Aspirin

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Aspirin
INN: acetylsalicylic acid
Aspirin-skeletal.svg
Aspirin-B-3D-balls.png
Clinical data
Pronunciationacetylsalicylic acid /əˌstəlˌsælɪˈsɪlɪk/
Trade names Bayer Aspirin, many others
Synonyms2-acetoxybenzoic acid
acetylsalicylate
acetylsalicylic acid
O-acetylsalicylic acid, Aspirin (BAN UK), Aspirin (USAN US)
AHFS/Drugs.com Monograph
MedlinePlus a682878
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)D in the 3rd trimester
    Routes of
    administration
    by mouth, rectal, lysine acetylsalicylate may be given intravenously or intramuscularly
    ATC code
    Legal status
    Legal status
    • AU: S2 (Pharmacy only)except when given intravenously (in which case it is schedule 4), used in animal medicine (schedule 5/6) or when the dose is higher than usual.
    • UK: General sales list (GSL, OTC)
    • US: OTC
    Pharmacokinetic data
    Bioavailability 80–100% [1]
    Protein binding 80–90% [2]
    Metabolism Liver, (CYP2C19 and possibly CYP3A), some is also hydrolysed to salicylate in the gut wall. [2]
    Elimination half-life Dose-dependent; 2 h to 3 h for low doses (100 mg or less), 15 h to 30 h for large doses. [2]
    Excretion Urine (80–100%), sweat, saliva, feces [1]
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    PDB ligand
    ECHA InfoCard 100.000.059 Blue pencil.svg
    Chemical and physical data
    Formula C9H8O4
    Molar mass 180.158 g/mol [3]  g·mol−1
    3D model (JSmol)
    Density 1.40 g/cm3
    Melting point 136 °C (277 °F) [3]
    Boiling point 140 °C (284 °F) (decomposes)
    Solubility in water 3 mg/mL (20 °C)
       (verify)

    Aspirin, also known as acetylsalicylic acid (ASA), is a medication used to treat pain, fever, or inflammation. [4] Specific inflammatory conditions which aspirin is used to treat include Kawasaki disease, pericarditis, and rheumatic fever. [4] Aspirin given shortly after a heart attack decreases the risk of death. [4] Aspirin is also used long-term to help prevent further heart attacks, ischaemic strokes, and blood clots in people at high risk. [4] It may also decrease the risk of certain types of cancer, particularly colorectal cancer. [5] For pain or fever, effects typically begin within 30 minutes. [4] Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) and works similarly to other NSAIDs but also suppresses the normal functioning of platelets. [4]

    Medication substance used to diagnose, cure, treat, or prevent disease

    A medication is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and relies on the science of pharmacology for continual advancement and on pharmacy for appropriate management.

    Pain type of unpleasant feeling

    Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain's widely used definition defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage"; however, due to it being a complex, subjective phenomenon, defining pain has been a challenge. In medical diagnosis, pain is regarded as a symptom of an underlying condition.

    Fever common medical sign characterized by elevated body temperature

    Fever, also known as pyrexia and febrile response, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using values between 37.5 and 38.3 °C. The increase in set point triggers increased muscle contractions and causes a feeling of cold. This results in greater heat production and efforts to conserve heat. When the set point temperature returns to normal, a person feels hot, becomes flushed, and may begin to sweat. Rarely a fever may trigger a febrile seizure. This is more common in young children. Fevers do not typically go higher than 41 to 42 °C.

    Contents

    One common adverse effect is an upset stomach. [4] More significant side effects include stomach ulcers, stomach bleeding, and worsening asthma. [4] Bleeding risk is greater among those who are older, drink alcohol, take other NSAIDs, or are on other blood thinners. [4] Aspirin is not recommended in the last part of pregnancy. [4] It is not generally recommended in children with infections because of the risk of Reye syndrome. [4] High doses may result in ringing in the ears. [4]

    In medicine, an adverse effect is an undesired harmful effect resulting from a medication or other intervention such as surgery.

    Asthma long-term disease involving poor airflow in the lungs

    Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include episodes of wheezing, coughing, chest tightness, and shortness of breath. These may occur a few times a day or a few times per week. Depending on the person, they may become worse at night or with exercise.

    Alcohol (drug) active ingredient in alcoholic beverages

    Alcohol, also known by its chemical name ethanol, is a psychoactive substance that is the active ingredient in drinks such as beer, wine, and distilled spirits. It is one of the oldest and most common recreational substances, causing the characteristic effects of alcohol intoxication ("drunkenness"). Among other effects, alcohol produces a mood lift and euphoria, decreased anxiety, increased sociability, sedation, impairment of cognitive, memory, motor, and sensory function, and generalized depression of central nervous system function. Ethanol is a type of chemical compound known as an alcohol, and is the only type of alcohol that is found in alcoholic beverages or is commonly used for recreational purposes; other alcohols such as methanol and isopropyl alcohol are toxic.

    A precursor to aspirin found in leaves from the willow tree has been used for its health effects for at least 2,400 years. [6] [7] In 1853, chemist Charles Frédéric Gerhardt treated the medicine sodium salicylate with acetyl chloride to produce acetylsalicylic acid for the first time. [8] For the next fifty years, other chemists established the chemical structure and came up with more efficient production methods. [8] :69–75 In 1897, scientists at the Bayer company began studying acetylsalicylic acid as a less-irritating replacement medication for common salicylate medicines. [8] :69–75 [9] By 1899, Bayer had named it "Aspirin" and sold it around the world. [10] Aspirin's popularity grew over the first half of the twentieth century leading to competition between many brands and formulations. [11] The word Aspirin was Bayer's brand name; however, their rights to the trademark were lost or sold in many countries. [11]

    In chemistry, a precursor is a compound that participates in a chemical reaction that produces another compound.

    Charles Frédéric Gerhardt French chemist

    Charles Frédéric Gerhardt was a French chemist.

    Sodium salicylate is a sodium salt of salicylic acid. It can be prepared from sodium phenolate and carbon dioxide under higher temperature and pressure. Historically, it has been synthesized by hydrolysis of methyl salicylate with an excess of sodium hydroxide and heating it under reflux.

