ACETYL SALICYLIC (2- (ACETYLOXY) -BENZOIC) ACID- a white crystalline substance, slightly soluble in water, well soluble in alcohol, in alkali solutions. This substance is obtained by the interaction of salicylic acid with acetic anhydride:
Acetylsalicylic acid has been widely used for over 100 years as a drug - antipyretic, analgesic and anti-inflammatory. There are more than 50 names - trade marks of drugs, the main active principle of which is this substance. This unusual drug can be called the record holder among drugs. Acetylsalicylic acid is a long-lived drug in the world of drugs, officially celebrated its centenary in 1999, and is still the most popular drug in the world. The annual consumption of medicinal products containing acetylsalicylic acid exceeds 40 billion tablets.
Another feature of acetylsalicylic acid is the first synthetic drug substance. From time immemorial, man has used medicinal plants, then he learned to isolate medicinal substances in pure form from plant extracts, but acetylsalicylic acid became the first medicine, a complete analogue of which does not exist in nature.
There is a similar substance in nature - salicylic acid. This compound is found in the bark of willow, and its medicinal properties have been known since antiquity. A decoction of willow bark as an antipyretic, analgesic and anti-inflammatory agent was recommended by Hippocrates. In 1828, the German chemist Buchner isolated a substance from the bark of a willow tree, which he called salicin (from the Latin name for willow - Salix). A little later, pure salicylic acid was obtained from salicin, and it was proven that it has medicinal properties. Salicin, isolated from willow bark, a waste from basket making, was used as a medicine, but it was produced in very small quantities and was expensive. In 1860, the German chemist A. Kolbe developed a method for the synthesis of salicylic acid by the interaction of sodium phenolate with carbon dioxide, and soon a plant for the production of this substance appeared in Germany:
Both salicin and cheaper synthetic salicylic acid have been used in medical practice, but salicylic acid has not received widespread use as a drug for internal use. Due to its high acidity, it causes severe irritation of the mucous membranes of the mouth, throat, stomach, and its salts - salicylates - have such a taste that most patients feel sick from them.
A new drug with the same therapeutic properties but less pronounced side effects as salicylic acid was discovered and patented by the German firm Bayer. According to the official version, the father of the chemist Felix Hoffman, who worked at the company, suffered from rheumatism, and the loving son set out to get a substance that would alleviate the suffering of a rheumatic father, but would have a more pleasant taste than salicylates and would not cause stomach pain. In 1893, he discovered the desired properties in acetylsalicylic acid, first obtained from salicylic acid forty years earlier, but did not find application. Hoffman developed a method for obtaining pure acetylsalicylic acid, and after testing the drug on animals (by the way, they were also carried out for the first time in history) in 1899, Bayer patented the trademark aspirin - the name by which this drug is best known. It is believed that the name of the medicine was given in honor of Saint Aspirinus - the patron saint of all headache sufferers, although there is a more prosaic explanation. Salicylic acid was often called spirsaeure at the time, as it is also found in the marsh plant spiraea. And the brand name is simply an abbreviation from the then accepted name of acetylsalicylic acid acetylspirsaeure. By the way, salicylic acid also found its place in medicine, its solution - salicylic alcohol, treats skin inflammation and is part of many cosmetic lotions.
Acetylsalicylic acid lowers the temperature, reduces local inflammatory processes, and relieves pain. And it also thins the blood and therefore is used when there is a risk of blood clots. It has been proven that long-term intake of a small dose of acetylsalicylic acid by people prone to diseases of the cardiovascular system significantly reduces the risk of stroke and myocardial infarction. At the same time, the drug is absolutely devoid of the terrible lack of many painkillers - addiction does not develop to it. It would seem to be the perfect medicine. Some people are so used to this drug that they take it for and without reason - at the slightest pain or just "just in case."
But in no case should we forget that drugs should not be abused. As with any medicine, acetylsalicylic acid is not safe. Overdose can lead to poisoning, manifested by nausea, vomiting, stomach pain, dizziness, and in severe cases - to toxic inflammation of the liver and kidneys, damage to the central nervous system (disorder of coordination of movements, confusion, convulsions) and hemorrhages.
If a person is taking several medications at the same time, you need to be especially careful. Some medicines are incompatible with each other, and poisoning can occur due to this. Acetylsalicylic acid increases the toxic effects of sulfonamides, enhances the effect of painkillers and anti-inflammatory drugs such as amidopyrine, butadione, analgin.
This medicine also has side effects. Just like salicylic acid, although to a much lesser extent, it leads to irritation of the gastric mucous membranes. In order to avoid negative effects on the gastrointestinal tract, it is recommended to take this medicine after meals with plenty of fluids. The irritant effect of acetylsalicylic acid is enhanced by tartaric alcohol.
Much of the irritating effect of aspirin is due to its poor solubility. If you swallow a pill, it is slowly absorbed, an undissolved particle of the substance can “stick” to the mucous membrane for some time, causing irritation. To reduce this effect, it is enough just to crush an aspirin tablet into powder and drink it with water, sometimes alkaline mineral water is recommended for this purpose, or buy soluble forms of aspirin - effervescent tablets. However, it should be borne in mind that these measures do not reduce the risk of gastrointestinal bleeding due to the effect of the drug on the synthesis of "protective" prostaglandins in the gastric mucosa. Therefore, it is better not to abuse acetylsalicylic acid, especially for people with gastritis or stomach ulcers.
Sometimes the effect of reducing blood clotting may be undesirable or even dangerous. In particular, preparations containing acetylsalicylic acid are not recommended to be taken within a week before surgery, as it increases the risk of unwanted bleeding. Pregnant women and young children should not take acetylsalicylic acid preparations unless absolutely necessary.
Despite the fact that acetylsalicylic acid has been known for so long and is very widely used as a medicine, an explanation of the mechanism of its action on the body appeared only in the 1970s. British scientist J. Wein for his work on the study of the physiological action of acetylsalicylic acid in 1982 received the Nobel Prize in Physiology or Medicine and the title of knight from Queen Elizabeth II. Wayne discovered that acetylsalicylic acid blocks the synthesis of certain hormone-like substances in the body - prostaglandins, which are responsible for the regulation of many body functions, in particular, inhibits the synthesis of prostaglandins that cause inflammation. Side effects of acetylsalicylic acid are explained by a slowdown in the synthesis of other prostaglandins, which are responsible for blood clotting and regulation of the formation of hydrochloric acid in the stomach.
Further research showed that not all properties of this substance are associated with blocking the synthesis of prostaglandins. The mechanism of action of acetylsalicylic acid is complex and not fully understood, and its properties are still the subject of research by many research teams. In 2003 alone, about 4000 scientific articles were published on the intricacies of the physiological action of this substance. Scientists, on the one hand, are finding new uses for the old medicine - for example, recent studies have revealed the mechanism of the effect of acetylsalicylic acid on lowering blood sugar levels, which is important for diabetics. On the other hand, based on research, new drugs are being developed for acetylsalicylic acid, the side effects of which are minimized. Obviously, acetylsalicylic acid will provide jobs for more than one generation of scientists - physiologists and pharmacists.
Materials on the Internet: http://www.remedium.ru
http://www.brandpro.ru/world/histories/h02.htm
http://www.inventors.ru/index.asp?mode\u003d4212
http://www.roche.ru/press_analitic_medpreparat_apr.shtml
Ekaterina Mendeleeva
The drug is based on gender. A couple of years ago, scientists undertook to investigate already conducted research. We took 23 tests concerning acetylsalicylic. It is popularly known as "Aspirin".
The research involved 113,000 people. Scientists undertook to find out the dependence of test results on the ratio of men and women in the groups of subjects.
It turned out that the effectiveness of the action was higher in men's groups. Why? For now, this is a mystery. Let's talk about what acetylsalicylic acid understandable. Let's start with the studied properties of the substance.
