Aspirin

Overview

Aspirin is a trade name for acetylsalicylic acid (ASA), a mild, nonnarcotic analgesic that was first marketed by the Bayer Company in 1899. Until the end of World War I, the name "Aspirin" (with a capital A) was a trademark of the German firm Bayer. Aspirin quickly became one of the most widely used drugs in the world, but disputes over the discovery of aspirin were still raging at the end of the twentieth century. Often called a miracle drug, aspirin was originally prescribed for the relief of inflammation, headaches, muscle pains, and fever. Before the introduction of antibiotics, aspirin was also used in the treatment of rheumatic fever, rheumatoid arthritis, and infections. Although aspirin generally does not modify or shorten the duration of these diseases, it does relieve some of their symptoms. One hundred years after it was first marketed, scientists continue to find new uses for aspirin. Indeed, statistical evidence indicates that taking aspirin can reduce the risk of a second heart attack and may reduce the risk of heart disease, colon cancer, and preeclampsia during pregnancy.

Background

During the time of Hippocrates (460-377 b.c.), a preparation made from the bark and leaves of the willow tree was prescribed as an analgesic and antipyretic. (Analgesics are drugs that alleviate pain without affecting consciousness and antipyretics are used to reduce fevers.) The antipyretic properties of willow bark were rediscovered in the eighteenth century, but the active ingredient, salicin, was not isolated until 1828. Many other important drugs were first isolated from plant sources during the nineteenth century. Among the alkaloids purified during this time period were narcotine, morphine, emetine, strychnine, brucine, piperine, colchicine, quinine, nicotine, atropine, cocaine, and physostigmine. Chemical purification made it possible to study the active factors of these substances and to eliminate the toxic effects of impurities. Progress in pharmacology also made it possible to prescribe accurate doses of purified compounds. As scientists elucidated the chemical structures of pharmacologically active compounds, they were able to synthesize important derivatives of existing drugs and create entirely new drugs in the laboratory.

Although salicin, salicylic acid, and sodium salicylate were introduced as pain relievers in the 1870s, the salicylates caused nausea, ringing in the ears, and irritation to the stomach lining. Based on experience with other drugs, Bayer chemists hoped that adding an acetyl group to salicylic acid would make it less irritating to the stomach. (Indeed, adding acetyl groups to the morphine molecule led to the production of another highly successful Bayer product that was sold under the trademarked name "Heroin" as a new and superior cough suppressant.)

In 1897 Felix Hoffman (1868-1946), a German chemist working for Bayer, synthesized and purified acetylsalicylic acid. Two years later, the drug was given the trademark name "Aspirin" (A for acetyl chloride, spir from the plant Spiraea ulmaria, and in being a common ending for names of medicines) and was distributed to physicians and hospitals for testing. Pleased by the enthusiastic response of patients and physicians, Bayer marketed the analgesic as a safe remedy for the treatment of arthritis, joint pains, muscle pains, and fever. Aspirin was sold as a powder until 1915, when Bayer began to market Aspirin tablets. Until 1915, Aspirin, which would become one of the most popular over-the-counter drugs for self-medication, was not available to patients unless they obtained a prescription from their doctor.

Within a few years of each other, Bayer had named and marketed both Aspirin and Heroin, two drugs that were to remain among the most widely used and abused in Western society over a hundred years later. Until the end of World War I, the Bayer Company maintained its valuable trademark protection for Aspirin and Heroin. After Germany's defeat, however, Bayer was forced to give up these trademarks as part of the country's war reparations. In 1919 the Treaty of Versailles assigned Bayer's trademarks to France, England, Russia, and the United States. Eventually, "aspirin" and "heroin" became the common names of these drugs. Bayer Aspirin, however, remained the most familiar brand in what would become a highly competitive analgesic market. Advertisements touted Bayer's product as "pure aspirin, not part aspirin" and claimed that "nine out of ten doctors recommend Bayer's aspirin." Other pharmaceutical companies sold aspirin in combination with caffeine, antacids, and special coatings, but no medical studies have found any version of the drug to be better than plain aspirin for headaches, fever, and inflammation.

Bayer had established its presence in the United States as early as 1903, when Friedrich Carl Duisberg Jr. (1861-1935) came from Germany to Rensselaer, New York, to build a chemical plant. The most important product of this plant was Bayer Aspirin. Duisberg was a chemist and the founder of the industrial empire known as I.G. Farbenindustrie (or I.G. Farben), the chemical empire that became identified with Nazi Germany. After World War II, the directors of I.G. Farben were tried along with Nazi war criminals at Nuremberg.

Impact

The Bayer Company had begun as Friedrich Bayer & Company, one of Germany's first dye factories. Friedrich Bayer and Johann Friedrich Weskott established the firm in 1863. After Weskott and Bayer died, the firm was managed by Carl Rumpff, Bayer's son-in-law. The firm then became officially known as Farbenfabriken vormals Friedrich Bayer & Company ("the Dye Factory formerly known as Friedrich Bayer & Company"). When Rumpff died in 1890, Duisberg assumed leadership of the company. As the director of Bayer's research and patent program, part of Duisberg's job was to diversify production and create new products. Duisberg thought that the market for antipyretics—then limited to salicylic acid, quinine, antipyrine, and acetanilid (Antifebrin)—was promising. Acetanilid, a coal-tar derivative whose antipyretic properties were discovered in 1886, was the first German drug to be marketed by a commercial name rather than its chemical or generic name. Seeing the successful marketing of Antifebrin, Duisberg decided to enter the market for fever and pain relievers.

Ernst Arthur Eichengrün (1867-1949), a research chemist who ran the pharmaceutical section of Bayer's drug laboratory, assigned the task of producing a form of salicylic acid with fewer side effects to Felix Hoffmann. According to Hoffmann's laboratory notes, he isolated acetylsalicylic acid (ASA), a derivative of salicylic acid, on October 10, 1897. Although the same compound had been produced by the French chemist Charles Frédéric Gerhardt in 1853 and by the German chemist Karl Johann Kraut in 1869, Hoffmann's methods were an improvement over those of his predecessors.

