Nonsteroidal anti-inflammatory drug

NSAIDs are often suggested for the treatment of acute or chronic conditions where pain and inflammation are present. NSAIDs are generally used for the symptomatic relief of the following conditions: • Osteoarthritis • Rheumatoid arthritis • Mild-to-moderate pain due to inflammation and tissue injury • Inflammatory arthropathies (e.g., ankylosing spondylitis, psoriatic arthritis, reactive arthritis) • Tennis elbow • Headache • Traumatic injury There have not been sufficient numbers of high-quality randomised controlled trials conducted. Any increased risk of surgical bleeding, bleeding in the gastrointestinal system, myocardial infarctions, or injury to the kidneys has not been well studied. Aspirin Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for antithrombosis through inhibition of platelet aggregation. This is useful for the management of arterial thrombosis, and prevention of adverse cardiovascular events like heart attacks. Aspirin inhibits platelet aggregation by inhibiting the action of thromboxane A2. Dentistry NSAIDs are useful in the management of post-operative dental pain following invasive dental procedures such as dental extraction. When not contra-indicated, they are favoured over the use of paracetamol alone due to the anti-inflammatory effect they provide. There is weak evidence suggesting that taking pre-operative analgesia can reduce the length of post operative pain associated with placing orthodontic spacers under local anaesthetic. Alzheimer's disease Based on observational studies and randomized controlled trials, NSAID use is not effective for the treatment or prevention of Alzheimer's disease. ==Contraindications==

NSAIDs may be used with caution by people with the following conditions: • Persons who are over age 50, and who have a family history of gastrointestinal (GI) problems • In third trimester of pregnancy • Persons who have a history of allergic or allergic-like NSAID hypersensitivity reactions, e.g., aspirin-exacerbated respiratory disease ==Adverse effects==

