Aspirin
Overview
Aspirin also known as acetylsalicylic acid (ə ; abbreviated ASA), is a salicylate drug
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

, often used as an analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

 to relieve minor aches and pains, as an antipyretic
Antipyretic
Antipyretics ; an-tee-pahy-ret-iks; from the Greek anti, against, and pyreticus, are drugs or herbs that reduce fever. Normally, they will not lower body temperature if one does not have a fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature...

 to reduce fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

, and as an anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....

 medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer
Bayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...

.

Salicylic acid
Salicylic acid
Salicylic acid is a monohydroxybenzoic acid, a type of phenolic acid and a beta hydroxy acid. This colorless crystalline organic acid is widely used in organic synthesis and functions as a plant hormone. It is derived from the metabolism of salicin...

, the main metabolite of aspirin, is an integral part of human and animal metabolism.
Encyclopedia
Aspirin also known as acetylsalicylic acid (ə ; abbreviated ASA), is a salicylate drug
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

, often used as an analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

 to relieve minor aches and pains, as an antipyretic
Antipyretic
Antipyretics ; an-tee-pahy-ret-iks; from the Greek anti, against, and pyreticus, are drugs or herbs that reduce fever. Normally, they will not lower body temperature if one does not have a fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature...

 to reduce fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

, and as an anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....

 medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer
Bayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...

.

Salicylic acid
Salicylic acid
Salicylic acid is a monohydroxybenzoic acid, a type of phenolic acid and a beta hydroxy acid. This colorless crystalline organic acid is widely used in organic synthesis and functions as a plant hormone. It is derived from the metabolism of salicin...

, 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.

Aspirin also has an antiplatelet
Antiplatelet drug
An antiplatelet drug is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation...

 effect by inhibiting the production of thromboxane
Thromboxane
Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring....

, which under normal circumstances binds platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes.  The average lifespan of a platelet is normally just 5 to 9 days...

 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
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...

, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...

s, and blood clot
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...

 formation in people at high risk of developing blood clots. It has also been established that low doses of aspirin may be given immediately after a heart attack to reduce the risk of another heart attack or of the death of cardiac tissue.

The main undesirable side-effects
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

 of aspirin taken by mouth are gastrointestinal ulcers, stomach bleeding, and tinnitus
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...

, especially in higher doses. In children and adolescents, aspirin is no longer indicated to control flu-like symptoms or the symptoms of chickenpox
Chickenpox
Chickenpox or chicken pox is a highly contagious illness caused by primary infection with varicella zoster virus . It usually starts with vesicular skin rash mainly on the body and head rather than at the periphery and becomes itchy, raw pockmarks, which mostly heal without scarring...

 or other viral illnesses, because of the risk of Reye's syndrome
Reye's syndrome
Reye's syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing a lower than usual level of blood sugar . The classic features are liver damage, aspirin use and a viral infection...

.

Aspirin is part of a group of medication called nonsteroidal anti-inflammatory drugs (NSAIDs), but differs from them in the mechanism of action. Though it, and others in its group called the salicylates, have similar effects (antipyretic, anti-inflammatory, analgesic) to the other NSAIDs and inhibit the same enzyme cyclooxygenase
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...

, aspirin (but not the other salicylates) does so in an irreversible manner and, unlike others, affect more the COX-1 variant than the COX-2 variant of the enzyme. For example, NSAIDs' antiplatelet effects normally last in the order of hours, whereas aspirin's effects last 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. In countries where Aspirin is a registered trademark
Trademark
A trademark, trade mark, or trade-mark is a distinctive sign or indicator used by an individual, business organization, or other legal entity to identify that the products or services to consumers with which the trademark appears originate from a unique source, and to distinguish its products or...

 owned by Bayer
Bayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...

, the generic term is acetylsalicylic acid (ASA).

Medical uses

Aspirin is used for the treatment of a number of conditions including: fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

, pain, rheumatic fever
Rheumatic fever
Rheumatic fever is an inflammatory disease that occurs following a Streptococcus pyogenes infection, such as strep throat or scarlet fever. Believed to be caused by antibody cross-reactivity that can involve the heart, joints, skin, and brain, the illness typically develops two to three weeks after...

, inflammatory diseases such as rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

, pericarditis
Pericarditis
Pericarditis is an inflammation of the pericardium . A characteristic chest pain is often present.The causes of pericarditis are varied, including viral infections of the pericardium, idiopathic causes, uremic pericarditis, bacterial infections of the precardium Pericarditis is an inflammation of...

, and Kawasaki disease
Kawasaki disease
Kawasaki disease , also known as Kawasaki syndrome, lymph node syndrome and mucocutaneous lymph node syndrome, is an autoimmune disease in which the medium-sized blood vessels throughout the body become inflamed. It is largely seen in children under five years of age...

. It is used in the prevention of transient ischemic attack
Transient ischemic attack
A transient ischemic attack is a transient episode of neurologic dysfunction caused by ischemia – either focal brain, spinal cord or retinal – without acute infarction...

s, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...

s, heart attacks
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...

, pregnancy loss, and cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

.

Pain

In general, aspirin works well for dull, throbbing pain; it is ineffective for pain caused by most muscle cramp
Cramp
Cramps are unpleasant, often painful sensations caused by muscle contraction or over shortening. Common causes of skeletal muscle cramps include muscle fatigue, low sodium, and low potassium...

s, bloating
Bloating
Bloating is any abnormal general swelling, or increase in diameter of the abdominal area. As a symptom, the patient feels a full and tight abdomen, which may cause abdominal pain sometimes accompanied by increased borborygmus or more seriously the total lack of borborygmus.-Symptoms:The most common...

, gastric distension
Gastric distension
Gastric Distension is bloating of the stomach when air is pumped into it. This may be done when someone is performing cardiopulmonary resuscitation and blowing air into the mouth of someone who is not breathing spontaneously...

, and acute skin irritation. The most studied example is pain after surgery, such as tooth extraction, for which the highest allowed dose of aspirin (1 g) is equivalent to 1 g of paracetamol
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...

 (acetaminophen), 60 mg of codeine
Codeine
Codeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...

, or 5 mg of oxycodone
Oxycodone
Oxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids: morphine, diacetylmorphine , and codeine.Oxycodone oral medications are generally...

. A combination of aspirin and caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...

, in general, affords greater pain relief than aspirin alone. Effervescent aspirin alleviates pain much faster than aspirin in tablets (15–30 min vs. 45–60 min).

Nevertheless, as a postsurgery painkiller, aspirin is inferior to ibuprofen
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....

 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. A combination of aspirin and codeine may have a slightly higher analgesic effect than aspirin alone; however, this difference is not clinically meaningful. It appears ibuprofen is at least equally, and possibly more, effective than this combination.