When the drug was tested by Heinrich Dreser (1860-1924), who, as the director of the pharmacological section of Bayer's drug laboratory, had to approve all the drugs prepared by Eichengrün and his associates, it was initially rejected. Apparently, Dreser thought that ASA might "enfeeble" or exhaust the heart, much like salicylic acid. Because these drugs were often given in large doses for the pain and swelling of rheumatic fever, many patients experienced severe reactions, including shortness of breath, panting, and the feeling that their hearts were racing. Thus, Bayer ignored ASA for over a year while the company promoted its successful new drug, Heroin. In 1898, at the Congress of German Naturalists and Physicians, Dreser announced that Heroin was ten times as effective as codeine as a cough medicine and only one-tenth as toxic. Heroin was promoted as a safe, nonhabit-forming drug that could be used to treat colic in babies and to cure morphine addiction.

Eichengrün, who resented Dreser's veto power, tested ASA himself and passed it on to doctors, who reported that it relieved fevers, aching joints, and headaches. When Dreser was finally forced to accept ASA, he wrote a paper on its beneficial properties but neglected to mention either Hoffmann or Eichengrün. Dreser earned royalties on sales of ASA and became wealthy, but Hoffmann and Eichengrün did not share in this wealth because they could only receive royalties for drugs that had been patented. The German patent office refused to patent ASA because it was not a new product nor did its synthesis involve a new process. Bayer fought for patent protection in other nations—with varying success. Notably, Bayer enjoyed both trademark and patent protection on Aspirin only in the United States. In 1899 Bayer began distributing Aspirin to doctors, medical professors, and hospitals. By 1902 about 160 scientific studies had been reported and a voluminous literature on Aspirin had been published. Most reports were very positive. The drug was taken for long periods of time in large doses for inflammation and arthritis. Smaller doses of Aspirin were prescribed for fevers and headaches.

One hundred years after Bayer introduced Aspirin, Walter Sneader, a Scottish scientist and an expert on the history of pharmacology, announced that the man who deserved credit for the discovery of aspirin was not Hoffmann but Eichengrün. Because Eichengrün was Jewish, he had been incarcerated in a concentration camp during World War II and his role in the success of Bayer Aspirin concealed by the Nazis. Although Hoffmann did indeed synthesize and purify acetylsalicylic acid in 1897, the project had been initiated and supervised by Eichengrün. It was not until 1934 that Hoffmann began to assert that he had discovered Aspirin. By that time, however, the Nazis were in power and Eichengrün was unable to challenge Hoffmann's story. After the war, Eichengrün attempted to correct the commonly accepted story of the discovery of aspirin, but he died in 1949, shortly after his account was published. While examining Hoffmann's laboratory notes, Sneader found that Hoffman had adapted methods previously developed by Eichengrün.

Of all the products sold by Bayer in the United States, Aspirin quickly became the most important. By 1909 it accounted for over 31% of Bayer's total sales in the United States. Because Bayer did not have patent protection for Aspirin in Canada, lower-priced Aspirin was smuggled into the United States from Canada, where it sold for about one-third the price. In 1910 the Bayer Company successfully sued a pharmaceutical dealer engaged in smuggling and its American patent was upheld. Bayer, however, estimated that counterfeit Aspirin held about 75% of the American market.

In anticipation of the expiration of patent protection in 1917, Bayer tried to boost sales by bringing the trademarked Bayer Aspirin name to the public. Aspirin tablets were stamped with the Bayer Cross and tablets were enclosed in Bayer packages. The change from powder to tablets had begun in 1914. In 1916 the company began placing ads for Bayer Aspirin in American newspapers. The American Medical Association, which was opposed to the advertising of trademarked or patented products, argued that ASA should be sold under its generic name and that Bayer should not have a monopoly on the drug. At the end of World War I, the U.S. government sold the American assets of Farbenfabriken Bayer to American businesses.

The mechanism by which aspirin works was discovered in the 1970s by the British pharmacologist John Vane (1927- ), a 1982 Nobel laureate, who found that aspirin inhibited the release of the hormone-like substances called prostaglandins. Prostaglandins were discovered in 1935 by the Swedish physiologist and 1970 Nobel laureate Ulf Svante von Euler (1905-1983). Prostaglandins are modified fatty acids that have diverse functions in the body; they affect blood-vessel elasticity, blood platelets and clotting, the functioning of the digestive tract, sensitivity to pain, and inflammation. The studies by these researchers have provided a molecular explanation for using aspirin in the treatment of cardiovascular disease and inflammatory diseases, including rheumatoid arthritis.

Of course, taking aspirin is not without risk. Aspirin can cause allergic reactions and gastrointestinal problems. In children with viral infections such as influenza or chicken pox, the use of aspirin has been linked to the onset of Reye's syndrome, an acute disorder of the liver and central nervous system.

Many other drugs, such as acetaminophen, ibuprofen, naproxyn sodium, and ketoprofen, have challenged aspirin's place as an analgesic. Other pain relievers, however, do not seem to mimic aspirin's beneficial impact on cardiovascular health. Although in the 1920s Bayer's advertisements assured consumers that Aspirin would not affect the heart, clinical studies in the 1940s indicated that men who took aspirin were less likely to suffer heart attacks. Some physicians began to suggest that all their patients should take an aspirin tablet every day to reduce the risk of a heart attack. By the end of the twentieth century, aspirin was being prescribed by physicians as a means of preventing heart attacks. Most of the 80 million aspirin tablets taken by Americans every day in the 1990s were taken to reduce the risk of heart disease and stroke. More medical uses for aspirin are still under study, including the treatment of migraine headaches, the prevention of various cancers, and the improvement of memory and brain function.

LOIS N. MAGNER

Further Reading

Ackerknecht, E. H. Therapeutics: From the Primitives to the 20th Century. New York: Hafner Press, 1973.

Barnett, H. J. M., and J. F. Mustard, eds. Acetylsalicylic Acid: New Uses for an Old Drug. New York: Raven Press, 1982.

Borkin, J. The Crime and Punishment of I.G. Farben. New York: The Free Press, 1978.

Fields, W., and N. Lemak. A History of Stroke. New York: Oxford University Press, 1989.

Irwin, Michael H. K. "Aspirin: Current Knowledge about an Old Medication." (Public Affairs Pamphlet, No. 614.) New York: Public Affairs Committee, 1983.

Jones, Charlotte Foltz. Mistakes That Work. New York: Doubleday, 1991.

