 to 8 chance of increasing your risk of complaints if an antiplatelet (inhibits clots to form) and anticoagulants are taken together.
=====Skin and Hypersensitivy Reactions=====
Undetected blood loss may lead to chromic anemia. Blood loss is associated with chronic use of aspirin. <ref>Graham, D.Y. (1986). Aspirin and the stomach. Annals of Internal Medicine, 104, 390-398.</ref> This study first performed on animals, mainly rats, was also proved by patients who reported cases of blood loss ceasing when aspirin is not in use and anemia reoccurring when aspirin use is continued (1986).
Abdominal pain, such as dyspepsia, is an upper gastrointestinal symptom caused by aspirin. <ref>Eisen, G.M., & Goldstein, J.L., & Hanna, D.B., & Rublee, D.A. (2005). Meta-analysis: upper gastrointestinal tolerability of valdecoxib, a cyclooxygenase-2-specific inhibitor, compared with nonspecific nonsteroidal anti-inflammatory drugs among patients with osteoarthritis and rheumatoid arthritis. Alimentary Pharmacology & Therapeutics. 21(5), 591-598.</ref> A study by Eisen proved that the incidence of abdominal pain was caused by anti-inflammatory drugs, such as aspirin (2005). The study was performed over a twelve week period with patients 18 or older. At 2, 6 and 12 weeks patients reported to study sites for safety assessments. Here the adverse effects were recorded as mild, moderate or severe (2005). About 21% of those using NAIDs (low dose aspirin) complained of dyspepsia.
Aspirin can cause heartburn. At a Coronary Care Unit blood samples were taken from acetylsalicylic acid (aspirin) using patients. <ref>Janson, J.B., & Verheugt, F.W., & Laheiji, R.J., & Drenth, J., & Huybers, S., & Peters, W.H., & Van Oijen M.G. (2005). Polymorphisms in genes encoding acetylsalicylic acid metabolizing enzymes are unrelated to upper gastrointestinal health in cardiovascular patients on acetylsalicylic acid. British Journal of Pharmacology, 60(6). Retrieved on December 6, 2007, from http://web.ebscohost.com/ehost/detail?vid=35&hid=104&sid =f58f6023-009b-4458-8f15-f772f52b63cc%40sessionmgr9</ref> Gastrointestinal complaints were reported in 160 users which were eligible for the study. Heartburn was a complaint reported by 22% of the 160 aspirin users (2005).
=====Special Senses=====
To avoid gastrointestinal complaints take aspirin in an enteric coated form. The difference between enteric coated aspirin and regular microencapsulated aspirin is their effects. <ref>Brown, N., & May, J.A., & Wilcox, R.G., & Allan, L.M., & Wilson, A.M., & Kiff, P.S. (1999). Comparison of antiplatelet activity of microencapsulated aspirin 162.5 Mg with enteric coated aspirin 75 mg and 150 mg in patients with atherosclerosis. British Journal of Clinical Pharmacology, 48, 57-62.</ref> 104 participants were given a 14 day trial on the different types of aspirin being tested. After day 14 the dosage was lowered and reductions in gastric effects were seen in those with the enteric coated aspirin (1999).
Severe gastrointestinal complaints require discontinuation of aspirin to recover.<ref>Blot, W.J., & Mellemkjaer, L., & Sorensen, H.T., & Thomassen, L., & McLaughlin, J.K., & Nielsen, G.L., & Olsen, J.H. (2002). Upper gastrointestinal bleeding among users of NAIDs: a population-baed cohort study in Denmark. Bristish Journal of Pharmacology, 53(2). Retrieved on December 6, 2007 from http://web.ebscohost.com/ehost/pdf?vid=54&hi d =6&sid=72548daa-0fa4-40e1-8488-643e25e96439%40SRCSM1</ref> 214, 846 patients using one or more NAIDs a day were recorded and observed. The data showed that in one year 4.8 incidents of gastrointestinal bleeding (UGIB) hospitalizations occur per every 1000 people who use NAIDS. Also only 1.2 UGIB hospitalizations occur per every 1000 non-users of NAIDs (2002).
