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In very rare cases, ibuprofen can cause aseptic meningitis.
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.<ref>Allergy Capital: [http://www.allergycapital.com.au/Pages/aspirin.html Adverse and allergic reactions to aspirin and NSAIDS]. Accessed 2009.03.23.</ref>


==Chirality==
==Chirality==

Revision as of 20:40, 23 March 2009

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.

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, 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.

Examples

NSAIDs can be broadly classified based on their chemical structure. 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 tended 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.

Paracetamol (acetaminophen) is sometimes grouped with the NSAIDs; however, it is not an NSAID and does not have any significant anti-inflammatory properties. Though the mechanism of action is unclear, it is suspected that the lack of anti-inflammatory action may be due to inhibition of cyclooxygenase predominantly in the central nervous system.[citation needed] There is also some speculation that paracetamol acts through the inhibition of the recently discovered COX-3 isoform (see below). It is believed as well that NSAIDs act centrally, possibly within the spinal cord.[citation needed] However, the mechanism of action in this case is not well-characterized.

COX-2 inhibitors

Sulphonanilides

  • Nimesulide (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:[4]

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.[6]

One study has suggested that taking NSAIDs while smoking marijuana may prevent the death of brain cells resulting from THC intoxication.[7] However, neurotoxicity of marijuana is still a matter of dispute.

Pharmacokinetics

Most NSAIDs 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 relatively safe 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.[6]

Combinational risk

If a COX-2 inhibitor is taken, one should not use a traditional NSAID (prescription or over-the-counter) concomitantly.[2] In addition, patients on daily aspirin therapy (as for reducing cardiovascular risk or colon cancer 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. (Kearney et al., BMJ 2006;332:1302–1308)

NSAIDs aside from 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.[8] 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.[8]

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.

Common gastrointestinal ADRs include:[4]

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.

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.[4]

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.[4]

Commonly, gastrointestinal adverse effects can be reduced through suppressing acid production, by concomitant use of a proton pump inhibitor, e.g. omeprazole; or the prostaglandin analogue misoprostol. Misoprostol is itself associated with a high incidence of gastrointestinal ADRs (diarrhoea). 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. Drugs such as Advil should be avoided in persons afflicted with IBD. Pain relievers such as Tylenol (containing acetaminophen) or drugs containing codeine (which slows down bowel activity) are safer medications than ibuprofen 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. By blocking this prostaglandin-mediated effect, NSAIDs ultimately may cause renal impairment. Horses are particularly prone to these adverse affects compared to other domestic animal species.

Common ADRs associated with altered renal function include:[4]

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.[10]

In rarer instances NSAIDs may also cause more severe renal conditions:[4]

NSAIDs in combination with excessive use of phenacetin and/or paracetamol may lead to analgesic nephropathy.[11]

Photosensitivity

Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs.[12] 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.[13] Aspirin, however, is used together with heparin in pregnant women with antiphospholipid antibodies.[14]

In contrast, paracetamol (acetaminophen) is regarded as being safe and well-tolerated during pregnancy.[15] Doses should be taken as prescribed, due to risk of hepatotoxicity with overdoses.[16]

In France, the country's health agency contra indicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy.[17]

Other

Common ADRs, other than listed above, include: raised liver enzymes, headache, dizziness.[4] Uncommon ADRs include: hyperkalaemia, confusion, bronchospasm, rash.[4] 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.[18]

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.[19] 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.[20] 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.[21]

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. ^ FDA Alert for Practitioners on Celebrex (celecoxib)
  2. ^ http://www.fda.gov/cder/drug/infopage/vioxx/PHA_vioxx.htm
  3. ^ Alert for Healthcare Professionals: Valdecoxib (marketed as Bextra)
  4. ^ a b c d e f g h Australian medicines handbook 2006. Adelaide, S. Aust: Australian Medicines Handbook Pty Ltd. 2006. ISBN 0-9757919-2-3.
  5. ^ Gøtzsche PC (1989). "Methodology and overt and hidden bias in reports of 196 double-blind trials of nonsteroidal antiinflammatory drugs in rheumatoid arthritis". Control Clin Trials. 10 (1): 31–56. PMID 2702836. {{cite journal}}: Unknown parameter |month= ignored (help)
  6. ^ a b Green GA (2001). "Understanding NSAIDs: from aspirin to COX-2". Clin Cornerstone. 3 (5): 50–60. PMID 11464731.
  7. ^ Hippocampal Neurotoxicity of Delta 9-Tetrahydrocannabinol - Chan et al. 18 (14): 5322 - Journal of Neuroscience
  8. ^ a b [1]
  9. ^ Traversa G, Walker AM, Ippolito FM; et al. (1995). "Gastroduodenal toxicity of different nonsteroidal antiinflammatory drugs". Epidemiology. 6 (1): 49–54. PMID 7888445. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Thomas MC (2000). "Diuretics, ACE inhibitors and NSAIDs--the triple whammy". Med. J. Aust. 172 (4): 184–5. PMID 10772593. {{cite journal}}: Unknown parameter |month= ignored (help)
  11. ^ De Broe ME, Elseviers MM (1998). "Analgesic nephropathy". N. Engl. J. Med. 338 (7): 446–52. PMID 9459649. {{cite journal}}: Unknown parameter |month= ignored (help)
  12. ^ Moore DE (2002). "Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management". Drug Saf. 25 (5): 345–72. PMID 12020173.
  13. ^ Østensen ME, Skomsvoll JF (2004). "Anti-inflammatory pharmacotherapy during pregnancy". Expert Opin Pharmacother. 5 (3): 571–80. doi:10.1517/14656566.5.3.571. PMID 15013926. {{cite journal}}: Unknown parameter |month= ignored (help)
  14. ^ Cervera R, Balasch J (2004). "The management of pregnant patients with antiphospholipid syndrome". Lupus. 13 (9): 683–7. PMID 15485103.
  15. ^ Graham GG, Scott KF, Day RO (2005). "Tolerability of paracetamol". Drug Saf. 28 (3): 227–40. PMID 15733027.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ Wilkes JM, Clark LE, Herrera JL (2005). "Acetaminophen overdose in pregnancy". South. Med. J. 98 (11): 1118–22. PMID 16351032. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ http://www.francesoir.fr/societe/2009/03/02/grossesse-mamans-attention.html
  18. ^ Allergy Capital: Adverse and allergic reactions to aspirin and NSAIDS. Accessed 2009.03.23.
  19. ^ Bombardier C, Laine L, Reicin A; et al. (2000). "Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group". N. Engl. J. Med. 343 (21): 1520–8, 2 p following 1528. PMID 11087881. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  20. ^ Chandrasekharan NV, Dai H, Roos KL; et al. (2002). "COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression". Proc. Natl. Acad. Sci. U.S.A. 99 (21): 13926–31. doi:10.1073/pnas.162468699. PMC 129799. PMID 12242329. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  21. ^ Kis B, Snipes JA, Busija DW (2005). "Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties". J. Pharmacol. Exp. Ther. 315 (1): 1–7. doi:10.1124/jpet.105.085431. PMID 15879007. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

External links

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