Properties of acetylsalicylic acid
Acetylsalicylic acid formula - C 9 H 8 O 4. The second name of the substance is 2-hydroxybenzoic. The prefix "hydroxy" is given for the presence of OH hydroxyl. to which it is attached is the simplest in the class.
Structural formula of acetylsalicylic acid
They have carboxyl groups COOH. In benzoic, like acetylsalicylic, it is only one. This is a prerequisite not only for simple ones, but also for fat ones. For the latter, there is one more condition - an open circuit.
This is exactly the article of the heroine. In esterified form, that is, the form of ether, fatty ones are present in fats. The acetylsalicylic compound is no exception.
Knowing that acetylsalicylic acid is "Aspirin"it is easy to guess what it looks like. The substance is crystalline, colorless. It is also known that the compound dissociates in water. The heroine easily dissolves in ethanol, diester.
The heroine of the article is also identified by the melting point. It is 156 degrees. The substance boils at 211 degrees Celsius. The reaction for the determination of acetylsalicylic takes place in its solution. If chloride is added, the liquid is colored in.
The heroine of the article can precipitate from solutions. This happens when the medium becomes acidic. It is at this moment that it is convenient to determine the compound by the melting temperature, because the experiment requires a crystalline one.
By the way, the form is also an identifier for acetylsalicylic. Its aggregates are monoclinic, that is, they are built on 3 vectors. They have different lengths. There are 2 right angles between the vectors and one not.
Crystals are stable only in dry air. In a humid environment, the powder absorbs water. In this case, two are formed - and salicylic. The first has a familiar smell.
When it appears, you can understand that the heroine of the article began to disintegrate. Chemists refer to the process as hydrolysis. Acetylsalicylic itself has almost no smell.
The acetylsalicylic compound is amenable to esterification. This is what chemists call the formation of esters. For their formation, they are not exposed to alkaline bicarbonates and hydroxides.
The reaction starts in boiling water. By the way, the solubility of aspirin in it depends on the Ph of the liquid. Best of all, the heroine of the article dissolves in water with an alkaline medium.
Obtaining acetylsalicylic acid
"Aspirin" is obtained by carboxylation of a phenolate. It is taken dry. Affect carbonate phenolate. The method is called "Kolbe-Schmitt". You need to withstand a pressure of 0.6 megapascals and a temperature of 185 degrees Celsius. Under these conditions, the reaction proceeds from 8 to 10.
Chemical formula of acetylsalicylic acid
An alternative method of industrial synthesis of the heroine of the article is the oxidation of o-cresol, that is, crude carbolic acid. They act on it with oxide. The reaction takes place when heated. Sometimes, pre-sulfonated cresol is oxidized. In this case, the yield of acetylsalicylic acid increases.
The use of acetylsalicylic acid
"And a painful sip of aspirin gives you an ease of spirit, the good benefits of illness and courage, an unkind chill." These lines are from a poem by Bella Akhmadulina.
The Silver Age poetess included them in Introducing the Cold. We conclude: in pharmacology, acetylsalicylic acid has been used for about a century and is significant from the very start.
It has been proven that Aspirin blocks the production of prostaglandins. These are lipids. They are formed in the body enzymatically from fatty ones. Prostaglandins lower blood pressure.
The second action is to stimulate myometrium contractions. This is the layer of cells that line the uterus. We conclude what acetylsalicylic acid helps, - from premature labor.
Acetylsalicylic acid is used for colds and headaches
Obstetricians-gynecologists prescribe a quarter of "Aspirin" to women with the threat of miscarriage, uterine hypertonicity. But, to the masses, acetylsalicylic is known as an antipyretic agent.
In this capacity, the drug is approved from the age of 12. In adolescents and adults, the medicine not only lowers the temperature, but also relieves pain. Respectively, acetylsalicylic acid instructions for usecontains a recommended remedy for cramps of the menstrual plan, headaches, aching sensations in the mouth.
Aspirin also extinguishes pain in muscles and joints. Note that Aspirin comes in several forms. Their action is different. Effervescent tablets, for example, are used exclusively for migraines and other pain c.
Acetylsalicylic acid is recommended for a number of cancers, as well as for their prevention. In patients regularly taking aspirin, malignant tumors of the bladder, prostate, and esophagus are less likely to be diagnosed.
Aspirin is not included in anti-cancer agents. So far, doctors cannot explain the mechanism of action of the drug, they do not exclude a random factor in statistics.
At the beginning of the article, it was said about another phenomenon not explained by scientists. We are talking about the different effectiveness of acetylsalicylic in relation to the organisms of men and women. There is an exception to the rule.
The heroine of the article blocks Alzheimer's disease, mainly in the fairer sex. In theory, the effect of the drug should be the same for everyone. "Aspirin" liquefies.
Accordingly, the obstructed blood supply to the brain improves. This is the main help in the fight against memory-consuming ailment. Why the method does not work for men with Alzheimer's remains a mystery.
Outside of pharmacology, acetylsalicylic acid is used in everyday life and in agriculture. The recommendation is passed from mouth to mouth to dissolve the Aspirin tablet in a vase with cut flowers.
In a medicinal solution, as in water with potassium permanganate, plants retain their freshness longer. In the fields, acid is used in the fight against fungal infections of the soil. Problem beds are spilled with Aspirin solution at the rate of one tablet per liter of water.
Motorists use the heroine of the article when starting their cars. Aspirin tablets help with dead batteries. The drug reacts with the electrolyte, giving a short-term charge.
The method is relevant for an unexpectedly shrunken device. Usually, it malfunctions in cold weather. As a permanent means for the battery plant "Aspirin", of course, is not suitable.
The hostesses know the heroine of the article as a means for removing sweat stains. They remain whitish stains on clothes. 2-hour soaking in solution helps to remove them. acetylsalicylic acid. Pricestore stain remover is many times more expensive. Take 4 tablets of "Aspirin" in a glass of water.
Aspirin's anti-inflammatory action has made it an acne fighter. used as a paste. The tablets are pounded and mixed with water.
The paste is applied pointwise to inflammation. The drug dries out the lesions, relieves redness. 2-3 minutes is enough. After, the ointment is washed off with warm, soapy water.
Acetylsalicylic acid for facecan also act as an exfoliating agent. True, given the tenderness of the skin on the forehead, cheeks, near the eyes, the heroine of the article is more often used for the heels.
Acetylsalicylic acid for acne
There, the corrosive action is in place, it fights corns. Crushed tablets "Aspirin" are mixed with juice. Take 5 tablets per teaspoon. You will also need a couple of drops of water.
The mixture is smeared on coarse areas, wrapped with cloth napkins. After that, the feet are wrapped in polyethylene. They remove it after 10-15 minutes. It remains to walk in the footsteps of a pumice stone. It will easily remove softened fabrics.
Acetylsalicylic acid for childrenand is useful for adults with bee stings. Places of skin punctures are moistened with clean water and rubbed with an "Aspirin" tablet. You can also rub your hair with the hero of the article.
The product is useful for stained, in contact with bleach. A typical situation for those who go to the pool. 6 Aspirin tablets are diluted into a glass of water, the curls are wiped, and after 15 minutes they are washed off with shampoo.
Dyed hair does not lose color, there is no question of porosity. So that, acetylsalicylic acid from temperature- just the tip of the iceberg of its application.
The benefits and harms of acetylsalicylic acid
Is it possible for acetylsalicylic acidto take without a doctor's prescription? Inside it is impossible, but outwardly not desirable. "Aspirin" is, nevertheless, acid. Having a corrosive effect on the skin, the substance does the same with mucous membranes. Accordingly, prolonged intake of the acetylsalicylic compound inside can lead to gastritis and stomach ulcers.
The irritating effect of the heroine of the article on the stomach is called acedosis. Gastroenterologist control is recommended. Internal bleeding may occur.