Mann, Charles C., and Mark L. Plummer. The Aspirin Wars: Money, Medicine, and 100 Years of Rampant Competition. New York: Alfred A. Knopf, 1991.

Vane, John R., and Regina M. Botting, eds. Aspirin and Other Salicylates. New York: Chapman & Hall Medical, 1992.

Young, James Harvey. The Toadstool Millionaires: A Social History of Patent Medicines before Federal Regulation. Princeton, NJ: Princeton University Press, 1961.

Aspirin

Background

Aspirin is one of the safest and least expensive pain relievers on the marketplace. While other pain relievers were discovered and manufactured before aspirin, they only gained acceptance as over-the-counter drugs in Europe and the United States after aspirin's success at the turn of the twentieth century.

Today, Americans alone consume 16,000 tons of aspirin tablets a year, equaling 80 million pills, and we spend about $2 billion a year for non-prescription pain relievers, many of which contain aspirin or similar drugs.

Currently, the drug is available in several dosage forms in various concentrations from .0021 to .00227 ounces (60 to 650 milligrams), but the drug is most widely used in tablet form. Other dosage forms include capsules, caplets, suppositories and liquid elixir.

Aspirin can be used to fight a host of health problems: cerebral thromboses (with less than one tablet a day); general pain or fever (two to six tablets a day; and diseases such as rheumatic fever, gout, and rheumatoid arthritis. The drug is also beneficial in helping to ward off heart attacks. In addition, biologists use aspirin to interfere with white blood cell action, and molecular biologists use the drug to activate genes.

The wide range of effects that aspirin can produce made it difficult to pinpoint how it actually works, and it wasn't until the 1970s that biologists hypothesized that aspirin and related drugs (such as ibuprofen) work by inhibiting the synthesis of certain hormones that cause pain and inflammation. Since then, scientists have made further progress in understanding how aspirin works. They now know, for instance, that aspirin and its relatives actually prevent the growth of cells that cause inflammation.

History

The compound from which the active ingredient in aspirin was first derived, salicylic acid, was found in the bark of a willow tree in 1763 by Reverend Edmund Stone of Chipping-Norton, England. (The bark from the willow tree—Salix Alba—contains high levels of salicin, the glycoside of salicylic acid.) Earlier accounts indicate that Hippocrates of ancient Greece used willow leaves for the same purpose—to reduce fever and relieve the aches of a variety of illnesses.

During the 1800s, various scientists extracted salicylic acid from willow bark and produced the compound synthetically. Then, in 1853, French chemist Charles F. Gerhardt synthesized a primitive form of aspirin, a derivative of salicylic acid. In 1897 Felix Hoffmann, a German chemist working at the Bayer division of I.G. Farber, discovered a better method for synthesizing the drug. Though sometimes Hoffmann is improperly given credit for the discovery of aspirin, he did understand that aspirin was an effective pain reliever that did not have the side effects of salicylic acid (it burned throats and upset stomachs).

Bayer marketed aspirin beginning in 1899 and dominated the production of pain relievers until after World War I, when Sterling Drug bought German-owned Bayer's New York operations. Today, "Aspirin" is a registered trademark of Bayer in many countries around the world, but in the United States and the United Kingdom aspirin is simply the common name for acetylsalicylic acid.

The manufacture of aspirin has paralleled advancements in pharmaceutical manufacturing as a whole, with significant mechanization occurring during the early twentieth century. Now, the manufacture of aspirin is highly automated and, in certain pharmaceutical companies, completely computerized.

While the aspirin production process varies between pharmaceutical companies, dosage forms and amounts, the process is not as complex as the process for many other drugs. In particular, the production of hard aspirin tablets requires only four ingredients: the active ingredient (acetylsalicylic acid), corn starch, water, and a lubricant.

Raw Materials

To produce hard aspirin tablets, corn starch and water are added to the active ingredient (acetylsalicylic acid) to serve as both a binding agent and filler, along with a lubricant. Binding agents assist in holding the tablets together; fillers (diluents) give the tablets increased bulk to produce tablets of adequate size. A portion of the lubricant is added during mixing and the rest is added after the tablets are compressed. Lubricant keeps the mixture from sticking to the machinery. Possible lubricants include: hydrogenated vegetable oil, stearic acid, talc, or aluminum stearate. Scientists have performed considerable investigation and research to isolate the most effective lubricant for hard aspirin tablets.

Chewable aspirin tablets contain different diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, which allow the tablet to dissolve at a faster rate and give the drug a pleasant taste. In addition, flavor agents, such as saccharin, and coloring agents are added to chewable tablets. The colorants currently approved in the United States include: FD&C Yellow No. 5, FD&C Yellow No. 6, FD&C Red No.3, FD&C Red No. 40, FD&C Blue No. 1, FD&C Blue No. 2, FD&C Green No. 3, a limited number of D&C colorants, and iron oxides.

The Manufacturing
Process

Aspirin tablets are manufactured in different shapes. Their weight, size, thickness, and hardness may vary depending on the amount of the dosage. The upper and lower surfaces of the tablets may be flat, round, concave, or convex to various degrees. The tablets may also have a line scored down the middle of the outer surface, so the tablets can be broken in half, if desired. The tablets may be engraved with a symbol or letters to identify the manufacturer.

Aspirin tablets of the same dosage amount are manufactured in batches. After careful weighing, the necessary ingredients are mixed and compressed into units of granular mixture called slugs. The slugs are then filtered to remove air and lumps, and are compressed again (or punched) into numerous individual tablets. (The number of tablets will depend on the size of the batch, the dosage amount, and the type of tablet machine used.) Documentation on each batch is kept throughout the manufacturing process, and finished tablets undergo several tests before they are bottled and packaged for distribution.

The procedure for manufacturing hard aspirin tablets, known as dry-granulation or slugging, is as follows:

Weighing

• 1 The corn starch, the active ingredient, and the lubricant are weighed separately in sterile canisters to determine if the ingredients meet pre-determined specifications for the batch size and dosage amount.

Mixing

• 2 The corn starch is dispensed into cold purified water, then heated and stirred until a translucent paste forms. The corn starch, the active ingredient, and part of the lubricant are next poured into one sterile canister, and the canister is wheeled to a mixing machine called a Glen Mixer. Mixing blends the ingredients as well as expels air from the mixture.
• 3 The mixture is then mechanically separated into units, which are generally from 7/8 to 1 inches (2.22 to 2.54 centimeters) in size. These units are called slugs.

