aspirin
aspirin or more accurately acetylsalicylic acid, is the best known and most commonly used drug after alcohol. Aspirin was originally a trade name, coined by the German company Bayer when the drug was introduced in 1899. The name comes from a combination of A for acetyl and spirin (from Spiraea, the plant family containing salicylates). In 1918 the US Supreme Court ruled that the name ‘aspirin’ had been so widely advertised that it had become the common name for the drug and the US Patent office cancelled Bayer's rights to the name.
Originally salicylates (salts of salicylic acid) were obtained from the bark and leaves of willow and poplar trees; indeed ‘salicylate’ derives from the title of the willow genus, Salix. From early times it was known that salicylates could reduce pain, temperature during fever, and inflammatory swelling (analgesic, antipyretic, and anti-inflammatory actions, respectively).
Instructions for the use of such extracts can be found in Eber's Papyrus (c.1550 bc) and in the writings of Celsus, Pliny the Elder, and Dioscorides in the first century, and of Galen in the second. The four cardinal signs of inflammation, namely rubor, calor, dolor, and tumor (redness, heat, pain, and swelling), were described in De Re Medica in 30 ad. Celsus described the use of ‘boiled vinegar extracts of willow leaves for the relief of pain from prolapse of the uterus and other conditions’. It is possible that this procedure with weak acetic acid (vinegar) may have converted naturally occurring salicylate to the acetyl form, that is aspirin itself. The acetyl derivative was thought by Bayer to reduce the nausea and gastrointestinal symptoms associated with salicylic acid itself. In 1980, 97 million kilograms of aspirin were produced in the US alone.
It was to take more than three thousand years after the first descriptions of the therapeutic value of salicylates before their actions were understood. Many of the effects of aspirin are now known to be due to the inhibition of an enzyme in the body, cyclooxygenase. This enzyme converts a lipid, arachidonic acid, into substances called endoperoxides, which are in turn converted to prostaglandins I2, E1, E2, D2, and F2α, and to thromboxanes A2 and B2. Inhibition of formation of prostaglandins and thromboxanes is what prevents many of the symptoms that are relieved by aspirin. The complex biochemical reactions involved in the conversion of arachidonic acid were worked out in Sweden by Bergstrom and Samuelsson, while the effects of prostaglandins and thromboxanes on biological systems were investigated by John Vane and his colleagues in England. All three shared the Nobel Prize for their work in 1982.
Prostaglandins E1 and E2 disturb the temperature-regulating centre in the brain, resetting body temperature to a higher level, resulting in fever. By inhibiting the production of prostaglandins, aspirin reduces the temperature in fever; but it has no effect on normal body temperature since no prostaglandins are usually being generated in the temperature-regulating centre. Tissue damage also leads to the production of prostaglandins, which sensitize the endings of the nerve fibres that convey the sensation of pain. Thus aspirin relieves the pain associated with injury or trauma by preventing the formation of prostaglandins. Prostaglandin E2 and prostaglandin I2 (prostacyclin) are powerful dilators of blood vessels, making injured areas appear reddened. Other agents released in inflammation (e.g. histamine and bradykinin) increase the permeability of blood vessels. The combination of increased permeability and vasodilation (enlargement of the vessels) allows fluid to escape from the circulation and collect in the damaged tissues, giving rise to swelling — another symptom that is reversed by aspirin.
Considerable interest centres on the recent discovery that low doses of aspirin, taken regularly, reduce the chances of heart attack and stroke caused by blood clots. Aggregation of blood platelets is one of the early processes of clot formation and anything that reduces platelet ‘stickiness’ will help to prevent clots. Platelets synthesize thromboxane A2, which promotes their aggregation, while the cells lining the blood vessel synthesize prostacyclin, a powerful anti-aggregatory agent as well as a vasodilator. Aspirin irreversibly inhibits the cyclooxygenase enzyme in platelets, so the platelets cannot generate thromboxane A2 until they are replaced (in 7–10 days). What is needed to prevent clot formation is the prevention of thromboxane formation together with the preservation of prostacyclin. This can be achieved with low concentrations of aspirin. Higher concentrations of aspirin inhibit the formation of both agents.
One of the common side effects of aspirin is a feeling of nausea, which may be accompanied by bleeding in the stomach. The stomach lining (mucosa) produces prostaglandins, which protect the mucosa itself from attack by gastric acid. Local suppression of prostaglandin formation by aspirin, especially when a tablet lies against the mucosa, can lead to acid attack of the mucosa, even ulceration. The chances of this are greatly reduced by using ‘soluble’ forms of aspirin which disperse the drug more effectively.
