Aspirin (USAN), also known as acetylsalicylic acid ( /əˌsɛtəlˌsælɪˈsɪlɪk/ ə-SET-əl-sal-

i-SIL-ik; abbreviated ASA), is a salicylate drug, often used as an analgesic to relieve

minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory
medication.

Salicylic acid, the main metabolite of aspirin, is an integral part of human and animal
metabolism. While much of it is attributable to diet, a substantial part is synthesized
endogenously.[1]

Aspirin also has an antiplatelet effect by inhibiting the production of thromboxane, which
under normal circumstances binds platelet molecules together to create a patch over
damaged walls of blood vessels. Because the platelet patch can become too large and also
block blood flow, locally and downstream, aspirin is also used long-term, at low doses, to
help prevent heart attacks, strokes, and blood clot formation in people at high risk for
developing blood clots.[2] 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.[3][4]

The main undesirable side effects of aspirin are gastrointestinal ulcers, stomach bleeding,
and tinnitus, especially in higher doses. In children and adolescents, aspirin is no longer
used to control flu-like symptoms or the symptoms of chickenpox or other viral illnesses,
because of the risk of Reye's syndrome.[5]

Aspirin is part of a group of medication called nonsteroidal anti-inflammatory drugs

(NSAIDs). Though it, and other in its group called the salicylates, have similar effects
(antipyretic, anti-inflammatory, analgesic) and inhibit the same enzyme cyclooxygenase
as their mechanism of action, they do so in a irreversible manner (see NSAID mechanism
of action).[6] For example, NSAIDs antiplatelet effects last in the order of hours, whereas
aspirin's effect lasts for days (until the body replaces the suppressed platelets). Hence,
when physicians tell patients to stop taking NSAIDs, they usually imply aspirin as well.

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.[7] In countries where Aspirin is a registered
trademark owned by Bayer, the generic term is acetylsalicylic acid (ASA).[8][9]

Contents
[hide]

• 1 Therapeutic uses
o 1.1 Headache
o 1.2 Pain
o 1.3 Prevention of heart attacks and strokes
o 1.4 Coronary and carotid arteries, bypasses and stents
o 1.5 Other uses
o 1.6 Experimental
 o 1.7 Resistance
o 1.8 Dosage
• 2 Adverse effects
o 2.1 Contraindications
o 2.2 Gastrointestinal
o 2.3 Central effects
o 2.4 Reye's syndrome
o 2.5 Hives and swelling
o 2.6 Other effects
o 2.7 Overdose
o 2.8 Interactions
• 3 Chemical properties
o 3.1 Synthesis
o 3.2 Polymorphism
• 4 Mechanism of action
o 4.1 Discovery of the mechanism
o 4.2 Suppression of prostaglandins and thromboxanes
o 4.3 COX-1 and COX-2 inhibition
o 4.4 Additional mechanisms
o 4.5 Effects upon hypothalamic-pituitary-adrenal activity
• 5 Pharmacokinetics
• 6 History
o 6.1 Trademark
• 7 Compendial status
• 8 Veterinary use
• 9 References

• 10 External links

[edit] Therapeutic uses

[edit] Headache

Aspirin is a first-line drug in the treatment of migraine, bringing relief in 50–60% of the
cases.[10] When used at a high dose of 1000 mg (as compared to 275-325 mg when used
as a pain killer or 81 mg as a antiplatelet therapy). no significant differences were seen as
compared to triptan medication, sumatriptan (Imitrex)[11] and other painkillers such as
paracetamol (acetaminophen)[12] or ibuprofen.[13] 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,[12] better than ibuprofen[14] 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.
[15]
Aspirin alleviates pain in 60–75% of patients with episodic tension headaches.[16][17] It is
equivalent to paracetamol (acetaminophen) in that respect, except for the higher
frequency of gastrointestinal side effects.[17] Comparative clinical trials indicated
metamizole and ibuprofen may relieve pain faster than aspirin, although the difference
becomes insignificant after about two hours. The addition of caffeine in a dose of 60–
130 mg to aspirin increases the analgesic effect in headache.[16][18] The combination of
aspirin, paracetamol (acetaminophen) and caffeine (Excedrin) is still more effective, but
at the cost of more stomach discomfort, nervousness and dizziness.[19]