Dry screening

• 4 Next, small batches of slugs are forced through a mesh screen by a hand-held stainless steel spatula. Large batches in sizable manufacturing outlets are filtered through a machine called a Fitzpatrick mill. The remaining lubricant is added to the mixture, which is blended gently in a rotary granulator and sifter. The lubricant keeps the mixture from sticking to the tablet machine during the compression process.

Compression

• 5 The mixture is compressed into tablets either by a single-punch machine (for small batches) or a rotary tablet machine (for large scale production). The majority of single-punch machines are power-driven, but hand-operated models are still available. On single-punch machines, the mixture is fed into one tablet mold (called a dye cavity) by a feed shoe, as follows:
  • The feed shoe passes over the dye cavity and releases the mixture. The feed shoe then retracts and scrapes all excess mixture away from the dye cavity.
  • A punch—a short steel rod—the size of the dye cavity descends into the dye, compressing the mixture into a tablet. The punch then retracts, while a punch below the dye cavity rises into the cavity and ejects the tablet.
  • As the feed shoe returns to fill the dye cavity again, it pushes the compressed tablet from the dye platform.
• On rotary tablet machines, the mixture runs through a feed line into a number of dye cavities which are situated on a large steel plate. The plate revolves as the mixture is dispensed through the feed line, rapidly filling each dye cavity. Punches, both above and below the dye cavities, rotate in sequence with the rotation of the dye cavities. Rollers on top of the upper punches press the punches down onto the dye cavities, compressing the mixture into tablets, while roller-activated punches beneath the dye cavities lift up and eject the tablets from the dye platform.

Testing

• 6 The compressed tablets are subjected to a tablet hardness and friability test, as well as a tablet disintegration test (see Quality Control section below).

Bottling and packaging

• 7 The tablets are transferred to an automated bottling assembly line where they are dispensed into clear or color-coated polyethylene or polypropylene plastic bottles or glass bottles. The bottles are topped with cotton packing, sealed with a sheer aluminum top, and then sealed with a plastic and rubber child-proof lid. A sheer, round plastic band is then affixed to the circular edge of the lid. It serves as an additional seal to discourage and detect product tampering.
• 8 The bottles are then labeled with product information and an expiration date is affixed. Depending on the manufacturer, the bottles are then packaged in individual cardboard boxes. The packages or bottles are then boxed in larger cardboard boxes in preparation for distribution to distributors.

Quality Control

Maintaining a high degree of quality control is extremely important in the pharmaceutical manufacturing industry, as well as required by the Food and Drug Administration (FDA). All machinery is sterilized before beginning the production process to ensure that the product is not contaminated or diluted in any way. In addition, operators assist in maintaining an accurate and even dosage amount throughout the production process by performing periodic checks, keeping meticulous batch records, and administering necessary tests. Tablet thickness and weight are also controlled.

Once the tablets have been produced, they undergo several quality tests, such as tablet hardness and friability tests. To ensure that the tablets won't chip or break under normal conditions, they are tested for hardness in a machine such as the Schleuniger (or Heberlein) Tablet Hardness Tester. They are also tested for friability, which is the ability of the tablet to withstand the rigors of packaging and shipping. A machine called a Roche Friabilator is used to perform this test. During the test, tablets are tumbled and exposed to repeated shocks.

Another test is the tablet disintegration test. To ensure that the tablets will dissolve at the desirable rate, a sample from the batch is placed in a tablet disintegration tester such as the Vanderkamp Tester. This apparatus consists of six plastic tubes open at the top and bottom. The bottoms of the tubes are covered with a mesh screen. The tubes are filled with tablets and immersed in water at 37 degrees Fahrenheit (2.77 degrees Celsius) and retracted for a specified length of time and speed to determine if the tablets dissolve as designed.

Where To Learn More

Books

HIJSA'S Pharmaceutical Dispensing, 6th edition, Mack Publishing Company, 1966.

History of Pharmacy, 4th edition, The American Institute of History of Pharmacy, 1986.

An Introduction to Pharmaceutical Formulation, Pergamon Press, 1965.

Mann, Charles C. The Aspirin Wars: Money, Medicine & One Hundred Years of Rampant Competition. Alfred A. Knopf, Inc. 1991.

Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing, 1985.

Periodicals

Draper, Roger. "A Pharmaceutical Cinderella (History of Aspirin)," The New Leader. January 13, 1992, p. 16.

Weissmann, Gerald. "Aspirin," Scientific American. January, 1991, pp. 84-90.

Wickens, Barbara. "Aspirin: What's in a Name?," Maclean's. July 16, 1990, p. 40.

—Greg Ling

Aspirin

Definition

Aspirin, acetylsalicylic acid, is a drug used to treat mild pain , reduce fever and inflammation, and prevent heart attacks and strokes.

Description

Aspirin is a derivative of salicylic acid, which has been used medicinally for thousands of years. The first record of its use survives from ancient Egypt, about 3,500 years ago. Plant products containing salicylates are described in the Ebers papyrus. Hippocrates, Celsus, Pliny the Elder, Dioscorides, and Galen all recommended decoctions containing salicylate for rheumatic pain. In 1763, Edward Stone reported in England what may have been the first clinical trial of salicylates using willow bark that had been dried and suspended in tea, beer, or water.

Natural preparations of salicylates, although effective for pain relief and reduction of fever, frequently caused stomach upset. According to the Aspirin Foundation, which is supported by Bayer Healthcare, a major international marketer of aspirin, salicylic acid was first synthesized in 1859 and was marketed as an antiseptic, although it was of no value for that purpose. Acetylsalicylic acid was first prepared by the French chemist Charles Gerhardt in 1853, but he did not succeed in identifying its structure and did not attempt to market the product. Aspirin was first marketed for medicinal uses around 1900. The name aspirin was used as a trademark by Bayer and is still a protected trademark in some nations, although in others, including the United States, the term is now considered the generic name for the compound.

The mechanism of action of aspirin was first reported by Sir John Vane (1927–2004) in 1971. For this achievement, he was awarded the 1982 Nobel Prize in Medicine and received his knighthood in 1983. He found that aspirin has both pain-killing and anti-inflammatory action.