According to a 1998 meta-analysis of clinical trials for menstrual pain
Dysmenorrhea
Dysmenorrhea is a gynecological medical condition of pain during menstruation that interferes with daily activities, as defined by ACOG and others. Still, dysmenorrhea is often defined simply as menstrual pain, or at least menstrual pain that is excessive...

, aspirin demonstrated higher efficacy than placebo, but lower than ibuprofen or naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...

, although maximum doses of aspirin were never used in these trials. The authors concluded ibuprofen has the best risk-benefit ratio.

Aspirin did not ease pain during cycling exercise, while caffeine was very effective. Likewise, aspirin, codeine, or paracetamol was not better than placebo for muscle soreness after exercise.

Headache

Aspirin is a first-line drug in the treatment of migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...

, bringing relief in 50–60% of the cases. 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 an antiplatelet therapy), no significant differences were seen as compared to triptan
Triptan
Triptans are a family of tryptamine-based drugs used as abortive medication in the treatment of migraines and cluster headaches. They were first introduced in the 1990s...

 medication, sumatriptan
Sumatriptan
Sumatriptan is a triptan sulfa drug containing a sulfonamide group. It is used for the treatment of migraine headaches. Sumatriptan is produced and marketed by various drug manufacturers with many different trade names such as Sumatriptan, Imitrex, Imigran, Imigran recovery.-Approval and...

 (Imitrex) and other painkillers such as paracetamol
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...

 (acetaminophen) or ibuprofen
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....

. The combination of aspirin, paracetamol (acetaminophen) and caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...

 (as found in the OTC brand Excedrin
Excedrin
Excedrin is an over-the-counter headache pain reliever, typically in the form of tablets or caplets. It contains acetaminophen , aspirin, and caffeine. Until late 2005 it was manufactured by Bristol-Myers Squibb, but in July 2005 it was purchased by Novartis, along with other products from BMS's...

) is even more potent. For the treatment of migraine headache, this formulation works better than any of its three components taken separately, better than ibuprofen and better than sumatriptan. As with all other medications for migraine, it is recommended to take aspirin at the first signs of the headache, and it is the way these medications were used in the comparative clinical trials.

Aspirin alleviates pain in 60–75% of patients with episodic tension headache
Tension headache
A tension headache is the most common type of primary headache. The pain can radiate from the neck, back, eyes, or other muscle groups in the body. Tension-type headaches account for nearly 90% of all headaches...

s. It is equivalent to paracetamol (acetaminophen) in that respect, except for the higher frequency of gastrointestinal side-effects. Comparative clinical trials indicated metamizole
Metamizole
Metamizole sodium or dipyrone is a powerful analgesic and antipyretic. It is marketed under various trade names, including Algozone, Algocalmin, Analgin, Dipirona, Novalgin, Neo-Melubrina and Optalgin. Metamizole was first synthesized by the German company Hoechst AG in 1920, and its mass...

 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. The combination of aspirin, paracetamol (acetaminophen) and caffeine is still more effective, but at the cost of more stomach discomfort, nervousness and dizziness.

There is some evidence low-dose aspirin has benefit for reducing the occurrence of migraines in susceptible individuals.

Prevention of heart attacks and strokes

There are two distinct uses of aspirin for prophylaxis of cardiovascular events: primary prevention and secondary prevention. Primary prevention is about decreasing stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...

s and heart attacks in the general population of those who have no diagnosed heart or vascular
Vascular
Vascular in zoology and medicine means "related to blood vessels", which are part of the circulatory system. An organ or tissue that is vascularized is heavily endowed with blood vessels and thus richly supplied with blood....

 problems. Secondary prevention concerns patients with known cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...

.

Low doses of aspirin are recommended for the secondary prevention of strokes and heart attacks. For both males and females diagnosed with cardiovascular disease, aspirin reduces the chance of a heart attack and ischaemic stroke by about a fifth. This translates to an absolute rate reduction from 8.2% to 6.7% of such events per year for people already with cardiovascular disease. Although aspirin also raises the risk of hemorrhagic stroke and other major bleeds
Bleeding
Bleeding, technically known as hemorrhaging or haemorrhaging is the loss of blood or blood escape from the circulatory system...

 by about twofold, these events are rare, and the balance of aspirin's effects is positive. Thus, in secondary prevention trials, aspirin reduced the overall mortality by about a tenth.

For persons without cardiovascular problems, the benefits of aspirin are unclear. In the primary prevention trials, aspirin decreased the overall incidence of heart attacks and ischaemic strokes by about a tenth. However, since these events were rare, the absolute reduction of their rate was low: from 0.57% to 0.51% per year. In addition, the risks of hemorrhagic strokes and gastrointestinal bleeding almost completely offset the benefits of aspirin. Thus, in the primary prevention trials, aspirin did not change the overall mortality rate. Further trials .

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
Polypill
A polypill is a medication that is a combination drug of multiple active ingredients, and that is aimed to be consumed widespread in the population, even currently healthy ones, as a means of preventive medicine...

 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. 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 statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...

s as the alternative and more effective preventive medication.

Coronary and carotid arteries, bypasses and stents

The coronary arteries supply blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....

 to the heart
Human heart
The human heart is a muscular organ that provides a continuous blood circulation through the cardiac cycle and is one of the most vital organs in the human body...

. Aspirin is recommended for one to six months after placement of stent
Stent
In the technical vocabulary of medicine, a stent is an artificial 'tube' inserted into a natural passage/conduit in the body to prevent, or counteract, a disease-induced, localized flow constriction. The term may also refer to a tube used to temporarily hold such a natural conduit open to allow...

s in the coronary arteries and for years after a coronary artery bypass graft.

The carotid arteries supply blood to the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...

. Patients with mild carotid artery stenosis
Carotid artery stenosis
Carotid stenosis is a narrowing or constriction of the inner surface of the carotid artery, usually caused by atherosclerosis .-Signs and symptoms:...

 benefit from aspirin; it is recommended after a carotid endarterectomy
Carotid endarterectomy
Carotid endarterectomy is a surgical procedure used to prevent stroke, by correcting stenosis in the common carotid artery...

 or carotid artery stent.

After vascular surgery
Vascular surgery
Vascular surgery is a specialty of surgery in which diseases of the vascular system, or arteries and veins, are managed by medical therapy, minimally-invasive catheter procedures, and surgical reconstruction. The specialty evolved from general and cardiac surgery...

 of the lower legs using artificial grafts
Medical grafting
Grafting refers to a surgical procedure to move tissue from one site to another on the body, or from another person, without bringing its own blood supply with it. Instead, a new blood supply grows in after it is placed. A similar technique where tissue is transferred with the blood supply intact...

 that are sutured to the arteries to improve blood supply, aspirin is used to keep the grafts open because it serves as type of blood thinner, reducing the likelihood of clots forming.

