Aspirin
Aspirin is the genericized trademark for acetylsalicylic acid, a nonsteroidal anti-inflammatory drug used to reduce pain, fever, and inflammation, and as an antithrombotic. Aspirin is used to treat inflammatory conditions including Kawasaki disease, pericarditis, and rheumatic fever.
Aspirin is also used long-term to help prevent further heart attacks, ischaemic strokes, and blood clots in people at high risk. For pain or fever, effects typically begin within 30 minutes. Aspirin works similarly to other NSAIDs but also suppresses the normal functioning of platelets.
One common adverse effect is an upset stomach. More significant side effects include stomach ulcers, stomach bleeding, and worsening asthma. Bleeding risk is greater among those who are older, drink alcohol, take other NSAIDs, or are on other blood thinners. Aspirin is not recommended in the last part of pregnancy. It is not generally recommended in children with viral infections because of the risk of Reye syndrome. High doses may result in ringing in the ears.
A precursor to aspirin found in the bark of the willow tree, salicin, is metabolized in the human gut into the medicinally active compound salicylic acid and has been used for its health effects for at least 2,400 years. Pharmacology sought a synthetic alternative. In 1853, the chemist Charles Frédéric Gerhardt treated the medicine sodium salicylate with acetyl chloride to produce acetylsalicylic acid for the first time. Over the next 50 years, other chemists, mostly of the German company Bayer, established the chemical structure and devised more efficient production methods. Felix Hoffmann of Bayer was the first to produce acetylsalicylic acid in a pure, stable form in 1897. By 1899, Bayer had dubbed this drug Aspirin and was selling it globally.
Aspirin is available without medical prescription as a proprietary or generic medication in most jurisdictions. It is one of the most widely used medications globally, with an estimated consumed each year, and is on the World Health Organization's List of Essential Medicines. In 2023, it was the 46th most commonly prescribed medication in the United States, with more than 14million prescriptions.
Brand vs. generic name
In 1897, scientists at the Bayer company began studying acetylsalicylic acid as a less-irritating replacement medication for common salicylate medicines. By 1899, Bayer had named it "Aspirin" and was selling it around the world.Aspirin's popularity grew over the first half of the 20th century, leading to competition between many brands and formulations. The word Aspirin was Bayer's brand name; however, its rights to the trademark were lost or sold in many countries. The name is ultimately a blend of the prefix a + spir, from Spirsäure, German for meadowsweet, the plant genus from which the aspirin precursor salicylic acid was first isolated + -in, the common suffix for drugs near the end of the 19th century.
Chemical properties
Aspirin decomposes rapidly in solutions of ammonium acetate or the acetates, carbonates, citrates, or hydroxides of the alkali metals. It is stable in dry air, but gradually hydrolyses in contact with moisture to acetic and salicylic acids. In a solution with alkalis, the hydrolysis proceeds rapidly and the clear solutions formed may consist entirely of acetate and salicylate.Like flour mills, factories producing aspirin tablets must control the amount of the powder that becomes airborne inside the building, because the powder-air mixture can be explosive. The National Institute for Occupational Safety and Health has set a recommended exposure limit in the United States of 5mg/m3. In 1989, the US Occupational Safety and Health Administration set a legal permissible exposure limit for aspirin of 5mg/m3, but this was vacated by the AFL-CIO v. OSHA decision in 1993.
Synthesis
The synthesis of aspirin is classified as an esterification reaction. Salicylic acid is treated with acetic anhydride, an acid derivative, causing a chemical reaction that turns salicylic acid's hydroxyl group into an ester group. This process yields aspirin and acetic acid, which is considered a byproduct of this reaction. Small amounts of sulfuric acid are almost always used as a catalyst. This method is commonly demonstrated in undergraduate teaching labs.Reaction between acetic acid and salicylic acid can also form aspirin but this esterification reaction is reversible and the presence of water can lead to hydrolysis of the aspirin. So, an anhydrous reagent is preferred.
;Reaction mechanism
Formulations containing high concentrations of aspirin often smell like vinegar because aspirin can decompose through hydrolysis in moist conditions, yielding salicylic and acetic acids.
