Non-steroidal anti-inflammatory drug

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File:200mg ibuprofen tablets.jpg
Coated 200 mg ibuprofen tablets, a common NSAID

Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs - but also referred to as nonsteroidal anti-inflammatory agents/analgesics (NSAIAs) or nonsteroidal anti-inflammatory medicines (NSAIMs) - are drugs with analgesic and antipyretic (fever-reducing) effects and which have, in higher doses, anti-inflammatory effects.

The term "nonsteroidal" is used to distinguish these drugs from steroids, which - among a broad range of other effects - have a similar eicosanoid-depressing, anti-inflammatory action. As analgesics, NSAIDs are unusual in that they are non-narcotic.

The most prominent members of this group of drugs are aspirin, ibuprofen, and naproxen, all of which are available over the counter in many areas.[1]

Mechanism of action

Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX), inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. 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 by John Vane (1927–2004), who later received a Nobel Prize for his work (see Mechanism of action of aspirin). Many aspects of the mechanism of action of NSAIDs remain unexplained, for this reason further COX pathways were hypothesized. The COX-3 pathway was believed to fill some of this gap but recent findings make it appear unlikely that it plays any significant role in humans and alternative explanation models are proposed.[2]

NSAIDS have antipyretic activity and can be used to treat fever.[3][4] Fever is caused by elevated levels of prostaglandin E2, which alters the firing rate of neurons within the hypothalamus that control thermoregulation.[3][5] Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis (PGE2) within the hypothalamus.[3][4] PGE2 signals to the hypothalamus to increase the body's thermal set point.[4][6] Ibuprofen has been shown to be more effective as an antipyretic than acetaminophen.[5][7] Arachidonic acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F,D & E.

Classification

NSAIDs can be broadly classified based on their chemical structure.

Propionic acid derivatives

Acetic acid derivatives

Enolic acid (Oxicam) derivatives

Fenamic acid derivatives

Selective COX-2 inhibitors (Coxibs)

Examples

NSAIDs within a group will tend to have similar characteristics and tolerability. There is little difference in clinical efficacy among the NSAIDs when used at equivalent doses. Rather, differences among compounds tend to be with regards to dosing regimens (related to the compound's elimination half-life), route of administration, and tolerability profile. Some more common examples are given below.

Sulphonanilides

  • Nimesulide (systemic preparations are banned by several countries for the potential risk of hepatotoxicity)

Others

Licofelone acts by inhibiting LOX (lipooxygenase) & COX and hence known as 5-LOX/COX inhibitor.

Uses

NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present. Research continues into their potential for prevention of colorectal cancer, and treatment of other conditions, such as cancer and cardiovascular disease.

NSAIDs are generally indicated for the symptomatic relief of the following conditions:[13]

Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for inhibition of platelet aggregation. This is useful in the management of arterial thrombosis and prevention of adverse cardiovascular events. Aspirin inhibits platelet aggregation by inhibiting the action of thromboxane -A.

In 2001 NSAIDs accounted for 70,000,000 prescriptions and 30 billion over-the-counter doses sold annually in the United States.[15]

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 metabolised in the liver by oxidation and conjugation to inactive metabolites which are typically excreted in the urine, although some drugs are partially excreted in bile. Metabolism may be abnormal in certain disease states, and accumulation may occur even with normal dosage.

Ibuprofen and diclofenac have short half-lives (2–3 hours). Some NSAIDs (typically oxicams) have very long half-lives (e.g. 20–60 hours).

Adverse effects

The widespread use of NSAIDs has meant that the adverse effects of these drugs have become increasingly prevalent. The two main adverse drug reactions (ADRs) associated with NSAIDs relate to gastrointestinal (GI) effects and renal effects of the agents.

These 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.[15]

NSAIDs, like all drugs, may interact with other medications. For example, concurrent use of NSAIDs and quinolones may increase the risk of quinolones' adverse central nervous system effects, including seizure.[16][17]

Combinational risk

If a COX-2 inhibitor is taken, one should not use a traditional NSAID (prescription or over-the-counter) concomitantly.[18] In addition, patients on daily aspirin therapy (e.g. for reducing cardiovascular risk) need to be careful if they also use other NSAIDs, as the latter may block[further explanation needed] the cardioprotective effects of aspirin.

Cardiovascular

A recent meta-analysis of all trials comparing NSAIDs found an 80% increase in the risk of myocardial infarction with both newer COX-2 antagonists and high dose traditional anti-inflammatories compared with placebo.[19]

NSAIDs aside from (low-dose) aspirin are associated with a doubled risk of symptomatic heart failure in patients without a history of cardiac disease. In patients with such a history, however, use of NSAIDs (aside from low-dose aspirin) was associated with more than 10-fold increase in heart failure.[20] If this link is found to be causal, NSAIDs are estimated to be responsible for up to 20 percent of hospital admissions for congestive heart failure.[20]

Gastrointestinal

The main adverse drug reactions (ADRs) associated with use of NSAIDs relate to direct and indirect irritation of the gastrointestinal tract (GIT). NSAIDs cause a dual insult on the GIT: the acidic molecules directly irritate the gastric mucosa, and inhibition of COX-1 and COX-2 reduces the levels of protective prostaglandins. Inhibition of prostaglandin synthesis in the GI tract causes increased gastric acid secretion, diminished bicarbonate secretion, diminished mucus secretion and diminished trophic[clarification needed] effects on epithelial mucosa.