Compliance with the instructions will help minimize the risks if you need to constantly take Aspirin. The tablets are taken with a small amount of water and, most importantly, taken with meals.
Acetylsalicylic is contraindicated in children under 12 years of age because of the risk of Reye's syndrome. It is also called white liver disease. The disease is rare, but deadly, it occurs in children and adolescents.
The syndrome develops against the background of treatment of febrile ailments such as ODS, measles or chickenpox. Not only the liver is affected, but also the brain. Moreover, Reye occurs exclusively in parallel with the treatment with Aspirin.
Overdose of acetylsalicylic in adults, at times, leads to deafness, skin rashes, prolonged bleeding with injuries. Actually, circulatory disorders are not only the result of the use of the heroine of the article, but also a contraindication to its use, as well as hypertension, asthma, chronic liver diseases.
However, in uncontrolled doses, everything can be fatal. The newspaper "HLS", for example, describes the death of a man who drank 2 liters of carrot juice daily. What is considered an elixir was caused only by the volume of the drink and the consistency of the intake.
Acidum acetylsalicylicum
Quantitation.
Acidimetry method.
An exact sample of the drug is placed in a flask with a ground stopper, dissolved in water, ether, a few drops of a mixed indicator (1 ml of methyl orange solution and 1 ml of methylene blue solution) are added and titrated with 0.5 M hydrochloric acid until a lilac color appears in the aqueous layer ...
Storage... In a well-closed container, protected from light, in a dry place.
Application. Antirheumatic, anti-inflammatory, analgesic, antipyretic agent.
Use only after meals, drink with milk, mucus, because free salicylic acid is secreted in the stomach, which has a keratolytic effect (melts the walls of the stomach, causes stomach bleeding → ulcers), it is prescribed with soda. It also has a toxic effect on the heart, therefore it is prescribed with caffeine.
Acetic acid salicylic ester
| C 9 H 8 O 4 | M. in. 180.16 |
Receiving. From salicylic acid and acetic anhydride.
Description... Colorless crystals or white crystalline powder; odorless or weak odor, slightly acidic taste. The drug is stable in dry air, in humid air it gradually hydrolyzes to form acetic and salicylic acids.
Solubility... We will slightly dissolve in water, we will easily dissolve in alcohol, we will dissolve in chloroform, ether, in solutions of caustic and carbonic alkalis.
Authenticity.
1) Alkaline hydrolysis the drug with the subsequent release of salicylic acid, the presence of which is proved by reaction with ferric chloride, and acetic acid - is proved by the reaction of formation of ethyl acetate. The preparation is boiled for 3 minutes with sodium hydroxide solution, then cooled and acidified with diluted sulfuric acid; a white crystalline precipitate is formed. The solution is poured into another test tube and alcohol and concentrated sulfuric acid are added to it; the solution has the smell of ethyl acetate. A few drops of ferric chloride solution are added to the precipitate; a violet color appears.
2) Reaction with Mark's reagent (in a porcelain cup). The preparation is placed in a porcelain cup, concentrated sulfuric acid is added, stirred and a few drops of water are added; there is a smell of acetic acid. Then formalin is added; a pink color appears.
quantitation.
1) Alkalimetry method.
An exact sample of the drug is dissolved in alcohol neutralized by phenolphthalein (5-6 drops) and cooled to 8 - 9 °. The solution is titrated with the same indicator with a 0.1M sodium hydroxide solution until it becomes pink.
Direct titration formula.
2) Method of acidimetry after hydrolysis.
NaOH + HCl \u003d NaCl + H 2 O
Back titration formula.
Storage... In a well-sealed container.
Application... Antirheumatic, anti-inflammatory, analgesic, antipyretic agent.
Preparations. Tablets 0.25; 0.5; is part of complex dosage forms.
Provides damping mixtures with urotropin, carbonates.
Structural formula
True, empirical, or gross formula: C 9 H 8 O 4
Acetylsalicylic acid chemical composition
Molecular mass: 180.159
Acetylsalicylic acid (colloquial aspirin; lat. Acidum acetylsalicylicum, salicylic ester of acetic acid) is a drug that has analgesic (analgesic), antipyretic, anti-inflammatory and antiplatelet effect. The mechanism of action and the safety profile of acetylsalicylic acid are well studied, its effectiveness has been clinically tested, and therefore this drug is included in the list of essential medicines of the World Health Organization, as well as in the list of vital and essential medicines of the Russian Federation. Acetylsalicylic acid is also widely known under the trademark Aspirin, patented by Bayer.
History
Traditional medicine has long recommended the bark of young white willow branches as an antipyretic agent, for example, for preparing a decoction. The cortex also received recognition from doctors under the name Salicis cortex. However, all existing willow bark therapies had a very serious side effect - they caused severe abdominal pain and nausea. In a stable form suitable for purification, salicylic acid was first isolated from willow bark by the Italian chemist Rafel Piria in 1838. It was first synthesized by Charles Frederic Gerard in 1853. In 1859, professor of chemistry Hermann Kolbe from the University of Marburg discovered the chemical structure of salicylic acid, which made it possible in 1874 to open the first factory for its production in Dresden. In 1875, sodium salicylate was used to treat rheumatism and as an antipyretic agent. Its glucosuric action was soon established, and salicin began to be prescribed for gout. On August 10, 1897, Felix Hoffman of Bayer AG laboratories first obtained samples of acetylsalicylic acid in a form that could be used for medical purposes; using the acetylation method, he became the first chemist in history who managed to obtain salicylic acid in a chemically pure and stable form. Along with Hoffman, the inventor of aspirin is also called Arthur Eichengrün. The raw material for the production of acetylsalicylic acid was the bark of a willow tree. Bayer has registered a new drug under the brand name aspirin. Hoffman discovered the medicinal properties of acetylsalicylic acid while trying to find a cure for his father, who suffered from rheumatism. In 1971, pharmacologist John Wayne demonstrated that acetylsalicylic acid suppresses the synthesis of prostaglandins and thromboxanes. For this discovery in 1982 he, as well as Sune Bergström and Bengt Samuelson were awarded the Nobel Prize in Medicine; in 1984 he was awarded the title of Knight Bachelor.
Trade name Aspirin
After long disputes, it was decided to take the already mentioned Latin name of the plant from which the Berlin scientist Karl Jakob Lovig first isolated salicylic acid, Spiraea ulmaria. The four letters "spir" were assigned "a" to emphasize the special role of the acetylation reaction, and on the right - for euphony and in accordance with the established tradition - "in". The result is a simple pronunciation and easy to remember name Aspirin. Already in 1899, the first batch of this drug appeared on the market. Initially, only the antipyretic effect of aspirin was known; later, its analgesic and anti-inflammatory properties were also revealed. In the early years, aspirin was sold as a powder, and since 1904 it has been sold as a tablet. In 1983, a study appeared in the New England Journal of Medicine, which proved a new important property of the drug - when used during unstable angina pectoris, the risk of such an outcome of the disease as myocardial infarction or death is halved. Acetylsalicylic acid also reduces the risk of developing cancer, particularly of the breast and colon.