The widespread use of NSAIDs has meant that the adverse effects of these drugs have become increasingly common. Use of NSAIDs increases the risk of a range of gastrointestinal (GI) problems, kidney disease, and adverse cardiovascular events. As commonly used for post-operative pain, there is evidence of increased risk of kidney complications. Their use following gastrointestinal surgery remains controversial, given mixed evidence of increased risk of leakage from any bowel anastomosis created. An estimated 10–20% of people taking NSAIDs experience indigestion. In the 1990s, high doses of prescription NSAIDs were associated with serious upper gastrointestinal adverse events, including bleeding. There is an argument over the benefits and risks of NSAIDs for treating chronic musculoskeletal pain. Each drug has a benefit-risk profile, and balancing the risk of no treatment with the competing potential risks of various therapies should be considered. For people over the age of 65 years old, the balance between the benefits of pain-relief medications such as NSAIDs and the potential for adverse effects has not been well determined. There is some evidence suggesting that, for some people, use of NSAIDs (or other anti-inflammatories) may contribute to the initiation of chronic pain. Side effects are dose-dependent, and in many cases, severe enough to pose the risk of ulcer perforation, upper gastrointestinal bleeding, and death, limiting the use of NSAID therapy. An estimated 10–20% of NSAID patients experience dyspepsia, and NSAID-associated upper gastrointestinal adverse events are estimated to result in 103,000 hospitalizations and 16,500 deaths per year in the United States, and represent 43% of drug-related emergency visits. Many of these events are avoidable; a review of physician visits and prescriptions estimated that unnecessary prescriptions for NSAIDs were written in 42% of visits. Aspirin should not be taken by people who have salicylate intolerance 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. Use of aspirin during dengue fever is not recommended owing to increased bleeding tendency. People with kidney disease, hyperuricemia, or gout should not take aspirin because it inhibits the ability of the kidneys to excrete uric acid, and thus may exacerbate these conditions. Combinational risk If a COX-2 inhibitor is taken, a traditional NSAID (prescription or over-the-counter) should not be taken at the same time. Rofecoxib (Vioxx) was shown to produce significantly fewer gastrointestinal adverse drug reactions (ADRs) compared with naproxen. The study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs (COX-2 inhibitors). A statistically significant increase in the incidence of myocardial infarctions was observed in patients on rofecoxib. Further data, from the APPROVe trial, showed a statistically significant relative risk of cardiovascular events of 1.97 versus placebo—which caused a worldwide withdrawal of rofecoxib in October 2004. Use of methotrexate together with NSAIDs in rheumatoid arthritis is safe if adequate monitoring is done. Cardiovascular NSAIDs, aside from aspirin, increase the risk of myocardial infarction and stroke. Evidence indicates that naproxen may be the least harmful out of these. NSAIDs, aside from (low-dose) aspirin, are associated with a doubled risk of heart failure in people without a history of cardiac disease. If this link is proven causal, researchers estimate that NSAIDs would be responsible for up to 20 percent of hospital admissions for congestive heart failure. In people with heart failure, NSAIDs increase mortality risk (hazard ratio) by approximately 1.2–1.3 for naproxen and ibuprofen, 1.7 for rofecoxib and celecoxib, and 2.1 for diclofenac. On 9 July 2015, the Food and Drug Administration (FDA) toughened warnings of increased heart attack and stroke risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin. Possible erectile dysfunction risk A 2005 Finnish survey study found an association between long-term (over three months) use of NSAIDs and erectile dysfunction. A 2011 publication in The Journal of Urology received widespread publicity. According to the study, men who used NSAIDs regularly were at significantly increased risk of erectile dysfunction. A link between NSAID use and erectile dysfunction still existed after controlling for several conditions. However, the study was observational and not controlled, with a low original participation rate, potential participation bias, and other uncontrolled factors. The authors warned against drawing any conclusions regarding cause. Gastrointestinal The main adverse drug reactions (ADRs) associated with NSAID use relate to direct and indirect irritation of the gastrointestinal (GI) tract. NSAIDs cause a dual assault on the GI tract: the acidic molecules directly irritate the gastric mucosa, and inhibition of COX-1 and COX-2 reduces the levels of protective prostaglandins. Common gastrointestinal side effects include: • Diarrhea Clinical NSAID ulcers are related to the systemic effects of NSAID administration. Such damage occurs irrespective of the route of administration of the NSAID (e.g., oral, rectal, or parenteral) and can occur even in people who have achlorhydria. Ulceration risk increases with therapy duration and with higher doses. To minimize GI side effects, it is prudent to use the lowest effective dose for the shortest period—a practice that studies show is often not followed. Over 50% of patients who take NSAIDs have sustained some mucosal damage to their small intestine. The risk and rate of gastric adverse effects are different depending on the type of NSAID medication a person is taking. Indomethacin, ketoprofen, and piroxicam use appears to lead to the highest rate of gastric adverse effects, while ibuprofen (lower doses) and diclofenac appear to have lower rates. Hydrogen sulfide NSAID hybrids prevent the gastric ulceration/bleeding associated with taking the NSAIDs alone. Hydrogen sulfide is known to have a protective effect on the cardiovascular and gastrointestinal system. Inflammatory bowel disease NSAIDs should be used with caution in individuals with inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) due