• Albanian: aspirinë
• Armenian: ասպիրին
• Bulgarian: аспирин
• Czech: aspirin
• Dutch: aspirine
• Estonian: aspiriin
• Finnish: aspiriini
• French: aspirine
• German: Aspirin
• Greek: ασπιρίνη (aspirini)
• Italian: aspirina
• Japanese: アスピリン (asupirin)
• Mandarin: (āsīpǐlíng)
• Portuguese: aspirina
• Romanian: aspirină
• Russian: аспирин (aspirin)
• Spanish: aspirina , aspirinar

• Albanian: aspirinë
• Dutch: aspirientje
• Finnish: aspiriini

Derived terms

• aspirinate

Related terms

• NSAID

Czech

Noun

1. aspirin

Indonesian

Etymology

From aspirine.

Noun

1. aspirin

Aspirin, or acetylsalicylic acid () is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It also has an antiplatelet or "anti-clotting" effect and is used in long-term, low doses to prevent heart attacks, strokes and blood clot formation in people at high risk for developing blood clots. It has also been established that low doses of aspirin may be given immediately after a heart attack to reduce the risk of another heart attack or of the death of cardiac tissue.

The main undesirable side effects of aspirin are gastrointestinal—ulcers and stomach bleeding—and tinnitus, especially in higher doses. In children under 16 years of age, aspirin is no longer used to control flu-like symptoms or the symptoms of chickenpox, due to the risk of Reye's syndrome.

Aspirin was the first-discovered member of the class of drugs known as non-steroidal anti-inflammatory drugs (NSAIDs), not all of which are salicylates, although they all have similar effects and most have some mechanism of action which involves non-selective inhibition of the enzyme cyclooxygenase. Today, aspirin is one of the most widely used medications in the world, with an estimated 40,000 metric tons of it being consumed each year.

History

Medicines containing derivatives of salicylic acid, structurally similar to aspirin, have been in medical use since antiquity. Salicylate-rich willow bark extract became recognized for its specific effects on fever, pain and inflammation in the mid-eighteenth century. By the nineteenth century pharmacists were experimenting with and prescribing a variety of chemicals related to salicylic acid, the active component of willow extract.

A French chemist, Charles Frederic Gerhardt, was the first to prepare acetylsalicylic acid (named aspirin in 1899) in 1853. In the course of his work on the synthesis and properties of various acid anhydrides, he mixed acetyl chloride with a sodium salt of salicylic acid (sodium salicylate). A vigorous reaction ensued, and the resulting melt soon solidified. Since no structural theory existed at that time, Gerhardt called the compound he obtained "salicylic-acetic anhydride" (wasserfreie Salicylsäure-Essigsäure). This preparation of aspirin ("salicylic-acetic anhydride") was one of the many reactions Gerhardt conducted for his paper on anhydrides, and he did not pursue it further.

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

In 1897, scientists at the drug and dye firm Bayer began investigating acetylsalicylic acid as a less-irritating replacement for standard common salicylate medicines. By 1899, Bayer had dubbed this drug Aspirin and was selling it around the world. Aspirin's popularity grew over the first half of the twentieth century, spurred by its effectiveness in the wake of Spanish flu pandemic of 1918, and aspirin's profitability led to fierce competition and the proliferation of aspirin brands and products.

Aspirin's popularity declined after the development of acetaminophen in 1956 and ibuprofen in 1962. In the 1960s and 1970s, John Vane and others discovered the basic mechanism of aspirin's effects, while clinical trials and other studies from the 1960s to the 1980s established aspirin's efficacy as an anti-clotting agent that reduces the risk of clotting diseases. Aspirin sales revived considerably in the last decades of the twentieth century, and remain strong in the twenty-first, thanks to widespread use as a preventive treatment for heart attacks and strokes.

Therapeutic uses

Aspirin is one of the most frequently used drugs in the treatment of mild to moderate pain, including that of migraines and fever. It is often combined with other non-steroidal anti-inflammatory drugs and opioid analgesics in the treatment of moderate to severe pain.

In high doses, aspirin and other salicylates are used in the treatment of rheumatic fever, rheumatic arthritis, and other inflammatory joint conditions. In lower doses, aspirin also has properties as an inhibitor of platelet aggregation, and has been shown to decrease the incidence of transient ischemic attacks and unstable angina in men, and can be used prophylactically. It is also used in the treatment of pericarditis, coronary artery disease, and acute myocardial infarction. Low doses of aspirin are also recommended for the prevention of stroke, and myocardial infarction in patients with either diagnosed coronary artery disease or who have an elevated risk of cardiovascular disease.

