Aspirin

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Aspirin

Chemical name	2-(acetyloxy)benzoic acid
Chemical formula	C₉H₈O₄ C₆H₄(O COCH₃)COOH
Synonyms	2-acetyloxybenzoic acid 2-acetoxybenzoic acid acetylsalicylate acetylsalicylic acid O-acetylsalicylic acid
Molecular mass	180.57 g/mol
CAS number	50-78-2
ATC code	B01AC06
Density	1.40 g/cm³
Melting point	136°C (277°F)
Boiling point	140°C (284°F)
SMILES	CC(=O)OC1=CC=CC=C1C(=O)O
Disclaimer and references

Aspirin or acetylsalicylic acid is a drug in the family of salicylates, often used as an analgesic (against minor pains and aches), antipyretic (against fever), and anti-inflammatory. It has also an anticoagulant (blood thinning) effect and is used in long-term low-doses to prevent heart attacks.

Low-dose long-term aspirin irreversibly blocks formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation, and this blood thinning property makes it useful for reducing the incidence of heart attacks. Aspirin produced for this purpose often comes in 75 or 81 mg dispersible tablets and is sometimes called "baby aspirin." High doses of aspirin are also given immediately after an acute heart attack. These doses may also inhibit the synthesis of prothrombin and may therefore produce a second and different anticoagulant effect.

Several hundred fatal overdoses of aspirin occur annually, but the vast majority of its uses are beneficial. Its primary undesirable side effects, especially in stronger doses, are gastrointestinal distress (including ulcers and stomach bleeding) and tinnitus. Another side effect, due to its anticoagulant properties, is increased bleeding in menstruating women. Because there appears to be a connection between aspirin and Reye's syndrome, aspirin is no longer used to control flu-like symptoms in minors.

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, though they all have similar effects and a similar action mechanism.

Name

The brand name Aspirin was coined by the Bayer company of Germany. In some countries the name is used as a generic term for the drug rather than the manufacturer's trademark. In countries in which Aspirin remains a trademark, the initialism ASA is used as a generic term (ASS in German language countries, for Acetylsalicylsäure; AAS in Spanish and Portuguese language countries, for ácido acetilsalicílico).

The name "aspirin" is composed of a- (from the acetyl group) -spir- (from the spiraea flower) and -in (a common ending for drugs at the time). Bayer registered it as a trademark on March 6, 1899.

However, the German company lost the right to use the trademark in many countries as the Allies seized and resold its foreign assets after World War I. The right to use "Aspirin" in the United States (along with all other Bayer trademarks) was purchased from the U.S. government by Sterling Drug, Inc. in 1918. Even before the patent for the drug expired in 1917, Bayer had been unable to stop competitors from copying the formula and using the name elsewhere, and so with a flooded market, the public was unable to recognize "Aspirin" as coming from only one manufacturer. Sterling was subsequently unable to prevent "Aspirin" from being ruled a genericized trademark in a U.S. federal court in 1921. Sterling was ultimately acquired by Bayer in 1994, but this did not restore the U.S. trademark. Other countries (such as Canada) still consider "Aspirin" a protected trademark.

Discovery

File:Acetylsalicylicacid.jpg

Acetylsalicylic acid crystals

Hippocrates, a Greek physician, wrote in the 5th century BC about a bitter powder extracted from willow bark that could ease aches and pains and reduce fevers. This remedy is also mentioned in texts from ancient Sumeria, Egypt and Assyria. Native Americans claim to have used it for headaches, fever, sore muscles, rheumatism, and chills. The Reverend Edward Stone, a vicar from Chipping Norton in Oxfordshire England, noted in 1763 that the bark of the willow was effective in reducing a fever.

The active extract of the bark, called salicin, after the Latin name for the White willow (Salix alba), was isolated to its crystalline form in 1828 by Henri Leroux, a French pharmacist, and Raffaele Piria, an Italian chemist, who then succeeded in separating out the acid in its pure state. Salicin is highly acidic when in a saturated solution with water (pH = 2.4), and is called salicylic acid for that reason.

