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AspirinAspirin is the most widely-used medicinal compound in the world, and it has a long history. Around 400 BC, Hippocrates, the "father of medicine" and the namesake of the Hippocratic oath taken by all physicians, administered willow-leaf tea (containing the natural compound from which aspirin is derived) to women during childbirth to ease pain. German chemist Friedrich Bayer developed aspirin (acetylsalicylic acid) in 1897, and it became an over-the-counter drug in 1915. By 1998, the FDA approved aspirin for use during a heart attack and for the prevention of a second heart attack, and for the prevention of stroke. Today, aspirin is found in hundreds of over-the-counter medicines worldwide, and remains at the forefront of medicine, with newly discovered applications for the prevention and treatment of several life-threatening diseases. In the past decade, more than 50 million people have been started on aspirin therapy by physicians to prevent a second heart attack, and this market is likely to increase as more uses for aspirin are discovered.
Aspirin is a derivative of salicylic acid, making it a member of the salicylate family of compounds. Salicylates are natural compounds found in plants such as the willow tree, and are among the oldest known and widely used therapeutics commonly used to relieve pain, fever, and inflammation. Aspirin is chemically designated as acetylsalicylic acid and has a chemical structure that is comprised of three chemical groups—an aromatic ring, an ester group, and a carboxylic acid group. Aspirin is prepared by chemical synthesis from salicylic acid by acetylation with acetic anhydride. In 1897, Felix Hoffman of Bayer patented a commercial process to achieve the synthesis of aspirin from salicylic acid. Aspirin became a generic drug in the 1930s when the Bayer patent expired. Approved and Common Usage of AspirinAspirin has several different approved uses. These include: Analgesic. Aspirin acts as a general analgesic (pain reliever) by blocking the action of the COX enzymes, which produce the prostaglandins needed for pain response. Aspirin effectively treats headaches, back and muscle pain, and other general aches and pains. Arthritis. Aspirin's pain relieving and anti-inflammatory effects make it an effective drug to combat the symptoms of arthritis and other rheumatologic diseases, including osteoarthritis, rheumatoid arthritis, the spondyloarthropathies (inflammatory disorders that involve arthritis with other inflammatory and autoimmune responses), and the arthritis and pleurisy that can accompany lupus. Heart Attack. Studies show that aspirin reduces the risk of death in patients who are having heart attacks (myocardial infarctions). Regular aspirin intake can also reduce the chance of a second heart attack, and reduce the risk of heart attack in patients with either unstable or chronic stable chest pain (angina pectoris). In treatment of heart attacks, for example, aspirin dramatically reduces platelet aggregation. Platelet aggregates adhere to the walls of blood vessels and block blood flow. Platelet aggregation is abated by irreversibly inhibiting the cyclooxygenase enzyme in platelets. Stroke. The blood-thinning properties of aspirin make it an effective weapon against strokes, which occur when a blood clot lodges in the brain. Aspirin is indicated in patients exhibiting symptoms of Transient ischemic attacks (TIA), also called mini-strokes, reducing the risk of strokes in these patients. Aspirin also lowers the risk of death due to stroke when given to patients during the acute stages of a stroke. Fever. Aspirin has antipyretic (fever-reducing) activity. Aspirin acts on the hypothalamus, a small gland at the base of the brain that helps regulate body temperature, by inhibiting the productions of the prostaglandins that stimulate the hypothalamus to elevate the body's temperature set-point. The reduction of body temperature is accomplished by vasodilation (dilation of the blood vessels close to the skin to increase heat loss), and sweating. The Biological Effects of AspirinAspirin acts by preventing the formation of prostaglandins. The name "prostaglandin" comes from the old belief that this hormone was produced by the prostate gland. It is now known that prostaglandins come in several different forms (named by the letters A through I) and are produced in almost all mammalian cells. Prostaglandins have a wide variety of effects in the tissues in which they are produced, including smooth (involuntary) muscle contractions, inflammatory responses, the production of pain and fever, the regulation of blood pressure and blood clotting, the control of some reproductive functions (such as embryo implantation), and more.
How does aspirin accomplish all these effects? The enzyme that metabolizes arachidonic acid, the precursor to the prostaglandin product, is called cyclooxygenase. There are two forms of cyclooxygenase—cyclooxygenase 1 (COX-1), which produces prostaglandins in a normal physiological state; and cyclooxygenase 2 (COX-2), which mediates pain and inflammation in response to tissue damage. Aspirin inhibits both COX-1 and COX-2 irreversibly. While COX-2 is the therapeutic target of aspirin, it is aspirin's interaction with COX-1 in the gastrointestinal tract that causes the drug's unwanted side effects. COX-1 is needed to maintain a thick stomach lining. Because aspirin disables the COX-1 enzyme, regular use of this drug can lead to a thinning of the mucus that protects the stomach from gastric juices. Ulcers, stomach bleeding, and, in some cases, perforation of the stomach can occur. Thus, aspirin has both good and bad effects. It is very effective in alleviating pain through inhibition of the COX-2 pathway. However, when used for long periods and in high doses, aspirin can cause substantial medical problems by stopping the action of COX-1. At the molecular level, aspirin inhibits COX activity by forming a covalent bond with the enzyme. This effectively barricades the COX active site and blocks the synthesis of prostaglandin. COX-2, the therapeutic target of aspirin, is made of two identical subunits that form a dimer.