===Central Effects===
=====Urogenital=====
Large doses of salicylate or salicylic acid, a compound in aspirin, produces hearing loss in humans.<ref>Guitton, M.J., & Caston, J., & Ruel, J., & Johnson, R.M., & Pujol, R., & Puel J. (2003). Salicylate induces tinnitus through activation of cochlear NMDA receptors. The Journal of Neuroscience, 23(9). Retrieved on December 6, 2007, from http://www.jneurosci.org/cgi/content/full/23/9/3944</ref> When this chemical is released into the body it blocks the prestin (the motor protein in the outer hairs of the ear). 112 rats were conditioned to respond to a stimulus of a 10 kHz tone. Over a four day period they were injected daily with either saline (a solution used as a plasma substitute) or 300mg/kg of salicylate. These injections were given two hours before the test period. By the fourth day the results indicated that the rats receiving saline did not show any results of hearing loss, in fact they improved their response to the sound. On day one they had a hearing score of 87%, day two 90% and on day four they received a hearing score of 88% (2003). However, the rats in the salicylate group decreased in their hearing ability over the four day period. On day one they were at a 91% positive response rate, on day two 83% and day four they had a response rate of 79%. The degree of sensitivity and frequency selectivity of the cochlea (spiral structure in inner ear containing tiny hairs whose movement is recognized by the brain as sound) is due to the active mechanism generated by the outer layer hair cells. They induce a nonlinearity of the cochlea that can be easily recorded by a sensitive microphone placed in the ear canal. Cumulative injections of salicylate decreased the amplitude in the ear canal. This leads up to the disappearance of the noise on the third and fourth days of the experiment (2003).
Large doses of salicylate or salicylic acid, the active component in aspirin, causes tinnitus in humans.(42) In normal conditions, before the drug is released in the body, the arachidonic acid, fatty acid, is completely metabolized in the cochlea by the process of a group of enzymes called cyclooxygenase. Salicylate decreases the amounts of some of these enzymes and increases the others. Arachidonic acid increases in the ear channel, which causes the cochlear receptors to dysfunction, resulting in a ringing or blurry sound. In the experiment 112 rats were used, weighing between 80-120 grams. The rats were trained to respond to a conditioned sound stimulus. The rats were conditioned to a 10 kHz tone and the control group, which was 10 of the 112 rats were conditioned to a 4 kHz tone which when they heard it they would jump on to the climbing pole in their test box. Once conditioned the rats were tested for 9 consecutive days (2003). The rats received injections daily for four days of either saline alone, 300mg/kg of salicylate, or 35 mg/kg of mefanamate, which was used for treatment. The injections were given two hours before the unconditioned response was measured. The animals in the saline group showed no change in false positive responses. The animals in the salicylate group showed a significant increase in the number of false positive responses. On the fourth day there were 6 times as many false positive responses than on the first day (2003). This means the rats jumped even when it was silent, resulting in tinnitus because they were hearing a ringing even though the sound wasn’t being projected.
===Pediatrics===
=====Miscellaneous=====
Reye's syndrome can occur when children or pediatric patients are given aspirin for a fever or other illnesses or infections. Rogers <ref>Rogers, M.F., & Schonberger, L.B., & Hurwitz, E.S., & Rowley, D. L. (1985). National Reye's syndrome surveillance, 1982. Pediatrics, 75(2), 260.</ref> studied 213 patients under the age of 18 who were reported for Reye syndrome from the nationwide Reye's syndrome surveillance system. Out of 213 patients 211 had known that had another antecedent illness: 89% reported being ill (severe vomiting, mental strain, respiratory illness, vericella or gastrointestinal illness) two weeks before onset of Reye's syndrome (1985). Salicylate levels, the active acid in aspirin, were present in 162 of the 213 patients.
Reye's syndrome is due to fatty deterioration of liver cells. In a study done by Rogan <ref>Rogan, W.J., & Yang, G.C., & Kimbrough, R.D. (1985). Aflatoxin and Reye’s syndrome: a study of livers from deceased cases. Archives of Environmental Health, 40, Issue 2.</ref> 12 livers were obtained from children who had died from Reye’s syndrome and than one liver for the control from a child who had accidentally died. The autopsy stated that seven of the 12 livers had micro vesicular fatty change was present (1985).
The fatality rate of Reye's syndrome is 35% (43). A study used the nationwide Reye's syndrome surveillance system to find voluntary cases of patients with Reye's syndrome eligible for this study (1985). The surveillance year goes from December 1 to November 30. 213 cases were reported out of 43 states across the United States. Out of the 213 patients, 200 were reported for short term outcome. Out of the 200, 70 died. This makes the fatality rate 35% (1985).