    Aspirin is one of the most widely used medications globally, with an estimated 40,000 tonnes (44,000 tons) (50 to 120 billion pills) consumed each year. [6] [12] It is on the World Health Organization's (WHO's) List of Essential Medicines, which lists the safest and most effective medicines needed in a health system. [13] As of 2014, the wholesale cost in the developing world is $0.002 to $0.025 USD per dose. [14] As of 2015, the cost for a typical month of medication in the United States is less than US$25.00. [15] It is available as a generic medication. [4] In 2016, it was the 38th most prescribed medication in the United States, with more than 19 million prescriptions. [16]

    A health system, also sometimes referred to as health care system or as healthcare system, is the organization of people, institutions, and resources that deliver health care services to meet the health needs of target populations.

    Medical use

    Aspirin is used in the treatment of a number of conditions, including fever, pain, rheumatic fever, and inflammatory conditions, such as rheumatoid arthritis, pericarditis, and Kawasaki disease. [17] Lower doses of aspirin have also been shown to reduce the risk of death from a heart attack, or the risk of stroke in people who are at high risk or who have cardiovascular disease, but not in elderly people who are otherwise healthy. [18] [19] [20] [21] [22] There is some evidence that aspirin is effective at preventing colorectal cancer, though the mechanisms of this effect are unclear. [23] In the United States, low-dose aspirin is deemed reasonable in those between 50 and 70 years old who have a risk of cardiovascular disease over 10%, are not at an increased risk of bleeding, and are otherwise healthy. [24]

    Rheumatic fever inflammatory disease that can involve the heart, joints, skin, and brain

    Rheumatic fever (RF) is an inflammatory disease that can involve the heart, joints, skin, and brain. The disease typically develops two to four weeks after a streptococcal throat infection. Signs and symptoms include fever, multiple painful joints, involuntary muscle movements, and occasionally a characteristic non-itchy rash known as erythema marginatum. The heart is involved in about half of the cases. Damage to the heart valves, known as rheumatic heart disease (RHD), usually occurs after repeated attacks but can sometimes occur after one. The damaged valves may result in heart failure, atrial fibrillation and infection of the valves.

    Rheumatoid arthritis An arthritis that is an autoimmune disease which attacks healthy cells and tissue located in joint.

    Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involved, with the same joints typically involved on both sides of the body. The disease may also affect other parts of the body. This may result in a low red blood cell count, inflammation around the lungs, and inflammation around the heart. Fever and low energy may also be present. Often, symptoms come on gradually over weeks to months.

    Pericarditis pericardium disease that is characterized by an inflammation of the pericardium and has symptom chest pain

    Pericarditis is inflammation of the pericardium. Symptoms typically include sudden onset of sharp chest pain. The pain may also be felt in the shoulders, neck, or back. It is typically better sitting up and worse when lying down or breathing deeply. Other symptoms may include fever, weakness, palpitations, and shortness of breath. Occasionally onset of symptoms is gradual.

    Pain

    Aspirin 325 mg / 5 grains for pain Aspirin1.jpg
    Aspirin 325 mg / 5 grains for pain
    Uncoated aspirin tablets, consisting of about 90% acetylsalicylic acid, along with a minor amount of inert fillers and binders Aspirine macro shot.jpg
    Uncoated aspirin tablets, consisting of about 90% acetylsalicylic acid, along with a minor amount of inert fillers and binders

    Aspirin is an effective analgesic for acute pain, although it is generally considered inferior to ibuprofen because aspirin is more likely to cause gastrointestinal bleeding. [25] Aspirin is generally ineffective for those pains caused by muscle cramps, bloating, gastric distension, or acute skin irritation. [26] As with other NSAIDs, combinations of aspirin and caffeine provide slightly greater pain relief than aspirin alone. [27] Effervescent formulations of aspirin relieve pain faster than aspirin in tablets, [28] which makes them useful for the treatment of migraines. [29] Topical aspirin may be effective for treating some types of neuropathic pain. [30]

    Ibuprofen chemical compound

    Ibuprofen is a medication in the nonsteroidal anti-inflammatory drug (NSAID) class that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arteriosus in a premature baby. It can be used by mouth or intravenously. It typically begins working within an hour.

    Gastrointestinal bleeding bleeding from any part of the gastrointestinal tract

    Gastrointestinal bleeding, also known as gastrointestinal hemorrhage, is all forms of bleeding in the gastrointestinal tract, from the mouth to the rectum. When there is significant blood loss over a short time, symptoms may include vomiting red blood, vomiting black blood, bloody stool, or black stool. Small amounts of bleeding over a long time may cause iron-deficiency anemia resulting in feeling tired or heart-related chest pain. Other symptoms may include abdominal pain, shortness of breath, pale skin, or passing out. Sometimes in those with small amounts of bleeding no symptoms may be present.

    Cramp Pathological, often painful, involuntary muscle contraction

    A cramp is a sudden, involuntary muscle contraction or over-shortening; while generally temporary and non-damaging, they can cause significant pain, and a paralysis-like immobility of the affected muscle. Onset is usually sudden, and it resolves on its own over a period of several seconds, minutes or hours. Cramps may occur in a skeletal muscle or smooth muscle. Skeletal muscle cramps may be caused by muscle fatigue or a lack of electrolytes such as low sodium, low potassium or low magnesium. Cramps of smooth muscle may be due to menstruation or gastroenteritis.

    Headache

    Aspirin, either by itself or in a combined formulation, effectively treats certain types of a headache, but its efficacy may be questionable for others. Secondary headaches, meaning those caused by another disorder or trauma, should be promptly treated by a medical provider.