There is some evidence low-dose asprin has benefit for reducing the occurrence of
migraines in susceptible individuals.[20][21][22][23]

[edit] Pain

In general, aspirin works well for dull, throbbing pain; it is ineffective for pain caused by
most muscle cramps, bloating, gastric distension and acute skin irritation.[24] 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, 60 mg of codeine and
5 mg of oxycodone. A 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).[25]

Nevertheless, as a postsurgery painkiller, aspirin is inferior to ibuprofen and has higher

gastrointestinal toxicity. The maximum dose of aspirin (1 g) provides weaker pain relief
than an intermediate dose of ibuprofen (400 mg), and this relief does not last as long.[25] A
combination of aspirin and codeine may have a slightly higher analgesic effect than
aspirin alone; however, this difference is not clinically meaningful.[26] It appears
ibuprofen is at least equally, and possibly more, effective than this combination.[27]

According to a meta-analysis of clinical trials for menstrual pain, aspirin demonstrated

higher efficacy than placebo, but lower than ibuprofen or naproxen, although maximum
doses of aspirin were never used in these trials. The authors concluded ibuprofen has the
best risk-benefit ratio.[28]

Aspirin did not ease pain during cycling exercise,[29] while caffeine, surprisingly, was
very effective.[30][31] Similarly, aspirin, codeine or paracetamol were not better than
placebo for muscle soreness after exercise.[32]

[edit] Prevention of heart attacks and strokes

There are two distinct uses of aspirin for prophylaxis of cardiovascular events: primary
prevention and secondary prevention. Primary prevention is about decreasing strokes and
heart attacks in the general population of those who have no diagnosed heart or vascular
problems. Secondary prevention concerns patients with known cardiovascular disease.[33]
Low doses of aspirin are recommended for the secondary prevention of strokes and heart
attacks. For both males and females diagnosed with cardiovascular disease, aspirin
reduces the chance of a heart attack and ischaemic stroke by about a fifth.[citation needed] This
translates to an absolute rate reduction from 8.2% to 6.7% of such events per year for
people already with cardiovascular disease.[citation needed] Although aspirin also raises the risk
of hemorrhagic stroke and other major bleeds by about twofold, these events are rare, and
the balance of aspirin's effects is positive. Thus, in secondary prevention trials, aspirin
reduced the overall mortality by about a tenth.[33]

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.[33] Further trials are in progress.[33]

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 choices based on the estimated future risk and patients'
preferences.[34][35] On the other hand, Antithrombotic Trialists’ Collaboration argued such
recommendations are unjustified, since the relative reduction of risk in the primary
prevention trials of aspirin was same for persons in high- and low-risk groups and did not
depend on the blood pressure. The Collaboration suggested statins as the alternative and
more effective preventive medication.[33]

[edit] Coronary and carotid arteries, bypasses and stents

The coronary arteries supply blood to the heart. Aspirin is recommended for one to six
months after placement of stents in the coronary arteries and for years after a coronary
artery bypass graft.

The carotid arteries supply blood to the brain. Patients with mild carotid artery stenosis
benefit from aspirin; it is recommended after a carotid endarterectomy or carotid artery
stent.

After vascular surgery of the lower legs using artificial grafts which are sutured to the
arteries to improve blood supply, aspirin is used to keep the grafts open.

[edit] 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. One gram of aspirin, on average, reduced the oral body temperature from
39.0 °C (102.2 °F) to 37.6 °C (99.7 °F) after three hours. The relief began after 30
minutes, and after six hours, the temperature still remained below 37.8 °C (100.0 °F).
Aspirin also helped with "achiness", discomfort and headache,[36] and with sore throat
pain, for those who had it.[37] Aspirin was indistinguishable from paracetamol in any
respect, except for, possibly, slightly higher rate of sweating and gastrointestinal side
effects.[36]

Fever and joint pain of acute rheumatic fever respond extremely well, often within three
days, to high doses of aspirin. The therapy usually lasts for one to two 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.[38] In addition, the high doses
of aspirin used caused liver toxicity in about 20% of the treated children,[39][40] who are the
majority of rheumatic fever patients, and increased the risk of their developing Reye's
syndrome.[38] Naproxen was shown to be as effective as aspirin and less toxic; due to the
limited clinical experience, however, naproxen is recommended only as a second-line
treatment.[38][41]