Experimental uses

Aspirin has been theorized to reduce cataract formation in diabetic patients, but one study showed it was ineffective for this purpose. The role of aspirin in reducing the incidence of many forms of cancer has also been widely studied. In several studies, aspirin use did not reduce the incidence of prostate cancer. Its effects on the incidence of pancreatic cancer are mixed; one study published in 2004 found a statistically significant increase in the risk of pancreatic cancer among women, while a meta-analysis of several studies, published in 2006, found no evidence that aspirin or other NSAIDs are associated with an increased risk for the disease. The drug may be effective in reduction of risk of various cancers, including those of the colon, lung, and possibly the upper GI tract, though some evidence of its effectiveness in preventing cancer of the upper GI tract has been inconclusive.

Veterinary uses

Aspirin has been used to treat pain and arthritis in veterinary medicine, primarily in cats and dogs, although it is often not recommended for this purpose, as there are newer medications available with fewer side effects in these animals. Dogs, for example, are particularly susceptible to the gastrointestinal side effects associated with salicylates. Horses have also been given aspirin for pain relief, although it is not commonly used due to its relatively short-lived analgesic effects. Horses are also fairly sensitive to the gastrointestinal side effects. Nevertheless, it has shown promise in its use as an anticoagulant, mostly in cases of laminitis. Aspirin should only be used in animals under the direct supervision of a veterinarian.

Mechanism of action

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

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

Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation. This anticoagulant property makes aspirin useful for reducing the incidence of heart attacks. 40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane 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 hormones produced in the body and have diverse effects in the body, including the transmission of pain information to the brain, modulation of the hypothalamic thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets that form blood clots. Heart attacks are primarily caused by blood clots, and low doses of aspirin are seen as an effective medical intervention for acute myocardial infarction. The major side-effect of this is that because the ability of blood to clot is reduced, excessive bleeding may result from the use of aspirin.

There are at least two different types of cyclooxygenase: COX-1 and COX-2. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. Normally COX-2 produces prostanoids, most of which are pro-inflammatory. Aspirin-modified COX-2 produces lipoxins, most of which are anti-inflammatory. Newer NSAID drugs called COX-2 selective inhibitors have been developed that inhibit only COX-2, with the intent to reduce the incidence of gastrointestinal side-effects. In short, aspirin buffers and transports the protons. When high doses of aspirin are given, aspirin may actually cause fever due to the heat released from the electron transport chain, as opposed to the antipyretic action of aspirin seen with lower doses. Additionally, aspirin induces the formation of NO-radicals in the body, which have been shown in mice to have an independent mechanism of reducing inflammation. This reduced leukocyte adhesion, which is an important step in immune response to infection; however, there is currently insufficient evidence to show that aspirin helps to fight infection. More recent data also suggests that salicylic acid and its derivatives modulate signaling through NF-κB. NF-κB is a transcription factor complex that plays a central role in many biological processes, including inflammation.

Chemistry

Aspirin is an acetyl derivative of salicylic acid that is a white, crystalline, weakly acidic substance, with melting point 135°C. Acetylsalicylic acid decomposes rapidly in solutions of ammonium acetate or of the acetates, carbonates, citrates or hydroxides of the alkali metals. Acetylsalicylic acid is stable in dry air, but gradually hydrolyses in contact with moisture to acetic and salicylic acids. In solution with alkalis, the hydrolysis proceeds rapidly and the clear solutions formed may consist entirely of acetate and salicylate.

Synthesis

The synthesis of aspirin is classified as an esterification reaction, where the alcohol group from the salicylic acid reacts with an acid derivative (acetic anhydride), yielding aspirin and acetic acid as a byproduct. Small amounts of sulfuric acid are often used as a catalyst. This method is commonly employed in undergraduate teaching labs.

Formulations containing high concentrations of aspirin often smell like vinegar. This is because aspirin can decompose in moist conditions, yielding salicylic acid and acetic acid.

The acid dissociation constant (pKa) for Acetylsalicylic acid is 3.5 at 25 °C.

Polymorphism

Polymorphism, or the ability of a substance to form more than one crystal structure, is important in the development of pharmaceutical ingredients. Many drugs are receiving regulatory approval for only a single crystal form or polymorph. For a long time, only one crystal structure for aspirin was known, although there had been indications that 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 co-crystallization of aspirin and levetiracetam from hot acetonitrile. The form II is only stable at 100 K and reverts back to form I at ambient temperature. In the (unambiguous) form I, two salicylic molecules form centrosymmetric dimers through the acetyl groups with the (acidic) methyl proton to carbonyl hydrogen bonds, and in the newly claimed form II, each salicylic molecule forms the same hydrogen bonds with two neighboring molecules instead of one. With respect to the hydrogen bonds formed by the carboxylic acid groups both polymorphs form identical dimer structures.

