Citizendia

Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and, in higher doses, anti-inflammatory effects - they reduce pain, fever and inflammation. Medication, also referred to as medicine, can be loosely defined as any substance intended for use in the diagnosis cure mitigation treatment or prevention of disease Antipyretics are Drugs that reduce body temperature in situations such as Fever. Anti-inflammatory refers to the property of a substance or treatment that reduces Inflammation. Pain, in the sense of physical pain, is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm Fever (also known as pyrexia, from the Greek pyretos meaning fire or a febrile response, from the Latin word Febris Inflammation ( Latin, inflamatio, to set on fire is the complex biological response of vascular tissues to harmful stimuli such as Pathogens 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. Glucocorticoids (GC are a class of Steroid hormones characterised by an ability to bind with the glucocorticoid receptor ( GR) and trigger similar effects In biochemistry eicosanoids are signaling molecules made by Oxygenation of twenty-carbon Essential fatty acids (EFAs As analgesics, NSAIDs are unusual in that they are non-narcotic. The term narcotic (ναρκωτικός is believed to have been coined by the Greek physician Galen to refer to agents that benumb or deaden causing loss 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. Aspirin, or acetylsalicylic acid (ASA (əˌsɛtɨlsælɨˌsɪlɨk ˈæsɨd is a Salicylate drug, often used as an Analgesic to relieve Ibuprofen ( INN) (ˌaɪbjuːˈpɹəʊfɛn (from the now outdated nomenclature i so- bu tyl- pro panoic- phen olic acid is a Non-steroidal Naproxen ( INN) (nəˈprɒksən is a Non-steroidal anti-inflammatory drug (NSAID commonly used for the reduction of moderate to severe Pain, Fever Paracetamol (acetaminophen) has negligible anti-inflammatory activity, and is not an NSAID. Paracetamol ( INN) (ˌpærəˈsiːtəmɒl -ˈsɛtə- or acetaminophen ( USAN) is a widely-used Analgesic and Antipyretic Medication

Beginning in 1829, with the isolation of salicin from the folk remedy willow bark, NSAIDs have become an important part of the pharmaceutical treatment of pain (at low doses) and inflammation (at higher doses). Salicin (C13H18O7 is an alcoholic β- Glycoside that contains D-glucose. A home remedy is a treatment to cure a Disease or ailment that employs certain spices vegetables or other common items Willows, sallows and osiers form the Genus Salix, around 400 species of Deciduous Trees and Shrubs found primarily Part of the popularity of NSAIDs is that, unlike opioids, they do not produce sedation or respiratory depression and have a very low addiction rate. An opioid is a chemical Substance that has a Morphine -like action in the body NSAIDs, however, are not without their own problems (see below). Certain NSAIDs, including ibuprofen and aspirin, have become accepted as relatively safe and are available over-the-counter without prescription.

Contents

Mode 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. Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins Isozymes (also known as isoenzymes) are Enzymes that differ in amino acid sequence but catalyze the same chemical reaction Cyclooxygenase catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A2). A prostaglandin is any member of a group of Lipid compounds that are derived enzymatically from Fatty acids and have important functions in the Animal body Thromboxane is a member of the family of Lipids known as Eicosanoids. Arachidonic acid (AA sometimes ARA is an Omega-6 fatty acid 204(ω-6 Phospholipids are a class of Lipids and are a major component of all Biological membranes All phospholipids contain a Diglyceride, a Phosphate Prostaglandins act (among other things) as messenger molecules in the process of inflammation. Inflammation ( Latin, inflamatio, to set on fire is the complex biological response of vascular tissues to harmful stimuli such as Pathogens This mechanism of action was elucidated by John Vane, who later received a Nobel Prize for his work (see Mechanism of action of aspirin). In Pharmacology, the term mechanism of action (MOA refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect Sir John Robert Vane ( March 29, 1927 &ndash November 19, 2004) was a British Pharmacologist. The Nobel Prize (Nobelpriset (Nobelprisen is a Swedish prize established in the 1895 will of Swedish chemist Alfred Nobel; it was first awarded in Peace, Literature Aspirin causes several different effects in the body mainly the reduction of inflammation, Analgesia (relief of pain Bleeding and the prevention of A newly discovered COX-3 may also have some role. Cyclo-oxygenase 3 Enzyme Two Cyclooxygenase isozymes COX-1 and COX-2 are known to convert Arachidonic acid into Prostaglandins and are the targets

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. The biological half-life of a substance is the time it takes for a substance (drug radioactive nuclide or other to lose half of its pharmacologic physiologic or radiologic activity Some more common examples are given below.

