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Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, are drugs with analgesic, antipyretic (lowering an elevated body temperature and relieving pain without impairing consciousness) and, in higher doses, with anti-inflammatory effects (reducing inflammation). The term "non-steroidal" 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.

NSAIDs are sometimes also referred to as non-steroidal anti-inflammatory agents/analgesics (NSAIAs) or non-steroidal anti-inflammatory medicines (NSAIMs). The most prominent members of this group of drugs are aspirin, ibuprofen, and naproxen partly because they are available over-the-counter in many areas.

Contents

Mechanism of action

Most NSAIDs act as non-selective inhibitors of the enzyme cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase 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). A newly discovered COX-3 may also have some role.

Classes

NSAIDs can be broadly classified based on their chemical structure.

Propionic acid derivatives

Acetic acid derivatives

  1. REDIRECT [[I6]]

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 (cyclooxygenase)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:[6]

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.[8]

One study has suggested that taking NSAIDs while smoking marijuana may prevent the death of brain cells resulting from THC intoxication.[9] However, neurotoxicity of marijuana is still a matter of dispute.

Pharmacokinetics

Most non-steroidal 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.[8]

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.[10][11]

Combinational risk

If a COX-2 inhibitor is taken, one should not use a traditional NSAID (prescription or over-the-counter) concomitantly.[12] 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 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.[13]

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.[14] 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.[14]

Gastrointestinal

The main ADRs (adverse drug reactions) 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 reduces the levels of protective prostaglandins. Inhibition of prostaglandin synthesis in the GI tract causes increased gastric acid secretion, diminished bicarbonate secretion, diminished mucous secretion and diminished trophic effects on epithelial mucosa.

Common gastrointestinal ADRs include:[6]

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.[16]

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.[6]

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.[6]

Commonly, gastrointestinal 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 or drugs containing codeine (which slows down bowel activity) are safer medications for pain relief in IBD.

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 ateriole 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 to other domestic animal species.

Common ADRs associated with altered renal function include:[6]

  • 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.[17]

In rarer instances NSAIDs may also cause more severe renal conditions:[6]

NSAIDs in combination with excessive use of phenacetin and/or paracetamol may lead to analgesic nephropathy.[18]

Photosensitivity

Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs.[19] 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.[20] Aspirin, however, is used together with heparin in pregnant women with antiphospholipid antibodies.[21]

In contrast, paracetamol (acetaminophen) is regarded as being safe and well-tolerated during pregnancy.[22] Doses should be taken as prescribed, due to risk of hepatotoxicity with overdoses.[23]

In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy.[24]

Other

Common ADRs, other than listed above, include: raised liver enzymes, headache, dizziness.[6] Uncommon ADRs include: hyperkalaemia, confusion, bronchospasm, rash.[6] 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 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.[25]

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 non-selective 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.

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 to naproxen.[26] 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.[27] 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.[28]