The professional labeling of aspirin, the information provided to physicians and surgeons, includes the following uses:

• Reduces the combined risk of death and nonfatal stroke in patients who have had ischemic stroke or transient ischemia of the brain due to fibrin platelet emboli
• Reduces the risk of vascular mortality in patients with a suspected acute myocardial infarction (MI, heart attack). A 2007 review indicated that aspirin may be more effective for this purpose in men than in women.
• Reduces the combined risk of death and nonfatal MI in patients with a previous MI or unstable angina pectoris. There is no evidence that aspirin can reduce the risk of a first heart attack, and daily aspirin has not been recommended for persons who have not had a heart attack.
• Reduces the combined risk of MI and sudden death in patients with chronic stable angina pectoris.
• Relieves signs and symptoms of rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, spondyloarthropathies, and arthritis and pleurisy associated with systemic lupus erythematosis (SLE)

For general use, aspirin serves for short-term relief of pain due to the following:

• Headache (including migraine and tension headaches)
• Pain and fever of colds
• Muscle aches and pains
• Menstrual pain
• Toothache pain
• Minor aches and pains of arthritis

There have been observations that people using aspirin on a regular basis may have a lower frequency of some conditions including breast and colon cancer and dementia. There are no conclusive studies to back these observations, which are anecdotal only. However, in one study, two non-steroidal anti-inflammatory drugs (NSAIDs), which would have been expected to have the same benefits as aspirin, failed to provide any protection against dementia.

Recommended dosage

For relief of minor pain and fever, the usual dose is 650 milligrams every 4 hours as needed. High dose regimens are normally discontinued when stomach upset occurs or when individuals experience tinnitus , ringing in the ears, which is a sign of aspirin toxicity.

• Ischemic stroke and TIA: 50 to 325 mg once a day; continue therapy indefinitely.
• Suspected acute MI: The initial dose of 160 to 162.5 mg administered as soon as an MI is suspected. The maintenance dose of 160 to 162.5 mg a day is continued for 30 days post-infarction. After 30 days, consider further therapy based on dosage and administration for prevention of recurrent MI.
• Prevention of recurrent MI: 75 to 325 mg once a day; continue therapy indefinitely. In the immediate aftermath of an MI, aspirin is commonly used in conjunction with other anticoagulant drugs such as warfarin, clopidogrel, or dipyridamole. The decision regarding how long to continue other drugs is usually left to the clinician.
• Unstable angina pectoris: 75 to 325 mg once a day; continue therapy indefinitely.
• Chronic stable angina pectoris: 75–325 mg once a day. Continue therapy indefinitely l CABG: 325 mg daily starting 6 hours post-procedure; Continue therapy for 1 year post-procedure.
• Rheumatoid arthritis: Initial dose is 3 g a day in divided doses. Increase as needed for anti-inflammatory efficacy with target plasma salicylate levels of 150 to 300 mcg/mL. At high doses (i.e., plasma levels of greater than 200 mcg/mL), the incidence of toxicity increases.
• Juvenile rheumatoid arthritis: Initial dose is 90 to 130 mg/kg/day in divided doses. Increase as needed for anti-inflammatory efficacy with target plasma salicylate levels of 150 to 300 mcg/mL. At high doses (i.e., plasma levels of greater than 200 mcg/mL), the incidence of toxicity increases.
• Spondyloarthropathies: Up to 4 g per day in divided doses.
• Osteoarthritis: Up to 3 g per day in divided doses.
• Arthritis and pleurisy of SLE: The initial dose is 3 g a day in divided doses. Increase as needed for anti-inflammatory efficacy with target plasma salicylate levels of 150 to 300 mcg/mL. At high doses (i.e., plasma levels of greater than 200 mcg/mL, the incidence of toxicity increases.

Precautions

Aspirin should not be used by people with known sensitivity to the drug, by people with liver or kidney insufficiency, or by people with blood coagulation disorders. People taking anti-coagulant drugs should consult their physician before taking aspirin.

QUESTIONS TO ASK YOUR PHARMACIST

• What are the benefits of special formulations of aspirin, including buffered and coated tablets?
• Is there a difference between generic and brand name products?
• What possible side interactions could there be with the medications I already take?

Because salicylates lower blood sugar, they should be used with caution by diabetics. Use of aspirin or other salicylate may require adjustment of insulin dosages.

Aspirin is particularly harmful to the stomach and should be avoided or used with caution by people with stomach ulcers or a history of stomach ulcers.

Side effects

The most common adverse effects of aspirin are related to harm to the stomach and intestines. The most frequently seen problems are nausea, vomiting, stomach pain, and heartburn .

Other side effects and adverse effects may be more serious. The following adverse effects require prompt medical attention: hives; rash;swelling of the eyes, face, lips, tongue, or throat; wheezing or difficulty breathing; hoarseness; fast heartbeat; fast breathing; cold, clammy skin;ringing in the ears; loss of hearing; bloody vomit; vomiting material that looks like coffee grounds; bright red blood in stools; and black or tarry stools.

Interactions

Aspirin may reduce the effectiveness of angiotensin converting enzyme (ACE) inhibitors, drugs used to lower blood pressure . If high dose aspirin is required, blood pressure must be monitored and dosages may need adjusting.

Aspirin, when used at the same time as acetazolamide (used for treatment of glaucoma ) may lead to elevated acetazolamide levels.

Aspirin should be used with care when taken with warfarin (an anticoagulant). Although it is common to use these two drugs in combination in patients after a heart attack , aspirin may increase blood levels of warfarin. Monitoring of coagulation time is essential.

Aspirin may reduce the effects of beta-blockers (used to lower blood pressure, regulate the heart rate, and for other purposes).

KEY TERMS

Angina pectoris —Severe chest pain caused by inadequate blood supply to the heart.

Embolus —Blockage of an artery by a blood clot.

Fibrin —A fibrous protein which is part of a blood clot.

Ischemic stroke —A form of stroke caused by a clot blocking the blood supply to the brain.

Juvenile arthritis —

Myocardial infarction —A heart attack caused by a blood clot blocking blood supply to the heart.

Osteoarthritis —A form of joint pain caused by deterioration of the cartilage at the ends of joint.