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.[42] 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.[43][44][45]

Taking aspirin before air travel in cramped conditions has been suggested to decrease the
risk of deep-vein thrombosis (DVT). The reason for taking aspirin is the long period of
sitting without exercise, not air travel itself. A large, randomized, controlled trial in 2000
of aspirin against placebo in 13,000 patients with hip fractures found "a 29% relative risk
reduction in DVT with 160 mg of aspirin taken daily for five weeks. Although there are
obvious problems with extrapolating the data to long-distance travelers, this is the best
evidence we could find to justify aspirin use".[46]

[edit] Experimental

Aspirin has been theorized to reduce cataract formation in diabetic patients, but one study
showed it was ineffective for this purpose.[47] The role of aspirin in reducing the incidence
of many forms of cancer has also been widely studied. In several studies, its use did not
reduce the incidence of prostate cancer.[48][49] 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,[50] while a meta-analysis of several studies,
published in 2006, found no evidence aspirin or other NSAIDs are associated with an
increased risk for the disease.[51] The drug may be effective in reduction of risk of various
cancers, including those of the colon,[52][53][54][55][56] lung,[57][58] and possibly the upper GI
tract, though some evidence of its effectiveness in preventing cancer of the upper GI tract
has been inconclusive.[59][59][60] Its preventative effect against adenocarcinomas may be
explained by its inhibition of PTGS2 (COX-2) enzymes expressed in them.[61]

A 2009 article published by the Journal of Clinical Investigation suggested that aspirin
might prevent liver damage. In their experiment, scientists from Yale University and The
University of Iowa induced damage in certain liver cells (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".[62]

In another 2009 article published by the Journal of the American Medical Association,
men and women who regularly took aspirin after colorectal cancer diagnosis were found
to have lower risks of overall and colorectal cancer death compared to patients not using
aspirin.[63][64]

A 2010 article in the Journal of Clinical Oncology has suggested aspirin may reduce the
risk of death from breast cancer.[65] While the information has been well-circulated by the
media,[66][67] official health bodies and medical groups have expressed concern over the
touting of aspirin as a "miracle drug".[68]

A 2010 study by Oxford University involving over 25000 patients showed taking a small
(75 mg) daily dose of aspirin for between four and eight years substantially reduces death
rates from a range of common cancers by at least a fifth and the reduction of risk
continued for 20 years in both men and women. For specific cancers the, reduction was
about 40% for bowel cancer, 30% for lung cancer, 10% for prostate cancer and 60% for
oesophageal cancer, while the reductions in pancreas, stomach, brain, breast and ovarian
cancers were difficult to quantify because there were not enough data, but other studies
are in progress. However, taking aspirin doubles the annual risk of major internal
bleeding that normally has a very low incidence (about 1 in 1000) in middle age, but
increased dramatically after 75 years old.[69]

[edit] Resistance

For some people, aspirin does not have as strong an effect on platelets as for others, an
effect known as aspirin resistance or insensitivity. One study has suggested women are
more likely to be resistant than men,[70] and a different, aggregate study of 2,930 patients
found 28% to be resistant.[71] A study in 100 Italian patients found that of the apparent
31% aspirin-resistant subjects, only 5% were truly resistant, and the others were
noncompliant.[72]

[edit] Dosage
Coated 325 mg aspirin tablets

Adult aspirin tablets are produced in standardised sizes which vary slightly from country
to country, for example 300 mg in Britain and 325 mg in the USA. Smaller doses are
based on these standards; thus 75 and 81 mg tablets are used—there is no medical
significance in the slight difference.

For adults, doses are generally taken four times a day for fever or arthritis,[73] with doses
near the maximal daily dose used historically for the treatment of rheumatic fever.[74] For
the prevention of myocardial infarction in someone with documented or suspected
coronary artery disease, much lower doses are taken once daily.[73]

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.[75] The WHI
study said regular low dose (75 or 81 mg) aspirin female users had a 25% lower risk of
death from cardiovascular disease and a 14% lower risk of death from any cause.[75] Low
dose aspirin use was also associated with a trend toward lower risk of cardiovascular
events, and lower aspirin doses (75 or 81 mg/day) may optimize efficacy and safety for
patients requiring aspirin for long-term prevention.[75]

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.[76]

