Nonsteroidal anti-inflammatory drugs ( NSAIDs ) are classes of drugs that relieve pain, reduce fever, prevent blood clotting and, in higher doses, reduce inflammation. Side effects depend on specific drugs, but most include increased risk of ulcers and gastrointestinal bleeding, heart attacks and kidney disease.
The term nonsteroidal distinguishes these drugs from steroids, which despite having eicosanoid depressive action, the same anti-inflammatory, has many other effects. First used in 1960, the term was used to keep these drugs from steroids.
NSAIDs work by inhibiting cyclooxygenase enzyme activity (COX-1 and/or COX-2). In cells, this enzyme is involved in the synthesis of key biological mediators, ie prostaglandins involved in inflammation, and thromboxanes involved in blood clotting.
There are two types of NSAIDs available: selective non-selective and COX-2. Most NSAIDs are not selective, and inhibit COX-1 and COX-2 activity. This NSAID, while reducing inflammation, also dilutes blood (especially aspirin) and increases the risk of gastrointestinal ulcers/bleeding. Selective inhibitors of COX-2 have fewer gastrointestinal side effects, but increase thrombosis and substantially increase the risk of heart attack. As a result, COX-2 selective inhibitors are generally contraindicated because of the high risk of undiagnosed blood vessel disease. These differential effects are due to the role and localization of different tissues of each COX isoenzyme. By inhibiting physiological COX activity, all NSAIDs increase the risk of kidney disease, and through related mechanisms, heart attacks.
The most prominent NSAIDs are aspirin, ibuprofen and naproxen, all available on the table in most countries. Paracetamol (acetaminophen) is generally not considered an NSAID because it has little anti-inflammatory activity. It treats pain primarily by blocking COX-2 especially in the central nervous system, but not much throughout the body.
Video Nonsteroidal anti-inflammatory drug
Medical use
NSAIDs are commonly used for the treatment of acute or chronic conditions where pain and inflammation are present.
NSAIDs are commonly used to relieve symptoms of the following conditions:
- Traumatic Injury
Aspirin, the only NSAID capable of inhibiting COX-1 irreversibly, is also indicated for antithrombosis by inhibition of platelet aggregation. It is useful for the management of arterial thrombosis and prevention of adverse cardiovascular events such as heart attack. Aspirin inhibits platelet aggregation by inhibiting the thromboxane action of A 2 .
In more specific applications, prostaglandin reduction is used to close patent ductus arteriosus in neonates if it has not been physiologically done after 24 hours.
NSAIDs are useful in the management of postoperative dental pain after invasive dental procedures such as tooth extraction. When not contra-indications they are favored on the use of paracetamol itself due to their anti-inflammatory effect. When used in combination with paracetamol, the analgesic effect has been shown to be enhanced. There is weak evidence suggesting that taking preoperative analgesia may reduce the length of postoperative pain associated with placing an orthodontic spacer under local anesthesia. The combination of NSAIDs with pregabalin as preemptive analgesia has shown promising results to reduce the intensity of postoperative pain.
Maps Nonsteroidal anti-inflammatory drug
Contraindications
NSAIDs can be used with caution by people with the following conditions:
- Irritated bowel syndrome
- People over the age of 50, and who have a family history of GI (gastrointestinal) problems
- People who have had GI issues from using NSAIDs
NSAIDs should normally be avoided by people with the following conditions:
Adverse effects
The widespread use of NSAIDs means that the ill effects of these drugs have become increasingly common. Use of NSAIDs increases the risk of various gastrointestinal (GI) problems, kidney disease and adverse cardiovascular events. As is commonly used for postoperative pain, there is evidence of an increased risk of kidney complications. Their use after gastrointestinal surgery is still controversial, providing evidence of a mixture of increased risk of leakage from anastomosis of the intestines made.
It is estimated that 10-20% of patients with NSAID have dyspepsia. In the 1990s, high doses of prescription NSAIDs were associated with serious upper gastrointestinal side effects, including bleeding. Over the last decade, deaths associated with gastric bleeding have declined.
NSAIDs, like all drugs, can interact with other drugs. For example, concurrent use of NSAIDs and quinolones may increase the risk of adverse central nervous system quinolone effects, including seizures.
