non-steroidal anti-inflammatory drug

Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs—but also referred to as nonsteroidal anti-inflammatory agents/analgesics (NSAIAs) or nonsteroidal anti-inflammatory medicines (NSAIMs)—are a class of anti-inflammatory effects.

The term “nonsteroidal” distinguishes these drugs from narcotic.

The most prominent members of this group of drugs are aspirin, ibuprofen, and naproxen, all of which are available over the counter in most countries.^[1][2]

Contents 1 Medical uses 2 Adverse effects 2.1 Combinational risk 2.2 Cardiovascular 2.3 Erectile dysfunction risk 2.4 Gastrointestinal 2.5 Inflammatory bowel disease 2.6 Renal 2.7 Photosensitivity 2.8 During pregnancy 2.9 Other 2.10 Drug interactions 3 Mechanism of action 3.1 Antipyretic activity 4 Classification 4.1 Salicylates 4.2 Propionic acid derivatives 4.3 Acetic acid derivatives 4.4 Enolic acid (Oxicam) derivatives 4.5 Fenamic acid derivatives (Fenamates ) 4.6 Selective COX-2 inhibitors (Coxibs) 4.7 Sulphonanilides 4.8 Others 4.8.1 Natural 4.9 Main practical differences 5 Pharmacokinetics 6 Chirality 7 Controversies with COX-2 inhibitors 8 Veterinary use 9 References

[edit] Medical uses

NSAIDs are usually indicated for the treatment of acute or chronic conditions where cardiovascular disease.

NSAIDs are generally indicated for the symptomatic relief of the following conditions:^[3]

thromboxane A₂.

In 2001, NSAIDs accounted for 70,000,000 prescriptions and 30 billion over-the-counter doses sold annually in the United States.^[5]

[edit] Adverse effects

The widespread use of NSAIDs has meant that the adverse effects of these drugs have become increasingly prevalent. The two main renal effects of NSAIDs.

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.^[5]

NSAIDs, like all drugs, may interact with other medications. For example, concurrent use of NSAIDs and [7]

[edit] Combinational risk

If a COX-2 inhibitor is taken, one should not use a traditional NSAID (prescription or over-the-counter) concomitantly.^[8] In addition, people on daily aspirin therapy (e.g., for reducing cardiovascular risk) must be careful if they also use other NSAIDs, as the latter may block^{[further explanation needed]} the cardioprotective effects of aspirin.

[edit] Cardiovascular

NSAIDs aside from aspirin, both newer selective COX-2 inhibitors and traditional anti-inflammatories, increase the risk of [10]

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 a more than 10-fold increase in heart failure.^[13]

[edit] Erectile dysfunction risk

A 2005 study linked long term (over 3 months) use of NSAIDs, including ibuprofen, with a 1.4 times increased risk of [15]

[edit] Gastrointestinal

The main adverse drug reactions (clarification needed] effects on epithelial mucosa.

Common gastrointestinal ADRs include:^[3]

• Nausea/Vomiting
• Dyspepsia
• Gastric ulceration/bleeding.^[17]
• 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 patients with achlorhydria.^[18]

Ulceration risk increases with therapy duration, and with higher doses. To minimise GI ADRs, it is prudent to use the lowest effective dose for the shortest period of time—a practice that studies show is often not followed. Recent studies show that over 50% of patients that take NSAIDs have sustained some mucosal damage to their small intestine.^[20]

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.^[3]

Certain NSAIDs, such as aspirin, have been marketed in enteric-coated formulations that manufacturers claim reduce the incidence of gastrointestinal ADRs. Similarly, some believe that rectal formulations may reduce gastrointestinal ADRs. However, considering the mechanism of such ADRs, and in clinical practice, these formulations have not demonstrated a reduced risk of GI ulceration.^[3]

Commonly, gastric (but not necessarily intestinal) adverse effects can be reduced through suppressing acid production, by concomitant use of a misoprostol. Misoprostol is itself associated with a high incidence of gastrointestinal ADRs (diarrhea). While these techniques may be effective, they are expensive for maintenance therapy.

[edit] Inflammatory bowel disease

NSAIDs should be used with caution in individuals with citation needed]

[edit] Renal

NSAIDs are also associated with a relatively high incidence of renal adverse drug reactions (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 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.

Common ADRs associated with altered renal function include:^[3]

• 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 (which removes angiotensin II’s vasoconstriction of the efferent arteriole) and a diuretic (which drops plasma volume, and thereby RPF) – the so-called “triple whammy” effect.^[21]

In rarer instances NSAIDs may also cause more severe renal conditions:^[3]

• Interstitial nephritis
• Nephrotic syndrome
• Acute renal failure
• Acute tubular necrosis

NSAIDs in combination with excessive use of phenacetin and/or paracetamol (acetaminophen) may lead to analgesic nephropathy.^[22]

[edit] Photosensitivity

Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs.^[23] 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 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 has weak absorption, it has been reported as a weak photosensitising agent.^{[citation needed]}

[edit] 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^[24] and miscarriage.^[25][26] Aspirin, however, is used together with heparin in pregnant women with antiphospholipid antibodies.^[27] Additionally, Indomethacin is used in pregnancy to treat polyhydramnios by reducing fetal urine production via inhibiting fetal renal blood flow.