Paracetamol (acetaminophen) is sometimes grouped with the NSAIDs, however, it does not have any significant anti-inflammatory properties and is not a true NSAID. Paracetamol ( INN) (ˌpærəˈsiːtəmɒl -ˈsɛtə- or acetaminophen ( USAN) is a widely-used Analgesic and Antipyretic Medication 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. In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges. There is also some speculation that paracetamol acts through the inhibition of the recently discovered COX-3 isoform (see below). It is also believed that NSAIDs act centrally, possibly within the spinal cord. However, the mechanism of action in this case is not well-characterised.

Salicylates

Arylalkanoic acids

2-Arylpropionic acids (profens)

N-Arylanthranilic acids (fenamic acids)

Pyrazolidine derivatives

Oxicams

COX-2 inhibitors

Sulphonanilides

Others

Licofelone acts by inhibiting LOX (lipooxygenase) & COX (cyclooxygenase)and hence known as 5-LOX/COX inhibitor. Ketorolac or ketorolac tromethamine (marketed under the trademarks Toradol and Acular in the US where generics have also been approved Loxoprofen ( INN) is a Non-steroidal anti-inflammatory drug in the propionic acid derivatives group which also includes Ibuprofen and Naproxen Naproxen ( INN) (nəˈprɒksən is a Non-steroidal anti-inflammatory drug (NSAID commonly used for the reduction of moderate to severe Pain, Fever Oxaprozin, also known as Oxaprozinum, (sold under the names Daypro or Duraprox) is a non- Narcotic, Non-steroidal anti-inflammatory drug Pirprofen is a Non-steroidal anti-inflammatory drug. Suprofen is an NSAID marketed in a 1% solution under the Trade name Profenal. Tiaprofenic acid is a Non-steroidal anti-inflammatory drug of the arylpropionic acid (profen class used to treat pain especially arthritic pain Fenamic acid is a molecule which serves as a parent structure for several Non-steroidal anti-inflammatory drugs including Mefenamic acid, Tolfenamic acid Mefenamic acid is a non-steroidal anti-inflammatory drug used to treat pain including menstrual pain Flufenamic acid is a Non-steroidal anti-inflammatory drug. Proprietary names Meclofenamic acid is a drug used for joint and muscular pain Tolfenamic acid (TA is one of the class of non steroidal anti-inflammatory drugs ( NSAIDs. Pyrazolidine is a Heterocyclic compound. See also Pyrazole Pyrazoline Phenylbutazone, often referred to as bute, is a Crystalline substance having the structure shown at right Ampyrone is a Metabolite of Aminopyrine with Analgesic, Anti-inflammatory, and Antipyretic properties Azapropazone is a Non-steroidal anti-inflammatory drug. It is manufacturered by Goldshield under the tradename Rheumox. Clofezone is a drug used for joint and muscular pain It is a combination of Clofexamide and Phenylbutazone. Kebuzone (or ketophenylbutazone) is a Non-steroidal anti-inflammatory drug. Metamizole sodium is a non-steroidal anti-inflammatory drug ( NSAID) commonly used in many countries as a powerful painkiller and fever reducer Mofebutazone (or monophenylbutazone) is a drug used for joint and muscular Pain. Oxyphenbutazone is a Metabolite of Phenylbutazone. Scrabble "Oxyphenbutazone" holds the title for the highest known theoretically possible Phenazone, or phenazon, is an Analgesic. It was first synthesised by Ludwig Knorr in 1883 Phenylbutazone, often referred to as bute, is a Crystalline substance having the structure shown at right Sulfinpyrazone is a Uricosuric medication used to treat Gout. An oxicam is a class of Non-steroidal anti-inflammatory drugs which binds closely to plasma proteins Piroxicam is a Non-steroidal anti-inflammatory drug used to relieve the symptoms of rheumatoid and Osteoarthritis, primary Dysmenorrhoea Droxicam is a Non-steroidal anti-inflammatory drug. Lornoxicam (chlortenoxicam is a Non-steroidal anti-inflammatory drug ( of the oxicam class with analgesic anti-inflammatory and antipyretic properties is available in Meloxicam is a Nonsteroidal anti-inflammatory drug used to relieve the symptoms of Arthritis, primary Dysmenorrhea, Fever; and as an Analgesic Tenoxicam is a Non-steroidal anti-inflammatory drug. It is manufactured by Roche under the tradename Mobiflex. COX-2 selective inhibitor is a form of Non-steroidal anti-inflammatory drug (NSAID that directly targets COX-2, an Enzyme responsible for Inflammation Celecoxib ( INN) (sɛlɨˈkɒksɪb is a Non-steroidal anti-inflammatory drug (NSAID used in the treatment of Osteoarthritis, Rheumatoid arthritis Etoricoxib (brand name Arcoxia worldwide also Algix and Tauxib in Italy is a new COX-2 selective inhibitor (approx Lumiracoxib ( rINN) is a COX-2 selective inhibitor Non-steroidal anti-inflammatory drug, manufactured by Novartis and still sold in few countries Parecoxib is a water soluble and injectable Prodrug of Valdecoxib. Rofecoxib (Rofecoxib is a nonsteroidal anti-inflammatory drug ( NSAID) marketed by Merck & Co Valdecoxib is a prescription drug used in the treatment of Osteoarthritis, Rheumatoid arthritis, and painful Menstruation and menstrual symptoms Nimesulide is a relatively COX-2 selective, Non-steroidal anti-inflammatory drug (NSAID with Analgesic and Antipyretic properties n −3 fatty acids (popularly referred to as ω−3 fatty acids or omega-3 fatty acids) are a family of unsaturated Fatty acids that