[edit] Adverse effects

[edit] Contraindications

Aspirin should not be taken by people who are allergic to ibuprofen or naproxen,[77][78] or
who have salicylate intolerance[79][80] or a more generalized drug intolerance to NSAIDs,
and caution should be exercised in those with asthma orNSAID-precipitated
bronchospasm. Owing to its effect on the stomach lining, manufacturers recommend
people with peptic ulcers, mild diabetes, or gastritis seek medical advice before using
aspirin.[77][81] Even if none of these conditions is present, there is still an increased risk of
stomach bleeding when aspirin is taken with alcohol or warfarin.[77][78] Patients with
hemophilia or other bleeding tendencies should not take aspirin or other salicylates.[77][81]
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.[82][83]Use of aspirin during dengue fever is not
recommended owing to increased bleeding tendency.[84] People with kidney disease,
hyperuricemia, or gout should not take aspirin because it inhibits the kidneys' ability to
excrete uric acid, and thus may exacerbate these conditions. Aspirin should not be given
to children or adolescents to control cold or influenza symptoms, as this has been linked
with Reye's syndrome.[5]

[edit] Gastrointestinal

Aspirin use has been shown to increase the risk of gastrointestinal bleeding.[85] 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.[85] Combining
aspirin with other NSAIDs has also been shown to further increase this risk.[85] Using
aspirin in combination with clopidogrel or warfarin also increases the risk of upper
gastrointestinal bleeding.[86]

In addition to enteric coating, "buffering" is the other main method companies have used
to try to mitigate the problem of gastrointestinal bleeding. Buffering agents are intended
to work by preventing the aspirin from concentrating in the walls of the stomach,
although the benefits of buffered aspirin are disputed. Almost any buffering agent used in
antacids can be used; Bufferin, for example, uses MgO. Other preparations use CaCO3.[87]

Taking it 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 compared to
taking aspirin alone.[88][89]

Deglycyrrhizinated licorice (DGL), 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 three adult-strength aspirin tablets (750 milligrams).[90]

A dose of 500 milligrams of S-adenosyl-methionine (SAMe, 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.[91]

[edit] Central effects

Large doses of salicylate, a metabolite of aspirin, have been proposed to cause tinnitus
(ringing in the ears) based on experiments in rats, via the action on arachidonic acid and
NMDA receptors cascade.[92]
[edit] Reye's syndrome

Main article: Reye's syndrome

Reye's syndrome, a rare but severe illness characterized by acute encephalopathy and
fatty liver, can occur when children or adolescents are given aspirin for a fever or other
illnesses or infections. From 1981 through 1997, 1207 cases of Reye's syndrome in
under-18 patients were reported to the U.S. Centers for Disease Control and Prevention.
Of these, 93% reported being ill in the three weeks preceding onset of Reye's syndrome,
most commonly with a respiratory infection, chickenpox, or diarrhea. Salicylates were
detectable in 81.9% of children for whom test results were reported.[93] After the
association between Reye's syndrome and aspirin was reported and safety measures to
prevent it (including a Surgeon General's warning and changes to the labeling of aspirin-
containing drugs) were implemented, aspirin taken by children declined considerably in
the United States, as did the number of reported cases of Reye's syndrome; a similar
decline was found in the United Kingdom after warnings against pediatric aspirin use
were issued.[93] The United States Food and Drug Administration now recommends
aspirin (or aspirin-containing products) should not be given to anyone under the age of 12
who has a fever,[5] and the British Medicines and Healthcare products Regulatory Agency
(MHRA) recommends children who are under 16 years of age should not take aspirin,
unless it is on the advice of a doctor.[94]

[edit] Hives and swelling

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

[edit] Other effects

Aspirin can induce angioedema (swelling of skin tissues) in some people. In one study,
angioedema appeared one to six hours after ingesting aspirin in some of the patients
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.[95]

Aspirin causes an increased risk of cerebral microbleeds having the appearance on MRI
scans of 5–10 mm or smaller hypointense (dark holes) patches.[96][97] Such cerebral
microbleeds are important since they often occur prior to ischemic stroke or intracerebral
hemorrhage, Binswanger disease and Alzheimer's disease.[original research?]