Pharmacokinetics

Salicylic acid is a weak acid, and very little of it is ionized in the stomach after oral administration. Acetylsalicylic acid is poorly soluble in the acidic conditions of the stomach, which can delay absorption of high doses for 8 to 24 hours. In addition to the increased pH of the small intestine, aspirin is rapidly absorbed there due to the increased surface area, which in turn allows more of the salicylate to dissolve. Due to the issue of solubility, however, aspirin is absorbed much more slowly during overdose, and plasma concentrations can continue to rise for up to 24 hours after ingestion. The half-life of the active salicylic acid following therapeutic doses is usually 2 to 4.5 hours, but overdoses can increase this to 18 to 36 hours.

As much as 80% of theraputic doses of salicylic acid is metabolised in the liver. Conjugation with glycine forms salicyluric acid and with glucuronic acid forms salicyl acyl and phenolic glucuronide. These metabolic pathways have only a limited capacity. Small amounts of salicylic acid are also hydroxylated to gentisic acid. With large salicylate doses, the kinetics switch from first order to zero order, as metabolic pathways become saturated and renal excretion becomes increasingly important. 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 pH above pH 6. The use of urinary alkalinization exploits this particular aspect of salicylate elimination.

About 50–80% of salicylate in the blood is bound by protein while the rest remains in the active, ionized state; protein binding is concentration-dependent. Saturation of binding sites leads to more free salicylate and increased toxicity. The volume of distribution is 0.1–0.2 l/kg. Acidosis increases the volume of distribution because of enhancement of tissue penetration of salicylates or a more generalized drug intolerance to NSAIDs, and caution should be exercised in those with asthma or NSAID-precipitated bronchospasm. Due to its effect on the stomach lining, manufacturers recommend that patients with kidney disease, peptic ulcers, mild diabetes, gout or gastritis talk to their doctors before using aspirin. Even if none of these conditions are present, there is still an increased risk of stomach bleeding when aspirin is taken with alcohol or warfarin. Aspirin should not be given to children or adolescents to control cold or influenza symptoms as this has been linked with Reye's syndrome. For some people, aspirin does not have as strong an effect on platelets as for others, an effect known as aspirin "resistance" or insensitivity. One study has suggested that women are more likely to be resistant than men and a different, aggregate study of 2,930 patients found 28% to be resistant.

Adverse effects

Gastrointestinal side effects

Aspirin use has been shown to increase the risk of gastrointestinal bleeding. Although some enteric coated formulations of aspirin are advertised as being "gentle to the stomach", in one study enteric coating did not seem to reduce this risk.

Central effects

Large doses of salicylate, a metabolite of aspirin, have been proposed to cause tinnitis, based on the experiments in rats, via the action on arachidonic acid and NMDA receptors cascade.

Pediatrics

Reye's syndrome can occur when children or pediatric patients are given aspirin for a fever or other illnesses or infections. In one study, 213 patients under the age of 18 were reported for Reye's syndrome from the nationwide Reye's syndrome surveillance system. Out of 213 patients 211 had known that had another antecedent illness: 89% reported being ill (severe vomiting, mental strain, respiratory illness, vericella or gastrointestinal illness) two weeks before onset of Reye's syndrome. Salicylate levels, the active acid in aspirin, were present in 162 of the 213 patients.

Reye's syndrome is due to fatty deterioration of liver cells. In another study, 12 livers were obtained from children who had died from Reye's syndrome, and another liver from a child who died of accidental causes was used as a control. The autopsy stated in seven of the 12 livers, micro vesicular fatty change was present.

Other effects

Aspirin can cause prolonged bleeding after operations for up to 10 days. In one study, thirty patients were observed after their various surgeries. Twenty of the thirty patients had to have an additional unplanned operation because of postoperative bleeding. This diffuse bleeding was associated with aspirin alone or in combination with another NSAID in 19 out of the 20 who had to have another operation due to bleeding after their operation. The average recovery time for the second operation was 11 days.

Aspirin can induce angioedema in some people. In one study, angioedema appeared 1-6 hours after ingesting aspirin in some of the patients participating in the study. However, when the aspirin was taken alone it did not cause angioedema in these patients; the aspirin was either taken in combination with another NSAID-induced drug when angioedema appeared.