to their tendency to cause gastric bleeding and form ulceration in the gastric lining. Renal NSAIDs are also associated with a fairly high incidence of adverse drug reactions (ADRs) on the kidney and over time can lead to chronic kidney disease. The mechanism of these kidney ADRs is due to changes in kidney blood flow. Prostaglandins normally dilate the afferent arterioles of the glomeruli. This helps maintain normal glomerular perfusion and glomerular filtration rate (GFR), an indicator of kidney function. This is particularly important in kidney failure, where the kidney is trying to maintain renal perfusion pressure by elevated angiotensin II levels. At these elevated levels, angiotensin II also constricts the afferent arteriole into the glomerulus in addition to the efferent arteriole it normally constricts. Since NSAIDs block this prostaglandin-mediated effect of afferent arteriole dilation, particularly in kidney failure, NSAIDs cause unopposed constriction of the afferent arteriole and decreased RPF (renal perfusion flow) and GFR. Common ADRs associated with altered kidney function include: In rarer instances NSAIDs may also cause more severe kidney conditions: Photosensitivity Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs. The 2-arylpropionic acids are the most likely to produce photosensitivity reactions, but other NSAIDs have also been implicated including piroxicam, diclofenac, and benzydamine. Benoxaprofen, since withdrawn due to its liver toxicity, was the most photoactive NSAID observed. The mechanism of photosensitivity, responsible for the high photoactivity of the 2-arylpropionic acids, is the ready decarboxylation of the carboxylic acid moiety. The specific absorbance characteristics of the different chromophoric 2-aryl substituents, affects the decarboxylation mechanism. During pregnancy While NSAIDs as a class are not direct teratogens, use of NSAIDs in late pregnancy can cause premature closure of the fetal ductus arteriosus and kidney ADRs in the fetus. Thus, NSAIDs are not recommended during the third trimester of pregnancy because of the increased risk of premature constriction of the ductus arteriosus. and miscarriage. Aspirin, however, is used together with heparin in pregnant women with antiphospholipid syndrome. Additionally, indomethacin can be used in pregnancy to treat polyhydramnios by reducing fetal urine production via inhibiting fetal renal blood flow. In contrast, paracetamol (acetaminophen) is regarded as being safe and well tolerated during pregnancy, but Leffers et al. released a study in 2010, indicating that there may be associated male infertility in the unborn. Doses should be taken as prescribed, due to risk of liver toxicity with overdoses. In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy. In October 2020, the U.S. Food and Drug Administration (FDA) required the prescribing information to be updated for all nonsteroidal anti-inflammatory medications, to describe the risk of kidney problems in unborn babies which can then lead to low amniotic fluid levels, as a result of the use of NSAIDs. They are recommending avoiding the use of NSAIDs by pregnant women at 20 weeks or later in pregnancy. Some NSAID hypersensitivity reactions are truly allergic in origin: 1) repetitive IgE-mediated urticarial skin eruptions, angioedema, and anaphylaxis following immediately to hours after ingesting one structural type of NSAID but not after ingesting structurally unrelated NSAIDs; and 2) Comparatively mild to moderately severe T cell-mediated delayed onset (usually more than 24 hour), skin reactions such as maculopapular rash, fixed drug eruptions, photosensitivity reactions, delayed urticaria, and contact dermatitis; or 3) far more severe and potentially life-threatening t-cell-mediated delayed systemic reactions such as the DRESS syndrome, acute generalized exanthematous pustulosis, the Stevens–Johnson syndrome, and toxic epidermal necrolysis. Other NSAID hypersensitivity reactions are allergy-like symptoms but do not involve true allergic mechanisms; rather, they appear due to the ability of NSAIDs to alter the metabolism of arachidonic acid in favor of forming metabolites that promote allergic symptoms. Affected individuals may be abnormally sensitive to these provocative metabolites or overproduce them and typically are susceptible to a wide range of structurally dissimilar NSAIDs, particularly those that inhibit COX-1. Symptoms, which develop immediately to hours after ingesting any of various NSAIDs that inhibit COX-1, are: 1) exacerbations of asthmatic and rhinitis (see aspirin-exacerbated respiratory disease) symptoms in individuals with a history of asthma or rhinitis and 2) exacerbation or first-time development of wheals or angioedema in individuals with or without a history of chronic urticarial lesions or angioedema. On the other hand, it has also been hypothesized that NSAIDs might speed recovery from soft tissue injuries by preventing inflammatory processes from damaging adjacent, non-injured muscles. There is moderate evidence that they delay bone healing. Their overall effect on soft-tissue healing is unclear. Ototoxicity Long-term use of NSAID analgesics and paracetamol is associated with an increased risk of hearing loss. Other The use of NSAIDs for analgesia following gastrointestinal surgery remains controversial, given mixed evidence of an increased risk of leakage from any bowel anastomosis created. This risk may vary according to the class of NSAID prescribed. Most NSAIDs penetrate poorly into the central nervous system (CNS). However, the COX enzymes are expressed constitutively in some areas of the CNS, meaning that even limited penetration may cause adverse effects such as somnolence and dizziness. NSAIDs may increase the risk of bleeding in patients with Dengue fever For this reason, NSAIDs are only available with a prescription in India. In very rare cases, ibuprofen can cause aseptic meningitis. As with other drugs, allergies to NSAIDs might exist. While many allergies are specific to one NSAID, up to 1 in 5 people may have unpredictable cross-reactive allergic responses to other NSAIDs as well. == Interactions ==