    Among primary headaches, the International Classification of Headache Disorders distinguishes between tension headache (the most common), migraine, and cluster headache. Aspirin or other over-the-counter analgesics are widely recognized as effective for the treatment of tension headache. [31]

    Aspirin, especially as a component of an aspirin/paracetamol/caffeine combination, is considered a first-line therapy in the treatment of migraine, and comparable to lower doses of sumatriptan. It is most effective at stopping migraines when they are first beginning. [32]

    Fever

    Like its ability to control pain, aspirin's ability to control fever is due to its action on the prostaglandin system through its irreversible inhibition of COX. [33] Although aspirin's use as an antipyretic in adults is well established, many medical societies and regulatory agencies, including the American Academy of Family Physicians, the American Academy of Pediatrics, and the Food and Drug Administration, strongly advise against using aspirin for treatment of fever in children because of the risk of Reye's syndrome, a rare but often fatal illness associated with the use of aspirin or other salicylates in children during episodes of viral or bacterial infection. [34] [35] [36] Because of the risk of Reye's syndrome in children, in 1986, the FDA required labeling on all aspirin-containing medications advising against its use in children and teenagers. [37]

    Inflammation

    Aspirin is used as an anti-inflammatory agent for both acute and long-term inflammation, [38] as well as for treatment of inflammatory diseases, such as rheumatoid arthritis. [17]

    Heart attacks and strokes

    Aspirin is an important part of the treatment of those who have had a heart attack. [39] It is generally not recommended in people without other health problems, including those over the age of 70. [40]

    High risk

    For people who have already had a heart attack or stroke, taking aspirin daily for two years prevented 1 in 50 from having a cardiovascular problem (heart attack, stroke, or death), but also caused non-fatal bleeding problems to occur in 1 of 400 people. [41] [42] [43] Low dose aspirin appears useful for people less than 70 kg while higher dose aspirin is required to benefit those over 70 kg. [44]

    The USPSTF as of 2016 recommends initiating low-dose aspirin use for the primary prevention of cardiovascular disease and colon cancer in adults aged 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years. [45]

    Lower risk

    In those with no previous history of heart disease, aspirin decreases the risk of a non-fatal myocardial infarction but increases the risk of bleeding and does not change the overall risk of death. [46] [47] Specifically over 5 years it decreased the risk of a cardiovascular event by 1 in 265 and increased the risk of bleeding by 1 in 210. [47]

    Aspirin appears to offer little benefit to those at lower risk of heart attack or stroke—for instance, those without a history of these events or with pre-existing disease. Some studies recommend aspirin on a case-by-case basis, [48] [49] while others have suggested the risks of other events, such as gastrointestinal bleeding, were enough to outweigh any potential benefit, and recommended against using aspirin for primary prevention entirely. [50] Aspirin has also been suggested as a component of a polypill for prevention of cardiovascular disease. [51] [52]

    Complicating the use of aspirin for prevention is the phenomenon of aspirin resistance. [53] [54] For people who are resistant, aspirin's efficacy is reduced. [55] Some authors have suggested testing regimens to identify people who are resistant to aspirin. [56]

    After surgery

    After percutaneous coronary interventions (PCIs), such as the placement of a coronary artery stent, a U.S. Agency for Healthcare Research and Quality guideline recommends that aspirin be taken indefinitely. [57] Frequently, aspirin is combined with an ADP receptor inhibitor, such as clopidogrel, prasugrel, or ticagrelor to prevent blood clots. This is called dual antiplatelet therapy (DAPT). United States and European Union guidelines disagree somewhat about how long, and for what indications this combined therapy should be continued after surgery. U.S. guidelines recommend DAPT for at least 12 months, while EU guidelines recommend DAPT for 6–12 months after a drug-eluting stent placement. [58] However, they agree that aspirin be continued indefinitely after DAPT is complete.

    Cancer prevention

    Aspirin is thought to reduce the overall risk of both getting cancer and dying from cancer. [59] This effect is particularly beneficial for colorectal cancer (CRC) [23] [60] [61] [62] but must be taken for at least 10–20 years to see this benefit. [63] It may also slightly reduce the risk of endometrial cancer, [64] breast cancer, and prostate cancer. [65]

    Some conclude the benefits are greater than the risks due to bleeding in those at average risk. [59] Others are unclear if the benefits are greater than the risk. [66] [67] Given this uncertainty, the 2007 United States Preventive Services Task Force guidelines on this topic recommended against the use of aspirin for prevention of CRC in people with average risk. [68] Nine years later however, the USPSTF issued a grade B recommendation for the use of low-dose aspirin (75 to 100 mg/day) "for the primary prevention of CVD [cardiovascular disease] and CRC in adults 50 to 59 years of age who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years". [69]

    Other uses

    Aspirin is a first-line treatment for the fever and joint-pain symptoms of acute rheumatic fever. The therapy often lasts for one to two weeks, and is rarely indicated for longer periods. After fever and pain have subsided, the aspirin is no longer necessary, since it does not decrease the incidence of heart complications and residual rheumatic heart disease. [70] [71] Naproxen has been shown to be as effective as aspirin and less toxic, but due to the limited clinical experience, naproxen is recommended only as a second-line treatment. [70] [72]

    Along with rheumatic fever, Kawasaki disease remains one of the few indications for aspirin use in children [73] in spite of a lack of high quality evidence for its effectiveness. [74]

    Low-dose aspirin supplementation has moderate benefits when used for prevention of pre-eclampsia. [75] [76] This benefit is greater when started in early pregnancy. [77] There is no evidence that aspirin prevents dementia. [78]

    Resistance

    For some people, aspirin does not have as strong an effect on platelets as for others, an effect known as aspirin-resistance or insensitivity. One study has suggested women are more likely to be resistant than men, [79] and a different, aggregate study of 2,930 people found 28% were resistant. [80] A study in 100 Italian people, though, found, of the apparent 31% aspirin-resistant subjects, only 5% were truly resistant, and the others were noncompliant. [81] Another study of 400 healthy volunteers found no subjects who were truly resistant, but some had "pseudoresistance, reflecting delayed and reduced drug absorption". [82]

    Dosage

    Coated 325 mg (5-grain) aspirin tablets Regular strength enteric coated aspirin tablets.jpg
    Coated 325 mg (5-grain) aspirin tablets
    The 5-grain aspirin. The usage guidance label on a bottle of aspirin indicates that the dosage is "325 mg (5 gr)". 5 grain aspirin.jpg
    The 5-grain aspirin. The usage guidance label on a bottle of aspirin indicates that the dosage is "325 mg (5 gr)".