Aspirin can cause prolonged bleeding after operations for up to 10 days. In one study, 30
of 6499 elective surgical patients required reoperations to control bleeding. Twenty had
diffuse bleeding and 10 had bleeding from a site. Diffuse, but not discrete, bleeding was
associated with the preoperative use of aspirin alone or in combination with other
NSAIDS in 19 of the 20 diffuse bleeding patients.[98]

Partial
Prothrombin Bleeding Platelet
Condition thromboplastin
time time count
time
Vitamin K deficiency or
prolonged prolonged unaffected unaffected
warfarin
Disseminated
prolonged prolonged prolonged decreased
intravascular coagulation
Von Willebrand disease unaffected prolonged prolonged unaffected
Haemophilia unaffected prolonged unaffected unaffected
Aspirin unaffected unaffected prolonged unaffected
Thrombocytopenia unaffected unaffected prolonged decreased
Early Liver failure prolonged unaffected unaffected unaffected
End-stage Liver failure prolonged prolonged prolonged decreased
Uremia unaffected unaffected prolonged unaffected
Congenital
prolonged prolonged prolonged unaffected
afibrinogenemia
Factor V deficiency prolonged prolonged unaffected unaffected
Factor X deficiency as
prolonged prolonged unaffected unaffected
seen in amyloid purpura
Glanzmann's
unaffected unaffected prolonged unaffected
thrombasthenia
Bernard-Soulier syndrome unaffected unaffected prolonged decreased

[edit] Overdose

Main article: 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.[99] Toxicity
is managed with a number of potential treatments, including activated charcoal,
intravenous dextrose and normal saline, sodium bicarbonate, and dialysis.[100] The
diagnosis of poisoning usually involves measurement of plasma salicylate, the active
metabolite of aspirin, by automated spectrophotometric methods. Plasma salicylate levels
generally range from 30–100 mg/L after usual therapeutic doses, 50–300 mg/L in patients
taking high doses and 700–1400 mg/L following acute overdose. Salicylate is also
produced as a result of exposure to bismuth subsalicylate, methyl salicylate and sodium
salicylate.[101][102]

[edit] Interactions
Aspirin is known to 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.[77][78] Aspirin is known to displace a number of drugs from protein binding sites in
the blood, including the antidiabetic drugs 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
nonsteroidal anti-inflammatory drug. Corticosteroids may also reduce the concentration
of aspirin. Ibuprofen can negate the antiplatelet effect of aspirin used for cardioprotection
and stroke prevention.[103] The pharmacological activity of spironolactone may be reduced
by taking aspirin, and aspirin is known to compete with Penicillin G for renal tubular
secretion.[104] Aspirin may also inhibit the absorption of vitamin C.[105][106][107]

[edit] Chemical properties

Aspirin, an acetyl derivative of salicylic acid, is a white, crystalline, weakly acidic
substance, with a melting point of135 °C (275 °F). 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
graduallyhydrolyses 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.[108]

[edit] 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.[109]

Formulations containing high concentrations of aspirin often smell like vinegar,.[110]

because aspirin can decompose through hydrolysis in moist conditions, yielding salicylic
acid and acetic acid.[111]

The acid dissociation constant (pKa) for acetylsalicylic acid is 3.5 at25 °C (77 °F).[112]

[edit] 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 there had been indications aspirin
might have a second crystalline form since the 1960s. The elusive second polymorph was
first discovered by Vishweshwar and coworkers in 2005,[113]and fine structural details
were given by Bond et al.[114] A new crystal type was found after attempted
cocrystallization of aspirin and levetiracetam from hot acetonitrile. The form II is only
stable at 100 K and reverts to form I at ambient temperature. In the (unambiguous) form
I, two salicylic molecules form centrosymmetric dimers through the acetyl groups with
the (acidic) methyl proton to carbonyl hydrogen bonds, and in the newly claimed form II,
each salicylic molecule forms the same hydrogen bonds with two neighboring molecules
instead of one. With respect to the hydrogen bonds formed by the carboxylic acid groups
both polymorphs form identical dimer structures.

[edit] Mechanism of action

Main article: Mechanism of action of aspirin

[edit] Discovery of the mechanism

In 1971, British pharmacologist John Robert Vane, then employed by the Royal College
of Surgeons in London, showed aspirin suppressed the production of prostaglandins and
thromboxanes.[115][116] For this discovery, he was awarded both a Nobel Prize in
Physiology or Medicine in 1982 and a knighthood.