There are arguments about the benefits and risks of NSAIDs for treating chronic musculoskeletal pain. Each drug has a risk-benefit profile and balancing the risk of no treatment with the potential risk of competing from various therapies is the responsibility of the physician.
Combinational risk
If a COX-2 inhibitor is taken, traditional NSAIDs (prescription or over-the-counter) should not be taken at the same time. In addition, people who undergo daily aspirin therapy (eg, to reduce cardiovascular risk) should be careful if they also use other NSAIDs, as this may inhibit the cardioprotective effects of aspirin.
Rofecoxib (Vioxx) has been shown to produce fewer adverse gastrointestinal (ADR) drug reactions compared with naproxen. This study, the VIGOR trial, raised the issue of cardiovascular safety from coxib. A statistically significant increase in the incidence of myocardial infarction was observed in rofecoxib patients. Further data, from the trial APPROVe, showed a statistically significant relative risk of cardiovascular events of 1.97 versus placebo - which led to worldwide rofecoxib recall in October 2004.
The use of methotrexate along with NSAIDS in rheumatoid arthritis is safe, if adequate monitoring is performed.
Cardiovascular
NSAIDs, in addition to aspirin, increase the risk of myocardial infarction and stroke. This happens for at least one week of use. They are not recommended in those who have had previous heart attacks because they increase the risk of death or recurrent MI. Evidence suggests that naproxen may be the least harmful of these.
NSAIDs other than aspirin (low dose) are associated with a doubling of the risk of heart failure in people without a history of heart disease. In people with such a history, the use of NSAIDs (other than low-dose aspirin) was associated with a 10-fold increase in heart failure. If this relationship is proven to be causal, researchers estimate that the NSAID will be responsible for up to 20 percent of hospital admissions for congestive heart failure. In people with heart failure, NSAIDs increase the risk of death (hazard ratio) by about 1.2-1.3 for naproxen and ibuprofen, 1.7 for rofecoxib and celecoxib, and 2,1 for diclofenac.
On July 9, 2015, the FDA tightened warnings of increased heart attacks and stroke risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs). Aspirin is an NSAID but is unaffected by new warnings.
Possible risk of erectile dysfunction
A 2005 Finnish study linked long-term use (more than 3 months) to NSAIDs with an increased risk of erectile dysfunction. This study is only correlational, and depends only on self-report (questionnaire).
The 2011 publication in The Journal of Urology received wide publicity. According to the study, men who regularly use NSAIDs have an increased risk of erectile dysfunction. The association between the use of NSAIDs and erectile dysfunction persists after controlling for some conditions. However, this study is observational and uncontrolled, with low initial participation rates, potential participation bias, and other uncontrollable factors. The authors warn not to draw conclusions about the cause.
Gastrointestinal
The main adverse drug reactions (ADRs) associated with the use of NSAIDs are associated with direct and indirect irritation of the gastrointestinal tract (GI). NSAIDs cause multiple attacks on GI tract: acid molecules directly irritate the gastric mucosa, and inhibition of COX-1 and COX-2 decreases protective prostaglandin levels. Inhibition of prostaglandin synthesis in the gastrointestinal tract causes increased gastric acid secretion, reduced bicarbonate secretion, reduced mucus secretion and reduced trophic effects on the epithelial mucosa.
Common gastrointestinal ADRs include:
- Nausea/vomiting
- Dispepsia
- Gastric ulcer/hemorrhage
- Diarrhea
NSAID clinical ulcers are associated with the systemic effects of NSAID administration. Such damage occurs regardless of the route of administration of NSAIDs (eg, Oral, rectal, or parenteral) and may occur even in patients with achlorhydria.
The risk of ulceration increases with duration of therapy, and with higher doses. To minimize GI ADR, it is wise to use the lowest effective dose for the shortest period of time - a practice often demonstrated by studies not being followed. Recent studies have shown that more than 50% of patients taking NSAIDs have mucosal damage to their small intestine.
There are also some differences in the tendency of individual agents to cause gastrointestinal ADRs. Indomethacin, ketoprofen and piroxicam appear to have the highest prevalence of gastric ADRs, while ibuprofen (low dose) and diclofenac appear to have lower levels.