Common gastrointestinal ADRs include:[13]

Risk of ulceration increases with duration of therapy, and with higher doses. In attempting to minimise GI ADRs, it is prudent to use the lowest effective dose for the shortest period of time, a practice which studies show is not often followed. Recent studies show that over 50% of patients taking NSAIDs have sustained damage to their small intestine.[22] Studies show that risk of ulceration is less with Nabumetone than with Ibuprofen alone.[23]

There are also some differences in the propensity of individual agents to cause gastrointestinal ADRs. Indomethacin, ketoprofen and piroxicam appear to have the highest prevalence of gastric ADRs, while ibuprofen (lower doses) and Diclofenac appear to have lower rates.[13]

Certain NSAIDs, such as aspirin, have been marketed in enteric-coated formulations which are claimed to reduce the incidence of gastrointestinal ADRs. Similarly, there is a belief that rectal formulations may reduce gastrointestinal ADRs. However, in consideration of the mechanism of such ADRs and indeed in clinical practice, these formulations have not been shown to have a reduced risk of GI ulceration.[13]

Commonly, gastric (but not necessarily intestinal) adverse effects can be reduced through suppressing acid production, by concomitant use of a proton pump inhibitor, e.g. omeprazole, esomeprazole; or the prostaglandin analogue misoprostol. Misoprostol is itself associated with a high incidence of gastrointestinal ADRs (diarrhea). While these techniques may be effective, they prove to be expensive for maintenance therapy.

Inflammatory bowel disease

NSAIDs are never to be used 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. Pain relievers such as paracetamol (also known as acetaminophen) or drugs containing codeine (which slows down bowel activity) are safer medications for pain relief in IBD.[citation needed]

Renal

NSAIDs are also associated with a relatively high incidence of renal adverse drug reactions (ADRs). The mechanism of these renal ADRs is due to changes in renal haemodynamics (blood flow), ordinarily mediated by prostaglandins, which are affected by NSAIDs. Prostaglandins normally cause vasodilation of the afferent arterioles of the glomeruli. This helps maintain normal glomerular perfusion and glomerular filtration rate (GFR), an indicator of renal function. This is particularly important in renal 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 one it normally constricts. Prostaglandins serve to dilate the afferent arteriole; by blocking this prostaglandin-mediated effect, particularly in renal failure, NSAIDs cause unopposed constriction of the afferent arteriole and decreased renal perfusion pressure. Horses are particularly prone to these adverse affects compared with other domestic animal species.

Common ADRs associated with altered renal function include:[13]

  • Salt and fluid retention
  • Hypertension (high blood pressure)

These agents may also cause renal impairment, especially in combination with other nephrotoxic agents. Renal failure is especially a risk if the patient is also concomitantly taking an ACE inhibitor and a diuretic - the so-called "triple whammy" effect.[24]

In rarer instances NSAIDs may also cause more severe renal conditions:[13]

NSAIDs in combination with excessive use of phenacetin and/or paracetamol may lead to analgesic nephropathy.[25]

Photosensitivity

Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs.[26] It is somewhat ironic that these anti-inflammatory agents may themselves produce inflammation in combination with exposure to sunlight. The 2-arylpropionic acids have proven to be 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 hepatotoxicity, 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. While ibuprofen is somewhat of an exception, having weak absorption, it has been reported to be a weak photosensitising agent.

During pregnancy

NSAIDs are not recommended during pregnancy, particularly during the third trimester. While NSAIDs as a class are not direct teratogens, they may cause premature closure of the fetal ductus arteriosus and renal ADRs in the fetus. Additionally, they are linked with premature birth.[27] Aspirin, however, is used together with heparin in pregnant women with antiphospholipid antibodies.[28]

In contrast, paracetamol (acetaminophen) is regarded as being safe and well-tolerated during pregnancy.[29] Doses should be taken as prescribed, due to risk of hepatotoxicity with overdoses.[30]

In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy.[31]

Other

Common adverse drug reactions (ADR), other than listed above, include: raised liver enzymes, headache, dizziness.[13] Uncommon ADRs include: hyperkalaemia, confusion, bronchospasm, rash.[13] Rapid and severe swelling of the face and/or body. Ibuprofen may also rarely cause irritable bowel syndrome symptoms.

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.