Other uses

Although aspirin has been used to combat fever and pains associated with common cold
Common cold
The common cold is a viral infectious disease of the upper respiratory system, caused primarily by rhinoviruses and coronaviruses. Common symptoms include a cough, sore throat, runny nose, and fever...

 for more than 100 years, its efficacy in this role was only recently confirmed in controlled clinical trials on adults. One gram of aspirin, on average, reduced the oral body temperature from 39 °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 °F). Aspirin also helped with "achiness", discomfort, and headache, and with sore throat pain, for those who had it. The effects of aspirin were indistinguishable from those obtained using paracetamol in any respect, except for, possibly, a slightly higher incidence of sweating and gastrointestinal side-effects.

Fever and joint pain of acute rheumatic fever
Rheumatic fever
Rheumatic fever is an inflammatory disease that occurs following a Streptococcus pyogenes infection, such as strep throat or scarlet fever. Believed to be caused by antibody cross-reactivity that can involve the heart, joints, skin, and brain, the illness typically develops two to three weeks after...

 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. In addition, the high doses of aspirin used caused liver toxicity in about 20% of the treated children, who are the majority of rheumatic fever patients, and increased the risk of their developing Reye's syndrome
Reye's syndrome
Reye's syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing a lower than usual level of blood sugar . The classic features are liver damage, aspirin use and a viral infection...

. Naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...

 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.

Along with rheumatic fever, Kawasaki disease
Kawasaki disease
Kawasaki disease , also known as Kawasaki syndrome, lymph node syndrome and mucocutaneous lymph node syndrome, is an autoimmune disease in which the medium-sized blood vessels throughout the body become inflamed. It is largely seen in children under five years of age...

 remains one of the few indications for aspirin use in children, although even this use has been questioned by some researchers. 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
Pericarditis
Pericarditis is an inflammation of the pericardium . A characteristic chest pain is often present.The causes of pericarditis are varied, including viral infections of the pericardium, idiopathic causes, uremic pericarditis, bacterial infections of the precardium Pericarditis is an inflammation of...

, coronary artery disease, and acute myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...

.

Taking aspirin before air travel
Air travel
Air travel is a form of travel in vehicles such as airplanes, helicopters, hot air balloons, blimps, gliders, hang gliding, parachuting or anything else that can sustain flight.-Domestic and international flights:...

 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".

Experimental

Aspirin has been theorized to reduce cataract
Cataract
A cataract is a clouding that develops in the crystalline lens of the eye or in its envelope, varying in degree from slight to complete opacity and obstructing the passage of light...

 formation in diabetic patients, but one study showed it was ineffective for this purpose. The role of aspirin in reducing the incidence of many forms of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

 has also been widely studied. In several studies, its use did not reduce the incidence of prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...

. Its effects on the incidence of pancreatic cancer
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...

 are mixed; one study published in 2004 found a statistically significant increase in the risk of pancreatic cancer among women, while a meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...

 of several studies, published in 2006, found no evidence aspirin or other NSAIDs are associated with an increased risk for the disease. The drug may be effective in reduction of risk of various cancers, including those of the colon,

lung
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...

, and possibly the upper GI tract, though some evidence of its effectiveness in preventing cancer of the upper GI tract has been inconclusive. Its preventative effect against adenocarcinoma
Adenocarcinoma
Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...

s may be explained by its inhibition of PTGS2 (COX-2)
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...

 enzymes expressed in them.

A 2009 article published by the Journal of Clinical Investigation suggested that aspirin might prevent liver damage. In their experiment, scientists from Yale University
Yale University
Yale University is a private, Ivy League university located in New Haven, Connecticut, United States. Founded in 1701 in the Colony of Connecticut, the university is the third-oldest institution of higher education in the United States...

 and The University of Iowa
University of Iowa
The University of Iowa is a public state-supported research university located in Iowa City, Iowa, United States. It is the oldest public university in the state. The university is organized into eleven colleges granting undergraduate, graduate, and professional degrees...

 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
TLR9
Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene. TLR9 has also been designated as CD289 .- Function :...

. The expression of TLR9 caused an inflammatory cascade involving pro–IL-1β and pro-IL-18. Aspirin was found to have a protective effect on hepatocytes because it led to the "downregulation of proinflammatory cytokines".

In another 2009 article published by the Journal of the American Medical Association, 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.

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

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
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...

, 10% for prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...

 and 60% for oesophageal cancer, while the reductions in pancreas, stomach
Stomach cancer
Gastric cancer, commonly referred to as stomach cancer, can develop in any part of the stomach and may spread throughout the stomach and to other organs; particularly the esophagus, lungs, lymph nodes, and the liver...

, brain, breast
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...

 and ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....

s 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.

Resistance

For some people, aspirin does not have as strong an effect on platelets as for others, an effect known as aspirin resistance or insensitivity. One study has suggested women are more likely to be resistant than men, and a different, aggregate study of 2,930 patients found 28% to be resistant.
A study in 100 Italian patients found that, of the apparent 31% aspirin-resistant subjects, only 5% were truly resistant, and the others were noncompliant
Compliance (medicine)
In medicine, compliance describes the degree to which a patient correctly follows medical advice...

.

Dosage

Adult aspirin tablets are produced in standardised sizes, which vary slightly from country to country, for example 300 mg in Britain and 325 mg in the USA. Smaller doses are based on these standards; e.g. 75- and 81-milligram tablets are used; there is no medical significance in the slight difference.
It is of historical interest that in the U.S., a 325 mg dose is equivalent to the historic 5-grain aspirin tablet in use prior to the metric system.

In general, for adults, doses are taken four times a day for fever or arthritis, with doses near the maximal daily dose used historically for the treatment of rheumatic fever. For the prevention of myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...

 in someone with documented or suspected coronary artery disease, much lower doses are taken once daily.

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
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...

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

In children with Kawasaki disease
Kawasaki disease
Kawasaki disease , also known as Kawasaki syndrome, lymph node syndrome and mucocutaneous lymph node syndrome, is an autoimmune disease in which the medium-sized blood vessels throughout the body become inflamed. It is largely seen in children under five years of age...

, 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.

Contraindications

Aspirin should not be taken by people who are allergic to ibuprofen
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....

 or naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...

, or who have salicylate intolerance or a more generalized drug intolerance
Drug intolerance
Drug intolerance or drug sensitivity is a lower threshold to the normal pharmacologic action of a drug. It is not to be confused with drug allergy. Drug intolerance is uncommon and idiopathic, thus extremely difficult to predict except in persons with a prior history or a family history of...

 to NSAIDs, and caution should be exercised in those with asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...

 or NSAID-precipitated bronchospasm
Bronchospasm
Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release of substances from mast cells or basophils under the influence of anaphylatoxins...