NSAIDs reduce kidney blood flow and thereby decrease the efficacy of diuretics, and inhibit the elimination of lithium and methotrexate. NSAIDs cause decreased ability to form blood clots, which can increase the risk of bleeding when combined with other drugs that also decrease blood clotting, such as warfarin. NSAIDs may aggravate hypertension (high blood pressure) and thereby antagonize the effect of antihypertensives, NSAIDs may interfere and reduce effectiveness of SSRI antidepressants through inhibiting TNFα and IFNγ, both of which are cytokine derivatives. NSAIDs, when used in combination with SSRIs, increase the risk of adverse gastrointestinal effects. NSAIDs, when used in combination with SSRIs, increase the risk of internal bleeding and brain hemorrhages. Various widely used NSAIDs enhance endocannabinoid signaling by blocking the anandamide-degrading membrane enzyme fatty acid amide hydrolase (FAAH). NSAIDs may reduce the effectiveness of antibiotics. An in-vitro study on cultured bacteria found that adding NSAIDs to antibiotics reduced their effectiveness by around 20%. The concomitant use of NSAIDs with alcohol and/or tobacco products significantly increases the already elevated risk of peptic ulcers during NSAID therapy. ==Mechanism of action==

Most NSAIDs act as nonselective inhibitors of the cyclooxygenase (COX) enzymes, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. This inhibition is competitively reversible (albeit at varying degrees of reversibility), as opposed to the mechanism of aspirin, which is irreversible inhibition. COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A2). Prostaglandins act (among other things) as messenger molecules in the process of inflammation. This mechanism of action was elucidated in 1970 by John Vane (1927–2004), who received a Nobel Prize for his work (see Mechanism of action of aspirin). COX-1 is a constitutively expressed enzyme with a "house-keeping" role in regulating many normal physiological processes. One of these is in the stomach lining, where prostaglandins serve a protective role, preventing the stomach mucosa from being eroded by its own acid. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs. When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels, ulcers of the stomach or duodenum and internal bleeding can result. The discovery of COX-2 led to research to the development of selective COX-2 inhibiting drugs that do not cause gastric problems characteristic of older NSAIDs. NSAIDs have been studied in various assays to understand how they affect each of these enzymes. While the assays reveal differences, unfortunately, different assays provide differing ratios. Paracetamol (acetaminophen) is not considered an NSAID because it has little anti-inflammatory activity. It treats pain mainly by blocking COX-2, mostly in the central nervous system, but not much in the rest of the body. NSAIDs are also used in the acute pain caused by gout because they inhibit urate crystal phagocytosis besides inhibition of prostaglandin synthase. Antipyretic activity NSAIDs have antipyretic activity and can be used to treat fever. Fever is caused by elevated levels of prostaglandin E2 (PGE2), which alters the firing rate of neurons within the hypothalamus that control thermoregulation. Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis (PGE2) within the hypothalamus. Ibuprofen has been shown more effective as an antipyretic than paracetamol (acetaminophen). Arachidonic acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D, and E. ==Classification==

package NSAIDs can be classified based on their chemical structure or mechanism of action. Older NSAIDs were known long before their mechanism of action was elucidated and were, for this reason, classified by chemical structure or origin. Newer substances are more often classified by mechanism of action. Salicylates • Aspirin (acetylsalicylic acid) • Diflunisal (Dolobid) • Ethenzamide • Salicylamide • Salicylic acid and its salts • Salsalate (Disalcid) • Choline salicylate • Methyl salicylate • Sodium salicylate Propionic acid derivatives • Ibuprofen • Dexibuprofen • Naproxen • Fenoprofen • Ketoprofen • Dexketoprofen • Flurbiprofen • Oxaprozin • Loxoprofen • Pelubiprofen • Zaltoprofen • Fenbufen • Tiaprofenic acid • Carprofen Acetic acid derivatives • Indomethacin • Acemetacin • Tolmetin • Sulindac • Etodolac • Ketorolac • Diclofenac • Fenclofenac • Aceclofenac • Bromfenac • Fentiazac • Nabumetone (drug itself is non-acidic, but the active, principal metabolite has a carboxylic acid group) Enolic acid (oxicam) derivatives • Piroxicam • Ampiroxicam • Meloxicam • Tenoxicam • Droxicam • Lornoxicam • Isoxicam (withdrawn from market 1985) • Phenylbutazone (Bute) Anthranilic acid derivatives (Fenamates) The following NSAIDs are derived from fenamic acid, which is a derivative of anthranilic acid, which in turn is a nitrogen isostere of salicylic acid, which is the active metabolite of aspirin. • Mefenamic acid • Meclofenamic acid • Flufenamic acid • Tolfenamic acid • Etofenamate Selective COX-2 inhibitors (Coxibs) • Celecoxib (FDA alert) • Rofecoxib (withdrawn from market) • Valdecoxib (withdrawn from market) • Parecoxib FDA withdrawn, licensed in the EU • Lumiracoxib TGA cancelled registration • Etoricoxib not FDA approved, licensed in the EU • Firocoxib used in dogs and horses • Deracoxib labeled for use in dogs • Robenacoxib labeled for use in dogs and cats Sulfonanilides • Nimesulide (systemic preparations are banned by several countries for the potential risk of hepatotoxicity) Others • Benzydamine (commonly branded as Tantum Verde or Difflam) is an indazole derivative with local anaesthetic and analgesic properties • Clonixin • Licofelone acts by inhibiting LOX (lipooxygenase) and COX and hence is known as a 5-LOX/COX inhibitor • H-harpagide in figwort or devil's claw • Some NSAIDs are also given intravenously, such as Ketorolac and Diclofenac sodium. Chirality Most NSAIDs are chiral molecules; diclofenac and the oxicams are exceptions. However, the majority are prepared as racemic mixtures. Typically, only a single enantiomer is pharmacologically active. For some drugs (typically profens), an isomerase enzyme in vivo converts the inactive enantiomer into the active form, although its activity varies widely in individuals. This phenomenon is likely responsible for the poor correlation between NSAID efficacy and plasma concentration observed in older studies when specific analysis of the active enantiomer was not performed. Ibuprofen and ketoprofen are now available in single-enantiomer preparations (dexibuprofen and dexketoprofen), which purport to offer quicker onset and an improved side-effect profile. Naproxen has always been marketed as the single active enantiomer. Main practical differences NSAIDs within a group tend to have similar characteristics and tolerability. There is little difference in clinical efficacy among the NSAIDs when used at equivalent doses. Except for naproxen, nonselective NSAIDs increase the risk of having a heart attack. ==Pharmacokinetics==