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.[32]

Drug Interactions

Drug Severity Adverse Effect Recommendations
ACE Inhibitors (e.g. Benazepril Hydrochloride) Moderate May decrease antihypertensive and natriuretic effects Monitor blood pressure and cardiovascular function
Probenecid Moderate May result in reversal of the uricosuric effects of the other drug Avoid concurrent use of high-dose aspirin with probenecid
Lithium Moderate May increase lithium plasma levels and decrease its clearance renally Monitor for lithium toxicity
Warfarin Moderate May result in an increased risk of bleeding Monitor PT (prothrombin time) and INR (international normalized ratio)
Methotrexate Severe May result in increased risk of methotrexate toxicity DO NOT administer NSAIDs within 10 days of high dose methotrexate

[33][34][35][36][37][37][35][38][39][40]

Chirality

Most NSAIDs are chiral molecules (diclofenac is a notable exception). However, the majority are prepared in a racemic mixture. Typically, only a single enantiomer is pharmacologically active. For some drugs (typically profens), an isomerase enzyme exists in vivo which converts the inactive enantiomer into the active form, although its activity varies widely in individuals. This phenomenon is likely to be 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, active 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.

Selective COX inhibitors

COX-2 inhibitors

The discovery of COX-2 in 1991 by Daniel L. Simmons at Brigham Young University raised the hope of developing an effective NSAID without the gastric problems characteristic of these agents. It was thought that selective inhibition of COX-2 would result in anti-inflammatory action without disrupting gastroprotective prostaglandins.

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. When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels, these protective effects are lost and ulcers of the stomach or duodenum and potentially internal bleeding can result. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs.

The relatively selective COX-2 inhibiting oxicam, meloxicam, was the first step towards developing a true COX-2 selective inhibitor. Coxibs, the newest class of NSAIDs, can be considered as true COX-2 selective inhibitors, and include celecoxib, rofecoxib, valdecoxib, parecoxib and etoricoxib.

Acetaminophen does also work mainly by blocking COX-2, unlike the newly developed COX-2 inhibitors it has weaker peripheral inhibitory activity.[2]

Controversies with COX-2 inhibitors

While it was hoped that this COX-2 selectivity would reduce gastrointestinal adverse drug reactions (ADRs), there is little conclusive evidence that this is true. The original study touted by Searle (now part of Pfizer), showing a reduced rate of ADRs for celecoxib, was later revealed to be based on preliminary data - the final data showed no significant difference in ADRs when compared with diclofenac.

Rofecoxib however, which has since been withdrawn, had been shown to produce significantly fewer gastrointestinal ADRs compared with naproxen.[41] This study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs - a statistically insignificant increase in the incidence of myocardial infarctions was observed in patients on rofecoxib. Further data, from the APPROVe trial, showed a relative risk of cardiovascular events of 1.97 versus placebo - a result which resulted in the worldwide withdrawal of rofecoxib in October 2004.

COX-3 inhibitors

Simmons also co-discovered COX-3 in 2002 and analyzed this new isozyme's relation to paracetamol (acetaminophen), arguably the most widely used analgesic drug in the world.[42] The authors postulated that inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.

The relevance of this research has been called into question as the putative COX-3 gene encodes proteins with completely different amino acid sequences than COX-1 or COX-2. The expressed proteins do not show COX activity and it is unlikely that they play a role in prostaglandin mediated physiological responses.[43]

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, most of the existing research data relates to ketoprofen while the only NSAID currently available for labelled use in the United States is flunixin meglumine, indicated for conditions other than post-operative pain.

References

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ar:مضادات التهاب لاستيرويدية bs:Nesteroidni antiupalni lijekovi bg:НСПВС ca:Antiinflamatori no esteroïdal cs:Nesteroidní antiflogistikum cy:Cyffur gwrthlid ansteroidol da:NSAID de:Nichtsteroidales Antirheumatikum es:Antiinflamatorio no esteroideo eu:Antiinflamatorio ez esteroideo fa:داروهای ضد التهاب غیر استروئیدی fr:Anti-inflammatoire non stéroïdien it:FANS hu:Nem-szteroid gyulladáscsökkentő gyógyszerek nl:NSAID ja:非ステロイド性抗炎症薬 no:Ikkesteroid antiinflammatorisk middel pl:Niesteroidowe leki przeciwzapalne pt:Anti-inflamatórios não esteroides ru:Нестероидные противовоспалительные препараты simple:Non-steroidal anti-inflammatory drug sk:Nesteroidné antiflogistikum sr:Нестероидни антиинфламаторни лек sh:Nesteroidni antiupalni lijekovi fi:Tulehduskipulääke sv:NSAID th:ยาแก้อักเสบชนิดไม่ใช่สเตรอยด์ tr:Non steroidal antienflamatuar ilaçlar ur:لااسٹیرودی مانع سوزش دوا vi:Thuốc chống viêm không steroid

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