    Adult aspirin tablets are produced in standardised sizes, which vary slightly from country to country, for example 300 mg in Britain and 325 mg (or 5 grains) in the United States. Smaller doses are based on these standards, e.g., 75 mg and 81 mg tablets. The 81 mg (114-grain) tablets are commonly called "baby aspirin" or "baby-strength", because they were originally—but no longer—intended to be administered to infants and children. [83] No medical significance occurs due to the slight difference in dosage between the 75 mg and the 81 mg tablets. The dose required for benefit appears to depend on a person's weight. [84] For those less than 70 kg low dose is effective for preventing cardiovascular disease while in those who weight more than 70 kg higher doses are required. [84]

    In general, for adults, doses are taken four times a day for fever or arthritis, [85] with doses near the maximal daily dose used historically for the treatment of rheumatic fever. [86] For the prevention of myocardial infarction (MI) in someone with documented or suspected coronary artery disease, much lower doses are taken once daily. [85]

    March 2009 recommendations from the USPSTF on the use of aspirin for the primary prevention of coronary heart disease encourage men aged 45–79 and women aged 55–79 to use aspirin when the potential benefit of a reduction in MI for men or stroke for women outweighs the potential harm of an increase in gastrointestinal hemorrhage. [87] The WHI study said regular low dose (75 or 81 mg) aspirin female users had a 25% lower risk of death from cardiovascular disease and a 14% lower risk of death from any cause. [87] Low-dose aspirin use was also associated with a trend toward lower risk of cardiovascular events, and lower aspirin doses (75 or 81 mg/day) may optimize efficacy and safety for people requiring aspirin for long-term prevention. [87]

    In children with Kawasaki disease, aspirin is taken at dosages based on body weight, initially four times a day for up to two weeks and then at a lower dose once daily for a further six to eight weeks. [88]

    Adverse effects

    Contraindications

    Aspirin should not be taken by people who are allergic to ibuprofen or naproxen, [89] [90] or who have salicylate intolerance [91] [92] or a more generalized drug intolerance to NSAIDs, and caution should be exercised in those with asthma or NSAID-precipitated bronchospasm. Owing to its effect on the stomach lining, manufacturers recommend people with peptic ulcers, mild diabetes, or gastritis seek medical advice before using aspirin. [89] [93] Even if none of these conditions is present, the risk of stomach bleeding is still increased when aspirin is taken with alcohol or warfarin. [89] [90] People with hemophilia or other bleeding tendencies should not take aspirin or other salicylates. [89] [93] Aspirin is known to cause hemolytic anemia in people who have the genetic disease glucose-6-phosphate dehydrogenase deficiency, particularly in large doses and depending on the severity of the disease. [94] Use of aspirin during dengue fever is not recommended owing to increased bleeding tendency. [95] People with kidney disease, hyperuricemia, or gout should not take aspirin because it inhibits the kidneys' ability to excrete uric acid, thus may exacerbate these conditions. Aspirin should not be given to children or adolescents to control cold or influenza symptoms, as this has been linked with Reye's syndrome. [96]

    Gastrointestinal

    Enteric-coated 325 mg aspirin pills Bayer Aspirin Pills.jpg
    Enteric-coated 325 mg aspirin pills

    Aspirin use has been shown to increase the risk of gastrointestinal bleeding. [97] Although some enteric-coated formulations of aspirin are advertised as being "gentle to the stomach", in one study, enteric coating did not seem to reduce this risk. [97] Combining aspirin with other NSAIDs has also been shown to further increase this risk. [97] Using aspirin in combination with clopidogrel or warfarin also increases the risk of upper gastrointestinal bleeding. [98]

    Blockade of COX-1 by aspirin apparently results in the upregulation of COX-2 as part of a gastric defense [99] and that taking COX-2 inhibitors concurrently with aspirin increases the gastric mucosal erosion. [100] Therefore, caution should be exercised if combining aspirin with any "natural" supplements with COX-2-inhibiting properties, such as garlic extracts, curcumin, bilberry, pine bark, ginkgo, fish oil, resveratrol, genistein, quercetin, resorcinol, and others.

    In addition to enteric coating, "buffering" is the other main method companies have used to try to mitigate the problem of gastrointestinal bleeding. Buffering agents are intended to work by preventing the aspirin from concentrating in the walls of the stomach, although the benefits of buffered aspirin are disputed. Almost any buffering agent used in antacids can be used; Bufferin, for example, uses magnesium oxide. Other preparations use calcium carbonate. [101]

    Taking it with vitamin C has been investigated as a method of protecting the stomach lining. Taking equal doses of vitamin C and aspirin may decrease the amount of stomach damage that occurs compared to taking aspirin alone. [102] [103]

    Central effects

    Large doses of salicylate, a metabolite of aspirin, cause temporary tinnitus (ringing in the ears) based on experiments in rats, via the action on arachidonic acid and NMDA receptors cascade. [104]

    Reye's syndrome

    Reye's syndrome, a rare but severe illness characterized by acute encephalopathy and fatty liver, can occur when children or adolescents are given aspirin for a fever or other illness or infection. From 1981 through 1997, 1207 cases of Reye's syndrome in people younger than 18 were reported to the U.S. Centers for Disease Control and Prevention. Of these, 93% reported being ill in the three weeks preceding the onset of Reye's syndrome, most commonly with a respiratory infection, chickenpox, or diarrhea. Salicylates were detectable in 81.9% of children for whom test results were reported. [105] After the association between Reye's syndrome and aspirin was reported, and safety measures to prevent it (including a Surgeon General's warning, and changes to the labeling of aspirin-containing drugs) were implemented, aspirin taken by children declined considerably in the United States, as did the number of reported cases of Reye's syndrome; a similar decline was found in the United Kingdom after warnings against pediatric aspirin use were issued. [105] The U.S. Food and Drug Administration now recommends aspirin (or aspirin-containing products) should not be given to anyone under the age of 12 who has a fever, [96] and the UK National Health Service recommends children who are under 16 years of age should not take aspirin, unless it is on the advice of a doctor. [106]

    Skin

    For a small number of people, taking aspirin can result in symptoms resembling an allergic reaction, including hives, swelling, and headache. The reaction is caused by salicylate intolerance and is not a true allergy, but rather an inability to metabolize even small amounts of aspirin, resulting in an overdose.