Certain NSAIDs, such as aspirin, have been marketed in enteric-coated formulations that manufacturers claim to reduce the incidence of gastrointestinal ADR. Similarly, some believe that rectal formulations may reduce gastrointestinal ADRs. However, consistent with the systemic mechanisms of ADR, and in clinical practice, this formulation has not shown a reduced risk of GI ulceration.
Generally, gastric side effects (but not necessarily gut) may be reduced through suppressing acid production, with concurrent use of a proton pump inhibitor, eg, omeprazole, esomeprazole, or prostaglandin analog misoprostol. Misoprostol itself is associated with high incidence of gastrointestinal ADRs (diarrhea). Although this technique may be effective, it is expensive for maintenance therapy.
Inflammatory bowel disease
NSAIDs should be used with caution in individuals with inflammatory bowel disease (eg, Crohn's disease or ulcerative colitis) because of their tendency to cause gastric bleeding and ulceration of the stomach lining.
Renal
NSAIDs are also associated with a high incidence of adverse drug reactions (ADRs) in the kidney and over time can cause chronic kidney disease. This kidney mechanism of ADRs is due to changes in renal blood flow. Prostaglandins usually dilate afferent arterioles from glomeruli. This helps maintain normal glomerular perfusion and glomerular filtration rate (GFR), an indicator of renal function. This is particularly important in kidney failure where the kidneys attempt to maintain the pressure of renal perfusion by elevated levels of angiotensin II. At this elevated level, angiotensin II also constricts afferent arterioles into the glomerulus in addition to normally narrowed efferent arterioles. Because NSAIDs block the prostaglandin-mediated effect of widening afferent arterioles, especially in renal failure, NSAIDs lead to uninterrupted afferent arterial constriction and decreased RPF (renal perfusion flow) and GFR.
Common ADRs associated with changing kidney function include:
- Salt (Sodium) and fluid retention
- Hypertension (high blood pressure)
These agents can also cause kidney damage, especially in combination with other nephrotoxic agents. Kidney failure is particularly risky if the patient also simultaneously takes an ACE inhibitor (which removes angiotensin II vasoconstriction from the efferent arterioles) and diuretics (which decreases plasma volume, and thus RPF) - so-called "triple whammy" effects.
In rare cases NSAIDs can also lead to more severe kidney conditions:
- Interstitial nephritis
- Nephrotic Syndrome
- Acute kidney injury
- Acute tubular necrosis
- Renal papillary necrosis
NSAIDs in combination with excessive use of phenacetin or paracetamol (acetaminophen) can cause analgesic nephropathy.
Photosensitivity
Photosensitivity is a frequently overlooked side effect of many NSAIDs. 2-arylpropionic acid is most likely to produce photosensitivity reactions, but other NSAIDs have also been implicated including piroxicam, diclofenac and benzidamine.
Benoxaprofen, due to withdrawal due to liver toxicity, is the most observable photoactive NSAID. The photosensitivity mechanism, responsible for high photoactivity of 2-arylpropionic acid, is a ready decarboxylated part of the carboxylic acid. The specific absorbance characteristics of different 2-aryl chromophoric substitutions, affecting the decarboxylation mechanism. While ibuprofen has a weak absorption, it has been reported as a weak photosensitising agent.
During pregnancy
NSAIDs are not recommended during pregnancy, especially during the third trimester. While NSAIDs as a class are not direct teratogens, they can cause early closure of fetal ductus arteriosus and ADR kidney in the fetus. In addition, they are associated with premature birth and miscarriage. Aspirin, however, is used in conjunction with heparin in pregnant women with antiphospholipid antibodies. In addition, indomethacin is used in pregnancy to treat polyhydramnios by reducing fetal urine production through inhibition of fetal renal blood flow.
In contrast, paracetamol (acetaminophen) is considered safe and well tolerated during pregnancy, but Leffers et al. releasing a study in 2010 showed that there may be male infertility linked to unborn babies. Dosage should be taken as prescribed, because of the risk of liver toxicity with overdose.
In France, the country's health agencies contraindicate the use of NSAIDs, including aspirin, after the sixth month of pregnancy.