Salicylates —Compounds formed from reactions with salicylic acid.

Tinnitus —Ringing in the ears.

Transient ischemic attack (TIA) —A mini-stroke, a short period of inadequate blood supply to the brain, usually marked by blurred vision, dizziness, numbness.

Vascular —Pertaining to the circulatory system, the arteries, veins, and microcirculation.

The effectiveness of diuretic drugs may be reduced when taken at the same time as aspirin.

Salicylate can inhibit renal clearance of methotrexate (used for treatment of some cancers, some skin diseases, and forms of arthritis), leading to bone marrow toxicity, especially in the elderly or renally impaired.

Aspirin should not be used in combination with other NSAIDs, since their adverse effects are very similar and additive toxicity may occur.

Caregiver concerns

The first warning of aspirin toxicity is tinnitus, ringing in the ears. This effect may be less pronounced in people with high frequency hearing loss , which is common in the elderly. Additional monitoring may required.

Aspirin with a strong vinegar-like order should not be used. This is a sign that the aspirin has degraded into acetic acid (vinegar) and salicylic acid. Store aspirin in a dry location, since moisture accelerates this break-down.

Aspirin should be taken with a full glass of water to reduce the risk that the tablets will get stuck in the throat.

Sustained action and delayed action aspirin tablets should never be crushed.

Resources

PERIODICALS

Newton, J. L. “Improving the Gastrointestinal Tolerability of Aspirin in Older People.” Clin Interv Aging 1, no. 1 (2006): 33–39.

Yerman, T., W. Q. Gan, and D. D. Sin. “The Influence of Gender on the Effects of Aspirin in Preventing Myocardial Infarction.” BMC Med 18, no. 5 (October 2007): 29.

Feskanich, D., C. Bain, A. T. Chan, et al. “Aspirin and Lung Cancer Risk in a Cohort Study of Women: Dosage, Duration, and Latency.” Br J Cancer 97, no. 9 (November 5, 2007): 1295–1299.

Aronow, W. S. “Antiplatelet Therapy in the Treatment of Atherothrombotic Disease: Considering the Evidence.” Geriatrics 62, no. 4 (April 2007): 12–24.

Sam Uretsky PharmD

Aspirin

Definition
Purpose
Description
Recommended dosage
Precautions
Side effects
Interactions

Definition

Aspirin is a medication given to relieve pain and reduce fever. The name “aspirin” was originally a trademark, first used when the drug was introduced in Europe in 1899. Aspirin was developed by a German chemist named Felix Hoffman as a treatment for his father’ arthritis.

Purpose

Aspirin is still used to relieve many kinds of minor aches and pains—headaches, toothaches, muscle pain, menstrual cramps, joint pains associated with arthritis, and the general achiness that many people experience with colds and flu. Some people take aspirin daily to reduce the risk of stroke, heart attack, or other heart problems.

Description

Aspirin, also known as acetylsalicylic acid, is not a prescription drug. It is sold over the counter in many forms, from the familiar white tablets to chewing gum and rectal suppositories. Coated, chewable, buffered, and extended-release forms are available. Many other over-the-counter (OTC) medications contain aspirin. Alka-Seltzer Original Effervescent Antacid Pain Reliever (R), for example, contains aspirin for pain relief as well as sodium bicarbonate to relieve acid indigestion, heartburn, and sour stomach.

Aspirin belongs to a group of drugs called salicylates. Other members of this group include sodium salicylate, choline salicylate, and magnesium salicylate. These drugs are more expensive and no more effective than aspirin; however, they are prefered by some patients who find that aspirin upsets their stomach. Aspirin is quickly absorbed into the bloodstream and provides rapid and relatively long-lasting pain relief. Aspirin in high doses also reduces inflammation. Researchers believe these effects are due to aspirin’s ability to block the production of pain-producing chemicals called prostaglandins.

In addition to relieving pain and reducing inflammation, aspirin also lowers fever by acting on the

KEY TERMS

Diuretic— A type of medication that increases the amount of urine produced and relieves excess fluid buildup in body tissues. Diuretics may be used in treating high blood pressure, lung disease, premenstrual syndrome, and other conditions.

Inflammation— A response to injury or illness characterized by pain, redness, swelling, and warmth.

Nonsteroidal anti-inflammatory drugs (NSAIDs)— Drugs that relieve pain and reduce inflammation but are not related chemically to cortisone. Common drugs in this class are aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve, Naprosyn), ketoprofen (Orudis), and several others.

Polyp— Any mass of tissue that grows out of a mucous membrane in the digestive tract, uterus, or elsewhere in the body.

Prostaglandin— A hormone like chemical produced in the body that has a variety of effects. Prostaglandins may be responsible for the production of some types of pain and inflammation.

Reye’s syndrome— A life-threatening disease that affects the liver and the brain and sometimes occurs after a viral infection, such as flu or chickenpox. Children or teenagers who are given aspirin for flu or chickenpox are at increased risk of developing Reye’s syndrome.

Rhinitis— Inflammation of the membranes inside the nose.

Salicylates— A group of drugs that includes aspirin and related compounds. Salicylates are used to relieve pain, reduce inflammation, and lower fever.

Stroke— An event that impairs the circulation of the brain. Ischemic stroke is caused by a blood clot in the brain. Hemorrhagic stroke is caused by bleeding into the brain.

hypothalamus, which is the part of the brain that regulates temperature. The brain then signals the blood vessels to dilate (widen), which allows heat to leave the body more quickly.

Recommended dosage

Adults

PAIN RELIEF OR FEVER REDUCTION . The usual dosage is one to two tablets every three to four hours, up to six times per day.

RISK REDUCTION FOR STROKE. One tablet four times a day or two tablets twice a day.

RISK REDUCTION FOR HEART ATTACK. Aspirin may be used as a first-line treatment for a heart attack. The patient should chew a single uncoated aspirin tablet, since chewing makes it easier for the body to absorb the medication rapidly. Aspirin will not stop a heart attack, and proper emergency care is essential; however, an aspirin tablet may reduce the amount of damage done by the heart attack.

Patients should check with a physician for the proper dose and number of times per week they should take aspirin to reduce the risk of a heart attack. The most common dose for this purpose is a single baby aspirin tablet taken daily. Enteric-coated aspirin is often used, since it reduces the risk of stomach irritation.