    Aspirin and other NSAIDs, such as ibuprofen, may delay the healing of skin wounds. [107] Aspirin may however help heal venous leg ulcers that have not healed following usual treatment. [108]

    Other adverse effects

    Aspirin can induce swelling of skin tissues in some people. In one study, angioedema appeared one to six hours after ingesting aspirin in some of the people. However, when the aspirin was taken alone, it did not cause angioedema in these people; the aspirin had been taken in combination with another NSAID-induced drug when angioedema appeared. [109]

    Aspirin causes an increased risk of cerebral microbleeds having the appearance on MRI scans of 5 to 10 mm or smaller, hypointense (dark holes) patches. [110] [111] Such cerebral microbleeds are important, since they often occur prior to ischemic stroke or intracerebral hemorrhage, Binswanger disease, and Alzheimer's disease.[ original research? ]

    A study of a group with a mean dosage of aspirin of 270 mg per day estimated an average absolute risk increase in intracerebral hemorrhage (ICH) of 12 events per 10,000 persons. [112] In comparison, the estimated absolute risk reduction in myocardial infarction was 137 events per 10,000 persons, and a reduction of 39 events per 10,000 persons in ischemic stroke. [112] In cases where ICH already has occurred, aspirin use results in higher mortality, with a dose of about 250 mg per day resulting in a relative risk of death within three months after the ICH around 2.5 (95% confidence interval 1.3 to 4.6). [113]

    Aspirin and other NSAIDs can cause abnormally high blood levels of potassium by inducing a hyporeninemic hypoaldosteronic state via inhibition of prostaglandin synthesis; however, these agents do not typically cause hyperkalemia by themselves in the setting of normal renal function and euvolemic state. [114]

    Aspirin can cause prolonged bleeding after operations for up to 10 days. In one study, 30 of 6499 people having elective surgery required reoperations to control bleeding. Twenty had diffuse bleeding and 10 had bleeding from a site. Diffuse, but not discrete, bleeding was associated with the preoperative use of aspirin alone or in combination with other NSAIDS in 19 of the 20 diffuse bleeding people. [115]

    On 9 July 2015, the FDA toughened warnings of increased heart attack and stroke risk associated with nonsteroidal anti-inflammatory drugs (NSAID). Aspirin is an NSAID but is not affected by the new warnings. [116]

    Overdose

    Aspirin overdose can be acute or chronic. In acute poisoning, a single large dose is taken; in chronic poisoning, higher than normal doses are taken over a period of time. Acute overdose has a mortality rate of 2%. Chronic overdose is more commonly lethal, with a mortality rate of 25%; [117] chronic overdose may be especially severe in children. [118] Toxicity is managed with a number of potential treatments, including activated charcoal, intravenous dextrose and normal saline, sodium bicarbonate, and dialysis. [119] The diagnosis of poisoning usually involves measurement of plasma salicylate, the active metabolite of aspirin, by automated spectrophotometric methods. Plasma salicylate levels in general range from 30–100 mg/l after usual therapeutic doses, 50–300 mg/l in people taking high doses and 700–1400 mg/l following acute overdose. Salicylate is also produced as a result of exposure to bismuth subsalicylate, methyl salicylate, and sodium salicylate. [120] [121]

    Interactions

    Aspirin is known to interact with other drugs. For example, acetazolamide and ammonium chloride are known to enhance the intoxicating effect of salicylates, and alcohol also increases the gastrointestinal bleeding associated with these types of drugs. [89] [90] Aspirin is known to displace a number of drugs from protein-binding sites in the blood, including the antidiabetic drugs tolbutamide and chlorpropamide, warfarin, methotrexate, phenytoin, probenecid, valproic acid (as well as interfering with beta oxidation, an important part of valproate metabolism), and other NSAIDs. Corticosteroids may also reduce the concentration of aspirin. Ibuprofen can negate the antiplatelet effect of aspirin used for cardioprotection and stroke prevention. [122] The pharmacological activity of spironolactone may be reduced by taking aspirin, and it is known to compete with penicillin G for renal tubular secretion. [123] Aspirin may also inhibit the absorption of vitamin C. [124] [125] [ unreliable medical source? ] [126]

    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 solution with alkalis, the hydrolysis proceeds rapidly and the clear solutions formed may consist entirely of acetate and salicylate. [127]

    Like flour mills, factories that make aspirin tablets must pay attention to how much of the powder gets into the air inside the building, because the powder-air mixture can be explosive. The National Institute for Occupational Safety and Health (NIOSH) has set a recommended exposure limit in the United States of 5 mg/m3 (time-weighted average). [128] In 1989, the Occupational Safety and Health Administration (OSHA) set a legal permissible exposure limit for aspirin of 5 mg/m3, but this was vacated by the AFL-CIO v. OSHA decision in 1993. [129]

    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 (R-OH → R-OCOCH3). This process yields aspirin and acetic acid, which is considered a byproduct of this reaction. Small amounts of sulfuric acid (and occasionally phosphoric acid) are almost always used as a catalyst. This method is commonly employed in undergraduate teaching labs. [130]

    Aspirin synthesis.png
    Reaction mechanism
    Acetylation of salicylic acid, mechanism.png

    Formulations containing high concentrations of aspirin often smell like vinegar [131] because aspirin can decompose through hydrolysis in moist conditions, yielding salicylic and acetic acids. [132]