<!--Drug Interactions-->
|drugInteractions=* Drug
:* Description
===Other effects===
<!--Use in Specific Populations-->
|useInPregnancyFDA=* '''Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
Aspirin causes prolonged bleeding after operations for up to 10 days. 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>Scher, K.S. (1996). Unplanned reoperation for bleeding. The American Surgeon, 62, 52-55. Retrieved December 1, 2007, from EbscoHost Research Databases.</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 due to bleeding after their operation. The average recovery time for the second operation was 11 days (1996).
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInNursing=There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
High doses of aspirin for long-term treatment for arthritis or rheumatic fever increase liver enzymes causing liver damage without any symptoms. Yuen <ref> Yuen, K.Y., & Chan, P. K.S., & Peiris, M., & Tsang, D.N.C., & Que, T.L., & Shortridge, K.F., & Cheung, P.T., & To, W.K., & Ho, E.T.F., & Sung, R., & Cheng, A.F.B. (1998). Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet, 351(351), 467.</ref> states that an analysis was taken of 12 patients who were diagnosed with influenza A virus. The patients were given liver-function tests and six of the patients showed evidence of liver dysfunction.
<!--Administration and Monitoring-->
|administration=* Oral
Aspirin can induce angioedema.<ref>Berges-Gimeno, M.P., & Stevenson, D. D. (2004). Nonsteroidal anti-inflammatory drug-induced reactions and desensitization. Journal of Asthma, (41)4. Retrieved on December 6, 2007 from http://web.ebscohost.com/ehost/pdf? vid=60&hid=6&sid=0d54ae57-68fe-4674-b549-37fb82e5c6bd%40SRCSM2</ref> Angioedema appeared 1-6 hours after ingesting an aspirin in the patients participating in the study (2004). However, when the aspirin was taken alone it did not cause angioedema. The aspirin was either taken in combination with another NSAID-induced drug when angioedema appeared.
* Intravenous
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.
Bronchospasm is likely in children with chronic asthma if they were aspirin users.<ref>Towns, S.J., & Mellis, C.M. (1984). Role of acetyl salicylic acid and sodium metabisulfite in chronic childhood asthma. Pediatrics, 73(5), 631.</ref> Twenty nine patients with asthma from the Chest and Asthma Clinic of the Royal Alexandra Hospital for Children participated in a study (1984). They were given symptom scores which they recorded activity through the day and night. The medication was given twice daily over a three week period. Then throughout the three weeks their diets were changed to make sure there was no interference with the aspirin and so the possible chronic ingestion wouldn’t occur. Bronchospasm is likely in 21% of these children if they continue to use aspirin because the study group had an incidence of hypersensitivity (1984).
* Description
==Interactions==
<!--IV Compatibility-->
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
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 enhances the gastrointestinal bleeding associated with these types of drugs as well. 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, Bertram G. (1998), p. 584.</ref> Aspirin may also inhibit the absorption of [[vitamin C]].<ref>[http://jcp.sagepub.com/cgi/content/abstract/13/11/480?ck=nck 'The Effects of Aspirin on the Metabolic Availability of Ascorbic Acid in Human Beings' The Journal of Clinical Pharmacology and New Drugs , 1973; 13:480–486] Published 1973. Accessed 31 July 2007.</ref><ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=6811490&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus 'Vitamin C-aspirin interactions' Int J Vitam Nutr Res Suppl. 1982;23:83–90.] Published 1982. Accessed 31 July 2007.</ref><ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=6818974&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVAbstractPlus 'Impairment of absorption of ascorbic acid following ingestion of aspirin in guinea pigs' Biochem Pharmacol. 1982 Dec 15;31(24):4035–8.] Published 1982. Accessed 31 July 2007.</ref>
<!--Overdosage-->
|overdose====Acute Overdose===
==Dosage==
====Signs and Symptoms====
For adults doses of 300 to 1000 mg are generally taken four times a day for fever or arthritis, with a maximum dose of 8000 mg (8 grams) a day.<ref>{{cite book | title=[[British National Formulary]] | edition=45 | date=March 2003 | publisher= [[British Medical Journal]] and [[Royal Pharmaceutical Society of Great Britain]]}}</ref> The correct dose of aspirin depends on the disease or condition that is being treated. For instance, for the treatment of rheumatic fever, doses near the maximal daily dose have been used historically.<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, doses as low as 75 mg daily (or possibly even lower) are sufficient.