This chemical was also isolated from meadowsweet flowers (genus Filipendula, formerly classified in Spiraea) by German researchers in 1839. While their extract was somewhat effective, it also caused digestive problems such as irritated stomach and diarrhea, and even death when consumed in high doses. In 1853, a French chemist named Charles Frederic Gerhardt neutralized salicylic acid by buffering it with sodium (sodium salicylate) and acetyl chloride, creating acetosalicylic anhydride. Gerhardt's product worked but he had no desire to market it and abandoned his discovery. In 1897, Felix Hoffmann, a researcher at Friedrich Bayer & Co. in Germany, derivatized one of the hydroxyl functional groups in salicylic acid with an acetyl group (forming the acetyl ester) which greatly reduced the negative effects. This was the first synthetic drug, not a copy of something that existed in nature, and the start of the pharmaceuticals industry. Hoffmann made some of the formula and gave it to his father, who was suffering from the pain of arthritis and could not stand the side effects of salicylic acid. With good results, he then convinced Bayer to market the new wonder drug. Aspirin was patented on March 6, 1899. It was marketed alongside another of Hoffmann's products, an acetylated synthetic of morphine called Heroin. Heroin was initially the more successful of the two painkillers, but as Heroin's shortcoming of addictiveness became more obvious, Aspirin stepped to the forefront. Aspirin was originally sold as a powder and was an instant success; in 1915, Bayer introduced Aspirin tablets.

Advertisement for Aspirin, Heroin, Lycetol, Salophen

Several claims to invention of aspirin have arisen. Acetylsalicylic acid was already being manufactured by the Chemische Fabrik von Heyden Company in 1897, although without a brand name. Arthur Eichengrün claimed in 1949 that he planned and directed the synthesis of aspirin while Hoffmann's role was restricted to the initial lab synthesis using Eichengrün's process. In 1999, Walter Sneader of the Department of Pharmaceutical Sciences at the University of Strathclyde in Glasgow reexamined the case and agreed with Eichengrün's account. Bayer continues to recognize Felix Hoffmann as aspirin's official inventor. Despite its argued origin, Bayer's marketing was responsible for bringing it to the world.

It was not until the 1970s that the mechanism of action of aspirin and similar drugs called NSAIDs was elucidated (see below).

Synthesis of aspirin

File:Aspirin-synthesis.gif

Aspirin (acetylsalicylic acid) can be synthesized from salicylic acid and acetic anhydride. It is a common experiment performed in organic chemistry labs, and generally tends to produce low yields due to the relative difficulty of its extraction from an aqueous state.

How it works

In a piece of research for which he was awarded both a Nobel prize in Physiology or Medicine in 1982 and a knighthood, John Robert Vane, who was then employed by the Royal College of Surgeons in London, showed in 1971 that aspirin suppresses the production of prostaglandins and thromboxanes. This happens because cyclooxygenase, an enzyme which participates in the production of prostaglandins and thromboxanes, is irreversibly inhibited when aspirin acetylates it. This makes aspirin different from other NSAIDS (such as diclofenac and ibuprofen) which are reversible inhibitors.

Prostaglandins are local hormones (paracrine) produced in the body and have diverse effects in the body, including but not limited to transmission of pain information to the brain, modulation of the 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 their reduction with the introduction of small amounts of aspirin has been seen to be an effective medical intervention. The side effect of this is that the ability of the blood in general to clot is reduced, and excessive bleeding may result from the use of aspirin.

3d-model of chemical structure of aspirin

More recent work has shown that there are at least two different types of cyclooxygenase: COX-1 and COX-2. Aspirin inhibits both of them. Newer NSAID drugs called COX-2 selective inhibitors have been developed that only inhibit COX-2, with the hope that this would reduce the gastrointestinal side effects.

However, several of the new COX-2 selective inhibitors have been recently withdrawn, after evidence emerged that COX-2 inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the arteries in the body express COX-2, and by selectively inhibiting COX-2, prostaglandins (specifically PGF2) are downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anti-coagulative effect of PGF2 is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, rendering them "useless": an important difference with reversible inhibitors.