    Physical properties

    Aspirin, an acetyl derivative of salicylic acid, is a white, crystalline, weakly acidic substance, with a melting point of 136 °C (277 °F), [3] and a boiling point of 140 °C (284 °F). [133] Its acid dissociation constant (pKa) is 3.5 at 25 °C (77 °F). [134]

    Polymorphism

    Polymorphism, or the ability of a substance to form more than one crystal structure, is important in the development of pharmaceutical ingredients. Many drugs are receiving regulatory approval for only a single crystal form or polymorph. For a long time, only one crystal structure for aspirin was known. That aspirin might have a second crystalline form was suspected since the 1960s. The elusive second polymorph was first discovered by Vishweshwar and coworkers in 2005, [135] and fine structural details were given by Bond et al. [136] A new crystal type was found after attempted cocrystallization of aspirin and levetiracetam from hot acetonitrile. The form II is only stable at 100  K and reverts to form I at ambient temperature. In the (unambiguous) form I, two salicylic molecules form centrosymmetric dimers through the acetyl groups with the (acidic) methyl proton to carbonyl hydrogen bonds, and in the newly claimed form II, each salicylic molecule forms the same hydrogen bonds with two neighboring molecules instead of one. With respect to the hydrogen bonds formed by the carboxylic acid groups, both polymorphs form identical dimer structures.[ citation needed ]

    Mechanism of action

    Discovery of the mechanism

    In 1971, British pharmacologist John Robert Vane, then employed by the Royal College of Surgeons in London, showed aspirin suppressed the production of prostaglandins and thromboxanes. [137] [138] For this discovery he was awarded the 1982 Nobel Prize in Physiology or Medicine, jointly with Sune Bergström and Bengt Ingemar Samuelsson. [139]

    Prostaglandins and thromboxanes

    Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX; officially known as prostaglandin-endoperoxide synthase, PTGS) 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 PTGS enzyme (Suicide inhibition). This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen), which are reversible inhibitors.

    Low-dose aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation during the lifetime of the affected platelet (8–9 days). 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. [140] 40 mg 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. [141]

    Prostaglandins, local hormones produced in the body, 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 for 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 PTGS2 produces lipoxins, most of which are anti-inflammatory. [142] [ verification needed ] Newer NSAID drugs, COX-2 inhibitors (coxibs), have been developed to inhibit only PTGS2, with the intent to reduce the incidence of gastrointestinal side effects. [12]

    However, several of the new COX-2 inhibitors, such as rofecoxib (Vioxx), have been withdrawn in the last decade, after evidence emerged that PTGS2 inhibitors increase the risk of heart attack and stroke. [143] [144] Endothelial cells lining the microvasculature in the body are proposed to express PTGS2, and, by selectively inhibiting PTGS2, prostaglandin production (specifically, PGI2; prostacyclin) is downregulated with respect to thromboxane levels, as PTGS1 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. Since platelets have no DNA, they are unable to synthesize new PTGS once aspirin has irreversibly inhibited the enzyme, an important difference with reversible inhibitors.

    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. [145] [146] [147]

    Additional mechanisms

    Aspirin has been shown to have at least three additional modes of action. It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, by diffusing from the inner membrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once again to release protons. [148] Aspirin buffers and transports the protons. When high doses are given, it may actually cause fever, owing to the heat released from the electron transport chain, as opposed to the antipyretic action of aspirin seen with lower doses. In addition, aspirin induces the formation of NO-radicals in the body, which have been shown in mice to have an independent mechanism of reducing inflammation. This reduced leukocyte adhesion is an important step in the immune response to infection; however, evidence is insufficient to show aspirin helps to fight infection. [149] More recent data also suggest salicylic acid and its derivatives modulate signaling through NF-κB. [150] NF-κB, a transcription factor complex, plays a central role in many biological processes, including inflammation.

    Aspirin is readily broken down in the body to salicylic acid, which itself has anti-inflammatory, antipyretic, and analgesic effects. In 2012, salicylic acid was found to activate AMP-activated protein kinase, which has been suggested as a possible explanation for some of the effects of both salicylic acid and aspirin. [151] [152] The acetyl portion of the aspirin molecule has its own targets. Acetylation of cellular proteins is a well-established phenomenon in the regulation of protein function at the post-translational level. Aspirin is able to acetylate several other targets in addition to COX isoenzymes. [153] [154] These acetylation reactions may explain many hitherto unexplained effects of aspirin.

    Pharmacokinetics

    Acetylsalicylic acid is a weak acid, and very little of it is ionized in the stomach after oral administration. Acetylsalicylic acid is quickly absorbed through the cell membrane in the acidic conditions of the stomach. The increased pH and larger surface area of the small intestine causes aspirin to be absorbed more slowly there, as more of it is ionized. Owing to the formation of concretions, aspirin is absorbed much more slowly during overdose, and plasma concentrations can continue to rise for up to 24 hours after ingestion. [155] [156] [157]

    About 50–80% of salicylate in the blood is bound to albumin protein, while the rest remains in the active, ionized state; protein binding is concentration-dependent. Saturation of binding sites leads to more free salicylate and increased toxicity. The volume of distribution is 0.1–0.2 L/kg. Acidosis increases the volume of distribution because of enhancement of tissue penetration of salicylates. [157]

    As much as 80% of therapeutic doses of salicylic acid is metabolized in the liver. Conjugation with glycine forms salicyluric acid, and with glucuronic acid to form two different glucuronide esters. The conjugate with the acetyl group intact is referred to as the acyl glucuronide; the deacetylated conjugate is the phenolic glucuronide. These metabolic pathways have only a limited capacity. Small amounts of salicylic acid are also hydroxylated to gentisic acid. With large salicylate doses, the kinetics switch from first-order to zero-order, as metabolic pathways become saturated and renal excretion becomes increasingly important. [157]