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

  1. ^ http://www.drugbank.ca/cgi-bin/getCard.cgi?CARD=APRD00372 Drugbank Card for Ibuprofen
  2. ^ http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm193047.htm
  3. ^ http://www.fda.gov/cder/drug/infopage/celebrex/celebrex-hcp.htm FDA Alert for Practitioners on Celebrex (celecoxib)
  4. ^ http://www.fda.gov/cder/drug/infopage/vioxx/PHA_vioxx.htm
  5. ^ http://www.fda.gov/cder/drug/InfoSheets/HCP/valdecoxibHCP.htm Alert for Healthcare Professionals: Valdecoxib (marketed as Bextra)
  6. ^ a b c d e f g h Simone Rossi, ed (2006). Australian medicines handbook 2006. Adelaide: Australian Medicines Handbook Pty Ltd. ISBN 0-9757919-2-3.  
  7. ^ Gøtzsche, Pc (March 1989). "Methodology and overt and hidden bias in reports of 196 double-blind trials of nonsteroidal antiinflammatory drugs in rheumatoid arthritis". Controlled clinical trials 10 (1): 31–56. doi:10.1016/0197-2456(89)90017-2. ISSN 0197-2456. PMID 2702836.  
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  9. ^ Chan, Gc; Hinds, Tr; Impey, S; Storm, Dr (15 July 1998). "Hippocampal neurotoxicity of Delta9-tetrahydrocannabinol" (Free full text). The Journal of neuroscience : the official journal of the Society for Neuroscience 18 (14): 5322–32. ISSN 0270-6474. PMID 9651215. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=9651215.  
  10. ^ Bayer HealthCare Pharmaceuticals Inc (September 2008). "CIPRO (ciprofloxacin hydrochloride) TABLETS CIPRO,(ciprofloxacin*) ORAL SUSPENSION" (PDF). USA: FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019537s68,19847s42,19857s49,20780s26,21473s24lbl.pdf. Retrieved 31 August 2009.  
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  12. ^ http://orthoinfo.aaos.org/fact/thr_report.cfm?Thread_ID=398&topcategory=About
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  14. ^ a b Page, J; Henry, D (March 2000). "Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem" (Free full text). Archives of internal medicine 160 (6): 777–84. doi:10.1001/archinte.160.6.777. ISSN 0003-9926. PMID 10737277. http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=10737277.  
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  17. ^ Thomas, Mc (February 2000). "Diuretics, ACE inhibitors and NSAIDs--the triple whammy". The Medical journal of Australia 172 (4): 184–5. ISSN 0025-729X. PMID 10772593.  
  18. ^ De, Broe, Me; Elseviers, Mm (February 1998). "Analgesic nephropathy". New England Journal of Medicine 338 (7): 446–52. doi:10.1056/NEJM199802123380707. ISSN 0028-4793. PMID 9459649.  
  19. ^ Moore, De (2002). "Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management". Drug safety : an international journal of medical toxicology and drug experience 25 (5): 345–72. doi:10.2165/00002018-200225050-00004. ISSN 0114-5916. PMID 12020173.  
  20. ^ Østensen, Me; Skomsvoll, Jf (March 2004). "Anti-inflammatory pharmacotherapy during pregnancy". Expert opinion on pharmacotherapy 5 (3): 571–80. doi:10.1517/14656566.5.3.571. ISSN 1465-6566. PMID 15013926.  
  21. ^ Cervera, R; Balasch, J (2004). "The management of pregnant patients with antiphospholipid syndrome". Lupus 13 (9): 683–7. doi:10.1191/0961203304lu1092oa. ISSN 0961-2033. PMID 15485103.  
  22. ^ Graham, Gg; Scott, Kf; Day, Ro (2005). "Tolerability of paracetamol". Drug safety : an international journal of medical toxicology and drug experience 28 (3): 227–40. doi:10.2165/00002018-200528030-00004. ISSN 0114-5916. PMID 15733027.  
  23. ^ Wilkes, Jm; Clark, Le; Herrera, Jl (November 2005). "Acetaminophen overdose in pregnancy". Southern medical journal 98 (11): 1118–22. doi:10.1097/01.smj.0000184792.15407.51. ISSN 0038-4348. PMID 16351032.  
  24. ^ Dreillard, Audrey (2009-03-02). "Grossesse - Mamans attention" (in French). France Soir. http://www.francesoir.fr/societe/2009/03/02/grossesse-mamans-attention.html. Retrieved 2009-06-01.  
  25. ^ Allergy Capital: Adverse and allergic reactions to aspirin and NSAIDS. Accessed 2009.03.23.
  26. ^ Bombardier, C; Laine, L; Reicin, A; Shapiro, D; Burgos-Vargas, R; Davis, B; Day, R; Ferraz, Mb; Hawkey, Cj; Hochberg, Mc; Kvien, Tk; Schnitzer, Tj; Vigor, Study, Group (November 2000). "Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis". New England Journal of Medicine 343 (21): 1520–8, 2 p following 1528. doi:10.1056/NEJM200011233432103. ISSN 0028-4793. PMID 11087881.  
  27. ^ Chandrasekharan, Nv; Dai, H; Roos, Kl; Evanson, Nk; Tomsik, J; Elton, Ts; Simmons, Dl (October 2002). "COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression" (Free full text). Proceedings of the National Academy of Sciences of the United States of America 99 (21): 13926–31. doi:10.1073/pnas.162468699. ISSN 0027-8424. PMID 12242329. PMC 129799. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=12242329.  
  28. ^ Kis, B; Snipes, Ja; Busija, Dw (October 2005). "Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties" (Free full text). The Journal of pharmacology and experimental therapeutics 315 (1): 1–7. doi:10.1124/jpet.105.085431. ISSN 0022-3565. PMID 15879007. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15879007.  

External links


Wiktionary

Up to date as of January 15, 2010

Definition from Wiktionary, a free dictionary

Contents

English

Wikipedia

Initialism

NSAID

  1. (pharmacology) Non-steroidal anti-inflammatory drug.

Noun

Singular
NSAID

Plural
NSAIDs

NSAID (plural NSAIDs)

  1. (pharmacology) Any drug of the non-steroidal anti-inflammatory class.

Related terms

Anagrams

  • Anagrams of adins
  • isnad







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