[edit] Suppression of prostaglandins and thromboxanes

Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to

its irreversible inactivation of the cyclooxygenase (PTGS) enzyme required for
prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an
acetyl group is covalently attached to a serine residue in the active site of the PTGS
enzyme. This makes aspirin different from other NSAIDs (such as diclofenac and
ibuprofen), which are reversible inhibitors.

Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A2 in

platelets, producing an inhibitory effect on platelet aggregation. This antithrombotic
property makes aspirin useful for reducing the incidence of heart attacks.[117] 40 mg of
aspirin a day is able to inhibit a large proportion of maximum thromboxane A2 release
provoked acutely, with the prostaglandin I2 synthesis being little affected; however,
higher doses of aspirin are required to attain further inhibition.[118]

Prostaglandins are local hormones produced in the body and have diverse effects,
including the transmission of pain information to the brain, modulation of the
hypothalamic thermostat, and inflammation. Thromboxanes are responsible for the
aggregation of platelets that form blood clots. Heart attacks are primarily caused by blood
clots, and low doses of aspirin are seen as an effective medical intervention for acute
myocardial infarction. An unwanted side effect of the effective anticlotting action of
aspirin is that it may cause excessive bleeding.

[edit] COX-1 and 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 proinflammatory. Aspirin-modified
PTGS2 produces lipoxins, most of which are anti-inflammatory. Newer NSAID drugs,
COX 2 inhibitors, have been developed to inhibit only PTGS2, with the intent to reduce
the incidence of gastrointestinal side effects.[7]

However, several of the new COX 2 inhibitors, such as rofecoxib (Vioxx), have been
withdrawn recently, after evidence emerged that PTGS2 inhibitors increase the risk of
heart attack. Endothelial cells lining the microvasculature in the body are proposed to
express PTGS2, and, by selectively inhibiting PTGS2, prostaglandin production
(specifically PGI2; prostacyclin) is downregulated with respect to thromboxane levels, as
PTGS1 in platelets is unaffected. Thus, the protective anticoagulative effect of PGI2 is
removed, increasing the risk of thrombus and associated heart attacks and other
circulatory problems. Since platelets have no DNA, they are unable to synthesize new
PTGS once aspirin has irreversibly inhibited the enzyme, an important difference with
reversible inhibitors.

[edit] 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.[119] In short, aspirin buffers and transports the
protons. When high doses of aspirin are given, it may actually cause fever owing to the
heat released from the electron transport chain, as opposed to the antipyretic action of
aspirin seen with lower doses. 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
aspirin helps to fight infection.[120] More recent data also suggests that salicylic acid and
its derivatives modulate signaling through NF-κB.[121] NF-κB, a transcription factor
complex, plays a central role in many biological processes, including inflammation.

[edit] Effects upon hypothalamic-pituitary-adrenal activity

Aspirin, like other medications affecting prostaglandin synthesis, has profound effects on
the pituitary gland, which indirectly affects a number of other hormones and
physiological functions.Effects on growth hormone, prolactin[122] and TSH (with relevant
effect on T3 and T4) were observed directly.[123] Aspirin reduces the effects of
vasopressin[124] and increases those of naloxone[125] upon the secretion of ACTH and
cortisol by the hypothalamic-pituitary-adrenal axis (HPA axis), which has been suggested
to occur through an interaction with endogenous prostaglandins and their role in
regulating the HPA axis.[124]

[edit] Pharmacokinetics
Salicylic acid is a weak acid, and very little of it is ionized in the stomach after oral
administration. Acetylsalicylic acid is poorly soluble in the acidic conditions of the
stomach, which can delay absorption of high doses for eight to 24 hours. The increased
pH and larger surface area of the small intestine causes aspirin to be absorbed rapidly
there, 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 plasma
concentrations can continue to rise for up to 24 hours after ingestion.[126][127][128]

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.[128]

As much as 80% of therapeutic doses of salicylic acid is metabolized in the liver.