    Salicylates are excreted mainly by the kidneys as salicyluric acid (75%), free salicylic acid (10%), salicylic phenol (10%), and acyl glucuronides (5%), gentisic acid (< 1%), and 2,3-dihydroxybenzoic acid. [158] When small doses (less than 250 mg in an adult) are ingested, all pathways proceed by first-order kinetics, with an elimination half-life of about 2.0 h to 4.5 h. [159] [160] When higher doses of salicylate are ingested (more than 4 g), the half-life becomes much longer (15 h to 30 h), [161] because the biotransformation pathways concerned with the formation of salicyluric acid and salicyl phenolic glucuronide become saturated. [162] Renal excretion of salicylic acid becomes increasingly important as the metabolic pathways become saturated, because it is extremely sensitive to changes in urinary pH. A 10- to 20-fold increase in renal clearance occurs when urine pH is increased from 5 to 8. The use of urinary alkalinization exploits this particular aspect of salicylate elimination. [163] It was found that short-term aspirin use in therapeutic doses might precipitate reversible acute renal failure when the patient was ill with glomerulonephritis or cirrhosis. [164] Aspirin for some patients with chronic renal insufficiency and some children with congestive heart failure was contraindicated. [164]

    History

    1923 advertisement Aspirine-1923.jpg
    1923 advertisement

    Medicines made from willow and other salicylate-rich plants appear in clay tablets from ancient Sumer as well as the Ebers Papyrus from ancient Egypt. [8] :8–13 [11] Hippocrates referred to their use of salicylic tea to reduce fevers around 400 BC, and were part of the pharmacopoeia of Western medicine in classical antiquity and the Middle Ages. [11] Willow bark extract became recognized for its specific effects on fever, pain and inflammation in the mid-eighteenth century. [165] By the nineteenth century pharmacists were experimenting with and prescribing a variety of chemicals related to salicylic acid, the active component of willow extract. [8] :46–55

    In 1853, chemist Charles Frédéric Gerhardt treated sodium salicylate with acetyl chloride to produce acetylsalicylic acid for the first time; [8] :46–48 in the second half of the nineteenth century, other academic chemists established the compound's chemical structure and devised more efficient methods of synthesis. In 1897, scientists at the drug and dye firm Bayer began investigating acetylsalicylic acid as a less-irritating replacement for standard common salicylate medicines, and identified a new way to synthesize it. [8] :69–75 By 1899, Bayer had dubbed this drug Aspirin and was selling it around the world. [10] :27 The word Aspirin was Bayer's brand name, rather than the generic name of the drug; however, Bayer's rights to the trademark were lost or sold in many countries. Aspirin's popularity grew over the first half of the twentieth century leading to fierce competition with the proliferation of aspirin brands and products. [11]

    Aspirin's popularity declined after the development of acetaminophen/paracetamol in 1956 and ibuprofen in 1962. In the 1960s and 1970s, John Vane and others discovered the basic mechanism of aspirin's effects, [8] :226–231 while clinical trials and other studies from the 1960s to the 1980s established aspirin's efficacy as an anti-clotting agent that reduces the risk of clotting diseases. [8] :247–257 The initial large studies on the use of low-dose aspirin to prevent heart attacks that were published in the 1970s and 1980s helped spur reform in clinical research ethics and guidelines for human subject research and US federal law, and are often cited as examples of clinical trials that included only men, but from which people drew general conclusions that did not hold true for women. [166] [167] [168]

    Aspirin sales revived considerably in the last decades of the twentieth century, and remain strong in the twenty-first with widespread use as a preventive treatment for heart attacks and strokes. [8] :267–269

    Trademark

    Bayer Aspirin and store-brand generic on Canadian drugstore shelf.jpg
    Aspirin for sale in Canada, next to generic store equivalent described as "ASA tablets"
    Bayer and store-brand aspirin containers on US drugstore shelf.jpg
    Aspirin for sale in the U.S., where the store brand can also be sold as aspirin

    Bayer lost its trademark for Aspirin in the United States in 1918 because it had failed to use the name for its own product and had for years allowed the use of "Aspirin" by other manufacturers . [169] Today, aspirin is a generic trademark in many countries. [170] Aspirin, with a capital "A", remains a registered trademark of Bayer in Germany, Canada, Mexico, and in over 80 other countries, for acetylsalicylic acid in all markets, but using different packaging and physical aspects for each. [171] [172]

    Compendial status

    Veterinary medicine

    Aspirin is sometimes used in veterinary medicine as an anticoagulant or to relieve pain associated with musculoskeletal inflammation or osteoarthritis. Aspirin should only be given to animals under the direct supervision of a veterinarian, as adverse effects—including gastrointestinal issues—are common. An aspirin overdose in any species may result in salicylate poisoning, characterized by hemorrhaging, seizures, coma, and even death. [175]

    Cats and dogs

    Dogs are better able to tolerate aspirin than cats are. [176] Cats metabolize aspirin slowly because they lack the glucuronide conjugates that aid in the excretion of aspirin, making it potentially toxic if dosing is not spaced out properly. [175] [177] No clinical signs of toxicosis occurred when cats were given 25 mg/kg of aspirin every 48 hours for 4 weeks, [176] but the recommended dose for relief of pain and fever and for treating blood clotting diseases in cats is 10 mg/kg every 48 hours to allow for metabolization. [175] [178]

    Horses

    Aspirin has shown some promise in the treatment of laminitis in horses. [179]

    See also

    Related Research Articles

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are a drug class that reduce pain, decrease fever, prevent blood clots and, in higher doses, decrease inflammation. Side effects depend on the specific drug, but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack and kidney disease.

    Salicylic acid chemical compound

    Salicylic acid (from Latin salix, willow tree) is a lipophilic monohydroxybenzoic acid, a type of phenolic acid, and a beta hydroxy acid (BHA). It has the formula C7H6O3. This colorless crystalline organic acid is widely used in organic synthesis and functions as a plant hormone. It is derived from the metabolism of salicin. In addition to serving as an important active metabolite of aspirin (acetylsalicylic acid), which acts in part as a prodrug to salicylic acid, it is probably best known for its use as a key ingredient in topical anti-acne products. The salts and esters of salicylic acid are known as salicylates.

    Gout Medical condition that results in recurrent pain and swelling of joints

    Gout is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot, and swollen joint. Pain typically comes on rapidly, reaching maximal intensity in less than twelve hours. The joint at the base of the big toe is affected in about half of cases. It may also result in tophi, kidney stones, or urate nephropathy.