Allergies/allergic reactions such as allergies
A variety of allergic or allergic hypersensitivity reactions such as follow the consumption of NSAIDs. This hypersensitivity reaction differs from the other adverse reactions listed here, ie the toxicity reaction, ie the unwanted reaction resulting from pharmacological action of the drug, associated with the dose, and may occur in each treated individual; The hypersensitivity reaction is an idiosyncratic reaction to the drug. Some of the hypersensitivity reactions of NSAIDs are derived entirely from allergies: 1) recurrent IgE-mediated skin eruption eruption, angioedema, and anaphylaxis soon after a few hours of swallowing a structural type of NSAID but not after ingesting structurally not related; and 2) have mild to moderate onset of T-mediate relatively mild to moderate T cells (usually more than 24 hours), skin reactions such as maculopapular rashes, fixed drug eruptions, photosensitivity reactions, delayed urticaria, and contact dermatitis; or 3) delayed systemic reactions that are much more severe and potentially life-threatening t-cells such as DRESS syndrome, comprehensive acute exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Another NSAID hypersensitivity reaction is an allergic-like symptom but does not involve a true allergic mechanism; Instead, they arise because of the NSAID's ability to alter arachidonic acid metabolism that supports the formation of metabolites that promote allergy symptoms. Individuals who are suffering may be abnormally sensitive to this provocative metabolite or produce excessively and are usually susceptible to a variety of structurally different NSAIDs, especially those that inhibit COX1. Symptoms, which soon develop into hours after ingesting various NSAIDs that inhibit COX-1, are: 1) exacerbation of asthma and rhinitis (see aspirin-induced asthma) in individuals with a history of asthma or rhinitis and 2) Exacerbations or first-time development in wheals or angioedema in individuals with or without a history of chronic urticarial lesions or angioedema. More
The use of NSAIDS for analgesia after gastrointestinal surgery is still controversial, providing a mixed evidence of increased risk of leakage from anastomosis of the intestines made. This risk may vary according to the specified NSAID class.
Adverse general drug reactions (ADRs), in addition to those listed above, include: elevated liver enzymes, headaches, dizziness. Rarely ADRs include high levels of abnormal potassium in the blood, confusion, airway spasms, and rashes. Ibuprofen may also rarely cause symptoms of irritable bowel syndrome. NSAIDs are also involved in some cases of Stevens-Johnson syndrome.
Most NSAIDs penetrate poorly into the central nervous system (CNS). However, the COX enzyme is expressed constitutively in some CNS areas, meaning that even limited penetration can cause adverse effects such as somnolence and dizziness.
In very rare cases, ibuprofen can cause aseptic meningitis.
Like other drugs, allergies to NSAIDs may be present. While many allergies are specific to one NSAID, up to 1 in 5 people may have an unpredictable cross-reactive allergic response to other NSAIDs as well.
Drug interactions
NSAIDs reduce renal blood flow and thereby decrease the effectiveness of diuretics, and inhibit the elimination of lithium and methotrexate.
NSAIDs cause a decrease in the ability to form blood clots, which can increase the risk of bleeding when combined with other drugs that also lower blood clotting, such as warfarin.
NSAIDs can exacerbate hypertension (high blood pressure) and thus antagonize antihypertensive effects, such as ACE inhibitors.
NSAIDs can interfere with and reduce the efficiency of SSRI antidepressants.
Various widely used nonsteroidal anti-inflammatory drugs (NSAIDs) increase endocannabinoid signaling by blocking anandamide-lowering enzyme membranes of fatty acid amide hydrolase (FAAH).
Action mechanism
Most NSAIDs act as non-selective inhibitors of cyclooxygenase enzyme (COX), inhibiting isoenzyme cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). This inhibition is reversible competitive (albeit at varying degrees of reversibility), compared to the mechanism of aspirin, which is an irreversible inhibition. COX catalyses the formation of prostaglandins and thromboxane from arachidonic acid (derived from cellular phospholipid bilayer by phospholipase A 2 ). Prostaglandins act (among other things) as messenger molecules in the inflammatory process. This mechanism of action has been described by John Vane (1927-2004), who received the Nobel Prize for his work (see Mechanism of aspirin work).