. Owing to its effect on the stomach lining, manufacturers recommend people with peptic ulcer
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...

s, mild diabetes, or gastritis
Gastritis
Gastritis is an inflammation of the lining of the stomach, and has many possible causes. The main acute causes are excessive alcohol consumption or prolonged use of nonsteroidal anti-inflammatory drugs such as aspirin or ibuprofen. Sometimes gastritis develops after major surgery, traumatic...

 seek medical advice before using aspirin. Even if none of these conditions is present, there is still an increased risk of stomach bleeding when aspirin is taken with alcohol
Alcoholic beverage
An alcoholic beverage is a drink containing ethanol, commonly known as alcohol. Alcoholic beverages are divided into three general classes: beers, wines, and spirits. They are legally consumed in most countries, and over 100 countries have laws regulating their production, sale, and consumption...

 or warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...

. Patients with hemophilia or other bleeding tendencies should not take aspirin or other salicylates. Aspirin is known to cause hemolytic anemia
Hemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...

 in people who have the genetic disease glucose-6-phosphate dehydrogenase deficiency
Glucose-6-phosphate dehydrogenase deficiency
Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive hereditary disease characterised by abnormally low levels of glucose-6-phosphate dehydrogenase , a metabolic enzyme involved in the pentose phosphate pathway, especially important in red blood cell metabolism. G6PD deficiency is...

 (G6PD), in particular in large doses and depending on the severity of the disease. Use of aspirin during dengue fever
Dengue fever
Dengue fever , also known as breakbone fever, is an infectious tropical disease caused by the dengue virus. Symptoms include fever, headache, muscle and joint pains, and a characteristic skin rash that is similar to measles...

 is not recommended owing to increased bleeding tendency. People with kidney disease, hyperuricemia
Hyperuricemia
Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...

, or gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...

 should not take aspirin because it inhibits the kidneys' ability to excrete uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of 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
Reye's syndrome
Reye's syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing a lower than usual level of blood sugar . The classic features are liver damage, aspirin use and a viral infection...

.

Gastrointestinal

Aspirin use has been shown to increase the risk of gastrointestinal bleeding
Gastrointestinal bleeding
Gastrointestinal bleeding or gastrointestinal hemorrhage describes every form of hemorrhage in the gastrointestinal tract, from the pharynx to the rectum. It has diverse causes, and a medical history, as well as physical examination, generally distinguishes between the main forms...

. Although some enteric coated
Enteric coating
An enteric coating is a barrier applied to oral medication that controls the location in the digestive system, where it is absorbed. Enteric refers to the small intestine, therefore enteric coatings prevent release of medication before it reaches the small intestine.Most enteric coatings work by...

 formulations of aspirin are advertised as being "gentle to the stomach", in one study enteric coating did not seem to reduce this risk. Combining aspirin with other NSAIDs has also been shown to further increase this risk. Using aspirin in combination with clopidogrel
Clopidogrel
Clopidogrel is an oral, thienopyridine class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is marketed by Bristol-Myers Squibb and Sanofi-Aventis under the trade name Plavix. The drug works by irreversibly...

 or warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...

 also increases the risk of upper gastrointestinal bleeding.

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

Taking it with vitamin C is a more recently investigated method of protecting the stomach lining. 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.

It is reported that deglycyrrhizinated licorice
Deglycyrrhizinated licorice
Deglycyrrhizinated licorice, also known as de-glycyrrhizinated licorice, or commonly referred to by the acronym DGL, is an herbal supplement typically used in the treatment of gastric and duodenal ulcers...

 (DGL), an extract of the popular herb licorice, 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).

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.

A study found that, in contrast to oral aspirin, intravenous injection of aspirin did not produce detectable histological damage or significantly alter gastric mucosal potential difference, and concluded that high blood levels of circulating salicylate did not acutely damage gastric mucosa, so that gastric mucosal damage produced acutely after single oral doses of aspirin are due to its topical
Topical
In medicine, a topical medication is applied to body surfaces such as the skin or mucous membranes such as the vagina, anus, throat, eyes and ears.Many topical medications are epicutaneous, meaning that they are applied directly to the skin...

, rather than systemic, action.

Central effects

Large doses of salicylate, a metabolite of aspirin, have been proposed to cause tinnitus
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...

 (ringing in the ears) based on experiments in rats, via the action on arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...

 and NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....

s cascade.

Reye's syndrome

Reye's syndrome, a rare but severe illness characterized by acute encephalopathy
Encephalopathy
Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...

 and fatty liver
Fatty liver
Fatty liver, also known as fatty liver disease , is a reversible condition where large vacuoles of triglyceride fat accumulate in liver cells via the process of steatosis...

, 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
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...

. Of these, 93% reported being ill in the three weeks preceding onset of Reye's syndrome, most commonly with a respiratory infection, chickenpox
Chickenpox
Chickenpox or chicken pox is a highly contagious illness caused by primary infection with varicella zoster virus . It usually starts with vesicular skin rash mainly on the body and head rather than at the periphery and becomes itchy, raw pockmarks, which mostly heal without scarring...

, or diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

. Salicylates were detectable in 81.9% of children for whom test results were reported. After the association between Reye's syndrome and aspirin was reported and safety measures to prevent it (including a Surgeon General
Surgeon General of the United States
The Surgeon General of the United States is the operational head of the Public Health Service Commissioned Corps and thus the leading spokesperson on matters of public health in the federal government...

's warning and changes to the labeling of aspirin-containing drugs) were implemented, aspirin taken by children declined considerably in the United States, as did the number of reported cases of Reye's syndrome; a similar decline was found in the United Kingdom after warnings against pediatric aspirin use were issued. The United States Food and Drug Administration now recommends aspirin (or aspirin-containing products) should not be given to anyone under the age of 12 who has a fever, and the British Medicines and Healthcare products Regulatory Agency
Medicines and Healthcare products Regulatory Agency
The Medicines and Healthcare products Regulatory Agency is the UK government agency which is responsible for ensuring that medicines and medical devices work and are acceptably safe....

 (MHRA) recommends children who are under 16 years of age should not take aspirin, unless it is on the advice of a doctor.

Hives and swelling

For a small number of people, taking aspirin can result in symptoms that resemble an allergic reaction, including hives, swelling and headache. The reaction is caused by salicylate intolerance and is not a true allergy
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...

, but rather an inability to metabolize even small amounts of aspirin, resulting in an overdose.

Other effects

Aspirin can induce angioedema
Angioedema
Angioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...

 (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.