Children

Parents should consult the child’s physician about the proper dosage for their child’s condition.

Precautions

Aspirin—even children’s aspirin—should never be given to children or teenagers with flu-like symptoms or chickenpox. Aspirin can cause Reye’s syndrome, a life-threatening condition that affects the nervous system and liver. As many as 30% of children and teenagers who develop Reye’s syndrome die. Those who survive may have permanent brain damage.

Parents should consult a physician before giving aspirin to a child under 12 years of age for arthritis, rheumatism, or any condition that requires long-term use of the drug.

No one should take aspirin for more than 10 days in a row unless instructed to do so by a physician. Anyone with fever should not take aspirin for more than three days without a physician’s advice. In addition, no one should take more than the recommended daily dosage.

People in the following categories should not use aspirin without first checking with their physician:

• Pregnant women. Aspirin can cause bleeding problems in both the mother and the developing fetus. Aspirin can also cause the infant’s weight to be too low at birth.
• Women who are breastfeeding. Aspirin can pass into breast milk and affect the baby.
• People with a history of bleeding problems.
• People who are taking such blood-thinning drugs as warfarin (Coumadin).
• People who have had recent surgery. Aspirin increases the risk of bleeding from an incompletely healed incision.
• People with a history of stomach ulcers.
• People with a history of asthma, nasal polyps, or both. Patients with these disorders are more likely to be allergic to aspirin.
• People who are allergic to fenoprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, naproxen, sulindac, tolmetin, or an orange food coloring known as tartrazine. They may also be allergic to aspirin.
• People with AIDS or AIDS-related complex who are taking AZT (zidovudine). Aspirin can increase the risk of bleeding in these patients.
• People taking any of the drugs listed below under Interactions.
• People with liver damage or severe kidney failure.

Aspirin should not be taken before a surgical procedure, as it can increase the risk of excessive bleeding during surgery. People scheduled for an operation should check with their surgeon to find out when they should discontinue taking aspirin.

Aspirin can cause stomach irritation. Taking aspirin with food or milk, or drinking an eight-ounce glass of water with it may help to prevent damage to the stomach lining. Some patients find that using coated or buffered aspirin reduces the risk of stomach upset. Patients should be aware, however, that drinking alcoholic beverages can make the stomach irritation worse.

Patients with any of the following symptoms should stop taking aspirin immediately and call their physician:

• a sensation of ringing or buzzing in the ears
• hearing loss
• dizziness
• stomach pain that does not go away

Patients should discard any aspirin that has developed a vinegary smell. That is a sign that the medication is too old and ineffective.

Side effects

The most common side effects of aspirin include upset stomach, heartburn, loss of appetite, and small amounts of blood in the stool. Less common side effects are rashes, hives, fever, vision problems, liver damage, thirst, stomach ulcers, and bleeding. People with asthma, rhinitis, polyps in the nose, or allergies to aspirin may have trouble breathing after taking the drug.

Interactions

Aspirin may increase, decrease, or change the effects of many drugs. Aspirin can increase the toxicity of such drugs as methotrexate (Rheumatrex) and valproic acid (Depakote, Depakene). Taken with such blood-thinning drugs as warfarin (Coumadin) and dicumarol, aspirin can increase the risk of excessive bleeding. Aspirin counteracts the effects of certain other drugs, including angiotensin-converting enzyme (ACE) inhibitors and beta blockers, which lower blood pressure, and medicines used to treat gout (probenecid and sulfinpyrazone). Blood pressure may drop unexpectedly and cause fainting or dizziness if aspirin is taken along with nitroglycerin tablets. Aspirin may also interact with diuretics, diabetes medications, other nonsteroidal anti-inflammatory drugs (NSAIDs), seizure medications, and steroids. Anyone who is taking these drugs should ask his or her physician whether they can safely take aspirin.

Resources

BOOKS

“Factors Affecting Drug Response: Drug Interactions.” Section 22, Chapter 301 in The Merck Manual of Diagnosis and Therapy, edited by Mark H. Beers, MD, and Robert Berkow, MD. Whitehouse Station, NJ: Merck Research Laboratories, 1999.

Wilson, Billie Ann, RN, PhD, Carolyn L. Stang, PharmD, and Margaret T. Shannon, RN, PhD. Nurses Drug Guide 2000. Stamford, CT: Appleton and Lange, 1999.

PERIODICALS

Cryer, B. “Gastrointestinal Safety of Low-Dose Aspirin.” American Journal of Managed Care 8 (December 2002)(22 Supply): S701-S708.

Grattan. C. E. “Aspirin Sensitivity and Urticaria.” Clinical and Experimental Dermatology 28 (March 2003): 123–127.

MacDonald, T. M., and L. Wei. “Effect of Ibuprofen on Cardioprotective Effect of Aspirin.” Lancet 361 (February 15, 2003): 573–574.

Nordenberg, Tamar. “‘An Aspirin a Day’—Just Another Cliché?” FDA Consumer (March-April 1999): 2–4.

ORGANIZATIONS

American Society of Health-System Pharmacists (ASHP). 7272 Wisconsin Avenue, Bethesda, MD 20814. (301) 657-3000. www.ashp.org.

Aspirin Foundation of America. (800) 432-3247; fax (202)737-8406. www.aspirin.org.

United States Food and Drug Administration (FDA). 5600 Fishers Lane, Rockville, MD 20857-0001. (888) INFO-FDA. www.fda.gov.

Nancy Ross-Flanigan

Sam Uretsky, PharmD

Fran Hodgkins

Atrial fibrillation surgery seeMaze procedure for atrial fibrillation

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Autograft seeSkin grafting

Aspirin

Definition

Aspirin is a medicine that relieves pain and reduces fever.

Purpose

Aspirin is used to relieve many kinds of minor aches and pains—headaches, toothaches, muscle pain, menstrual cramps, the joint pain from arthritis, and aches associated with colds and flu. Some people take aspirin daily to reduce the risk of stroke, heart attack, or other heart problems.