COX-1 is a constitutive enzyme expressed with the role of "keeping the house" in regulating many normal physiological processes. One is in the lining of the stomach, where prostaglandins serve a protective role, preventing the gastric mucosa from being eroded by the acids themselves. COX-2 is an enzyme expressed facultatively in inflammation, and is a COX-2 inhibition that produces the desired effect of NSAIDs.
When COX-1/COX-2 inhibitors are not selective (such as aspirin, ibuprofen, and naproxen) lowering prostaglandin levels of the stomach, gastric or duodenal ulcers can cause internal bleeding.
NSAIDs have been studied in various tests to understand how they affect each of the enzymes. While tests reveal differences, unfortunately, different tests provide different ratios.
The discovery of COX-2 led to a study of the development of selective COX-2 inhibitors that did not cause gastric problems that characterized older NSAIDs.
Paracetamol (acetaminophen) is not considered an NSAID because it has little anti-inflammatory activity. It treats pain primarily by blocking COX-2 especially in the central nervous system, but not much throughout the body.
However, many aspects of the NSAID action mechanism remain unexplained, and for this reason, the COX path is further hypothesized. The COX-3 line is believed to fill some of this gap but recent findings make it seem unlikely that it plays any significant role in humans and alternative explanatory models are proposed.
NSAIDs interact with their endocannabinoid and endocannabinoid systems, as COX2 has been shown to utilize endocannabinoids as a substrate, and may have a key role in both the therapeutic and adverse effects of NSAIDs, as well as the NSAID-induced placebo response.
NSAIDs are also used in acute pain caused by uric acid because they inhibit phagocytosis of urate crystals in addition to 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, which alters the rate of burning of neurons within the hypothalamus that controls thermoregulation. Antipyretics works by inhibiting the COX enzyme, which causes the general inhibition of prostanoid biosynthesis (PGE2) within the hypothalamus. Signal PGE2 to the hypothalamus to increase the body's thermal set point. Ibuprofen has been shown to be more effective as an antipyretic than paracetamol (acetaminophen). Arachidonic acid is a precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D & amp; E.
Classification
NSAIDs can be classified according to their chemical structure or mechanism of action. Older NSAIDs are known long before their mechanism of action has been described and for this reason are classified by chemical structure or origin. Newer substances are more often classified by the mechanism of action.
Salisilat
Propionic acid derivatives
Acetic acid derivation
Folic acid derivatives (Oxicam)
Anthranilic acid derivatives (Fenamates)
The following NSAIDs are derived from phenolic acid. which is a derivative of anthranilic acid, which in turn is the nitrogen isostere of salicylic acid, which is an aspirin active metabolite.
Selective Cox-2 (Coxibs) Inhibitors
Sulfonanilides
- Nimesulide (systemic preparation prohibited by some countries for potential risk of hepatotoxicity)
More
- Clonixin
- Licofelone acts by inhibiting LOX (lipooxygenase) & amp; COX and hence known as the 5-LOX/COX inhibitor
- H-harpagide in Figwort or Devil's Claw
Chirality
Most NSAIDs are chiral molecules (diclofenac is an exception). However, the majority are prepared in racemic mixtures. Usually, only single enantiomers are pharmacologically active. For some drugs (usually profens), enzyme isomerase in vivo converts inactive enantiomers into active forms, although their activity varies widely across individuals. This phenomenon is likely to be responsible for a poor correlation between NSAID efficacy and plasma concentrations observed in older studies, when specific analyzes of the active enantiomers were not performed.
Ibuprofen and ketoprofen are now available in one, active enantiomer preparations (dexibuprofen and dexketoprofen), which are intended to offer faster onset and better side-effect profiles. Naproxen is always marketed as a single active enantiomer.
The main practical differences
NSAIDs in the group tend to have similar characteristics and tolerability. There is little difference in clinical efficacy among NSAIDs when used at equivalent doses. In contrast, differences between compounds are usually associated with dosing regimens (related to the elimination half of the compound), route of administration, and tolerability profile.
Regarding side-effects, selective COX-2 inhibitors have a lower risk of gastrointestinal bleeding, and there is no significant increased risk of myocardial infarction. With the exception of naproxen, non-selective NSAIDs increase the risk of heart attack. Some data also support that selective partial nabumetone is less likely to cause gastrointestinal events.