* Description
For those under 12 years of age, the dose previously varied with the age, but aspirin is no longer routinely used in children due to the association with [[Reye's syndrome]]; [[paracetamol]] or other NSAIDs, such as [[ibuprofen]], are now used instead. [[Kawasaki disease]] remains one of the few indications for aspirin use in children, with aspirin initially started at 7.5–12.5 mg per kilogram of body weight, taken four times a day for up to two weeks and then continued at 5 mg/kg once daily for a further six to eight weeks.<ref>{{cite book | title=[[British National Formulary for Children]] | date=2006 | publisher= [[British Medical Journal]] and [[Royal Pharmaceutical Society of Great Britain]]}}</ref>
====Management====
==Overdose==
* Description
Aspirin overdose can be acute or chronic. In acute poisoning, a single large dose is taken; in chronic poisoning, supratherapeutic 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>
===Chronic Overdose===
=== Symptoms ===
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
Aspirin overdose has potentially serious consequences, sometimes leading to significant morbidity and mortality. Patients with mild intoxication frequently have [[nausea]] and [[vomiting]], abdominal pain, lethargy, [[tinnitus]], and [[dizziness]]. More significant symptoms occur in more severe poisonings and include [[hyperthermia]], [[tachypnea]], [[respiratory alkalosis]], [[metabolic acidosis]], [[hyperkalemia]], [[hypoglycemia]], [[hallucinations]], [[Mental confusion|confusion]], [[seizure]], [[cerebral edema]], and [[coma]]. The most common cause of [[death]] following an aspirin overdose is cardiopulmonary arrest usually due to [[pulmonary edema]].<ref name="ActaAnaesthesiol1987-Thisted">{{cite journal | author=Thisted B, Krantz T, Stroom J, Sorensen MB. | title=Acute salicylate self-poisoning in 177 consecutive patients treated in ICU | journal=Acta Anaesthesiol Scand | year=1987 | pages=312-6 | volume=31 | issue=4 | pmid= 3591255}}</ref>
===Toxicity===
<!--Pharmacology-->
The [[toxic]] dose of aspirin is generally considered greater than 150 mg per kg of body mass. Moderate toxicity occurs at doses up to 300 mg/kg, severe toxicity occurs between 300 to 500 mg/kg, and a potentially lethal dose is greater than 500 mg/kg.<ref name="ArchInternMed1981-Temple">{{cite journal | author=Temple AR. | title=Acute and chronic effects of aspirin toxicity and their treatment | journal=Arch Intern Med | year=1981 | pages=364-9 | volume=141 | issue=3 Spec No | pmid= 7469627}}</ref> This is the equivalent of many dozens of the common 325 mg tablets, depending on body weight. However children cannot tolerate as much aspirin per unit body weight as adults can.
<!--Drug box 2-->
|drugBox=<!--Mechanism of Action-->
|mechAction=*
===Treatment===
<!--Structure-->
|structure=*
All overdose patients should be conveyed to hospital for assessment immediately. Initial treatment of an acute overdose includes gastric decontamination. This is achieved by administering activated charcoal which adsorbs the aspirin in the [[gastrointestinal tract]]. [[gastric lavage|Stomach pumps]] are no longer routinely used in the treatment of poisonings but are sometimes considered if the patient has ingested a potentially lethal amount less than 1 hour previously.<ref name=”jtoxclintox2004-vale”>{{cite journal | author=Vale JA, Kulig K; American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. | title=Position paper: gastric lavage. | journal=J Toxicol Clin Toxicol | year=2004 | pages=933-43 | volume=42 | issue=7 | pmid= 15641639}}</ref> Repeated doses of charcoal have been proposed to be beneficial in aspirin overdose.<ref name="BMJ1985-hillman">{{cite journal | author=Hillman RJ, Prescott LF. | title=Treatment of salicylate poisoning with repeated oral charcoal | journal=Br Med J (Clin Res Ed) | year=1985 | pages=1472 | volume=291 | issue=6507 | pmid= 3933714}}</ref> A study performed found that repeat dose charcoal might not be of significant value.<ref name="ArchInternMed1990-Kirshenbaum">{{cite journal | author=Kirshenbaum LA, Mathews SC, Sitar DS, Tenenbein M. | title=Does multiple-dose charcoal therapy enhance salicylate excretion? | journal=Arch Intern Med | year=1990 | pages=1281–3 | volume=150 | issue=6 | pmid= 2191636}}</ref> However, most toxicologists will administer additional charcoal if serum salicylate levels are increasing.