Description

Aspirin-also known as acetylsalicylic acid-is sold over the counter and comes in many forms, from the familiar white tablets to chewing gum and rectal suppositories. Coated, chewable, buffered, and extended release forms are available. Many other over-the-counter medicine contain aspirin. Alka-Seltzer Original Effervescent Antacid Pain Reliever, for example, contains aspirin for pain relief and sodium bicarbonate to relieve acid indigestion, heartburn, and sour stomach.

Aspirin belongs to a group of drugs called salicylates. Other members of this group include sodium salicylate, choline salicylate, and magnesium salicylate. These drugs are more expensive and no more effective than aspirin. However, they are a little easier on the stomach. Aspirin is quickly absorbed into the bloodstream and provides quick and relatively long-lasting pain relief. Aspirin also reduces inflammation. Researchers believe these effects come about because aspirin blocks the production of pain-producing chemicals called prostaglandins.

In addition to relieving pain and reducing inflammation, aspirin also lowers fever by acting on the part of the brain that regulates temperature. The brain then signals the blood vessels to widen, which allows heat to leave the body more quickly.

Recommended dosage

Adults

TO RELIEVE PAIN OR REDUCE FEVER. One to two tablets every three to four hours, up to six times per day.

TO REDUCE THE RISK OF STROKE. One tablet four times a day or two tablets twice a day.

TO REDUCE THE RISK OF HEART ATTACK. Check with a physician for the proper dose and number of times per week aspirin should, if at all, be taken.

Children

Check with a physician.

Precautions

Aspirin-even children's aspirin-should never be given to children or teenagers with flu-like symptoms or chickenpox. Aspirin can cause Reye's syndrome, a life-threatening condition that affects the nervous system and liver. As many as 30% of children and teenagers who develop Reye's syndrome die. Those who survive may have permanent brain damage.

Check with a physician before giving aspirin to a child under 12 years for arthritis, rheumatism, or any condition that requires long-term use of the drug.

No one should take aspirin for more than 10 days in a row unless told to do so by a physician. Anyone with fever should not take aspirin for more than 3 days without a physician's consent. Do not to take more than the recommended daily dosage.

KEY TERMS

Diuretic— Medicine that increases the amount of urine produced and relieves excess fluid buildup in body tissues. Diuretics may be used in treating high blood pressure, lung disease, premenstrual syndrome, and other conditions.

Inflammation— Pain, redness, swelling, and heat that usually develop in response to injury or illness.

NSAIDs— Nonsteroidal anti-inflammatory drugs. Drugs such as ketoprofen and ibuprofen which relieve pain and reduce inflammation.

Polyp— A lump of tissue protruding from the lining of an organ, such as the nose, bladder, or intestine. Polyps can sometimes block the passages in which they are found.

Prostaglandin— A hormonelike chemical produced in the body. Prostaglandins have a wide variety of effects, and may be responsible for the production of some types of pain and inflammation.

Reye's syndrome— A life-threatening disease that affects the liver and the brain and sometimes occurs after a viral infection, such as flu or chickenpox. Children or teenagers who are given aspirin for flu or chickenpox are at increased risk of developing Reye's syndrome.

Rhinitis— Inflammation of the membranes inside the nose.

Salicylates— A group of drugs that includes aspirin and related compounds. Salicylates are used to relieve pain, reduce inflammation, and lower fever.

People in the following categories should not use aspirin without first checking with their physician:

• Pregnant women. Aspirin can cause bleeding problems in both the mother and the developing fetus. Aspirin can also cause the infant's weight to be too low at birth.
• Women who are breastfeeding. Aspirin can pass into breast milk and may affect the baby.

• People with a history of bleeding problems.
• People who are taking blood-thinning drugs, such as warfarin (Coumadin).
• People with a history of ulcers.
• People with a history of asthma, nasal polyps, or both. These people are more likely to be allergic to aspirin.
• People who are allergic to fenoprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, naproxen, sulindac, tolmetin, or the orange foodcoloring tartrazine. They may also be allergic to aspirin.
• People with AIDS or AIDS-related complex who are taking AZT (zidovudine). Aspirin can increase the risk of bleeding in these patients.
• People taking certain other drugs (discussed in Interactions).
• People with liver damage or severe kidney failure.

Aspirin should not be taken before surgery, as it can increase the risk of excessive bleeding. Anyone who is scheduled for surgery should check with his or her surgeon to find out how long before surgery to avoid taking aspirin.

Aspirin can cause stomach irritation. To reduce the likelihood of that problem, take aspirin with food or milk or drink a full 8-oz glass of water with it. Taking coated or buffered aspirin can also help. Be aware that drinking alcohol can make the stomach irritation worse.

Stop taking aspirin immediately and call a physician if any of these symptoms develop:

• ringing or buzzing in the ears
• hearing loss
• dizziness
• stomach pain that does not go away

Do not take aspirin that has a vinegary smell. That is a sign that the aspirin is too old and ineffective. Flush such aspirin down the toilet.

Because aspirin can increase the risk of excessive bleeding, do not take aspirin daily over long periods-to reduce the risk of stroke or heart attack, for example-unless advised to do so by a physician.

Side effects

The most common side effects include stomachache, heartburn, loss of appetite, and small amounts of blood in stools. Less common side effects are rashes, hives, fever, vision problems, liver damage, thirst, stomach ulcers, and bleeding. People who are allergic to aspirin or those who have asthma, rhinitis, or polyps in the nose may have trouble breathing after taking aspirin.

Interactions

Aspirin may increase, decrease, or change the effects of many drugs. Aspirin can make drugs such as methotrexate (Rheumatrex) and valproic acid (Depakote, Depakene) more toxic. If taken with blood-thinning drugs, such as warfarin (Coumadin) and dicumarol, aspirin can increase the risk of excessive bleeding. Aspirin counteracts the effects of other drugs, such as angiotensin-converting enzyme (ACE) inhibitors and beta blockers, which lower blood pressure, and medicines used to treat gout (probenecid and sulfinpyrazone). Blood pressure may drop unexpectedly and cause fainting or dizziness if aspirin is taken along with nitroglycerin tablets. Aspirin may also interact with diuretics, diabetes medicines, other nonsteroidal anti-inflammatory drugs (NSAIDs), seizure medications, and steroids. Anyone who is taking these drugs should ask his or her physician whether they can safely take aspirin.

Resources

PERIODICALS

"What's the Best Pain Reliever? Depends on Your Pain." Consumer Reports May 1996: 62.