A consumer report noted that ibuprofen, naproxen, and salsalate are cheaper than other NSAIDs, and are essentially just as effective and safe when used appropriately to treat osteoarthritis and pain.
Pharmacokinetics
Most nonsteroidal anti-inflammatory drugs are a weak acid, with pKa 3-5. They are well absorbed from the mucosa of the stomach and intestines. They are heavily bound to proteins in plasma (typically 95%), usually for albumin, so their distribution volume is usually close to plasma volume. Most NSAIDs are metabolized in the liver by oxidation and conjugation to inactive metabolites that are normally excreted in the urine, although some drugs are partially excreted in the bile. Metabolism may be abnormal in certain disease states, and accumulation may occur even with normal doses.
Ibuprofen and diclofenac have a short half-life (2-3 hours). Some NSAIDs (usually oxicams) have very long half-life (eg 20-60 hours).
History
From the era of Greek medicine until the mid-19th century, the discovery of drug agents was classified as empirical art; folklore and mythological guides were combined in spreading the vegetable and mineral products that made up the vast pharmacopoeia of the time. The Myrtle Leaves were used in 1500 BC. Hippocrates (460-377 BC) was first reported using willow bark and at 30 BC Celsus described the signs of inflammation and also used the willow bark to relieve it. On April 25, 1763, Edward Stone wrote to the Royal Society which explains his observations on the use of willow-based bark medicines in febrile patients. The active ingredient of the bark of a willow tree, a glycoside called salicin, was first isolated by Johann Andreas Buchner in 1827. In 1829, French chemist Henri Leroux has improved the extraction process to obtain about 30g of purified salicin of 1.5 kg bark.
By hydrolysis, salicin releases glucose and salicylate alcohol which can be converted to salicylic acid, both in vivo and by chemical methods. Acid is more effective than salicin and, in addition to its reducing fever, is anti-inflammatory and analgesic. In 1869, Hermann Kolbe synthesized salicylates, although too acidic for the gastric mucosa. The reaction used to synthesize aromatic acid from phenol in the presence of CO2 is known as the Kolbe-Schmitt reaction.
In 1897, German chemist Felix Hoffmann and the Bayer company pushed the new pharmacological epoch by converting salicylic acid to acetylsalicylic acid - called aspirin by Heinrich Dreser. Other NSAIDs were developed from the 1950s onwards. In 2001, NSAIDs accounted for 70 million recipes and 30 billion over-the-counter doses sold annually in the United States.
Research
While studies have been conducted to see if various NSAIDs can improve behavior on transgenic mouse models of Alzheimer's disease and observational studies in humans have shown promise, there is no good evidence from randomized clinical trials that NSAIDs can treat or prevent Alzheimer's in humans; NSAID clinical trials for the treatment of Alzheimer's have found more harm than good. NSAIDs coordinate with metal ions that affect cellular function.
Veterinary use
Research supports the use of NSAIDs to control pain associated with veterinary procedures such as dehorning and castration of calves. The best effects are obtained by combining short-term local anesthesia such as lidocaine with NSAIDs that act as long-term analgesics. However, since different species have varied reactions to different drugs in the NSAID family, little of the existing research data can be extrapolated to animal species other than those specifically studied, and relevant government agencies in one area sometimes prohibit approved use in other jurisdictions.
For example, the effect of ketoprofen has been studied on horses rather than on ruminants but, due to the controversy of its use on racehorses, veterinarians treating cattle in the United States more often prescribe flunixin meglumine, which, while labeled for use in these animals, is not indicated for post-operative pain.
In the United States, meloxicam is approved for use only on canine teeth, whereas (due to concern about liver damage), it issues warnings against its use in cats except for one-time use during surgery. Apart from these warnings, meloxicam is often prescribed "off-label" for non-dog animals including cats and livestock species. In other countries, such as the European Union (EU), there are label claims for use in cats.
See also
- The discovery and development of cyclooxygenase inhibitors 2
References
External links
- Media related to non-steroidal anti-inflammatory drugs in Wikimedia Commons
Source of the article : Wikipedia
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