Mechanism of action
Suppression of the synthesis of prostaglandins and thromboxanes. Acetylsalicylic acid is an inhibitor of cyclooxygenase (PTGS), an enzyme involved in the synthesis of prostaglandins and thromboxanes. Acetylsalicylic acid works in the same way as other non-steroidal anti-inflammatory drugs (notably diclofenac and ibuprofen), which are reversible inhibitors. Thanks to the remark of the Nobel laureate John Wayne, which he expressed as a hypothesis in one of his articles, it was long believed that acetylsalicylic acid acts as a suicidal inhibitor of cyclooxygenase, acetylating the hydroxyl group in the active center of the enzyme. Further research has shown that this is not the case.
pharmachologic effect
Acetylsalicylic acid has anti-inflammatory, antipyretic and analgesic effects, and it is widely used for fever, headache, neuralgia, etc., and as an antirheumatic agent. The anti-inflammatory effect of acetylsalicylic acid (and other salicylates) is explained by its effect on the processes occurring in the focus of inflammation: a decrease in capillary permeability, a decrease in hyaluronidase activity, a limitation of the energy supply of the inflammatory process by inhibiting the formation of ATP, etc. In the mechanism of anti-inflammatory action, the inhibition of biosynthesis is important. The antipyretic effect is also associated with the effect on the hypothalamic centers of thermoregulation. The analgesic effect is due to the effect on the centers of pain sensitivity, as well as the ability of salicylates to reduce the algogenic effect of bradykinin. The blood thinning effect of acetylsalicylic acid makes it possible to use it to reduce intracranial pressure in case of headaches. Salicylic acid served as the basis for a whole class of medicinal substances called salicylates, an example of which is dioxybenzoic acid.
Application
Acetylsalicylic acid is widely used as an anti-inflammatory, antipyretic and analgesic agent. It is used alone and in combination with other drugs. There are a number of finished medicines containing acetylsalicylic acid (tablets "Citramon", "Kofitsil", "Asfen", "Askofen", "Acelisin", etc.). Recently, injectable preparations have been obtained, the main active principle of which is acetylsalicylic acid (see Acelizin, Aspizol). In the form of tablets, acetylsalicylic acid is prescribed orally after meals. The usual doses for adults as an analgesic and antipyretic agent (for febrile diseases, headache; migraine, neuralgia, etc.) 0.25-0.5-1 g 3-4 times a day; for children, depending on age, from 0.1 to 0.3 g per dose. For rheumatism, infectious-allergic myocarditis, rheumatoid arthritis, adults are prescribed for a long time, 2-3 g (less often 4 g) per day, for children 0.2 g per year of life per day. A single dose for children aged 1 year is 0.05 g, 2 years old - 0.1 g, 3 years old - 0.15 g, 4 years old - 0.2 g. Starting from the age of 5, it can be prescribed in tablets of 0 , 25 g per admission. Acetylsalicylic acid is an effective, readily available agent that is widely used in outpatient practice. It should be borne in mind that the use of the drug should be carried out in compliance with precautions due to the possibility of a number of side effects. Many cases have been described where the ingestion of even 40 grams of ethanol (100 grams of vodka) in combination with such conventional drugs as aspirin or amidopyrin, was accompanied by severe allergic reactions, as well as gastric bleeding. The use of acetylsalicylic acid in everyday life is widespread, as a means to relieve suffering the next morning after alcohol poisoning (to relieve a hangover). It is an integral component of the well-known drug "Alka-Seltzer". According to research by Professor Peter Rothwell (University of Oxford), based on an analysis of the health status of 25,570 patients, regular intake of acetylsalicylic acid reduces the 20-year risk of prostate cancer by about 10%, lung cancer by 30%, and bowel cancer - by 40%, cancer of the esophagus and throat - by 60%. Regular intake of acetylsalicylic acid for more than 5 years at a dose of 75 to 100 mg reduces the risk of colorectal cancer by up to 16%.
Antiplatelet action
An important feature of acetylsalicylic acid is its ability to have an antiplatelet effect, that is, to prevent spontaneous and induced platelet aggregation. Substances that have an antiplatelet effect are widely used in medicine to prevent the formation of blood clots in people who have had myocardial infarction, cerebrovascular accident, other manifestations of atherosclerosis (for example, exertional angina, intermittent claudication), as well as with high cardiovascular risk. The risk is considered “high” when the risk of non-fatal myocardial infarction or death due to heart disease in the next 10 years exceeds 20%, or the risk of dying from any cardiovascular disease (including stroke) in the next 10 years is greater than 5%. With bleeding disorders, such as hemophilia, the possibility of bleeding increases. Acetylsalicylic acid, as a means of primary prevention of complications of atherosclerosis, can be effectively used at a dose of 75-100 mg / day, this dose is well balanced in the ratio of effectiveness / safety. Acetylsalicylic acid is the only antiplatelet drug, the effectiveness of which, when administered in the acute period of ischemic stroke, is supported by evidence-based medicine. In the course of studies, a tendency towards a decrease in mortality was demonstrated both during the first 10 days and within 6 months after ischemic stroke, in the absence of pronounced hemorrhagic complications.
Side effect
Safe daily dose of acetylsalicylic acid: 4 g. Overdose leads to severe pathologies of the kidneys, brain, lungs and liver. Medical historians believe that the massive use of acetylsalicylic acid (10-30 g each) significantly increased mortality during the 1918 influenza pandemic. When using the drug, profuse sweating may also develop, tinnitus and hearing loss, angioedema, skin and other allergic reactions may appear. The so-called ulcerogenic (causing the appearance or exacerbation of gastric and / or duodenal ulcers) action is characteristic to one degree or another of all groups of anti-inflammatory drugs: both corticosteroid and non-steroidal (for example, butadione, indomethacin, etc.). The appearance of stomach ulcers and gastric bleeding with the use of acetylsalicylic acid is explained not only by the resorptive effect (inhibition of blood coagulation factors, etc.), but also by its direct irritating effect on the gastric mucosa, especially if the drug is taken in the form of uncrushed tablets. This also applies to sodium salicylate. With prolonged, without medical supervision, the use of acetylsalicylic acid, side effects such as dyspeptic disorders and gastric bleeding can be observed. To reduce the ulcerogenic effect and gastric bleeding, acetylsalicylic acid (and sodium salicylate) should be taken only after meals; it is recommended to grind the tablets thoroughly and drink plenty of liquid (preferably milk). There is, however, evidence that stomach bleeding can also be observed when taking acetylsalicylic acid after meals. Sodium bicarbonate promotes a more rapid release of salicylates from the body, however, to reduce the irritating effect on the stomach, they resort to taking mineral alkaline waters or sodium bicarbonate solution after acetylsalicylic acid. Abroad, acetylsalicylic acid tablets are produced in an enteric (acid-resistant) shell in order to avoid direct contact of ASA with the stomach wall. With prolonged use of salicylates, the possibility of anemia should be taken into account and systematic blood tests should be performed and the presence of blood in the stool should be checked. Due to the possibility of allergic reactions, care should be taken when prescribing acetylsalicylic acid (and other salicylates) to persons with hypersensitivity to penicillins and other "allergenic" drugs. With increased sensitivity to acetylsalicylic acid, aspirin asthma may develop, for the prevention and treatment of which methods of desensitizing therapy have been developed using increasing doses of acetylsalicylic acid. It should be borne in mind that under the influence of acetylsalicylic acid, the effect of anticoagulants (coumarin derivatives, heparin, etc.), sugar-lowering drugs (sulfonylurea derivatives) increases, the risk of gastric bleeding increases with the simultaneous use of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs), side effects of methotrexate increase. The effect of furosemide, uricosuric agents, spironolactone is somewhat weakened.
In children and pregnant women
In connection with the available experimental data on the teratogenic effect of acetylsalicylic acid, it is not recommended to prescribe it and preparations containing it to women in the first 3 months of pregnancy. Taking non-narcotic pain relievers (aspirin, ibuprofen and paracetamol) during pregnancy increases the risk of genital disorders in newborn boys in the form of cryptorchidism. The results of the study showed that the simultaneous use of two of the three listed drugs during pregnancy increases the risk of having a baby with cryptorchidism up to 16 times compared with women who did not take these drugs. Currently, there is evidence of the possible danger of using acetylsalicylic acid in children for the purpose of lowering the temperature with influenza, acute respiratory and other febrile diseases in connection with the observed cases of the development of Reye's syndrome (Reye) (hepatogenic encephalopathy). The pathogenesis of Reye's syndrome is unknown. The disease proceeds with the development of acute liver failure. The incidence of Reye's syndrome among children under 18 in the United States is approximately 1 in 100,000, with a case fatality rate exceeding 36%.