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. Colorectal cancer, also called colon cancer or large bowel cancer, includes Cancerous growths in the colon, Rectum and Cardiovascular disease or cardiovascular diseases refers to the class of diseases that involve the Heart or Blood vessels ( arteries and

NSAIDs are generally indicated for the symptomatic relief of the following conditions: (Rossi, 2006)[4]

Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for inhibition of platelet aggregation. Ankylosing spondylitis ( AS; previously known as Bechterew's disease, Bechterew syndrome, Marie Strümpell disease and a form of Spondyloarthritis Psoriatic arthritis (also arthritis psoriatica, arthropathic psoriasis or psoriatic arthropathy) is a type of Inflammatory Arthritis Reactive arthritis (ReA is an Autoimmune condition that develops in response to an infection in another part of the body Gout (also called metabolic arthritis) is a disease created by a buildup of Uric acid. Dysmenorrhea (or dysmenorrhoea) is a medical condition characterized by severe Uterine Pain during Menstruation. Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled A headache ( cephalalgia in medical terminology is a condition of pain in the Head; sometimes Neck or upper back pain may also be interpreted Migraine is a neurological Syndrome characterized by altered bodily experiences painful headaches and nausea Fever (also known as pyrexia, from the Greek pyretos meaning fire or a febrile response, from the Latin word Febris Ileus is a disruption of the normal propulsive gastrointestinal motor activity from non-mechanical mechanisms Renal colic is a type of Pain commonly caused by Kidney stones. In the developing Fetus, the ductus arteriosus ( DA) is a shunt connecting the Pulmonary artery to the aortic arch that allows most Platelets, or Thrombocytes, are small cytoplasmic bodies derived from cells They circulate in the Blood of Mammals and are involved ; an indication useful in the management of arterial thrombosis and prevention of adverse cardiovascular events. Thrombosis is the formation of a blood Clot ( Thrombus) inside a Blood vessel, obstructing the flow of Blood through the Circulatory It shows inhibition of platelet aggregation because it inhibits 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 (Green, 2001). The United States of America —commonly referred to as the With the aging of the Baby Boomer generation and the associated rise in the incidence of osteoarthritis and other such conditions for which NSAIDs are indicated, the use of NSAIDs may increase further still. Baby boomer is a term used to describe a person who was born during the Post-World War II baby boom between 1946 and 1964