Aspirin causes an increased risk of cerebral microbleeds having the appearance on MRI scans of 5–10 mm or smaller hypointense (dark holes) patches. Such cerebral microbleeds are important since they often occur prior to ischemic stroke or intracerebral hemorrhage, Binswanger disease and Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

.

Aspirin and other NSAIDs can cause hyperkalemia
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...

 by inducing a hyporenin hypoaldosteronic state via inhibition of prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....

 synthesis; however, these agents do not typically cause hyperkalemia
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...

 by themselves in the setting of normal renal function and euvolemic state.

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

Overdose

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
Mortality rate
Mortality rate is a measure of the number of deaths in a population, scaled to the size of that population, per unit time...

 of 2%. Chronic overdose is more commonly lethal, with a mortality rate of 25%; chronic overdose may be especially severe in children. Toxicity is managed with a number of potential treatments, including activated charcoal, intravenous dextrose and normal saline, sodium bicarbonate
Sodium bicarbonate
Sodium bicarbonate or sodium hydrogen carbonate is the chemical compound with the formula Na HCO3. Sodium bicarbonate is a white solid that is crystalline but often appears as a fine powder. It has a slightly salty, alkaline taste resembling that of washing soda . The natural mineral form is...

, and dialysis. The diagnosis of poisoning usually involves measurement of plasma salicylate, the active metabolite of aspirin, by automated spectrophotometric methods. Plasma salicylate levels in general 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
Bismuth subsalicylate
Bismuth subsalicylate, with a nominal chemical formula of C7H5BiO4, It is a colloidal substance obtained by hydrolysis of bismuth salicylate . The actual structure is unknown and the formulation is only approximate. Recent evidence indicates that it is composed of a bismuth oxide core structure...

, methyl salicylate
Methyl salicylate
Methyl salicylate is a natural product of many species of plants. Some of the plants which produce it are called wintergreens, hence the common name.-Botanical background:...

 and sodium salicylate
Sodium salicylate
Sodium salicylate is a sodium salt of salicylic acid. It can be prepared from sodium phenolate and carbon dioxide under higher temperature and pressure...

.

Interactions

Aspirin is known to interact
Drug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...

 with other drugs. For example, acetazolamide
Acetazolamide
Acetazolamide, sold under the trade name Diamox, is a carbonic anhydrase inhibitor that is used to treat glaucoma, epileptic seizures, Idiopathic intracranial hypertension , altitude sickness, cystinuria, and dural ectasia...

 and ammonium chloride
Ammonium chloride
Ammonium chloride NH4Cl is an inorganic compound with the formula NH4Cl. It is a white crystalline salt that is highly soluble in water. Solutions of ammonium chloride are mildly acidic. Sal ammoniac is a name of natural, mineralogical form of ammonium chloride...

 have been known to enhance the intoxicating effect of salicyclates, and alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....

 also increases the gastrointestinal bleeding associated with these types of drugs. Aspirin is known to displace a number of drugs from protein binding sites in the blood, including the antidiabetic drugs tolbutamide
Tolbutamide
Tolbutamide is a first generation potassium channel blocker, sulfonylurea oral hypoglycemic drug sold under the brand name Orinase. This drug may be used in the management of type II diabetes if diet alone is not effective. Tolbutamide stimulates the secretion of insulin by the pancreas...

 and chlorpropamide
Chlorpropamide
Chlorpropamide is a drug in the sulphonylurea class used to treat type 2 diabetes mellitus. It is a long-acting sulphonylurea. It has more side effects than other sulphonylureas and its use is no longer recommended.-Mechanism of action:...

, the immunosuppressant
Immunosuppressant
An immunosuppressant is any substance that performs immunosuppression of the immune system. They may be either exogenous, as immunosuppressive drugs, or endogenous, as ,e. g., testosterone...

 methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...

, phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...

, probenecid
Probenecid
Probenecid is a uricosuric drug that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia.Probenecid was developed as an alternative to caronamide...

, valproic acid
Valproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...

 (as well as interfering with beta oxidation
Beta oxidation
Beta oxidation is the process by which fatty acids, in the form of Acyl-CoA molecules, are broken down in mitochondria and/or in peroxisomes to generate Acetyl-CoA, the entry molecule for the Citric Acid cycle....

, an important part of valproate metabolism) and any nonsteroidal anti-inflammatory drug. Corticosteroids may also reduce the concentration of aspirin. Ibuprofen
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....

 can negate the antiplatelet effect of aspirin used for cardioprotection and stroke prevention. The pharmacological activity of spironolactone
Spironolactone
Spironolactone , commonly referred to as simply spiro, is a diuretic and is used as an antiandrogen.It is a synthetic 17-lactone drug that is a renal competitive aldosterone antagonist in a class of pharmaceuticals called...

 may be reduced by taking aspirin, and aspirin is known to compete with Penicillin G
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....

 for renal tubular secretion. Aspirin may also inhibit the absorption of vitamin C
Vitamin C
Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress...

.

Chemical properties

Aspirin, an acetyl
Acetyl
In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...

 derivative of salicylic acid, is a white, crystalline, weakly acidic substance, with a melting point
Melting point
The melting point of a solid is the temperature at which it changes state from solid to liquid. At the melting point the solid and liquid phase exist in equilibrium. The melting point of a substance depends on pressure and is usually specified at standard atmospheric pressure...

 of 135 °C (275 °F). Acetylsalicylic acid decomposes rapidly in solutions of ammonium acetate
Ammonium acetate
Ammonium acetate is a chemical compound with the formula CH3COONH4 . It is a white solid, which can be derived from the reaction of ammonia and acetic acid...

 or of the acetates, carbonates, citrates or hydroxides of the alkali metals. Acetylsalicylic acid is stable in dry air, but gradually hydrolyses in contact with moisture to acetic and salicylic acids. In solution with alkalis, the hydrolysis proceeds rapidly and the clear solutions formed may consist entirely of acetate and salicylate.

Synthesis

The synthesis of aspirin is classified as an ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...

ification reaction. Salicylic acid
Salicylic acid
Salicylic acid is a monohydroxybenzoic acid, a type of phenolic acid and a beta hydroxy acid. This colorless crystalline organic acid is widely used in organic synthesis and functions as a plant hormone. It is derived from the metabolism of salicin...

 is treated with acetic anhydride
Acetic anhydride
Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula 2O. Commonly abbreviated Ac2O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis...

, an acid derivative, causing a chemical reaction
Chemical reaction
A chemical reaction is a process that leads to the transformation of one set of chemical substances to another. Chemical reactions can be either spontaneous, requiring no input of energy, or non-spontaneous, typically following the input of some type of energy, such as heat, light or electricity...

 that turns salicylic acid's hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...

 group into an ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...

 group (R-OH → R-OCOCH3). This process yields aspirin and acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...