Aspirin's acetyl group attaches to serine 530, an amino acid that extends into a narrow, hydrophobic channel within the COX-2 enzyme that leads to its active site. When this amino acid is acetylated, the channel is blocked and arachidonic acid, the precursor to prostaglandin, can no longer reach the COX-2 catalytic site.
By binding the COX enzymes, aspirin prevents the production of prostaglandins. Prostaglandins act as messenger molecules to control various physiological processes in different areas of the body. One of the functions of prostaglandins is to trigger pain and inflammation. Aspirin's analgesic and anti-inflammatory effects are due to the drug's ability to stop the production of prostaglandins that cause tissue swelling and pain. Aspirin's antipyretic (fever-reducing) effect is due to its direct action on the hypothalamus gland, which results in vasodilation of peripheral blood vessels and sweating. Prostaglandins are also the key mediators of platelet aggregation. By modifying the COX enzymes within platelets, aspirin causes platelets to lose the "stickiness" that is needed to stimulate blood clotting. Promising New Uses of AspirinAspirin's efficacy in the treatment and prevention of cancer and AIDS is a research area of active investigation. Both cancer and AIDS are pathological inflammatory conditions and studies show that aspirin interferes with the inflammatory processes associated with these diseases. Cancer Recent studies show that aspirin is a promising candidate to prevent cancer. Several studies indicate that aspirin use may provide a moderate reduction in the risk of colon cancer, especially in patients who have already beaten the disease once. However, more studies need to be done before doctors can say with certainty that the potential benefit of colon cancer risk reduction outweighs the possible serious side effects of aspirin therapy. Similar studies that examined the effect of daily aspirin therapy on the risk of mouth and throat cancers, lung cancers and pancreatic cancer appear promising, but more studies are needed.
Although a definitive mechanism for aspirin's apparent ability to prevent certain types of cancer has not been determined, one possibility is that aspirin may be involved in scavenging reactive oxygen species that cause oxidative DNA strand breaks. Excessive DNA damage can cause healthy cells to begin dividing uncontrollably and become cancerous. By rounding up these oxygen free radicals, aspirin may reduce cellular DNA damage and thus lower the chance of carcinogenesis. There is also evidence that tumors produce the COX-2 enzyme as part of their out-of-control growth process. Thus, by inhibiting COX-2, aspirin (and similar compounds, collectively called nonsteroidal anti-inflammatory drugs, or NSAIDs) may be able to suppress the growth of cancerous tumors. Other evidence regarding NSAIDs' effects on cellular pathways that become mutated in cancers, such as the ras/mek/erk pathway, is mounting, and this continues to be a promising area of medical research. Alzheimer's Disease/Dementia Alzheimer's disease is caused by the proliferation of beta-amyloid plaques in the brains of affected patients. NSAIDs are of particular interest to Alzheimer's researchers because some studies appear to indicate that patients who take NSAIDs for other ailments appear to have a lower incidence of Alzheimer's disease. Secondly, aspirin and other anti-inflammatory drugs are being researched because brain lesions in Alzheimer's patients are often accompanied by inflammation of the brain tissue. Inflammation can in and of itself cause nerve damage, and researchers are investigating if the use of anti-inflammatory drugs can reduce inflammation and the accompanying nerve damage in the brain caused by Alzheimer's. Pregnancy Complications Preeclampsia is a serious condition in pregnant women that is marked by high blood pressure. If not treated, it can lead to eclampsia, a potentially fatal condition for mother or child marked by seizures, convulsions, and coma. The cause of preeclampsia is unknown, although researchers believe it may be linked to the ability of platelets to clot blood. Aspirin may provide a small reduction in the risk of developing preeclampsia, but this needs to be weighed against the possible harmful effects of the drug. Current recommendations state that aspirin should be avoided especially in the last trimester of pregnancy, because it can increase the risk of placental abruption or excessive bleeding during delivery, and may cause complications in heart development in the fetus. Diabetes Many complications from diabetes are due to vascular diseases—including damage of small blood vessels that result in nerve and tissue damage in organs and extremities (leading to organ failure or amputation), and the destruction of blood vessels of the retina (leading to blindness). Because aspirin's anti-clotting (blood-thinning) properties aid the circulation, aspirin can help diabetic patients prevent these devastating effects. Important Information About AspirinAspirin is not for everyone. The clear benefits of aspirin in the treatment and prevention of heart attack and stroke, and in reducing pain and inflammation of arthritis, need to be weighed against serious potential side effects. Young children, pregnant women, persons with a history of ulcers, and patients taking other medications need to be especially careful, and should consult a physician before beginning an aspirin regimen.