Physical properties
Aspirin, an acetyl derivative of salicylic acid, is a white, crystalline, weakly acidic substance that melts at, and decomposes around. Its acid dissociation constant is 3.5 at.Polymorphism
is the ability of a substance to form more than one crystal structure. Until 2005, there was only one proven polymorph of aspirin, though the existence of another polymorph was debated since the 1960s, and one report from 1981 reported that when crystallized in the presence of aspirin anhydride, the diffractogram of aspirin has weak additional peaks. Though at the time it was dismissed as mere impurity, it was, in retrospect, form II aspirin.Form II was reported in 2005, found after attempted co-crystallization of aspirin and levetiracetam from hot acetonitrile. Pure form II aspirin can be prepared by seeding the batch with aspirin anhydrate in 15% weight.
In form I, pairs of aspirin molecules form centrosymmetric dimers through the acetyl groups with the methyl proton to carbonyl hydrogen bonds. In form II, each aspirin molecule forms the same hydrogen bonds, but with two neighbouring molecules instead of one. With respect to the hydrogen bonds formed by the carboxylic acid groups, both polymorphs form identical dimer structures. The aspirin polymorphs contain identical 2-dimensional sections and are therefore more precisely described as polytypes.
Form III was reported in 2015 by compressing Form I above 2 GPa, but it reverts to form I when pressure is removed. Form IV was reported in 2017, which is stable at ambient conditions.
Mechanism of action
Discovery of the mechanism
In 1971, the British pharmacologist John Robert Vane, then employed by the Royal College of Surgeons in London, showed that aspirin suppressed the production of prostaglandins and thromboxanes. For this discovery, he was awarded the 1982 Nobel Prize in Physiology or Medicine, jointly with Sune Bergström and Bengt Ingemar Samuelsson.Prostaglandins and thromboxanes
Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase enzyme required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the COX enzyme. This makes aspirin different from other NSAIDs, which are reversible inhibitors.Low-dose aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, which inhibits platelet aggregation during the lifetime of the affected platelet. This antithrombotic property makes aspirin useful for reducing the incidence of heart attacks in people who have had a heart attack, unstable angina, ischemic stroke or transient ischemic attack. 40mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A2 release provoked acutely, with the prostaglandin I2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition.
Prostaglandins, a type of hormone, have diverse effects, including the transmission of pain information to the brain, modulation of the hypothalamic thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets that form blood clots. Heart attacks are caused primarily by blood clots, and low doses of aspirin are seen as an effective medical intervention to prevent a second acute myocardial infarction.
COX-1 and COX-2 inhibition
At least two different types of cyclooxygenases, COX-1 and COX-2, are acted on by aspirin. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. COX-2 normally produces prostanoids, most of which are proinflammatory. Aspirin-modified COX-2 produces epi-lipoxins, most of which are anti-inflammatory. Newer NSAID drugs, COX-2 inhibitors, have been developed to inhibit only COX-2, with the intent to reduce the incidence of gastrointestinal side effects.Several COX-2 inhibitors, such as rofecoxib, have been withdrawn from the market, after evidence emerged that COX-2 inhibitors increase the risk of heart attack and stroke. Endothelial cells lining the microvasculature in the body are proposed to express COX-2, and, by selectively inhibiting COX-2, prostaglandin production is downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anticoagulative effect of PGI2 is removed, increasing the risk of thrombus and associated heart attacks and other circulatory problems.
Furthermore, aspirin, while inhibiting the ability of COX-2 to form pro-inflammatory products such as the prostaglandins, converts this enzyme's activity from a prostaglandin-forming cyclooxygenase to a lipoxygenase-like enzyme: aspirin-treated COX-2 metabolizes a variety of polyunsaturated fatty acids to hydroperoxy products which are then further metabolized to specialized proresolving mediators such as the aspirin-triggered lipoxins, aspirin-triggered resolvins, and aspirin-triggered maresins. These mediators possess potent anti-inflammatory activity. It is proposed that this aspirin-triggered transition of COX-2 from cyclooxygenase to lipoxygenase activity and the consequential formation of specialized proresolving mediators contributes to the anti-inflammatory effects of aspirin.