, which is considered a byproduct of this reaction. Small amounts of sulfuric acid
Sulfuric acid
Sulfuric acid is a strong mineral acid with the molecular formula . Its historical name is oil of vitriol. Pure sulfuric acid is a highly corrosive, colorless, viscous liquid. The salts of sulfuric acid are called sulfates...

 (and occasionally phosphoric acid
Phosphoric acid
Phosphoric acid, also known as orthophosphoric acid or phosphoric acid, is a mineral acid having the chemical formula H3PO4. Orthophosphoric acid molecules can combine with themselves to form a variety of compounds which are also referred to as phosphoric acids, but in a more general way...

) are almost always used as a catalyst. This method is commonly employed in undergraduate teaching labs.


Reaction Mechanism


Formulations containing high concentrations of aspirin often smell like vinegar
Vinegar
Vinegar is a liquid substance consisting mainly of acetic acid and water, the acetic acid being produced through the fermentation of ethanol by acetic acid bacteria. Commercial vinegar is produced either by fast or slow fermentation processes. Slow methods generally are used with traditional...

 because aspirin can decompose through hydrolysis in moist conditions, yielding salicylic acid and acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...

.

The acid dissociation constant (pKa
Acid dissociation constant
An acid dissociation constant, Ka, is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction known as dissociation in the context of acid-base reactions...

) for acetylsalicylic acid is 3.5 at 25 °C (77 °F).

Polymorphism

Polymorphism
Polymorphism (materials science)
Polymorphism in materials science is the ability of a solid material to exist in more than one form or crystal structure. Polymorphism can potentially be found in any crystalline material including polymers, minerals, and metals, and is related to allotropy, which refers to chemical elements...

, or the ability of a substance to form more than one crystal structure
Crystal structure
In mineralogy and crystallography, crystal structure is a unique arrangement of atoms or molecules in a crystalline liquid or solid. A crystal structure is composed of a pattern, a set of atoms arranged in a particular way, and a lattice exhibiting long-range order and symmetry...

, 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, and fine structural details were given by Bond et al. A new crystal type was found after attempted cocrystallization of aspirin and levetiracetam from hot acetonitrile
Acetonitrile
Acetonitrile is the chemical compound with formula . This colourless liquid is the simplest organic nitrile. It is produced mainly as a byproduct of acrylonitrile manufacture...

. The form II is only stable at 100 K
Kelvin
The kelvin is a unit of measurement for temperature. It is one of the seven base units in the International System of Units and is assigned the unit symbol K. The Kelvin scale is an absolute, thermodynamic temperature scale using as its null point absolute zero, the temperature at which all...

 and reverts to form I at ambient temperature. In the (unambiguous) form I, two salicylic molecules form centrosymmetric dimers through the acetyl
Acetyl
In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...

 groups with the (acidic) methyl proton to carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....

 hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...

s, and in the newly claimed form II, each salicylic molecule forms the same hydrogen bonds with two neighboring molecules instead of one. With respect to the hydrogen bonds formed by the carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...

 groups both polymorphs form identical dimer structures.

Discovery of the mechanism

In 1971, British pharmacologist John Robert Vane
John Robert Vane
Sir John Robert Vane FRS was an English pharmacologist and Nobel Laureate, born in Tardebigg, Worcestershire. His father was the son of Russian immigrants and his mother came from a Worcestershire farming family. He was educated at King Edward's School in Edgbaston, Birmingham, and studied...

, then employed by the Royal College of Surgeons
Royal College of Surgeons of England
The Royal College of Surgeons of England is an independent professional body and registered charity committed to promoting and advancing the highest standards of surgical care for patients, regulating surgery, including dentistry, in England and Wales...

 in London, showed aspirin suppressed the production of prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....

s and thromboxane
Thromboxane
Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring....

s. For this discovery, he was awarded both a Nobel Prize
Nobel Prize
The Nobel Prizes are annual international awards bestowed by Scandinavian committees in recognition of cultural and scientific advances. The will of the Swedish chemist Alfred Nobel, the inventor of dynamite, established the prizes in 1895...

 in Physiology or Medicine
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...

 in 1982 and a knighthood.

Suppression of prostaglandins and thromboxanes

Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...

 (PTGS) enzyme required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl
Acetyl
In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...

 group is covalently attached to a serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...

 residue in the active site of the PTGS enzyme. This makes aspirin different from other NSAIDs (such as diclofenac
Diclofenac
Diclofenac is a non-steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic reducing pain in certain conditions....

 and ibuprofen
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....

), which are reversible inhibitors.

Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A2
Thromboxane A2
Thromboxane A2 is a thromboxane. It is produced by activated platelets and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by mediating expression of the glycoprotein complex GP IIb/IIIa in the cell membrane of...

 in platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes.  The average lifespan of a platelet is normally just 5 to 9 days...

s, producing an inhibitory effect on platelet aggregation
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes.  The average lifespan of a platelet is normally just 5 to 9 days...

. This antithrombotic property makes aspirin useful for reducing the incidence of heart attacks. 40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A2 release provoked acutely, with the prostaglandin I2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition.

Prostaglandins are local hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...

s produced in the body and have diverse effects, including the transmission of pain information to the brain, modulation of the hypothalamic
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...

 thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets that form blood clots. Heart attacks are caused primarily by blood clots, and low doses of aspirin are seen as an effective medical intervention for acute myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...

. An unwanted side-effect of the effective anticlotting action of aspirin is that it may cause excessive bleeding.

COX-1 and COX-2 inhibition

There are at least two different types of cyclooxygenase: COX-1 and COX-2. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. COX-2 normally produces prostanoids, most of which are proinflammatory. Aspirin-modified PTGS2 produces lipoxins, most of which are anti-inflammatory. Newer NSAID drugs, COX 2 inhibitors, have been developed to inhibit only PTGS2, with the intent to reduce the incidence of gastrointestinal side-effects.

However, several of the new COX 2 inhibitors, such as rofecoxib
Rofecoxib
Rofecoxib is a nonsteroidal anti-inflammatory drug that has now been withdrawn over safety concerns. It was marketed by Merck & Co. to treat osteoarthritis, acute pain conditions, and dysmenorrhoea...

 (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 (to be specific, PGI2; prostacyclin) is downregulated with respect to thromboxane levels, as PTGS1 in platelets is unaffected. Thus, the protective anticoagulative effect of PGI2 is removed, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new PTGS once aspirin has irreversibly inhibited the enzyme, an important difference with reversible inhibitors.