One study has suggested that taking NSAIDs (or COX inhibitors in general) while smoking marijuana may prevent the death of brain cells resulting from THC intoxication. Cannabis, also known as marijuana or marihuana, or ganja (from Hindi / Sanskrit: गांजा gānjā hemp) is a Neurotoxicity occurs when the exposure to natural or artificial toxic substances which are called Neurotoxins alters the normal activity of the Nervous system in [5] 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. In Human anatomy, the stomach is a J-shaped hollow muscular organ of the Gastrointestinal tract involved in the second phase of Digestion, following They are highly protein-bound in plasma (typically >95%), usually to albumin, so that their volume of distribution typically approximates to plasma volume. Human serum albumin is the most abundant Protein in Human Blood plasma. The volume of distribution (VD, also known as apparent volume of distribution, is a pharmacological term used to quantify the distribution 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. The liver is a vital organ in the human body and is present in Vertebrates and some other animals Urine is a liquid waste product of the body secreted by the Kidneys by a process of filtration from Blood and Excreted through the Urethra. Bile or gall is a bitter yellow or green Alkaline fluid secreted by Hepatocytes from the Liver of most Vertebrates In many species 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. An adverse drug reaction (abbreviated ADR) or adverse drug event (abbreviated ADE) is an expression that describes the unwanted negative consequences The kidneys are complicated organs that have numerous biological roles

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. Dyspepsia (from the Greek "δυς-" (Dys- and "πέψη" (Pepse known in plain English as indigestion, meaning hard 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. (Green, 2001)

Combinational risk

If a COX-2 inhibitor is taken, one should not use a traditional NSAID (prescription or over-the-counter) concomitantly. [1] 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 risk

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. [2] 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. [3]

Gastrointestinal ADRs

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. The mucous membranes (or mucosae; singular mucosa) are linings of mostly endodermal origin covered in Epithelium, which are involved in A prostaglandin is any member of a group of Lipid compounds that are derived enzymatically from Fatty acids and have important functions in the Animal body

Common gastrointestinal ADRs include: (Rossi, 2006)[4]

Risk of ulceration increases with duration of therapy, and with higher doses. Dyspepsia (from the Greek "δυς-" (Dys- and "πέψη" (Pepse known in plain English as indigestion, meaning hard A peptic ulcer, also known as PUD or peptic ulcer disease, is an Ulcer (defined as mucosal erosions equal to or greater than 0 In Medicine, diarrhea, also spelled diarrhoea (see spelling differences) is frequent loose or liquid Bowel movements Acute diarrhea 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. Indometacin ( INN Ketoprofen, (RS2-(3-benzoylphenyl-propionic acid (chemical formula C16H14O3is one of the propionic acid class of non-steroidal anti-inflammatory Piroxicam is a Non-steroidal anti-inflammatory drug used to relieve the symptoms of rheumatoid and Osteoarthritis, primary Dysmenorrhoea Ibuprofen ( INN) (ˌaɪbjuːˈpɹəʊfɛn (from the now outdated nomenclature i so- bu tyl- pro panoic- phen olic acid is a Non-steroidal Diclofenac (marketed as Flector patch, Voltaren, Voltarol, Diclon, Dicloflex Difen, Difene, Cataflam (Rossi, 2006)[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. (Rossi, 2006)[4]

Commonly, gastrointestinal adverse effects can be reduced through suppressing acid production, by concomitant use of a proton pump inhibitor, e. Proton pump inhibitors (or "PPI"s are a group of drugs whose main action is pronounced and long-lasting reduction of Gastric acid production g. omeprazole; or the prostaglandin analogue misoprostol. Omeprazole ( INN) (oʊˈmɛprəzoʊl is a Proton pump inhibitor used in the treatment of Dyspepsia, peptic ulcer disease (PUD Gastroesophageal Misoprostol is a drug that is FDA -approved in the United States for the prevention of non-steroidal anti-inflammatory drug ( NSAID)-induced 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 (IBD)

NSAIDs are never to be used in individuals with Inflammatory Bowel Disease (IBD-Crohn's Disease and Ulcerative Colitis) due to its ability 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 methods than Ibuprofen for pain relief in IBD.