Gastrointestinal discomfort. As noted earlier, COX-1, the cyclooxygenase that produces prostaglandins in a normal physiological state, plays a role in maintaining a thick stomach lining. Aspirin and most other NSAIDs non-selectively inhibit the COX-1 enzyme, causing a thinning of the stomach lining and increasing the likelihood of irritation from digestive juices. Gastrointestinal maladies (which range from abdominal pain, bloating and diarrhea to heartburn, ulcers, and bleeding) are the major NSAID side effect, affecting 10-50% of users. Approximately 15% of patients who take these medicines on a long-term basis develop ulcers, and 1 to 4% of chronic users suffer serious gastrointestinal complications annually, including stomach bleeding, stomach perforation and even death. Excessive bleeding. Although aspirin proves to be a very effective therapeutic agent for preventing blood clotting (a great help for preventing heart attack of stroke), under certain circumstances this function of aspirin can have undesired consequences. For this reason, aspirin is not administered before surgery because of the complications that could arise from excessive bleeding.
Reye's Syndrome. Children with certain viral sicknesses (including the flu, chicken pox, or colds) who are administered aspirin can develop a rare, yet potentially lethal condition known as Reye's syndrome that can lead to permanent brain injury or death. Although the cause of RS is unknown and children and adults can develop RS without ingesting aspirin, research has shown that aspirin use during viral illnesses increases the likelihood of RS. For this reason, the Centers of Disease Control recommend that aspirin not be administered to children and teens younger than 19 years of age while they are suffering from fever-producing illnesses. Since the first synthetic virus has already been created (see box 1), and we appear to be well on our way toward creating the first synthetic bacterium, it may be moot to ask whether pursuing artificial life is something we, as a society, ought to be doing. But as it turns out, the scientists at TIGR did ask a panel of scientific ethicists to study the implications of the project back in 1999, when the group first began working towards creating a minimal microbe from essential Mycoplasma genes. The panel deliberated for over a year, and in the end decided that it was not inherently unethical to create such an organism for the purposes of scientific study. They noted, however, that it would depend on how such knowledge was used. And that may be exactly the problem. Once the roles of individual genes in organizing life are better understood, and the gene-swapping technologies become available, the proverbial genie may be out of the bottle. While the construction of even a feeble synthetic bug is likely years away, even Venter admits that his research might inevitably create a national security risk. If microbes can be made-to-order by labs working for the good of mankind, they can also be made by others with less-than-altruistic motives. But, Venter suggests, his work could also lead to better detection methods for existing biological weapons. One thing is clear: such research will continue to be closely watched by scientists, ethicists, governments, and citizens the world over for years to come. Remember to consult a doctor before using aspirin for any type of symptom. Also, be aware that there are over-the-counter (OTC) remedies that contain "hidden" aspirin. Be sure to read the label of any medication that you purchase over the counter.
Aspirin AlternativesAlternatives to aspirin include other pain relievers such as acetaminophen (Tylenol), other NSAIDs, and corticosteroids. Acetaminophen (Tylenol). Acetaminophen is a pain reliever that works by directly affecting nerves (unlike aspirin and other NSAIDs that control prostaglandin levels). Because it is in a different class of compounds than aspirin, it can be used by people who have aspirin sensitivity or allergic reactions to aspirin or other drugs in the NSAID family. Acetaminophen is effective as a pain reliever and fever reducer, but does not have any anti-inflammatory properties. Rare but serious side effects can include liver damage (especially if large doses are ingested, or if used in conjunction with heavy alcohol use) and blood problems. COX-2 Inhibitors. The new COX-2 inhibitor drugs (such as Vioxx and Celebrex) have been specifically designed to target the COX-2 enzyme responsible for inflammation and pain in arthritic joints. Because these drugs do not inhibit the COX-1 enzyme that is needed to protect the stomach, they don't have the gastrointestinal side effects commonly associated with NSAIDs. Corticosteroids. Corticosteriods are effective anti-inflammatory agents that work by inhibiting an enzyme called phospholipase A2. Phospholipase A2 is responsible for catalyzing a pathway that produces arachidonic acid, the precursor of prostaglandins. Corticosteroids are extremely potent medicines and can have very serious side effects.
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The chemical structure of aspirin.
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Copyright 2006, John Wiley & Sons Publishers, Inc. |
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