Contraindications
Peptic ulcer and duodenal ulcer and bleeding are contraindications to the use of acetylsalicylic acid and sodium salicylate. The use of acetylsalicylic acid is also contraindicated in case of a history of peptic ulcer disease, with portal hypertension, venous stasis (due to a decrease in the resistance of the gastric mucosa), and in violation of blood coagulation. Acetylsalicylic acid preparations should not be prescribed to children under 12 years of age to lower body temperature in viral diseases due to the possibility of Reye's syndrome. It is recommended to replace acetylsalicylic acid with paracetamol or ibuprofen. Some people may experience so-called aspirin asthma.
Substance properties
Acetylsalicylic acid is a white, fine needle-like crystals or a light crystalline powder of slightly acidic taste, slightly soluble in water at room temperature, soluble in hot water for 30 minutes. After cooling. Acetylsalicylic acid, when heated above 200 degrees Celsius, becomes an extremely active flux that dissolves oxides of copper, iron and other metals. in the presence of sulfuric acid. For purification, the product is recrystallized. The yield is about 80%.
Facts
- In Russia, the traditional household name for acetylsalicylic acid is aspirin. Based on the tradition of the term, Bayer was denied registration of the aspirin brand in Russia.
- More than 80 billion aspirin tablets are consumed annually.
- In 2009, researchers discovered that salicylic acid, which is derived from acetylsalicylic acid, can be produced by the human body.
- Acetylsalicylic acid is used as an active acid flux for brazing and tinning with low-melting alloys.
- Scientists have found that aspirin can help treat many cases of infertility in women. it counteracts the inflammation caused by the protein that is high in miscarriages. Women can increase their chances of getting pregnant by taking limited doses of aspirin.
Systematic (IUPAC) name: 2-acetoxybenzoic acid
Legal status: dispensed by pharmacist only (S2) (Australia); allowed for free sale (UK); available over the counter (USA).
In Australia, the drug is in Schedule 2, with the exception of intravenous use (in which case the drug is included in Schedule 4), and is used in veterinary medicine (Schedule 5/6).
Application: most often orally, also rectally; lysine acetylsalicylate can be used intravenously or intramuscularly
Bioavailability: 80-100%
Protein binding: 80-90%
Metabolism: hepatic, (CYP2C19 and possibly CYP3A), some of it is hydrolyzed into salicylate in the walls of the esophagus.
Half-life: dose dependent; 2-3 hours when taking small doses, and up to 15-30 hours when taking large doses.
Excretion: urine (80-100%), sweat, saliva, feces
Synonyms: 2-acetoxybenzoic acid; acetylsalicylate;
acetylsalicylic acid; O-acetylsalicylic acid
Formula: C9H8O4
Mol. mass: 180.157 g / mol
Density: 1.40 g / cm³
Melting point: 136 ° C (277 ° F)
Boiling point: 140 ° C (284 ° F) (decomposes)
Solubility in water: 3 mg / ml (20 ° C)
Aspirin (acetylsalicylic acid) is a salicylate drug used as an analgesic for mild pain relief, as well as an antipyretic and anti-inflammatory agent. Aspirin is also an antiplatelet agent and inhibits the production of thromboxane, which normally binds platelet molecules and creates a patch over damaged blood vessel walls. Because this patch can also grow and block blood flow, aspirin is also used to prevent heart attacks, strokes, and blood clots. Low-dose aspirin is used immediately after a heart attack to reduce the risk of a second attack or death of heart tissue. Aspirin can be effective in preventing certain cancers, especially colon and rectal cancers. The main side effects of aspirin are stomach ulcers, stomach bleeding, and tinnitus (especially when taken in high doses). Aspirin is not recommended for children and adolescents with flu-like symptoms or viral illnesses due to the risk of Reye's syndrome. Aspirin belongs to a group of drugs called "nonsteroidal anti-inflammatory drugs" (NSAIDs), but has a different mechanism of action from most other NSAIDs. Although aspirin and drugs with a similar structure act similarly to other NSAIDs (exhibiting antipyretic, anti-inflammatory, analgesic effects) and inhibit the same cyclooxygenase (COX) enzyme, aspirin differs from them in that it acts irreversibly and, unlike other drugs, affects more on COX-1 than COX-2.
The active ingredient in aspirin was first discovered in willow bark in 1763 by Edward Stone of Wadham College, Oxford. The doctor discovered salicylic acid, the active metabolite of aspirin. Aspirin was first synthesized by Felix Hoffmann, a chemist at the German company Bayer, in 1897. Aspirin is one of the most widely used medicines in the world. Approximately 40,000 tonnes of aspirin are consumed worldwide each year. In countries where aspirin is a registered trademark of Bayer, the generic acetylsalicylic acid is sold. The drug is included in the list of essential medicines of the World Health Organization.
The use of aspirin in medicine
Aspirin is used to treat a variety of symptoms, including fever, pain, rheumatic fever, and inflammatory conditions such as rheumatoid arthritis, pericarditis, and Kawasaki disease. In low doses, aspirin is used to reduce the risk of death from heart attack or stroke. There is evidence that aspirin can be used to treat bowel cancer, but its mechanism of action in this case has not been proven.
Aspirin-analgesic
Aspirin is an effective analgesic for the treatment of acute pain, but is inferior to ibuprofen in that the latter is associated with a lower risk of gastric bleeding. Aspirin is not effective for pain caused by muscle cramps, flatulence, bloating, or severe skin damage. As with other NSAIDs, the effectiveness of aspirin is increased when taken in combination with. Effervescent aspirin tablets such as Alkoselzer or Blowfish relieve pain faster than conventional tablets and are effective in treating migraines. Aspirin is used as an ointment to treat certain types of neuropathic pain.
Aspirin and headache
Aspirin, alone or in combination formulas, is effective in treating some types of headaches. Aspirin may not be effective for treating secondary headaches (caused by other illnesses or injuries). The International Classification of Diseases Associated with Headaches distinguishes tension headache (the most common type of headache), migraine and cluster headaches among primary headaches. Aspirin or other over-the-counter analgesics are used to treat tension headache. Aspirin, especially as a component of the acetaminophen / aspirin / Excedrin Migraine formula, is considered an effective first-line treatment for migraines, and is comparable in effectiveness to low-dose sumatriptan. The drug is most effective in stopping migraines at the onset.
Aspirin and fever
Aspirin acts not only on pain, but also on fever through the prostaglandin system by irreversibly inhibiting COX. Although aspirin is widely approved for use in adults, many medical societies and regulatory agencies (including the American Academy of Family Therapists, the American Academy of Pediatrics, and the FDA) do not recommend the use of aspirin as a febrifuge for children. Aspirin may be associated with a risk of Reye's syndrome, a rare but often fatal illness associated with the use of aspirin or other salicylates in children with viral or bacterial infections. In 1986, the FDA ordered manufacturers to place a warning on the risks of aspirin use in children and adolescents on all aspirin labels.
Aspirin and heart attacks
The first studies of the effects of aspirin on the heart and heart attacks were carried out in the early 1970s by Professor Peter Slate, Professor Emeritus of Heart Medicine at the University of Oxford, who formed the Aspirin Research Society. In some cases, aspirin can be used to prevent heart attacks. At lower doses, aspirin is effective in preventing the development of existing cardiovascular diseases, as well as in reducing the risk of developing these diseases in individuals with a history of similar diseases. Aspirin is less effective for people with a low risk of heart attack, such as people who have never had a similar condition in the past. Some studies recommend taking aspirin on an ongoing basis, while others discourage this use due to side effects such as stomach bleeding, which usually outweigh any potential benefits of the drug. When aspirin is used prophylactically, the phenomenon of aspirin resistance can be observed, manifested in a decrease in the effectiveness of the drug, which can lead to an increase in the risk of a heart attack. Some authors suggest testing for resistance to aspirin or other antithrombotic drugs before starting treatment. Aspirin has also been proposed as a component of a drug for the treatment of cardiovascular diseases.