Renal ADRs

NSAIDs are also associated with a relatively high incidence of renal ADRs. The kidneys are complicated organs that have numerous biological roles 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. The afferent arterioles are a group of Blood vessels that supply the Nephrons in many excretory systems. A glomerulus is a Capillary tuft surrounded by Bowman's capsule in Nephrons of the vertebrate Kidney. This helps maintain normal glomerular perfusion and glomerular filtration rate (GFR), an indicator of renal function. Renal function, in Nephrology, is an indication of the state of the Kidney and its role in Renal physiology. Renal function, in Nephrology, is an indication of the state of the Kidney and its role in Renal physiology. 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: (Rossi, 2006)[4]

These agents may also cause renal impairment, especially in combination with other nephrotoxic agents. Hypertension, also referred to as high blood pressure, HTN or HPN, is a medical condition in which the Blood pressure is chronically elevated 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. ACE inhibitors, or inhibitors of '''A'''ngiotensin-'''C'''onverting '''E'''nzyme, are a group of Pharmaceuticals that are used primarily in treatment of Hypertension A diuretic is any Drug that elevates the rate of urination ( Diuresis) (Thomas, 2000)

In rarer instances NSAIDs may also cause more severe renal conditions: (Rossi, 2006)[4]

Photosensitivity

Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs. Interstitial nephritis (or Tubulo-interstitial nephritis) is a form of Nephritis affecting the Interstitium of the Kidneys surrounding the Not to be confused with Nephritic syndrome Nephrotic syndrome is a nonspecific disorder in which the Kidneys are damaged to leak large Acute renal failure ( ARF) also known as acute kidney failure or acute kidney injury, is a rapid loss of Renal function due to damage to the Acute tubular necrosis or ( ATN) is a medical condition involving the death of tubular cells that form the Tubule that transports Urine to the Ureters Photodermatitis, or sometimes called by the nonscientific term sun poisoning, is a reaction of the Skin to UV rays of the Sun, or Photoallergy (Moore, 2002) 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. Piroxicam is a Non-steroidal anti-inflammatory drug used to relieve the symptoms of rheumatoid and Osteoarthritis, primary Dysmenorrhoea Diclofenac (marketed as Flector patch, Voltaren, Voltarol, Diclon, Dicloflex Difen, Difene, Cataflam Benzydamine, available as the hydrochloride is a locally-acting Nonsteroidal anti-inflammatory drug with local Anaesthetic and Analgesic properties providing

Benoxaprofen, since withdrawn due to its hepatotoxicity, was the most photoactive NSAID observed. Benoxaprofen is a Non-steroidal anti-inflammatory drug. It was marketed by Eli Lilly and Company under the brand name Oraflex in the US and as Drug metabolism in liver The human body identifies almost all drugs as foreign substances (i The mechanism of photosensitivity, responsible for the high photoactivity of the 2-arylpropionic acids, is the ready decarboxylation of the carboxylic acid moiety. Decarboxylation is any Chemical reaction in which a Carboxyl group (-COOH is split off from a compound as Carbon dioxide (CO2 Carboxylic acids are Organic acids characterized by the presence of a Carboxyl group, which has the formula -C(=OOH usually written -COOH or -CO2H In Organic chemistry, functional groups are specific groups of Atoms within Molecules that are responsible for the characteristic Chemical reactions The specific absorbance characteristics of the different chromophoric 2-aryl substituents, affects the decarboxylation mechanism. A chromophore is part (or moiety) of a Molecule responsible for its Color. While ibuprofen is somewhat of an exception, having weak absorption, it has been reported to be a weak photosensitising agent. Ibuprofen ( INN) (ˌaɪbjuːˈpɹəʊfɛn (from the now outdated nomenclature i so- bu tyl- pro panoic- phen olic acid is a Non-steroidal