See also analgesia; fever; prostaglandins.
Originally salicylates (salts of salicylic acid) were obtained from the bark and leaves of willow and poplar trees; indeed ‘salicylate’ derives from the title of the willow genus, Salix. From early times it was known that salicylates could reduce pain, temperature during fever, and inflammatory swelling (analgesic, antipyretic, and anti-inflammatory actions, respectively).
Instructions for the use of such extracts can be found in Eber's Papyrus (c.1550 bc) and in the writings of Celsus, Pliny the Elder, and Dioscorides in the first century, and of Galen in the second. The four cardinal signs of inflammation, namely rubor, calor, dolor, and tumor (redness, heat, pain, and swelling), were described in De Re Medica in 30 ad. Celsus described the use of ‘boiled vinegar extracts of willow leaves for the relief of pain from prolapse of the uterus and other conditions’. It is possible that this procedure with weak acetic acid (vinegar) may have converted naturally occurring salicylate to the acetyl form, that is aspirin itself. The acetyl derivative was thought by Bayer to reduce the nausea and gastrointestinal symptoms associated with salicylic acid itself. In 1980, 97 million kilograms of aspirin were produced in the US alone.
It was to take more than three thousand years after the first descriptions of the therapeutic value of salicylates before their actions were understood. Many of the effects of aspirin are now known to be due to the inhibition of an enzyme in the body, cyclooxygenase. This enzyme converts a lipid, arachidonic acid, into substances called endoperoxides, which are in turn converted to prostaglandins I2, E1, E2, D2, and F2α, and to thromboxanes A2 and B2. Inhibition of formation of prostaglandins and thromboxanes is what prevents many of the symptoms that are relieved by aspirin. The complex biochemical reactions involved in the conversion of arachidonic acid were worked out in Sweden by Bergstrom and Samuelsson, while the effects of prostaglandins and thromboxanes on biological systems were investigated by John Vane and his colleagues in England. All three shared the Nobel Prize for their work in 1982.
Prostaglandins E1 and E2 disturb the temperature-regulating centre in the brain, resetting body temperature to a higher level, resulting in fever. By inhibiting the production of prostaglandins, aspirin reduces the temperature in fever; but it has no effect on normal body temperature since no prostaglandins are usually being generated in the temperature-regulating centre. Tissue damage also leads to the production of prostaglandins, which sensitize the endings of the nerve fibres that convey the sensation of pain. Thus aspirin relieves the pain associated with injury or trauma by preventing the formation of prostaglandins. Prostaglandin E2 and prostaglandin I2 (prostacyclin) are powerful dilators of blood vessels, making injured areas appear reddened. Other agents released in inflammation (e.g. histamine and bradykinin) increase the permeability of blood vessels. The combination of increased permeability and vasodilation (enlargement of the vessels) allows fluid to escape from the circulation and collect in the damaged tissues, giving rise to swelling — another symptom that is reversed by aspirin.
Considerable interest centres on the recent discovery that low doses of aspirin, taken regularly, reduce the chances of heart attack and stroke caused by blood clots. Aggregation of blood platelets is one of the early processes of clot formation and anything that reduces platelet ‘stickiness’ will help to prevent clots. Platelets synthesize thromboxane A2, which promotes their aggregation, while the cells lining the blood vessel synthesize prostacyclin, a powerful anti-aggregatory agent as well as a vasodilator. Aspirin irreversibly inhibits the cyclooxygenase enzyme in platelets, so the platelets cannot generate thromboxane A2 until they are replaced (in 7–10 days). What is needed to prevent clot formation is the prevention of thromboxane formation together with the preservation of prostacyclin. This can be achieved with low concentrations of aspirin. Higher concentrations of aspirin inhibit the formation of both agents.
One of the common side effects of aspirin is a feeling of nausea, which may be accompanied by bleeding in the stomach. The stomach lining (mucosa) produces prostaglandins, which protect the mucosa itself from attack by gastric acid. Local suppression of prostaglandin formation by aspirin, especially when a tablet lies against the mucosa, can lead to acid attack of the mucosa, even ulceration. The chances of this are greatly reduced by using ‘soluble’ forms of aspirin which disperse the drug more effectively.
Alan W. Cuthbert
See also analgesia; fever; prostaglandins.
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aspirin