Most nonsteroidal anti-inflammatory drugs are weak acids, with a pKa of 3–5. They are absorbed well from the stomach and intestinal mucosa. They are highly protein-bound in plasma (typically >95%), usually to albumin, so that their volume of distribution typically approximates to plasma volume. Most NSAIDs are metabolized in the liver by oxidation and conjugation to inactive metabolites that typically are excreted in the urine, though some drugs are partially excreted in bile. Metabolism may be abnormal in certain disease states, and accumulation may occur even with normal dosage. NSAIDs can also be divided into short-acting (plasma half-life less than 6 h) such as aspirin, diclofenac and ibuprofen and long-acting (half-life approximately greater than 10 h) such as naproxen, celecoxib. ==History==

'' in 1917 It is widely believed that naturally occurring salicin in willow trees and other plants was used by the ancients as a form of analgesic or anti-inflammatory drug, but this story, although compelling, is not entirely true. Hippocrates does not mention willow at all. Dioscorides's De materia medica was arguably the most influential herbal from Roman to Medieval times but, if he mentions willow at all (there is doubt about the identity of 'Itea'), then he used the ashes, steeped in vinegar, as a treatment for corns, which corresponds well with modern uses of salicylic acid. Willow bark (from trees of the Salix genus) was widely known to be used as a medicine by multiple First Nations communities. The bark would be chewed or steeped in water for its pain relieving and antipyretic effects. The effects are a result of the bark's salicin content. Meadowsweet, another plant to contain salicin, has strong roots in British folk medicine for the same maladies. Willow bark was first reported in Western science by Edward Stone in 1763 as a treatment for ague (fever) according to the pseudoscientific doctrine of signatures. In the body, salicin is turned into salicylic acid, which produces the antipyretic and analgesic effects that the plants are known for. Salicin was first isolated by Johann Andreas Buchner in 1827. By 1829, French chemist Henri Leroux had improved the extraction process to obtain about 30g of purified salicin from 1.5kg of willow bark. By hydrolysis, salicin releases glucose and salicyl alcohol which can be converted into salicylic acid, both in vivo and through chemical methods. In 1869, Hermann Kolbe synthesised salicylic acid, although it was too acidic for the gastric mucosa. By 1897, the German chemist Felix Hoffmann and the Bayer company prompted a new age of pharmacology by converting salicylic acid into acetylsalicylic acid—named aspirin by Heinrich Dreser. Other NSAIDs like ibuprofen were developed from the 1950s forward. ==Veterinary use==

Research supports the use of NSAIDs for the control of pain associated with veterinary procedures such as dehorning and castration of calves. The best effect is obtained by combining a short-term local anesthetic such as lidocaine with an NSAID acting as a longer term analgesic. However, as different species have varying reactions to different medications in the NSAID family, little of the existing research data can be extrapolated to animal species other than those specifically studied, and the relevant government agency in one area sometimes prohibits uses approved in other jurisdictions. In the United States, meloxicam is approved for use only in canines, whereas (due to concerns about kidney damage) it carries warnings against its use in cats except for one-time use during surgery. In spite of these warnings, meloxicam is frequently prescribed "off-label" for non-canine animals including cats and livestock species. In other countries, for example the European Union (EU), there is a label claim for use in cats. ==See also==