During pregnancy

NSAIDs are not recommended during pregnancy, particularly during the third trimester. Pregnancy ( Latin graviditas) is the carrying of one or more offspring known as a Fetus or Embryo, inside the Uterus of a Female 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. Teratology stems from the Greek ( Genitive) meaning monster, or marvel and, meaning word, speech. In the developing Fetus, the ductus arteriosus ( DA) is a shunt connecting the Pulmonary artery to the aortic arch that allows most Additionally, they are linked with premature birth (Ostensen & Skomsvoll, 2004). Premature birth (also known as preterm birth) is the Birth of a Baby before the standard period of Pregnancy is completed Aspirin, however, is used together with heparin in pregnant women with antiphospholipid antibodies (Cervera & Balasch, 2004). Heparin, a highly-sulfated Glycosaminoglycan, is widely used as an injectable Anticoagulant and has the highest negative Charge density of any known Antiphospholipid syndrome (APS or APLS or antiphospholipid antibody syndrome is a disorder of Coagulation, which causes blood clots ( Thrombosis) in both

In contrast, paracetamol (acetaminophen) is regarded as being safe and well-tolerated during pregnancy (Graham et al. Paracetamol ( INN) (ˌpærəˈsiːtəmɒl -ˈsɛtə- or acetaminophen ( USAN) is a widely-used Analgesic and Antipyretic Medication , 2005). Doses should be taken as prescribed, due to risk of hepatotoxicity with overdoses (Wilkes et al. Drug metabolism in liver The human body identifies almost all drugs as foreign substances (i , 2005).

Other ADRs

Common ADRs, other than listed above, include: raised liver enzymes, headache, dizziness (Rossi, 2006).

Uncommon ADRs include: hyperkalaemia, confusion, bronchospasm, rash (Rossi, 2006). Hyperkalemia ( AE) or Hyperkalaemia ( BE) is an elevated blood level of the Electrolyte Potassium. Bronchospasm is a sudden constriction of the muscles in the walls of the Bronchioles It is caused by the release ( Degranulation) of substances from Mast cells Ibuprofen may also rarely cause irritable bowel syndrome symptoms. In Gastroenterology, irritable bowel syndrome ( IBS) is a Functional bowel disorder characterized by mild to severe Abdominal pain, discomfort

Most NSAIDs penetrate poorly into the central nervous system (CNS). In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges. 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.

Chirality

Most NSAIDs are chiral molecules (diclofenac is a notable exception). The term chiral (pronounced /ˈkaɪɹ(əl̩/ is used to describe an object that is non- superimposable on its mirror image Diclofenac (marketed as Flector patch, Voltaren, Voltarol, Diclon, Dicloflex Difen, Difene, Cataflam However, the majority are prepared in a racemic mixture. In Chemistry, a racemic mixture, or racemate, is one that has equal amounts of left- and right-handed enantiomers of a chiral Typically, only a single enantiomer is pharmacologically active. In Chemistry, an enantiomer ( from the Greek ἐνάντιος opposite and μέρος part or portion is one of two Stereoisomers that are nonsuperimposable 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. In Biochemistry, an isomerase is an Enzyme that catalyses the structural rearrangement of Isomers Isomerases thus catalyze reactions of the form Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins 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. Ibuprofen ( INN) (ˌaɪbjuːˈpɹəʊfɛn (from the now outdated nomenclature i so- bu tyl- pro panoic- phen olic acid is a Non-steroidal Ketoprofen, (RS2-(3-benzoylphenyl-propionic acid (chemical formula C16H14O3is one of the propionic acid class of non-steroidal anti-inflammatory Naproxen has always been marketed as the single active enantiomer. Naproxen ( INN) (nəˈprɒksən is a Non-steroidal anti-inflammatory drug (NSAID commonly used for the reduction of moderate to severe Pain, Fever