Post-surgical treatment
The US Agency for Health Research and Quality Guidelines recommends the long-term use of aspirin after a percutaneous coronary intervention procedure such as coronary artery stent placement. Aspirin is often combined with an adenosine diphosphate receptor inhibitor such as clopidogrel, prasugrel, or ticagreol to prevent blood clots (dual antiplatelet therapy). Recommendations for the use of aspirin in the United States and Europe differ somewhat regarding how long and for what reasons such combination therapy should be given after surgery. In the United States, dual antiplatelet therapy is recommended for a minimum of 12 months, and in Europe, 6–12 months after using a drug stent. However, the recommendations in both countries are consistent on the issue of indefinite use of aspirin after the completion of antiplatelet therapy.
Aspirin and cancer prevention
The effects of aspirin on cancer, especially colon cancer, have been widely studied. Numerous meta-analyzes and reviews indicate that continued use of aspirin reduces the long-term risk of bowel cancer and mortality. However, no relationship was found between the dose of aspirin, duration of use, and various indicators of risk, including mortality, disease progression, and disease risk. Although most of the data on aspirin and the risk of bowel cancer comes from observational studies rather than randomized controlled trials, the available data from randomized trials indicate that long-term use of low-dose aspirin may be effective in preventing some types of colon cancer. In 2007, the US Preventive Service issued a directive on this issue, giving the use of aspirin to prevent colon cancer a “D” rating. The service also discourages doctors from using aspirin for this purpose.
Other uses of aspirin
Aspirin is used as a first-line therapy for fever symptoms and joint pain in acute rheumatic fever. Treatment often lasts for one to two weeks, and the drug is rarely prescribed for long periods of time. Once the fever and pain are relieved, aspirin is no longer necessary, but it does not reduce the risk of heart complications or residual rheumatic heart disease. Naproxen is as effective as aspirin and is less toxic, however, due to limited clinical data, naproxen is only recommended as a second-line treatment. Aspirin is recommended for children only for Kawasaki disease and rheumatic fever due to the lack of high quality data on its effectiveness. At low doses, aspirin is moderately effective in preventing preeclampsia.
Aspirin resistance
In some people, aspirin is not as effective on platelets as in others. This effect is called "aspirin resistance" or insensitivity. One study showed that women are more prone to resistance than men. An aggregation study involving 2930 patients showed that 28% of patients develop aspirin resistance. A study of 100 Italian patients showed that, on the other hand, of the 31% of patients who were resistant to aspirin, only 5% had actual resistance, while the rest had non-compliance (non-compliance with drug intake). Another study in 400 healthy volunteers showed that none of the patients showed actual resistance, but some showed "pseudo-resistance, reflecting delayed or reduced drug absorption."
Aspirin dosage
Adult aspirin tablets are manufactured in standard dosages that vary slightly from country to country, such as 300 mg in the UK and 325 mg in the US. Reduced dosages are also linked to existing standards such as 75 mg and 81 mg. Tablets of 81 mg are conventionally referred to as "children's dose", although they are not recommended for use in children. The difference between 75 mg and 81 mg tablets is not of significant medical significance. Interestingly, in the United States, 325 mg tablets are equivalent to 5 grains of aspirin used up to the metric system used today. In general, to treat fever or arthritis, adults are advised to take aspirin 4 times a day. Historically, doses close to the maximum have been used to treat rheumatic fever. For the prevention of rheumatoid arthritis in individuals with present or suspected coronary artery disease, lower doses are recommended once daily. The US Preventive Service recommends the use of aspirin for the primary prevention of coronary heart disease in men aged 45–79 and women aged 55–79 only if the potential benefits (reducing the risk of myocardial infarction in men or stroke in women) outweigh the potential risk gastric damage. A study by the Women's Health Initiative showed that regular low-dose aspirin (75 or 81 mg) in women reduces the risk of death from cardiovascular disease by 25% and 14% - the risk of death from other causes. Low-dose aspirin use is also associated with a reduced risk of cardiovascular disease, and doses of 75 or 81 mg / day may optimize efficacy and safety for patients taking aspirin for long-term prophylaxis. In children with Kawasaki disease, the dose of aspirin is based on weight. The drug is started four times a day for a maximum of four weeks, and then, over the next 6-8 weeks, the drug is taken in lower doses once a day.
Side effects of aspirin
Contraindications
Aspirin is not recommended for individuals with an allergy to ibuprofen or naproxen, or for individuals with salicylate intolerance, or more generalized intolerance to NSAIDs. Caution should be observed in persons suffering from asthma or bronchospasm caused by taking NSAIDs. Because aspirin works on the stomach wall, manufacturers recommend that patients with stomach ulcers, diabetes, or gastritis consult a doctor before using aspirin. Even in the absence of the above conditions, the risk of stomach bleeding increases when aspirin or alcohol is taken together. Patients with hemophilia or other bleeding disorders are not advised to take aspirin or other salicylates. Aspirin can cause hemolytic anemia in people with a genetic disorder of glucose-6-phosphate dehydrogenase deficiency, especially at high doses and depending on the severity of the disease. The use of aspirin for dengue fever is not recommended because of the increased risk of bleeding. Aspirin is also not recommended for people with kidney disease, hyperuricemia, or gout because aspirin inhibits the kidney's ability to excrete uric acid and thus may exacerbate these diseases. Aspirin is not recommended for children and adolescents to treat symptoms of flu and colds, as this use may be associated with the development of Reye's syndrome.
Gastrointestinal tract
Aspirin has been shown to increase the risk of stomach bleeding. Even though enteric coated aspirin tablets are marketed as "soft for the stomach," one study showed that even this did not help reduce the harmful effects of aspirin on the stomach. When aspirin is combined with other NSAIDs, the risk also increases. When using aspirin in combination with clopidogrel or the risk of stomach bleeding is also increased. Aspirin blockade of COX-1 induces a protective response in the form of increased COX-2. The use of COX-2 inhibitors and aspirin leads to increased erosion of the gastric mucosa. Thus, caution should be exercised when combining aspirin with any natural COX-2 inhibiting supplements such as garlic extracts, curcumin, blueberry, pine bark, ginkgo, fish oil, genistein, quercetin, resorcinol, and others. To reduce the harmful effects of aspirin on the stomach, in addition to the use of enteric coatings, manufacturing companies use the "buffer" method. Buffering agents are used to prevent the accumulation of aspirin on the stomach walls, but the effectiveness of such drugs is disputed. Almost any agent used in antacids is used as "buffers". Bufferin, for example, uses MgO. Other drugs use CaCO3. Not so long ago, vitamin C was added to protect the stomach when taking aspirin. When taken together, there is a decrease in the amount of damage compared to using aspirin alone.
The central effect of aspirin
In experiments on rats, high doses of salicylate, a metabolite of aspirin, have been shown to cause temporary ringing in the ears. This occurs as a result of exposure to arachidonic acid and the NMDA receptor cascade.
Aspirin and Reye's syndrome
Reye's syndrome, a rare but very dangerous disease, is characterized by acute encephalopathy and fatty liver, and develops when children and adolescents take aspirin to reduce fever or to treat other symptoms. From 1981 to 1997, 1207 cases of Reye's syndrome were recorded in the United States among patients under the age of 18. In 93% of cases, patients felt unwell three weeks before the development of Reye's syndrome, and most often complained of respiratory infections, chickenpox, or diarrhea. Salicylates were found in 81.9% of children. After the connection between Reye's syndrome and aspirin use was proven and safety measures were taken (including a request from the chief sanitary doctor and changes on the packaging), aspirin intake by children in the United States fell sharply, which led to a decrease in the incidence of Reye's syndrome; a similar situation was observed in the UK. The US FDA does not recommend taking aspirin or aspirin-containing foods for children under 12 years of age with fever symptoms. The UK Medicines and Medicines Regulatory Agency does not recommend taking aspirin to children under 16 without a doctor's prescription.