Interactions

Aspirin is known to interact with other drugs. For example, acetazolamide and ammonium chloride have been known to enhance the intoxicating effect of salicyclates, and alcohol also enhances the gastrointestinal bleeding associated with these types of drugs as well. Aspirin is known to displace a number of drugs from protein binding sites in the blood, including the anti-diabetic drugs tolbutamide and chlorpropamide, the immunosuppressant methotrexate, phenytoin, probenecid, valproic acid (as well as interfering with beta oxidation, an important part of valproate metabolism) and any nonsteroidal anti-inflammatory drug. Corticosteroids may also reduce the concentration of aspirin. The pharmacological activity of spironolactone may be reduced by taking aspirin, and aspirin is known to compete with Penicillin G for renal tubular secretion. Aspirin may also inhibit the absorption of vitamin C.

Dosage

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

Overdose

Aspirin overdose can be acute or chronic. In acute poisoning, a single large dose is taken; in chronic poisoning, supratherapeutic doses are taken over a period of time. Acute overdose has a mortality rate of 2%. Chronic overdose is more commonly lethal with a mortality rate of 25%; chronic overdose may be especially severe in children.

Symptoms

Aspirin overdose has potentially serious consequences, sometimes leading to significant morbidity and mortality. Patients with mild intoxication frequently have nausea and vomiting, abdominal pain, lethargy, tinnitus, and dizziness. More significant symptoms occur in more severe poisonings and include hyperthermia, tachypnea, respiratory alkalosis, metabolic acidosis, hyperkalemia, hypoglycemia, hallucinations, confusion, seizure, cerebral edema, and coma. The most common cause of death following an aspirin overdose is cardiopulmonary arrest usually due to pulmonary edema.

Toxicity

The toxic dose of aspirin is generally considered greater than 150 mg per kg of body mass. Moderate toxicity occurs at doses up to 300 mg/kg, severe toxicity occurs between 300 to 500 mg/kg, and a potentially lethal dose is greater than 500 mg/kg. This is the equivalent of many dozens of the common 325 mg tablets, depending on body weight. However children cannot tolerate as much aspirin per unit body weight as adults can.

Treatment

All overdose patients should be conveyed to a hospital for assessment immediately. Initial treatment of an acute overdose includes gastric decontamination. This is achieved by administering activated charcoal, which adsorbs the aspirin in the gastrointestinal tract. Stomach pumps are no longer routinely used in the treatment of poisonings but are sometimes considered if the patient has ingested a potentially lethal amount less than 1 hour previously. Repeated doses of charcoal have been proposed to be beneficial in aspirin overdose; however, one study found that repeat dose charcoal might not be of significant value. However, most toxicologists will administer additional charcoal if serum salicylate levels are increasing.

Patients are monitored until their peak salicylate blood level has been determined. Blood levels are usually assessed four hours after ingestion and then every two hours after that to determine the maximum level. Maximum levels can be used as a guide to toxic effects expected.

There is no antidote to salicylate poisoning. Frequent blood work is performed to check metabolic, salicylate, and blood sugar levels; arterial blood gas assessments are performed to test for respiratory alkalosis and metabolic acidosis. Patients are monitored and often treated according to their individual symptoms, patients may be given intravenous potassium chloride to counteract hypokalemia, glucose to restore blood sugar levels, benzodiazepines for any seizure activity, fluids for dehydration, and importantly sodium bicarbonate to restore the blood's sensitive pH balance. Sodium bicarbonate also has the effect of increasing the pH of urine, which in turn increases the elimination of salicylate. Additionally, hemodialysis can be implemented to enhance the removal of salicylate from the blood. Hemodialysis is usually used in severely poisoned patients; for example, patients with significantly high salicylate blood levels, significant neurotoxicity (agitation, coma, convulsions), renal failure, pulmonary edema, or cardiovascular instability are hemodialyzed.

See also

• Aspergum
• Copper aspirinate
• Non-steroidal anti-inflammatory drug
• History of aspirin
• Salicylic acid

References

External links

• DrugBank Aspirin Entry
• Reappraisal
• An aspirin a day keeps the doctor away
• Colour-enhanced scanning electron micrograph of aspirin crystals
• Aspirin research in the 1990s
• The History of Aspirin
• Aspirin and heart disease
• How Aspirin works
• Molview from bluerhinos.co.uk See Aspirin in 3D
• History of Aspro
• The science behind aspirin
• Take two: Aspirin, New uses and new dangers are still being discovered as aspirin enters its second century. Shauna Roberts, American Chemical Society
• http://www.madehow.com/Volume-1/Aspirin.html