In contrast, [30]

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

[edit] Other

Common adverse drug reactions (ADR), other than listed above, include: raised liver Stevens–Johnson syndrome.

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]

[edit] Drug interactions

NSAIDs reduce renal blood flow and thereby decrease the efficacy of diuretics, and inhibit the elimination of lithium and methotrexate.^[33]

NSAIDs cause hypocoagulability, which may be serious when combined with other drugs that also decrease blood clotting, such as warfarin.^[33]

NSAIDs may aggravate [34]

NSAIDs may interfere and reduce efficiency of [36]

[edit] Mechanism of action

Most 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 Brigham Young University. 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, bleeding can result.

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.,^[38]

The discovery of COX-2 led to research to development of selective COX-2 inhibiting drugs that do not cause gastric problems characteristic of older NSAIDs.

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.^[39]

However, many aspects of the mechanism of action of NSAIDs remain unexplained, for this reason further COX pathways are 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.^[39]

NSAIDs are also used in the acute pain caused by gout because they inhibit urate crystal phagocytosis besides inhibition of prostaglandin synthase.^[40]

[edit] Antipyretic activity

Arachidonic acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D & E.

[edit] Classification

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.

• Lysine clonixinate

[edit] Natural

• Hyperforin
• Figwort

A related drug, Paracetamol or “acetaminophen” is often considered in the same category as NSAIDS due to its use as a non-narcotic analgesic and fever-reducing agent, but is not classified as a NSAID because it only exerts weak anti-inflammatory effects.

[edit] 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.^[51] Rather, differences among compounds usually relate to dosing regimens (related to the compound’s elimination half-life), route of administration, and tolerability profile.

Regarding adverse effects, selective COX-2 inhibitors have lower risk of gastrointestinal bleeding, but a substantially more increased risk of [51]

A consumer report noted that ibuprofen, naproxen, and salsalate are less expensive than other NSAIDs, and essentially as effective and safe when used appropriately to treat osteoarthritis and pain.^[52]

[edit] Pharmacokinetics

Most nonsteroidal anti-inflammatory drugs are weak acids, with a pKa of 3-5. They are absorbed well from the 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).

[edit] Chirality

Most NSAIDs are 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, 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.

[edit] Controversies with COX-2 inhibitors

[54]—which caused a worldwide withdrawal of rofecoxib in October 2004.

[edit] 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.

For example, flunixin meglumine, which, while labeled for use in such animals, is not indicated for post-operative pain.

In the United States, citation needed]

[edit] References

v t e Non-steroidal anti-inflammatory drugs (NSAIDs) (primarily N02BA) Pyrazolidines Ampyrone Azapropazone Clofezone Kebuzone Metamizole Mofebutazone Nifenazone Oxyphenbutazone Phenazone Phenylbutazone Sulfinpyrazone Suxibuzone‡ Feprazone Salicylates Aspirin (acetylsalicylic acid) Aloxiprin Benorylate Carbasalate calcium Diflunisal Dipyrocetyl Ethenzamide Guacetisal Magnesium salicylate Methyl salicylate Salsalate Salicin Salicylamide Sodium salicylate Acetic acid derivatives and related substances Aceclofenac Acemetacin Alclofenac Amfenac Bendazac Bromfenac Bumadizone Bufexamac Diclofenac Difenpiramide Etodolac Felbinac Fentiazac Indometacin Indometacin farnesil Ketorolac Lonazolac Oxametacin Proglumetacin Sulindac Tolmetin Zomepirac Oxicams Ampiroxicam Droxicam Lornoxicam Meloxicam Piroxicam Tenoxicam Propionic acid derivatives (profens) Alminoprofen Benoxaprofen Carprofen‡ Dexibuprofen Dexketoprofen Fenbufen Fenoprofen Flunoxaprofen Flurbiprofen Ibuprofen Ibuproxam Indoprofen† Ketoprofen Loxoprofen Miroprofen Naproxen Oxaprozin Pirprofen Suprofen Tarenflurbil Tepoxalin‡ Tiaprofenic acid Vedaprofen‡ Naproxcinod N-Arylanthranilic acids (fenamates) Azapropazone Etofenamate Flufenamic acid Flunixin Meclofenamic acid Mefenamic acid Morniflumate Niflumic acid Tolfenamic acid Coxibs Celecoxib Cimicoxib‡ Deracoxib‡ Etoricoxib Firocoxib‡ Lumiracoxib† Mavacoxib‡ Parecoxib Robenacoxib‡ Rofecoxib† Valdecoxib† Other Aminopropionitrile Benzydamine Chondroitin sulfate Diacerein Fluproquazone Glucosamine Glycosaminoglycan Magnesium salicylate Nabumetone Nimesulide Oxaceprol Proquazone Superoxide dismutase/Orgotein Tenidap Items listed in bold indicate initially developed compounds of specific groups. †Veterinary use medications. DRCT hist noco(injr 3)

 

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