Conjugation with glycine forms salicyluric acid, and with glucuronic acid it 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 pathways
become saturated and renal excretion becomes increasingly important.[128]

Salicylates are excreted mainly by the kidneys as salicyluric acid (75%), free salicylic
acid (10%), salicylic phenol (10%) and acyl glucuronides (5%), and gentisic acid (< 1%).
When small doses (less than 250 mg in an adult) are ingested, all pathways proceed by
first-order kinetics, with an elimination half-life of about 2.0 to 4.5 hours.[129][130] When
higher doses of salicylate are ingested (more than 4 g), the half-life becomes much longer
(15–30 hours),[131] because the biotransformation pathways concerned with the formation
of salicyluric acid and salicyl phenolic glucuronide become saturated.[132] Renal excretion
of salicylic acid becomes increasingly important as the metabolic pathways become
saturated, because it is extremely sensitive to changes in 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.[133]

[edit] History
Main article: History of aspirin
1923 advertisement

Plant extracts, including willow bark and spiraea, of which salicylic acid was the active
ingredient, had been known to help alleviate headaches, pains and fevers since antiquity.
The father of modern medicine, Hippocrates, who lived sometime between 460 BC and
377 BC, left historical records describing the use of powder made from the bark and
leaves of the willow tree to help these symptoms.[134]

A French chemist, Charles Frederic Gerhardt, was the first to prepare acetylsalicylic acid
in 1853. In the course of his work on the synthesis and properties of various acid
anhydrides, he mixed acetyl chloride with a sodium salt of salicylic acid (sodium
salicylate). A vigorous reaction ensued, and the resulting melt soon solidified.[135] 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.
Advertisement for Aspirin, Heroin, Lycetol and 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.[136] In 1869, Schröder, Prinzhorn and Kraut repeated both Gerhardt's
(from sodium salicylate) and von Gilm's (from salicylic acid) syntheses and concluded
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.[137]

In 1897, chemists working at Bayer AG produced a synthetically altered version of

salicin, derived from the species, which caused less digestive upset than pure salicylic
acid. The identity of the lead chemist on this project is a matter of controversy. Bayer's
official story is the work was done by Felix Hoffmann, but the Jewish chemist Arthur
Eichengrün later claimed he was the lead investigator and records of his contribution
were expunged under the Nazi regime. The new drug, formally acetylsalicylic acid, was
named Aspirin by Bayer AG after the old botanical name for meadowsweet, Spiraea
ulmaria. By 1899, Bayer was selling it around the world.[138] The name Aspirin is derived
from acetyl and spirsäure, an old German name for salicylic acid.[139] The popularity of
aspirin grew over the first half of the 20th century, spurred by its supposed effectiveness
in the wake of the Spanish flu pandemic of 1918. However, recent research suggests the
high death toll of the 1918 flu was partly due to aspirin, as the doses used at times can
lead to toxicity, fluid in the lungs, and, in some cases, contribute to secondary bacterial
infections and mortality.[140] 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.[141][142]

The popularity of aspirin declined after the market releases of paracetamol

(acetaminophen) in 1956 and ibuprofen in 1969.[143] In the 1960s and 1970s, John Vane
and others discovered the basic mechanism of aspirin's effects, while clinical trials and
other studies from the 1960s to the 1980s established aspirin's efficacy as an anticlotting
agent that reduces the risk of clotting diseases.[144] Aspirin sales revived considerably in
the last decades of the 20th century, and remain strong in the 21st century, because of its
widespread use as a preventive treatment for heart attacks and strokes.[145]

[edit] Trademark

As part of war reparations specified in the 1919 Treaty of Versailles following Germany's
surrender after World War I, Aspirin (along with heroin) lost its status as a registered
trademark in France, Russia, the United Kingdom, and the United States, where it
became a generic name.[146][147][148] Today, "aspirin" is a generic word in Australia, France,
India, Ireland, New Zealand, Pakistan, Jamaica, the Philippines, South Africa, United
Kingdom and the United States.[149] 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 acetylsalicylic acid in all markets, but using
different packaging and physical aspects for each.[150][151]
[edit] Compendial status
• United States Pharmacopeia [152][clarification needed]
• British Pharmacopoeia [153]

[edit] Veterinary use

Aspirin has been used to treat pain and arthritis in veterinary medicine, primarily in dogs,
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.[154] Horses 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.[155] Aspirin should only be used in animals
under the direct supervision of a veterinarian. It should never be given to cats, because
they lack the ability to form glucuronide conjugates, which makes it more likely it will be
toxic. Toxicity may be reduced by administering dosages at longer intervals.[156]