Allergic reactions to aspirin
In some people, aspirin can cause allergy-like symptoms, including skin redness and swelling and headache. This reaction is caused by an intolerance to salicylate and is not an allergy in the literal sense of the word, but rather an inability to metabolize even a small amount of aspirin, which can quickly lead to an overdose.
Other side effects of aspirin
In some people, aspirin can cause angioedema (swelling of skin tissue). One study showed that some patients develop angioedema 1-6 hours after taking aspirin. However, angioedema developed only when aspirin was taken in combination with other NSAIDs. Aspirin increases the risk of cerebral microbleeding, which on MRI shows as dark spots 5-10 mm in diameter or less. These bleeding may be the first signs of ischemic stroke or hemorrhagic stroke, Binswanger's disease and Alzheimer's disease. A study of a group of patients taking an average dose of aspirin 270 mg per day showed a mean absolute increase in the risk of hemorrhagic stroke equal to 12 cases among 10,000 people. In comparison, the absolute reduction in the risk of myocardial infarction was 137 cases among 10,000 people, and the reduction in the risk of ischemic stroke was 39 cases among 10,000 people. In the case of pre-existing hemorrhagic stroke, aspirin use increases the risk of mortality, with doses of about 250 mg per day lowering the risk of mortality within three months after hemorrhagic stroke. Aspirin and other NSAIDs can cause hyperkalemia by inhibiting prostaglandin synthesis; however, these drugs are not likely to cause hyperkalemia when hepatic function is normal. Aspirin can increase postoperative bleeding for up to 10 days. One study showed that 30 of 6499 patients with elective surgery required reoperations due to bleeding. Diffuse bleeding was observed in 20 patients, and local bleeding in 10. In 19 of 20 patients, diffuse bleeding was associated with preoperative aspirin use alone or in combination with other NSAIDs.
Aspirin overdose
Aspirin overdose can be acute or chronic. Acute overdose is associated with a single large dose of aspirin. Chronic overdose is associated with prolonged intake of doses above the recommended rate. Acute overdose is associated with a 2% mortality risk. Chronic overdose is more dangerous and more often fatal (in 25% of cases); chronic overdose is especially dangerous in children. For poisoning, various agents are used, including activated charcoal, sodium dicarbonate, intravenous dextrose and salt, and dialysis. For the diagnosis of poisoning, measurements of salicylate, an active metabolite of aspirin, in plasma are used using automated spectrophotometric methods. Plasma salicylate levels are 30-100 mg / L, 50-300 mg / L for high doses, and 700-1400 mg / L for acute overdose. Salicylate is also produced from the use of bismuth subsalicylate, methyl salicylate and sodium salicylate.
Interactions of aspirin with other drugs
Aspirin can interact with other medications. For example, azetazolamide and ammonium chloride increase the harmful effects of salicylates, while alcohol increases gastric bleeding when taking aspirin. Aspirin can displace some drugs from protein binding sites, including the antidiabetic drugs tolbutamil and chlorpropamide, methotrexate, phenytoin, probenecid, valproic acid (by interfering with beta-oxidation, an important part of valproate metabolism), and other NSAIDs. Corticosteroids can also lower aspirin concentrations. Ibuprofen can reduce the antiplatelet effect of aspirin, which is used to protect the heart and prevent stroke. Aspirin can reduce the pharmacological activity of spironolactone. Aspirin competes with pinicillin G for renal tubular secretion. Aspirin can also inhibit the absorption of vitamin C.
Chemical characteristics of aspirin
Aspirin is rapidly degraded in solutions of ammonium acetate or acetates, carbonates, citrates or hydroxides of alkali metals. It is dry stable, but it undergoes significant hydrolysis on contact with acetyl or salicylic acid. In the reaction with alkali, hydrolysis occurs rapidly, and the formed pure solutions can consist entirely of acetate or salicylate.
Physical characteristics of aspirin
Aspirin, an acetyl derivative of salicylic acid, is a white, crystalline, weakly acidic compound with a melting point of 136 ° C (277 ° F) and a boiling point of 140 ° C (284 ° F). The acid dissociation constant of the substance (pKa) is 25 ° C (77 ° F).
Aspirin synthesis
Aspirin synthesis is classified as an esterification reaction. Salicylic acid is treated with acetyl anhydride, an acid derivative, causing a chemical reaction that converts the hydroxy group of salicylic acid to an ester group (R-OH → R-OCOCH3). As a result, aspirin and acetylic acid are formed, which is considered a by-product of this reaction. Small amounts of sulfuric acid (and sometimes phosphoric acid) are usually used as catalysts.
The mechanism of action of aspirin
Discovery of the mechanism of action of aspirin
In 1971, British pharmacologist John Robert Wayne, who was later admitted to the Royal College of Surgeons in London, demonstrated that aspirin suppresses the production of prostaglandins and thromboxanes. For this discovery, the scientist was awarded the 1982 Nobel Prize in Medicine, together with Sune Bergström and Bengt Samuelson. In 1984 he was awarded the title of Knight Bachelor.
Suppression of prostaglandins and thromboxanes
The ability of aspirin to suppress the production of prostaglandins and thromboxanes is associated with its irreversible inactivation of the enzyme cyclooxygenase (COX; officially called prostaglandin endoperoxide synthase), associated with the synthesis of prostaglandin and thromboxane. Aspirin acts as an acetylating agent when an acetyl group is covalently attached to a residue on the active site of the COX enzyme. This is the main difference between aspirin and other NSAIDs (such as diclofenac and ibuprofen), which are reversible inhibitors. Low-dose aspirin irreversibly blocks the formation of thromboxane A2 in platelets, inhibiting platelet aggregation during their life cycle (8–9 days). Due to this antithrombotic action, aspirin is used to reduce the risk of heart attack. Aspirin at 40 mg per day can inhibit a large percentage of the maximum release of thromboxane A2, with little effect on prostaglandin I2 synthesis; however, high doses of aspirin may increase inhibition. Prostaglandins, a local hormone produced in the body, have a variety of effects, including the transmission of pain signals to the brain, modulation of the hypothalamic thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets, which form blood clots. The main cause of heart attack is blood clotting, and low-dose aspirin is recognized as an effective means of preventing acute myocardial infarction. An undesirable side effect of the antithrombotic action of aspirin is that it can cause excessive bleeding.
Inhibition of COX-1 and COX-2
There are at least two types of cyclooxygenase: COX-1 and COX-2. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. COX-2 usually produces prostanoids, most of which are pro-inflammatory. Aspirin-modified PTGS2 produces lipoxins, most of which are anti-inflammatory. To inhibit PTGS2 alone and reduce the risk of gastrointestinal side effects, a new generation of NSAIDs, COX-2 inhibitors, have been developed. However, more recently, new generation COX-2 inhibitors such as rofecoxib (Vioxx) have been taken off the market following reports that PTGS2 inhibitors increase the risk of heart attack. Endothelial cells express PTGS2 and, by selectively inhibiting PTGS2, reduce prostaglandin (ie, PGI2; prostacyclin) production, depending on thromboxane levels. Thus, the protective anticoagulant effect of PGI2 decreases and the risk of blood clots and heart attacks increases. Since platelets do not have DNA, they cannot synthesize new PTGS. Aspirin irreversibly inhibits the enzyme, which is its most important difference from reversible inhibitors.