: [[File:{{PAGENAME}}01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
Patients are monitored until their peak salicylate blood level has been determined.<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}}</ref> Blood levels are usually performed 4 hours after ingestion and then every 2 hours after that to determine the maximum level. Maximum levels can be used as a guide to toxic effects expected.<ref name="drugs1986-Meredith">{{cite journal | author=Meredith TJ, Vale JA. | title=Non-narcotic analgesics. Problems of overdosage | journal=Drugs | year=1986 | pages=117–205 | volume=32 | issue=Suppl 4 | pmid= 3552583}}</ref>
<!--Pharmacodynamics-->
|PD=There is limited information regarding <i>Pharmacodynamics</i> of {{PAGENAME}} in the drug label.
There is no antidote to salicylate poisoning. Frequent blood work is performed to check [[metabolic]], [[salicylate]], and [[blood sugar]] levels; [[arterial blood gas]] assessments are performed to test for [[alkalosis|respiratory alkalosis]] and [[metabolic acidosis]]. Patients are monitored and often treated according to their individual symptoms, patients may be given [[intravenous]] [[potassium chloride]] to counteract [[hypokalemia]], [[glucose]] to restore [[blood sugar]] levels, [[benzodiazepines]] for any seizure activity, fluids for [[dehydration]], and importantly [[sodium bicarbonate]] to restore the blood's sensitive [[pH]] balance. Sodium bicarbonate also has the effect of increasing the pH of urine, which in turn increases the elimination of salicylate. Additionally, [[hemodialysis]] can be implemented to enhance the removal of salicylate from the blood. Hemodialysis is usually used in severely poisoned patients; for example, patients with significantly high salicylate blood levels, significant neurotoxicity (agitation, coma, convulsions), renal failure, pulmonary edema, or cardiovascular instability are hemodialyzed.<ref name="EmergMed2002-Dargan"/> Hemodialysis also has the advantage of restoring [[electrolyte]] and acid-base abnormalities; hemodialysis is often life-saving in severely ill patients.
<!--Pharmacokinetics-->
|PK=There is limited information regarding <i>Pharmacokinetics</i> of {{PAGENAME}} in the drug label.
===Epidemiology===
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|nonClinToxic=There is limited information regarding <i>Nonclinical Toxicology</i> of {{PAGENAME}} in the drug label.
In the later part of the 20th century the number of salicylate poisonings has declined mainly due to the popularity of other over-the-counter analgesics such as [[paracetamol]] (acetaminophen). Fifty-two deaths involving single-ingredient aspirin were reported in the United States in 2000. However, in all but three cases, the reason for the ingestion of lethal doses was intentional, predominantly suicides.<ref name="AmJEmergMed2001-Litovitz">{{cite journal | author=Litovitz TL, Klein-Schwartz W, White S, Cobaugh DJ, Youniss J, Omslaer JC, Drab A, Benson BE | title=2000 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System | journal=Am J Emerg Med | year=2001 | pages=337-95 | volume=19 | issue=5 | pmid= 11555795}}</ref>
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==Mechanism of Action==
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|fdaPatientInfo=There is limited information regarding <i>Patient Counseling Information</i> of {{PAGENAME}} in the drug label.
[[Image:COX-2 inhibited by Aspirin.png|thumb|220px|Structure of COX-2 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.]]
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|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
In 1971, the British [[pharmacologist]] John Robert Vane, then employed by the Royal College of Surgeons in London, showed that aspirin suppresses the production of [[prostaglandin]]s and [[thromboxane]]s.<ref>{{cite journal
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| title = Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.
|brandNames=* ®<ref>{{Cite web | title = | url = }}</ref>
| author = John Robert Vane
| journal = Nature - New Biology
| year = 1971
| volume = 231
| issue = 25
| pages = 232–5
| pmid= 5284360
}}</ref><ref>[http://www.eao.chups.jussieu.fr/polys/certifopt/saule_coxib/theme/1vane2003.pdf J.R.Vane and R.M.Butting (2003) "The mechanism of action of aspirin" (review)] Thrombosis Research 110, 255-258.</ref> For this discovery, he was awarded both a Nobel Prize in Physiology in 1982 and a knighthood.
Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its competitive and irreversible inactivation of the [[cyclooxygenase]] (COX) 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 COX enzyme. This makes aspirin different from other NSAIDs (such as [[diclofenac]] and [[ibuprofen]]), which are reversible inhibitors.
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|lookAlike=* A® — B®<ref name="www.ismp.org">{{Cite web | last = | first = | title = http://www.ismp.org | url = http://www.ismp.org | publisher = | date = }}</ref>
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. 40 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
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| 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 = Vol 23 | pages = 1400–1403 | accessdate = 2007-09-05}}</ref>
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Prostaglandins are local [[hormone]]s (paracrine) produced in the body and have diverse effects in the body, including but not limited to 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 their reduction with the introduction of small amounts of aspirin has been seen to be an effective medical intervention. The side-effect of this is that the ability of the blood in general to clot is reduced, and excessive bleeding may result from the use of aspirin.
[[Image:Aspirin-rod-povray.png|thumb|right|220px|3D model of chemical structure of aspirin]]
There are at least two different types of cyclooxygenase: COX-1 and COX-2. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. Normally COX-2 produces prostanoids, most of which are pro-inflammatory. Aspirin-modified COX-2 produces lipoxins, most of which are anti-inflammatory. Newer NSAID drugs called [[COX-2 selective inhibitor]]s have been developed that inhibit only COX-2, with the hope for reduction of gastrointestinal side-effects.
However, several of the new [[COX-2 selective inhibitor]]s have been recently withdrawn, after evidence emerged that COX-2 inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the microvasculature in the body express COX-2, and, by selectively inhibiting COX-2, prostaglandins (specifically PGI2; prostacyclin) are downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anti-coagulative effect of PGI2 is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, an important difference with reversible inhibitors.
Furthermore, aspirin has two additional modes of actions, contributing to its strong analgesic, antipyretic and anti-inflammatory properties:
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* It uncouples [[oxidative phosphorylation]] in cartilaginous (and hepatic) mitochondria, by diffusing from the inner membrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once again to release protons. In short, aspirin buffers and transports the protons. (Note: This effect in high doses of aspirin actually causes fever due to the heat released from the electron transport chain, instead of its normal antipyretic action.)
* It induces the formation of NO-radicals in the body that enable the white blood cells (leukocytes) to fight infections more effectively. This has been found recently by Dr. Derek W. Gilroy, winning Bayer's International Aspirin Award 2005.<ref>[http://www.medicalnewstoday.com/medicalnews.php?newsid=31435 "New mechanism of action of Aspirin discovered,"] in ''Medical News Today'', October 2, 2005.</ref>
More recent data suggest that salicylic acid and its derivatives will modulate signaling through NF-κB.<ref>{{cite journal | last = McCarty| first = MF| coauthors = KI 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 = Vol 5 |issue = 3 | pages = 252-268 | PMID= 16880431 }}</ref> NF-κB is a [[transcription factor]] complex that plays a central role in many biological processes, including inflammation.
==Polymorphism==
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 had been indications that aspirin might have a second crystalline form since the 1960s. The elusive 2nd 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 }}</ref>, 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 }}</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]]s through the [[acetyl]] groups with the (acidic) [[methyl]] proton to carbonyl hydrogen bonds and in the newly claimed form II each salicylic molecule forms the same hydrogen bonds but then 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.
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Black Box Warning
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Overview
Aspirin (delayed release tablet) is a {{{drugClass}}} that is FDA approved for the treatment of {{{indication}}}. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
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Off-Label Use and Dosage (Adult)
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Pediatric Indications and Dosage
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There is limited information regarding Clinical Trial Experience of Aspirin (delayed release tablet) in the drug label.
Body as a Whole
Cardiovascular
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Postmarketing Experience
There is limited information regarding Postmarketing Experience of Aspirin (delayed release tablet) in the drug label.
There is limited information regarding Patient Counseling Information of Aspirin (delayed release tablet) in the drug label.
Precautions with Alcohol
Alcohol-Aspirin (delayed release tablet) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
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