Additionally, aspirin has 2 additional modes of actions, contributing to its strong analgesic, antipyretic and antiinflammitive properties :

It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria.
It induces the formation of NO-radicals in the body that enable the white blood cells (leucocyts) to fight infections more effectively. This has been found recently by Dr. Derek W. Gilroy, winning Bayer's International Aspirin Award 2005.

Also recently aspirin has been proven to prevent carcinoma of the colon, if given in low doses over years.

Indications

Aspirin, as with many older drugs, has proven to be useful in many conditions, and despite its well-known toxicity, it is widely used, since physicians are familiar with its properties. Indications for its use include:

Fever
Pain (especially useful for conditions involving osteoid osteoma, arthritis and chronic pain)
Migraine
Myocardial infarction prophylaxis (low dose)
Rheumatic fever (drug of choice)

Contraindications and warnings

Do not take this medicine if you are allergic to aspirin, ibuprofen or naproxen.
Talk to your doctor if your symptoms do not improve after a few days of therapy.
If you have kidney disease, ulcers, mild diabetes, gout or gastritis, talk to your doctor before using this medicine.
Taking aspirin with alcohol increases the chance of stomach bleeding. Avoid alcohol with this medicine.
Giving aspirin to children, including teenagers having a cold or flu can cause a serious condition known as Reye's syndrome.
Patients with hemophilia, other bleeding tendencies, or a bleeding ulcer should not take salicylates.

Common side effects

Gastrointestinal complaints (stomach upset, dyspepsia, heartburn, small blood loss). To help avoid these problems, it is recommended that aspirin be taken at or after meals. Undetected blood loss may lead to hypochromic anemia.
Severe gastrointestinal complaints (gross bleeding and/or ulceration), requiring discontinuation and immediate treatment. Patients receiving high doses and/or long-term treatment should receive gastric protection with high dosed antacids, ranitidine or omeprazol.
Frequently central effects (dizziness, tinnitus, hearing loss, vertigo, centrally mediated vision disturbances, and headaches). The higher the daily dose is, the more likely it is that central nervous system side effects will occur.
Sweating, seen with high doses, independent from antipyretic action
Long-term treatment with high doses (arthritis and rheumatic fever): often increased liver enzymes without symptoms, rarely reversible liver damage. The potentially fatal Reye's syndrome may occur, if given to pediatric patients with fever and other signs of infections. The syndrome is due to fatty degeneration of liver cells. Up to 30 percent of those afflicted will eventually die. Prompt hospital treatment may be life-saving.
Chronic nephritis with long-term use, usually if used in combination with certain other painkillers. This condition may lead to chronic renal failure.
Prolonged and more severe bleeding after operations and post-traumatic for up to 10 days after the last aspirin dose. If one wishes to counteract the bleeding tendency, fresh thrombocyte concentrate will usually work.
Skin reactions, angioedema, and bronchospasm have all been seen infrequently.

Overdose

Aspirin overdose has serious consequences and is potentially lethal. Possible effects of overdose include tinnitus, abdominal pain, hypokalemia, hypoglycemia, pyrexia, hyperventilation, dysrhythmia, hypotension, hallucination, renal failure, confusion, seizure, coma and death.

Overdose can be acute or chronic; that is, a person can overdose by taking one very large dose or smaller doses 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%. The most common cause of death during an aspirin overdose is noncardiogenic pulmonary edema.

An acute overdose patient must be taken to a hospital immediately. Contrary to the urban legend, you can die from eating a bottle of pills, even if you subsequently throw up. Treatment of an acute overdose requires ingestion of activated charcoal to neutralize the acetylsalicylic acid in the gastrointestinal tract, followed by a stomach pump with subsequent re-ingestion of activated charcoal. Patients are then monitored for at least 24 hours and typically given intravenous potassium chloride to counteract hypokalemia, sodium bicarbonate to neutralize salicylate in the blood and restore the blood's sensitive pH balance, and dextrose to restore blood sugar levels. 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. If the overdose was intentional, the patient will undergo psychiatric evaluation as with any suicide attempt.

Fifty-two deaths involving single-ingredient aspirin were reported in the United States in the year 2000.^[1]

External links

References

^ Litovitz TL. 2000 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2001;19(5):337-395

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