Additional mechanisms of action of aspirin
Aspirin has at least three additional mechanisms of action. It blocks oxidative phosphorylation in cartilaginous (and renal) mitochondria by diffusing from a portion of the inner membrane as a proton carrier back into the mitochondrial space, where it re-ionizes to release protons. In short, aspirin buffers and transports protons. When taken in high doses, aspirin can cause fever due to the thermal release from the electron transport chain. In addition, aspirin promotes the formation of NO-radicals in the body, which, as shown in experiments on mice, is an independent mechanism for reducing inflammation. Aspirin reduces leukocyte adhesion, which is an important immune defense mechanism against infections; however, these data are not conclusive evidence of the effectiveness of aspirin against infections. Newer data also show that salicylic acid and its derivatives modulate signaling through NF-κB. NF-κB, a transcription factor complex, plays an important role in many biological processes, including inflammation. In the body, aspirin rapidly breaks down to salicylic acid, which itself has anti-inflammatory, anti-temperature and analgesic effects. In 2012, salicylic acid was shown to activate AMP-activated protein kinase, which may be a possible explanation for some of the effects of salicylic acid and aspirin. The acetyl in the aspirin molecule also has a special effect on the body. Acetylation of cellular proteins is an important phenomenon that affects the regulation of protein function at the post-translational level. Recent research shows that aspirin can acetylate more than COX isoenzymes. These acetylation reactions may explain many of the hitherto unexplained effects of aspirin.
Hypothalamic-pituitary-adrenal activity
Aspirin, like other drugs that affect prostaglandin synthesis, has a powerful effect on the pituitary gland, and indirectly affects some hormones and physiological functions. The effects of aspirin on growth hormone, prolactin and thyroid-stimulating hormone have been directly proven (with relative effects on T3 and T4). Aspirin reduces the effect of vasopressin and increases the effect of naloxone by secreting adrenocorticotropic hormone and cortisol in the hypothalamic-pituitary-adrenal axis, which occurs through interaction with endogenous prostaglandins.
Pharmacokinetics of aspirin
Salicylic acid is a weak acid and very little of it ionizes in the stomach after oral administration. Acetylsalicylic acid is poorly soluble in the acidic environment of the stomach, due to which its absorption can be delayed for 8-24 hours when taken in high doses. The increased pH and large intestinal lining area promotes rapid absorption of aspirin in this area, which in turn promotes greater dissolution of salicylate. However, in overdose, aspirin dissolves much more slowly, and its plasma concentrations may increase within 24 hours after ingestion. About 50–80% of salicylate in the blood binds to protein, and the rest remains in the active ionized form; protein binding is concentration dependent. The saturation of the binding sites leads to an increase in the amount of free salicylate and an increase in toxicity. The volume of distribution is 0.1–0.2 l / kg. Acidosis increases the volume of distribution due to increased cellular penetration of salicylates. 80% of the therapeutic dose of salicylic acid is metabolized in the liver. When bound with, salicylic acid is formed, and with glucuronic acid, salicylic acid and phenolic glucuronide are formed. These metabolic pathways have only limited capabilities. A small amount of salicylic acid is also hydrolyzed to gentisic acid. When high doses of salicylate are taken, kinetics shifts from first order to zero order as metabolic pathways become saturated and the importance of renal excretion increases. Salicylates are excreted from the body by the kidneys in the form of salicylic acid (75%), free salicylic acid (10%), salicylic phenol (10%) and acyl glucuronides (5%), gentisic acid (< 1%) и 2,3-дигидроксибензойной кислоты. При приеме небольших доз (меньше 250 мг у взрослых), все пути проходят кинетику первого порядка, при этом период полувыведения составляет от 2.0 до 4.5 часов. При приеме больших доз салицилата (больше 4 г), период полураспада увеличивается (15–30 часов), поскольку биотрансформация включает в себя образование салицилуровой кислоты и насыщение салицил фенольного глюкоронида. При увеличении pH мочи с 5 до 8 наблюдается увеличение почечного клиренса в 10-20 раз.
History of the discovery of aspirin
Herbal extracts, including willow bark and meadowsweet (spirea), whose active ingredient is salicylic acid, have been used since ancient times to relieve headaches, pain and fever. The father of modern medicine, Hippocrates (460 - 377 BC), described the use of willow bark and leaf powder to relieve such symptoms. French chemist Charles Frederic Gerhard first made acetylsalicylic acid in 1853. While working on the synthesis and properties of various acidic anhydrides, he mixed acetyl chloride with the sodium salt of salicylic acid (sodium salicylate). A violent reaction ensued and the resulting alloy was modified. Gerhard named this compound "salicylacetyl anhydride" (wasserfreie Salicylsäure-Essigsäure). 6 years later, in 1859, von Gilm obtained analytically pure acetylsalicylic acid (which he called acetylierte Salicylsäure, acetylated salicylic acid) by the reaction of salicylic acid and acetyl chloride. In 1869, Schroeder, Prinzorn and Kraut repeated the experiments of Gerhard and von Hilm and reported that both reactions lead to the synthesis of the same substance - acetylsalicylic acid. They were the first to describe the correct structure of a substance (in which an acetyl group is attached to phenolic oxygen). In 1897, chemists at Bayer AG produced a synthetically modified version of salicin, extracted from the plant Filipendula ulmaria (meadowsweet), which causes less stomach irritation than pure salicylic acid. It is still not clear who was the main chemist who conceived this project. Bayer said the work was done by Felix Hoffmann, but Jewish chemist Arthur Eichengrun later stated that he was the main developer and that his contributions were destroyed during the Nazi regime. The new drug, formally acetylsalicylic acid, has been named "Aspirin" by Bayer AG, after the old botanical name of the plant that contains it (meadowsweet), Spiraea ulmaria. The word "Aspirin" is derived from the words "acetyl" and "Spirsäure", an old German word for salicylic acid, which in turn comes from the Latin "Spiraea ulmaria". By 1899, Bayer was already selling aspirin around the world. The popularity of aspirin increased in the first half of the 20th century, thanks to its supposed effectiveness in treating the 1918 Spanish flu epidemic. Recent research, however, suggests that aspirin caused part of the 1918 flu deaths, but this claim is controversial and not widely accepted in academia. The popularity of aspirin led to fierce competition and divisions of aspirin brands, especially after Bayer's US patent expired in 1917. After the introduction of (acetaminophen) on the market in 1956 and ibuprofen in 1969, the popularity of aspirin declined somewhat. In the 1960s and 1970s, John Wayne and his team discovered the basic mechanisms of action of aspirin, and clinical trials and other studies conducted between the 1960s and 1980s. demonstrated that aspirin is an effective anti-clotting drug. In the last decades of the 20th century, sales of aspirin increased again, and remain at a fairly high level to this day.
Aspirin brand
As part of the 1919 Treaty of Versailles reparations following Germany's defeat in World War I, aspirin (as well as heroin) lost their registered trademark status in France, Russia, Great Britain and the United States, where they became generics. Aspirin is currently considered generic in Australia, France, India, Ireland, New Zealand, Pakistan, Jamaica, Colombia, the Philippines, South Africa, the United Kingdom and the United States. Aspirin, capital "A", remains a registered trademark of Bayer in Canada, Germany, Mexico and over 80 other countries where the trademark is owned by Bayer.
Veterinary use of aspirin
Aspirin is sometimes used to relieve pain or as an anticoagulant in veterinary medicine, primarily in dogs and sometimes in horses, although newer drugs with fewer side effects are currently being used. Dogs and horses have gastrointestinal side effects of aspirin associated with salicylates, but aspirin is often used to treat arthritis in older dogs. Aspirin has been shown to be effective against laminitis (inflammation of the foot) in horses, but is no longer used for this purpose. Aspirin can only be used in animals under close medical supervision; in particular, the cat's body lacks glucoronide conjugates that promote the excretion of aspirin, as a result of which even small doses of the drug can be potentially toxic to them.
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