Additional mechanisms

Aspirin has been shown to have at least three additional modes of action. It uncouples oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...

 in cartilaginous (and hepatic) mitochondria, by diffusing from the inner membrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once again to release protons. In short, aspirin buffers and transports the protons. When high doses of aspirin are given, it may actually cause fever, owing to the heat released from the electron transport chain, as opposed to the antipyretic action of aspirin seen with lower doses. In addition, aspirin induces the formation of NO-radicals in the body, which have been shown in mice to have an independent mechanism of reducing inflammation. This reduced leukocyte adhesion, which is an important step in immune response to infection; however, there is currently insufficient evidence to show that aspirin helps to fight infection. More recent data also suggests that salicylic acid and its derivatives modulate signaling through NF-κB. NF-κB, a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...

 complex, plays a central role in many biological processes, including inflammation.

Effects upon hypothalamic-pituitary-adrenal activity

Aspirin, like other medications affecting prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....

 synthesis, has profound effects on the pituitary gland, which indirectly affects a number of other hormones and physiological functions. Effects on growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...

, prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...

, and TSH
Thyroid-stimulating hormone
Thyrotrophin-stimulating hormone is a peptide hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid gland.- Physiology :...

 (with relevant effect on T3
Triiodothyronine
Triiodothyronine, C15H12I3NO4, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate....

 and T4
Thyroxine
Thyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:...

) were observed directly.
Aspirin reduces the effects of vasopressin
Vasopressin
Arginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...

 and increases those of naloxone
Naloxone
Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...

 upon the secretion of ACTH and cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...

 by the hypothalamic-pituitary-adrenal axis
Hypothalamic-pituitary-adrenal axis
The hypothalamic-pituitary-adrenal axis , also known as thelimbic-hypothalamic-pituitary-adrenal axis and, occasionally, as the hypothalamic-pituitary-adrenal-gonadotropic axis, is a complex set of direct influences and feedback interactions among the hypothalamus, the pituitary gland ,...

 (HPA axis), which has been suggested to occur through an interaction with endogenous prostaglandins and their role in regulating the HPA axis.

Pharmacokinetics

Salicylic acid
Salicylic acid
Salicylic acid is a monohydroxybenzoic acid, a type of phenolic acid and a beta hydroxy acid. This colorless crystalline organic acid is widely used in organic synthesis and functions as a plant hormone. It is derived from the metabolism of salicin...

 is a weak acid, and very little of it is ionized
Acid dissociation constant
An acid dissociation constant, Ka, is a quantitative measure of the strength of an acid in solution. It is the equilibrium constant for a chemical reaction known as dissociation in the context of acid-base reactions...

 in the stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...

 after oral administration. Acetylsalicylic acid is poorly soluble in the acidic
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...

 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
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...

 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
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 concentrations can continue to rise for up to 24 hours after ingestion.

About 50–80% of salicylate in the blood is bound by protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

, 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.

As much as 80% of therapeutic doses of salicylic acid is metabolized
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

 in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

. Conjugation with glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...

 forms salicyluric acid, and with glucuronic acid
Glucuronic acid
Glucuronic acid is a carboxylic acid. Its structure is similar to that of glucose. However, glucuronic acid's sixth carbon is oxidized to a carboxylic 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
Gentisic acid
Gentisic acid is a dihydroxybenzoic acid. It is a derivative of benzoic acid and a minor product of the metabolic break down of aspirin, excreted by the kidneys.-Production:...

. With large salicylate doses, the kinetics switch from first order to zero order, as metabolic pathway
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...

s become saturated and renal
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

 excretion becomes increasingly important.

Salicylates are excreted mainly by the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

s as salicyluric acid (75%), free salicylic acid (10%), salicylic phenol (10%), and acyl glucuronides (5%), gentisic acid
Gentisic acid
Gentisic acid is a dihydroxybenzoic acid. It is a derivative of benzoic acid and a minor product of the metabolic break down of aspirin, excreted by the kidneys.-Production:...

 (< 1%), and 2,3-dihydroxybenzoic acid
2,3-Dihydroxybenzoic acid
2,3-Dihydroxybenzoic acid is a dihydroxybenzoic acid, a type of organic compound. The colourless solid occurs naturally, being formed via the chorismic acid pathway. It is incorporated into various siderophores, which are molecules that strongly complex iron ions for absorption into bacteria...

. 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. When higher doses of salicylate are ingested (more than 4 g), the half-life becomes much longer (15–30 hours), because the biotransformation pathways concerned with the formation of salicyluric acid and salicyl phenolic glucuronide become saturated. Renal excretion of salicylic acid becomes increasingly important as the metabolic pathways become saturated, because it is extremely sensitive to changes in urinary
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...

 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.

History

Plant extracts, including willow
Willow
Willows, sallows, and osiers form the genus Salix, around 400 species of deciduous trees and shrubs, found primarily on moist soils in cold and temperate regions of the Northern Hemisphere...

 bark
Bark
Bark is the outermost layers of stems and roots of woody plants. Plants with bark include trees, woody vines and shrubs. Bark refers to all the tissues outside of the vascular cambium and is a nontechnical term. It overlays the wood and consists of the inner bark and the outer bark. The inner...

 and spiraea
Spiraea
Spiraea , is a genus of about 80-100 species of shrubs in the family Rosaceae, subfamily Spiraeoideae. They are native to the temperate Northern Hemisphere, with the greatest diversity in eastern Asia....

, 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
Hippocrates
Hippocrates of Cos or Hippokrates of Kos was an ancient Greek physician of the Age of Pericles , and is considered one of the most outstanding figures in the history of medicine...

, 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.

A French chemist, Charles Frederic Gerhardt
Charles Frédéric Gerhardt
Charles Frédéric Gerhardt was a French chemist.-Biography:He was born in Strasbourg, where he attended the gymnasium. He then studied at the Karlsruhe Institute of Technology, where Friedrich Walchner's lectures first attracted his interest to chemistry...

, 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
Acetyl chloride
Acetyl chloride, CH3COCl, also known as ethanoyl chloride or acyl chloride, is an acid chloride derived from acetic acid. It belongs to the class of organic compounds called acyl halides. It is a colorless liquid. Acetyl chloride does not exist in nature, because contact with water would hydrolyze...

 with a sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...

 salt of salicylic acid (sodium salicylate
Sodium salicylate
Sodium salicylate is a sodium salt of salicylic acid. It can be prepared from sodium phenolate and carbon dioxide under higher temperature and pressure...

). A vigorous reaction ensued, and the resulting melt soon solidified. Since no structural theory
Structural theory
In physics, structural theory explains the large variety in chemical compounds in terms of atoms making up molecules, the order in which atoms are put together in molecules and the electrons that hold them together...

 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.