Newer NSAIDs: 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. In Human anatomy, the stomach is a J-shaped hollow muscular organ of the Gastrointestinal tract involved in the second phase of Digestion, following The mucous membranes (or mucosae; singular mucosa) are linings of mostly endodermal origin covered in Epithelium, which are involved in 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. A peptic ulcer, also known as PUD or peptic ulcer disease, is an Ulcer (defined as mucosal erosions equal to or greater than 0 In Human anatomy, the stomach is a J-shaped hollow muscular organ of the Gastrointestinal tract involved in the second phase of Digestion, following In Anatomy of the Digestive system, the duodenum is a hollow jointed tube about 25-30 cm (10-12 in long connecting the Stomach to the Jejunum Bleeding, technically known as hemorrhaging / haemorrhaging (see American and British spelling differences) is the loss of Blood from 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. Meloxicam is a Nonsteroidal anti-inflammatory drug used to relieve the symptoms of Arthritis, primary Dysmenorrhea, Fever; and as an Analgesic COX-2 selective inhibitor is a form of Non-steroidal anti-inflammatory drug (NSAID that directly targets COX-2, an Enzyme responsible for Inflammation Coxibs, the newest class of NSAIDs, can be considered as true COX-2 selective inhibitors, and include celecoxib, rofecoxib, valdecoxib, parecoxib and etoricoxib. Celecoxib ( INN) (sɛlɨˈkɒksɪb is a Non-steroidal anti-inflammatory drug (NSAID used in the treatment of Osteoarthritis, Rheumatoid arthritis Rofecoxib (Rofecoxib is a nonsteroidal anti-inflammatory drug ( NSAID) marketed by Merck & Co Valdecoxib is a prescription drug used in the treatment of Osteoarthritis, Rheumatoid arthritis, and painful Menstruation and menstrual symptoms Parecoxib is a water soluble and injectable Prodrug of Valdecoxib. Etoricoxib (brand name Arcoxia worldwide also Algix and Tauxib in Italy is a new COX-2 selective inhibitor (approx

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. Pfizer Incorporated ( is a major Pharmaceutical company, which ranks number one in the world in sales

Rofecoxib however, which has since been withdrawn, had been shown to produce significantly fewer gastrointestinal ADRs compared to naproxen. Rofecoxib (Rofecoxib is a nonsteroidal anti-inflammatory drug ( NSAID) marketed by Merck & Co (Bombardier et al, 2000). 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. Myocardial infarction ( MI or AMI for acute myocardial infarction) also known as a heart attack, occurs when the blood supply 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. Cyclo-oxygenase 3 Enzyme Two Cyclooxygenase isozymes COX-1 and COX-2 are known to convert Arachidonic acid into Prostaglandins and are the targets Paracetamol ( INN) (ˌpærəˈsiːtəmɒl -ˈsɛtə- or acetaminophen ( USAN) is a widely-used Analgesic and Antipyretic Medication (Chandrasekharan et al, 2002). 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. Cyclo-oxygenase 3 Enzyme Two Cyclooxygenase isozymes COX-1 and COX-2 are known to convert Arachidonic acid into Prostaglandins and are the targets The expressed proteins do not show COX activity and it is unlikely that they play a role in prostaglandin mediated physiological responses. (Kis, 2005)

The clinical ramifications and knowledge of COX isozymes are rapidly expanding and may offer significant hope for future treatments of pain, inflammation, and fever.

Veterinary Use

NSAID Analgesia

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 meglamine, 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 Rossi S, editor. Australian Medicines Handbook 2006. The Australian Medicines Handbook or AMH is a medical reference text commonly used in practice by health professionals (particularly General practitioners Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  5. ^ Hippocampal Neurotoxicity of Delta 9-Tetrahydrocannabinol - Chan et al. 18 (14): 5322 - Journal of Neuroscience

External links


Dictionary

non-steroidal anti-inflammatory drug

-noun

  1. (pharmacology) Alternative spelling of nonsteroidal anti-inflammatory drug.
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