    Peptic ulcer disease Ulcer of an area of the gastrointestinal tract

    Peptic ulcer disease (PUD) is a break in the inner lining of the stomach, first part of the small intestine or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while that in the first part of the intestines is a duodenal ulcer. The most common symptoms of a duodenal ulcer are waking at night with upper abdominal pain or upper abdominal pain that improves with eating. With a gastric ulcer the pain may worsen with eating. The pain is often described as a burning or dull ache. Other symptoms include belching, vomiting, weight loss, or poor appetite. About a third of older people have no symptoms. Complications may include bleeding, perforation and blockage of the stomach. Bleeding occurs in as many as 15% of people.

    An antiplatelet drug (antiaggregant) is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effective in the arterial circulation, where anticoagulants have little effect.

    Diclofenac chemical compound

    Diclofenac, sold under the trade names Voltaren among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammatory diseases such as gout. It is taken by mouth or applied to the skin. Improvements in pain typically occur within half an hour and last for as much as eight hours. It is also available in combination with misoprostol in an effort to decrease stomach problems.

    Naproxen chemical compound

    Naproxen, sold under the brand names Aleve and Naprosyn among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, inflammatory diseases such as rheumatoid arthritis, and fever. It is taken by mouth. It is available in immediate and delayed release formulations. Onset of effects is within an hour and last for up to twelve hours.

    Celecoxib chemical compound

    Celecoxib, sold under the brand name Celebrex among others, is a COX-2 selective nonsteroidal anti-inflammatory drug (NSAID). It is used to treat the pain and inflammation of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute pain in adults, painful menstruation, and juvenile rheumatoid arthritis in people two years or older.

    Selective COX-2 inhibitors are a type of nonsteroidal anti-inflammatory drug (NSAID) that directly targets cyclooxygenase-2, COX-2, an enzyme responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration, and is the main feature of celecoxib, rofecoxib and other members of this drug class.

    Methyl salicylate chemical compound

    Methyl salicylate (oil of wintergreen or wintergreen oil) is an organic compound with the formula C6H4(OH)(CO2CH3). It is the methyl ester of salicylic acid. It is a colorless, viscous liquid with a sweet odor. It is produced by many species of plants, particularly wintergreens. It is also synthetically produced, used as a fragrance, in foods and beverages, and in liniments.

    Thromboxane group of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2

    Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring.

    Indometacin chemical compound

    Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of prostaglandins, endogenous signaling molecules known to cause these symptoms. It does this by inhibiting cyclooxygenase, an enzyme that catalyzes the production of prostaglandins.

    Aspirin exacerbated respiratory disease human disease

    Aspirin exacerbated respiratory disease (AERD), also termed aspirin-induced asthma, is a medical condition initially defined as consisting of three key features: asthma, respiratory symptoms exacerbated by aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and nasal polyps. The symptoms of respiratory reactions in this syndrome are hypersensitivity reactions to NSAIDs rather than the typically described true allergic reactions that trigger other common allergen-induced asthma, rhinitis, or hives. The NSAID-induced reactions do not appear to involve the common mediators of true allergic reactions, immunoglobulin E or T cells. Rather, AERD is a type of NSAID-induced hypersensitivity syndrome. EAACI/WHO classifies the syndrome as one of five types of NSAID hypersensitivity or NSAID hypersensitivity reactions.

    Ketorolac chemical compound

    Ketorolac, sold under the brand name Toradol among others, is a nonsteroidal anti-inflammatory drug (NSAID) and is used as a pain medication. It is considered a first-generation NSAID.

    Megavitamin therapy is the use of large doses of vitamins, often many times greater than the recommended dietary allowance (RDA) in the attempt to prevent or treat diseases. Megavitamin therapy is typically used in alternative medicine by practitioners who call their approach orthomolecular medicine. Vitamins are useful in preventing and treating illnesses specifically associated with dietary vitamin shortfalls, but the conclusions of medical research are that the broad claims of disease treatment by advocates of megavitamin therapy are unsubstantiated by the available evidence. It is generally accepted that doses of any vitamin greatly in excess of nutritional requirements will result either in toxicity or in the excess simply being metabolised; thus evidence in favour of vitamin supplementation supports only doses in the normal range. Critics have described some aspects of orthomolecular medicine as food faddism or even quackery. Research on nutrient supplementation in general suggests that some nutritional supplements might be beneficial, and that others might be harmful; several specific nutritional therapies are associated with an increased likelihood of the condition they are meant to prevent.

    Diflunisal chemical compound

    Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. It was developed by Merck Sharp & Dohme in 1971, as MK647, after showing promise in a research project studying more potent chemical analogs of aspirin. It was first sold under the brand name Dolobid, marketed by Merck & Co., but generic versions are now widely available. It is classed as a nonsteroidal anti-inflammatory drug (NSAID) and is available in 250 mg and 500 mg tablets.

    Salsalate chemical compound

    Salsalate is a medication that belongs to the salicylate and nonsteroidal anti-inflammatory drug (NSAID) classes.

    Mechanism of action of aspirin

    Aspirin causes several different effects in the body, mainly the reduction of inflammation, analgesia, the prevention of clotting, and the reduction of fever. Much of this is believed to be due to decreased production of prostaglandins and TXA2. Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX) enzyme. Cyclooxygenase is 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. However, other effects of aspirin, such as uncoupling oxidative phosphorylation in mitochondria, and the modulation of signaling through NF-κB, are also being investigated. Some of its effects are like those of salicylic acid, which is not an acetylating agent.

    Salicylate poisoning

    Salicylate poisoning, also known as aspirin poisoning, is the acute or chronic poisoning with a salicylate such as aspirin. The classic symptoms are ringing in the ears, nausea, abdominal pain, and a fast breathing rate. Early on these may be subtle while larger doses may result in fever. Complications can include swelling of the brain or lungs, seizures, low blood sugar, or cardiac arrest.

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