Six years later, in 1859, von Gilm obtained analytically pure acetylsalicylic acid (which he called acetylierte Salicylsäure, acetylated salicylic acid) by a reaction of salicylic acid and acetyl chloride. In 1869, Schröder, Prinzhorn and Kraut repeated both Gerhardt's (from sodium salicylate) and von Gilm's (from salicylic acid) syntheses and concluded both reactions gave the same compound—acetylsalicylic acid. They were first to assign to it the correct structure with the acetyl group connected to the phenolic oxygen.

In 1897, chemists working at Bayer AG
Bayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...

 produced a synthetically altered version of salicin, derived from the species meadowsweet (filipendula ulmaria), which caused less digestive upset than pure salicylic acid
Salicylic acid
Salicylic acid is a monohydroxybenzoic acid, a type of phenolic acid and a beta hydroxy acid. This colorless crystalline organic acid is widely used in organic synthesis and functions as a plant hormone. It is derived from the metabolism of salicin...

. The identity of the lead chemist on this project is a matter of controversy. Bayer's states that the work was done by Felix Hoffmann
Felix Hoffmann
Felix Hoffmann was a German chemist, credited for the first synthesized medically useful forms of heroin and aspirin, though some sources maintain that Arthur Eichengrün was the real creator of the latter. Hoffmann was born in Ludwigsburg and studied Chemistry in Munich...

, but the Jewish chemist Arthur Eichengrün
Arthur Eichengrün
Arthur Eichengrün was a German chemist, best known through a controversy about who invented aspirin.- Life :Arthur Eichengrün was born in Aachen as the son of a Jewish cloth merchant and manufacturer...

 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
Bayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...

 after the old botanical
Botany
Botany, plant science, or plant biology is a branch of biology that involves the scientific study of plant life. Traditionally, botany also included the study of fungi, algae and viruses...

 name for meadowsweet
Meadowsweet
Filipendula ulmaria, commonly known as Meadowsweet, is a perennial herb in the family Rosaceae that grows in damp meadows. It is native throughout most of Europe and Western Asia...

, Spiraea ulmaria. By 1899, Bayer was selling it around the world. The name Aspirin is derived from acetyl and spirsäure, an old German name for salicylic acid. The popularity of aspirin grew over the first half of the 20th century, spurred by its supposed effectiveness in the wake of the Spanish flu pandemic of 1918. However, recent research suggests 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. Aspirin's profitability led to fierce competition and the proliferation of aspirin brands and products, especially after the American patent held by Bayer expired in 1917.

The popularity of aspirin declined after the market releases of paracetamol
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...

 (acetaminophen) in 1956 and ibuprofen
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....

 in 1969. In the 1960s and 1970s, John Vane
John Robert Vane
Sir John Robert Vane FRS was an English pharmacologist and Nobel Laureate, born in Tardebigg, Worcestershire. His father was the son of Russian immigrants and his mother came from a Worcestershire farming family. He was educated at King Edward's School in Edgbaston, Birmingham, and studied...

 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. 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 stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...

s.

Trademark

As part of war reparations
World War I reparations
World War I reparations refers to the payments and transfers of property and equipment that Germany was forced to make under the Treaty of Versailles following its defeat during World War I...

 specified in the 1919 Treaty of Versailles
Treaty of Versailles
The Treaty of Versailles was one of the peace treaties at the end of World War I. It ended the state of war between Germany and the Allied Powers. It was signed on 28 June 1919, exactly five years after the assassination of Archduke Franz Ferdinand. The other Central Powers on the German side of...

 following Germany's surrender after World War I
World War I
World War I , which was predominantly called the World War or the Great War from its occurrence until 1939, and the First World War or World War I thereafter, was a major war centred in Europe that began on 28 July 1914 and lasted until 11 November 1918...

, Aspirin (along with heroin) lost its status as a registered trademark in France
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...

, Russia
Russia
Russia or , officially known as both Russia and the Russian Federation , is a country in northern Eurasia. It is a federal semi-presidential republic, comprising 83 federal subjects...

, the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...

, and the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

, where it became a generic name. Today, "aspirin" is a generic word in Australia, France, India, Ireland, New Zealand, Pakistan
Pakistan
Pakistan , officially the Islamic Republic of Pakistan is a sovereign state in South Asia. It has a coastline along the Arabian Sea and the Gulf of Oman in the south and is bordered by Afghanistan and Iran in the west, India in the east and China in the far northeast. In the north, Tajikistan...

, Jamaica, the Philippines, South Africa, United Kingdom and the United States.
Aspirin, with a capital "A", remains a registered trademark of Bayer in Germany, Canada, Mexico, and in over 80 other countries, where the trademark is owned by Bayer
Bayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...

, using acetylsalicylic acid in all markets, but using different packaging and physical aspects for each.

Compendial status

  • United States Pharmacopeia
    United States Pharmacopeia
    The United States Pharmacopeia is the official pharmacopeia of the United States, published dually with the National Formulary as the USP-NF. The United States Pharmacopeial Convention is the nonprofit organization that owns the trademark and copyright to the USP-NF and publishes it every year...

     
  • British Pharmacopoeia
    British Pharmacopoeia
    The British Pharmacopoeia is an annual published collection of quality standards for UK medicinal substances. It is used by individuals and organizations involved in pharmaceutical research, development, manufacture and testing....


Veterinary use

Aspirin is sometimes used for pain relief or as an anti-coagulant in veterinary medicine, primarily in dog
Dog
The domestic dog is a domesticated form of the gray wolf, a member of the Canidae family of the order Carnivora. The term is used for both feral and pet varieties. The dog may have been the first animal to be domesticated, and has been the most widely kept working, hunting, and companion animal in...

s and sometimes horse
Horse
The horse is one of two extant subspecies of Equus ferus, or the wild horse. It is a single-hooved mammal belonging to the taxonomic family Equidae. The horse has evolved over the past 45 to 55 million years from a small multi-toed creature into the large, single-toed animal of today...

s, although newer medications with fewer side-effects are generally used instead. Both dogs and horses are susceptible to the gastrointestinal side-effects associated with salicylates, but it is a convenient treatment for arthritis in older dogs and has shown some promise in cases of laminitis
Laminitis
Laminitis is a disease that affects the feet of ungulates. It is best known in horses and cattle. Symptoms include lameness, and increased temperature in the hooves...

 in horses. Aspirin should be used in animals only under the direct supervision of a veterinarian
Veterinarian
A veterinary physician, colloquially called a vet, shortened from veterinarian or veterinary surgeon , is a professional who treats disease, disorder and injury in animals....

; in particular, cat
Cat
The cat , also known as the domestic cat or housecat to distinguish it from other felids and felines, is a small, usually furry, domesticated, carnivorous mammal that is valued by humans for its companionship and for its ability to hunt vermin and household pests...

s lack the glucuronide
Glucuronide
A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond...

conjugates that aid in the excretion of aspirin, making even low doses potentially toxic.

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